How does Chronic Atrial Fibrillation Influence Mortality in the Modern Treatment Era?

Curr Cardiol Rev. 2015 Aug; 11(3): 190–198.

Rajiv Sankaranarayanan

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Graeme Kirkwood

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Rajaverma Visweswariah

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

David J. Fox

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

^* Address correspondence to this author at the Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK; Tel: 00447525826672; Fax: 00441612751234; E-mail ku. [email protected]

Received 2014 Apr 23; Revised 2014 Aug 22; Accepted 2014 Aug 27.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been cited by other articles in PMC.

Abstract

Atrial fibrillation (AF) continues to impose a significant burden upon healthcare resources. A sustained increase in the ageing population and better survival from conditions such as ischaemic heart disease have ensured that both the incidence and prevalence of AF continue to increase significantly. AF can lead to complications such as embolism and heart failure and these acting in concert with its associated co-morbidities portend increased mortality risk. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i. e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of various therapeutic strategies (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures). Despite several treatment advances including newer anti-arrhythmic drugs and developments in catheter ablation, anti-coagulation remains the only effective means to reduce the mortality due to AF. Warfarin has been used as the oral anticoagulant in the treatment of AF for many years but suffers from disadvantages such as unpredictable INR levels, bleeding risks and need for haematological monitoring. This has therefore spurred a renewed interest in research and clinical studies directed towards developing safer and more efficacious anti-coagulants. We shall review in this article the epidemiological features of AF-related mortality from several studies as well as the cardiovascular and non-cardiac mortality mechanisms. We shall also elucidate why a rhythm control strategy has appeared to be counter-productive and attempt to predict the likely future impact of novel anti-coagulants upon mortality reduction in AF.

Keywords: Atrial fibrillation, arrhythmia, mortality, anti-arrhythmic drugs.

INTRODUCTION

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. 2.2 million people in America and 4.5 million people in Europe are affected by either paroxysmal or persistent AF [1]. It is usually associated with cardiovascular co-morbidities such as hypertension, coronary artery disease, valvular heart disease and heart failure [2]. The presence of AF has been shown to independently increase the risk of death [3-7] and the mortality risk is highest during the first year after AF manifests [5-8]. The incidence of death due to AF has been shown to vary from 1.6-4.2% per annum in various controlled trials [9, 10]. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of the various therapeutic strategies for AF (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures).

EPIDEMIOLOGY

Large population studies both in North America and Europe have demonstrated incontrovertibly the impact of AFupon mortality. The landmark Framingham Heart Study analysed a cohort of 621 individuals who developed AF (out of a study population of over 5000) during 40 years of follow-up; the excess in all-cause mortality rates attributable to AF was 50% for men, and 90% for women, even when controlled for the presence of a wide range of cardiovascular co-morbidities [5]. This effect on mortality became apparent early, with 15% of deaths occurring within 30 days of diagnosis. Amongst the group of patients aged between 55-74 years, the 10 year mortality was 61.5% in men with AF compared to 30% in men without AF. Amongst women in a similar age group, the 10 year mortality was 57.6% in the AF group versus 20.9% in women without AF. Similar findings have been found from many other cohorts. The Renfrew-Paisley study followed-up 100 patients with AF for 20 years out of a cohort of over 15,000 men and women aged between 45-64 years in two Scottish towns and showed that AF increased all-cause mortality by 50% amongst men and 120% amongst women [3]. Ruigomez et al. followed a cohort of 1035 chronic AF patients in the UK for a mean duration of 2 years and reported a trebling of all cause mortality after matching for confounding factors [7]. The Olmsted County study was a community based study of 4618 patients with AF, followed-up for 5.3±5 years and demonstrated that relative to the general age and sex-matched population, AF significantly increased the mortality risk especially during the first four months following diagnosis (HR 9.62; 95% CI 8.93 to 10.32) and also thereafter (HR 1.66; 95% CI 1.59 to 1.73) [8]. The Manitoba study followed-up nearly 4000 young Canadian male air crew for 44 years and demonstrated that AF increased total mortality by 31% [11].

As might be expected, the annual mortality rates associated with AF vary substantially depending on the population demographics. Based on medical insurance claim data, values range from 2.6% in asymptomatic untreated individuals, to 24.2% amongst an elderly population with high rates of co-morbidities [12, 13]. There do not appear to have been significant reductions in AF-associated mortality between the years 1993 – 2007; this population-based data is supported by recent trials of novel anticoagulants and anti-arrhythmic therapies, which report annual mortality rates between 1.9 and 6.6% even with optimal contemporary treatment [14-16].

It is unambiguous from the epidemiological data that, although the presence of AF has a significant and dramatic effect to increase the mortality rate within a population, the effect on an individual is less clear-cut and is highly dependent on demographic risk factors and the presence of co-morbidities as discussed below.

AGE

Age is a major risk factor for developing AF, and older patients are more likely to have co-morbidities that might impact on survival. Nevertheless, patient age is the most powerful and consistent independent factor in determining the AF-associated mortality risk. Although the Framingham study found that all age groups demonstrated an excess mortality attributable to AF, the absolute risk increase seen in those aged over 75 years was approximately 3 times that seen in those under 65 years [5]. This was confirmed in the Paisley/Renfrew study, where the excess mortality was increased 3.5 times in the age group 60–64 years compared to 45–49 years [3]. Essentially, amongst all age groups, individuals with AF are more likely to die early than those without, and older patients with AF are substantially more at risk than younger patients. The annual mortality in 2007 amongst a large cohort of AF patients who were also Medicare beneficiaries aged >65 years was as high as 25% [13].

SEX

In developed societies, healthy females possess a survival advantage over males [17]. The mortality associated with AF is slightly but significantly higher in females than in males, such that this survival advantage is lost and the life expectancy of a woman with AF is similar to that of an age-matched man [5]. The Renfrew-Paisley study showed AF portends a higher all-cause and cardiovascular mortality amongst women [3]. There is also evidence that stroke-related mortality in AF is higher in women [18].

RACE /ETHNIC DIFFERENCES

During AF-related hospitalisations, in-hospital mortality has been shown to be highest amongst African-Americans in comparison to other ethnic groups [19].

LONE AF VS. CO-MORBIDITIES

‘Lone AF’ is defined as AF in the absence of structural heart disease or additional cardiovascular co-morbidities such as diabetes or hypertension. In reality, lone AF is an uncommon entity; 70% of patients with AF have additional risk factors at the time of diagnosis and of the remaining 30% many will have unrecognised co-morbidities such as sleep apnoea or obesity [20]. With a 15 year mortality of only 8%, survival amongst patients with lone AF has been shown to be not significantly different to that of age and sex-matched population control data [21-23]; this is in keeping with subgroup analysis from the Paisley/ Renfrew study which also did not identify a significant mortality excess attributable to lone AF [3].

In contrast, multivariate analysis from the afore-mentioned population studies indicates that cardiovascular and non-cardiovascular co-morbidities impact dramatically upon survival. Factors such as smoking, lung disease, hypertension, diabetes and obesity act to increase mortality by around 20 – 60% each, and the effects are additive with additional risk factors. These findings have led to the development of clinical scoring systems to aid therapeutic decisions.

TEMPORAL PROFILE OF AF

There is convincing evidence that AF burden may impact upon stroke rates [24], however the stroke risk due to paroxysmal AF is comparable to that of chronic AF [25]. In contrast, permanent AF is associated with higher mortality risk whereas paroxysmal AF has been shown to portend similar mortality risk as that of age and gender-matched general population [26, 27]. However, analysis of the mortality effect due to persistent AF in comparison to paroxysmal AF, has shown contrasting results [26, 28].

ISCHAEMIC HEART DISEASE (IHD) AND HEART FAILURE

AF and coronary artery disease share risk factors, but there is no clear evidence linking AF with increased risk of acute coronary syndromes [29]. Co-existing IHD has been shown to increase all-cause mortality due to AF three fold with up to 21% of deaths shown to be related to IHD [7]. Nevertheless, there is a clear association between AF and poor prognosis in myocardial infarction; multiple studies have shown that the development of AF following myocardial infarction is associated with a substantial increase in in-hospital as well as post-discharge mortality (reviewed in [30]). Many studies (including large-scale RCTs such as the OPTIMAAL trial, GUSTO-3 trial and TRACE study) have shown that chronic AF independently increases post-MI mortality (reviewed in [30]). A study by one of the authors of this paper (Sankaranarayanan et al. [31]) showed that chronic AF could increase post-MI mortality risk by increasing the risk of ventricular fibrillation in this setting [31]. The OPTIMAAL trial noted a significant increase in 30 day mortality only where new AF complicated acute MI, but that both acute and pre-existing AF were associated with reduced survival over the subsequent 3 years [32].

AF in congestive heart failure (CHF) has recently attracted substantial interest; AF can either exacerbate or complicate CHF [33], and in the modern era of device therapy it is becoming apparent that AF in CHF is under-recognised [34]. 24% out of 3288 individuals with AF in the Olmsted County study developed CHF over a mean follow-up of 6.1±5.2 years, leading to a significant increase in mortality (HR 3.4) [35]. The Framingham study illustrated the close relationship between these two pathologies showing that amongst 1470 participants who developed either or both these conditions, 382 individuals had both (36% of these developed AF first, 41% CHF first and 21% were diagnosed with both on the same day) [36]. The incidence of CHF amongst AF patients was 33 per 1000 person years, with 4 out of 10 AF subjects developing heart failure at some point during their lifetime and also significantly increasing mortality (men HR 1.6, women HR 2.7). Further analysis also demonstrated a significant mortality impact where AF complicated CHF, (incidence 54 per 1000 person years) with relative increases of 60% and 170% in men and women respectively compared to individuals with CHF in sinus rhythm. The Manitoba follow-up study showed that AF increases the risk of development of CHF by three-fold and increased cardiac mortality by 37% [11].

However, therapeutic CHF studies demonstrated conflicting results as to whether the presence of AF conferred an independent impact on mortality, or simply reflected disease state at baseline [37-40]. A recent meta-analysis of 16 studies including 53,969 patients appears to confirm that AF increases total mortality in CHF patients by around 40%, with an independent effect remaining after controlling for demographics and disease severity irrespective of impaired or preserved LV function [41]. Nevertheless, it remains controversial whether it is the arrhythmia or the co-morbidities that impacts upon mortality, with a recent analysis [42] suggesting that this effect is only seen where heart failure results from ischaemic heart disease. A post hoc analysis of the AFFIRM trial sub-set of patients with CHF and preserved ejection fraction showed a lower all-cause and cardiovascular mortality in comparison to patients with impaired systolic function [43].

In view of the strong association of AF with co-morbidities, several studies have attempted to analyse if the effects of AF upon mortality are truly independent or simply a risk marker for the cumulative pre-terminal effects of co-morbidities. The Olmsted County study for instance illustrated the very high 4 month and 1 year mortality following AF diagnosis, however there were no changes in early (<4 months) versus late mortality (after 4 months) in the whole cohort or within the sub-group of patients without pre-morbid cardiovascular disease [8]. These results and others showing that lone AF does not increase mortality, suggest that AF could simply represent a risk marker for mortality in a very sick population with multiple co-morbidities [3, 6, 8].

1. MECHANISMS OF AF-RELATED MORTALITY

Cardiac

Several large population-based studies have shown that AF independently increases cardiac mortality [3, 5, 11]. Increased cardiovascular mortality risk due to AF varies between 2 to 12 times [44]. The cardiac causes include heart failure, arrhythmia and possibly coronary heart disease.

AF has an intricate relationship with CHF whereby one can precipitate the other [45]. AF leads to a loss of atrial systole (which usually contributes up to 30% of pre-load in sinus rhythm). In addition to this, the loss of atrio-ventricular synchrony and irregular, uncontrolled ventricular rates contribute to development of CHF (“tachycardia-induced cardiomyopathy”) [46-48]. Uncontrolled ventricular rates during AF can also worsen mitral regurgitation and cause rate-related left bundle branch block, thereby reducing cardiac output [49].

AF can lead to arrhythmic sudden death by potentiating VT or VF in patients with ICDs [50], pre-excitation syndromes [49] and in the acute MI setting [31].

AF can also impair coronary perfusion and increase myocardial oxygen demand especially due to uncontrolled ventricular rates and this could worsen coronary ischaemia and thus increase mortality especially in the subset of patients with pre-existing ischaemic heart disease [48-50].

2. Vascular

AF contributes to 15-25% of all strokes and these contribute to a significant proportion of AF-related mortality [51, 52]. AF-related strokes tend to be associated with higher mortality, and more severe disability [52, 53]. The Olmsted County study followed up 4117 individuals with AF and reported a 11% incidence of stroke over a mean follow-up period of 5.5±5 years, with AF–related stroke significantly increasing the mortality hazard ratio to 3.03 for men and 3.8 for women in comparison to the general population [18]. The Manitoba follow-up study showed that AF increased cardiovascular mortality including fatal stroke by 41% [11]. Even amongst anti-coagulated patients with therapeutic INR, stroke risk due to AF can be up to 3% in high-risk individuals such as those with prior stroke [54, 55]. Un-coordinated atrial contraction leads to stasis of blood in the left atrium [56]. In addition to this, thrombogenesis is also perpetuated by haematological abnormalities such as platelet activation, inflammation and structural factors such as atrial dilatation, loss of endothelium and progressive fibrosis [56]. The left atrial appendage is the site responsible for the majority of thrombi in non-valvular AF [56]. However, it has been demonstrated that not all thrombo-embolic events necessarily predict mortality risk. For instance, the ACTIVE-W trial showed that only disabling strokes (both ischaemic and haemorrhagic with Rankin score ≥3) increase mortality risk whereas transient ischaemic attacks do not [57]. Major bleeding secondary to anti-coagulation can also contribute to mortality [57].

3. Non-cardiovascular Deaths

Most therapeutic strategies for AF such as anti-arrhythmic drugs, anti-thrombotics and catheter ablation can increase mortality risk in AF as a side-effect or serious adverse event. Anti-arrhythmic drugs can lead to potentially lethal pro-arrhythmic effects (such as torsade de pointes) but also cause multi-systemic side-effects and thus contribute to non-cardiovascular deaths [10, 58, 59]. A rhythm control strategy has also been shown to unmask non-cardiovascular co-morbidities such as malignancies or lung pathology, thus contributing to mortality burden (covered in greater detail in section on AADs) [10, 48]. Bleeding risk is inextricably linked to use of anti-thrombotics and can be fatal. Severe bleeding events (such as fatal events, drop in haemoglobin of at least 5 g/decilitre), need for inotropic agents, loss of vision due to intra-ocular bleeding, surgical intervention due to bleeding, symptomatic intra-cranial haemorrhage, need for transfusion of at least 4 units of blood) treble the mortality risk (HR. 3.35; 95% CI, 2.12-5.27) whilst non-severe major bleeding or minor bleeding events do not increase mortality.

RISK PREDICTION FOR AF-RELATED MORTALITY

In view of the significant mortality risk due to AF and the associated co-morbidities, several useful risk-predictors have been identified. The CHADS₂ Score (1 point each for Congestive Heart Failure, Hypertension, Age≥75 years, Diabetes Mellitus and 2 points for Stroke/TIA) was introduced over a decade back as a scoring system to assess thrombo-embolic risk due to AF [60] but can also predict mortality risk. Khumri et al. showed in a study that patients with CHADS₂ score of ≥5 have a 50 fold higher mortality risk in comparison to patients with a score of 0 [61]. Similarly, while the HAS-BLED score has been mainly used in clinical practice to predict risk of major haemorrhagic episodes due to anti-coagulation [62], this risk score has also been shown to predict adverse cardiovascular events as well as all-cause mortality, thus illustrating that thrombogenesis and haemorrhage are inextricably linked by sharing many common risk predictors [63]. Whilst the CHA₂DS₂Vasc score has been recommended in the latest guidelines to supersede CHADS₂ as a better risk predictor for thrombo-embolic risk, its role as a risk predictor for mortality remains to be established.

Abnormal ankle brachial index (ratio of ankle and brachial systolic blood pressure) has been shown to independently predict all-cause mortality after adjusting for CHADS2 score and also predict major haemorrhagic episodes irrespective of the HAS-BLED score [64]. Cardiovascular related hospitalisation in AF patients also significantly predicts risk of death (HR 2.69; 95% CI 1.96-3.68) and it has been suggested that this end-point could be used as a surrogate for mortality in trials [65].

Clinical investigations also help to identify patients at increased risk of AF-related averse events. Serum bio-markers such as interleukin-6, high sensitivity troponin T and von Willebrand factor have been shown to predict all-cause mortality independent of CHADS2 score in anti-coagulated AF patients, possibly reflecting coronary micro-vascular dysfunction, global endothelial dysfunction or athero-thrombosis [66-68]. High sensitivity CRP has also been shown to predict all-cause and cardiovascular mortality amongst AF patients [69]. Patients with renal failure (eGFR <45 ml/min and proteinuria) have been shown to have increased risk of AF-related thrombo-embolism, bleeding and mortality [70]. Echocardiographic markers such as mitral annular calcification, presence of spontaneous left atrial contrast, severe LV impairment and greater than moderate mitral regurgitation also help to predict increased mortality risk amongst chronic AF patients [61, 71].

TREATMENTS

Anti-arrhythmic Drugs (AADs)

Several AADs have been shown to cause pro-arrhythmic side-effects and thus increased mortality in patients [58]. The class I agent flecainide gained particular attention following the CAST trial [72] where increased mortality was observed in patients with history of myocardial infarction. These results have been extrapolated to extend its contraindication to patients with coronary artery disease, heart failure or left ventricular hypertrophy. Coplen, in a meta-analysis published in 1990, showed that treatment with quinidine was more effective than no anti-arrhythmic therapy in suppressing recurrences of atrial fibrillation but appeared to be associated with increased total mortality [73]. Class III medications such as amiodarone and sotalol, have also received similar attention, and are also well known for their risk of QT prolongation and Torsades de Pointes.

Indeed all AADs have the potential to have serious, pro-arrhythmic side effects [58]. This has implications when determining the optimal treatment strategy for atrial fibrillation (AF): the restoration and maintenance of sinus rhythm (rhythm control strategy) or control of heart rate alone (rate control strategy). Several studies have sought to answer this question, including the Strategies of Treatment of Atrial Fibrillation (STAF) [74], Pharmacological Intervention in Atrial Fibrillation (PIAF) [75], Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) [10], Rate Control vs. Electrical Cardioversion (RACE) [76], the HOT CAFÉ [77] and J-RHYTHM Study [78]. None of these studies has shown any significant difference in all-cause or cardiovascular mortality and stroke outcome between rate and rhythm control and in fact a meta-analysis of five major trials showed a trend towards reduced risk of death (rate vs. rhythm control; OR 0.87, 0.74-1.02- P=0.09) [79]. This has generally led to the adoption of rate control strategy as the pragmatic approach especially in the elderly or in presence of significant co-morbidities.

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) in particular showed a non-significant trend toward increased all-cause mortality in the rhythm control group (hazard ratio 1.14; 95% CI, 1-1.32) [10]. A retrospective analysis of the cause-specific mortality in the AFFIRM trial showed that the incidence of cardiac (including arrhythmic, heart failure and MI deaths) and vascular (including ischaemic and haemorrhagic strokes) deaths was not significantly different between the rhythm control and rate-control groups [48]. Thus the increased all-cause mortality in the rhythm-control group could be entirely accounted for by the significant difference between the incidences of non-cardiovascular deaths (47.5% in rhythm control group versus 36.5% in rate-control group; p=0.0008). These non-cardiovascular deaths were mainly due to malignancies and pneumonia. This was attributed to earlier discontinuation of warfarin and higher incidence of stroke rather than risk of the anti-arrhythmic itself which highlights the importance of anticoagulation in atrial fibrillation. Even in patients with heart failure (LVF<35%) complicated by AF, the AF-CHF trial did not demonstrate that rhythm control could lead to mortality benefit [33]. However, there has been some evidence demonstrating the benefits of rhythm control particularly in the longer term. For instance, a retrospective, “on-treatment analysis” of the AFFIRM study that analysed presence of sinus rhythm and use of anti-arrhythmic drugs as separate variables, showed a significant reduction in death due to presence of sinus rhythm [80]. Thus the mortality increase of 49% due to anti-arrhythmic drugs could have overshadowed the 53% mortality reduction due to maintenance of sinus rhythm [48]. The survival benefits of sinus rhythm were similar to that seen in the DIAMOND AF (dofetilide versus placebo in AF patients with LV dysfunction) study which did not show an all-cause mortality benefit; however, restoration and maintenance of sinus rhythm significantly reduced mortality (risk ratio 0.44; 95% CI 0.30-0. 64) and risk of hospitalisation [81]. In a population-based study of rate versus rhythm control strategies among 26, 130 AF patients, showed that the rhythm control group demonstrated a small increase in mortality within six months of treatment initiation which then became similar to mortality in the rate-control group until year 4. In the longer term however (after year 5), the mortality was lower in the rhythm control group in comparison to that in the rate-control group (HR 0.89; 95% CI 0.81-0.96 after 5 years and HR 0.77; 95% CI 0.62-0.95 after 8 years) [82]. From the above studies, it is likely that the pro-arrhythmic effects and multi-systemic side-effects of existing AADs dilute and even offset the survival advantage provided by maintenance of sinus rhythm.

The most commonly used AAD for rhythm control in all these trials was amiodarone, which was shown in the studies to have a low pro-arrhythmic potential, with its adverse side effects being mainly extra-cardiac [59]. Amiodarone has been demonstrated to be the most efficacious drug in maintaining sinus rhythm [59, 79]. Some studies have found it to be associated with an increased risk of non-cardiac mortality (particularly cancer-related and pulmonary) [83-85] whilst this was not observed in other studies [86, 87]. Recently Freemantle et al. included thirty nine randomised controlled trials in a mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide and propafenone used for the management of AF and reported (from eighteen trials including about 10,000 patients) that sotalol in particular was associated with increased mortality whereas amiodarone (but not dronedarone) showed a trend towards increased all-cause mortality [59]. A meta-analysis by Piccini et al. also demonstrated an insignificant trend towards increased mortality due to amiodarone [88].

More recently, there has been the arrival of dronedarone, an AAD developed to have fewer side effects and improved safety profile compared to amiodarone [88]. The EURIDIS and ADONIS trials showed dronedarone was significantly more effective than placebo in maintaining sinus rhythm, and in reducing ventricular rate during recurrence of arrhythmia, with post hoc analysis also suggesting a 44% reduction in cardiovascular hospitalisation or death at 12 months [89]. Although dronedarone is less efficacious than amiodarone [88], a subsequent trial (ATHENA) showed that dronedarone reduces the composite endpoint of cardiovascular hospitalisation or death by 24% [14]. However, subsequent studies have shown that dronedarone can lead to increased early mortality in certain sub-sets of patients. For instance, in the ANDROMEDA trial (Anti-arrhythmic trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease), dronedarone (in comparison with placebo) led to a doubling of mortality (95%CI, 1.07-4.25) due to worsening heart failure after a median follow-up of only 2 months [90] Dronedarone also led to increased cardiovascular deaths (hazard ratio 2.11; 95% CI, 1-4.49), arrhythmic deaths (hazard ratio 3.26; 95% CI, 1.06-10) in addition to increased incidence of stroke and heart failure hospitalisations when used in patients with high-risk permanent AF (PALLAS) [91].

ANTI-COAGULATION

Effective anticoagulation is the most effective method of reducing mortality in AF patients [92]. In the absence of anti-coagulation, AF patients who develop a stroke have a 1 month mortality of nearly 25% [92]. In a meta-analysis of 29 trials of anti-thrombotic therapy for AF, compared to control, adjusted-dose warfarin reduced significantly stroke risk by 64% and all-cause mortality by 26%. Aspirin in contrast showed a non-significant 19% reduction in stroke risk and did not reduce mortality significantly [93]. In addition to anti-coagulation with warfarin, it is also important to closely monitor the therapeutic range of INR closely to both prevent thrombo-embolic complications as well as avoid major bleeding complications. Patients who spend at least 70% of the time with INR within therapeutic range demonstrate significantly lower mortality compared to patients whose INR is therapeutic <70% of the time [94]. Analysis of 30-day mortality due to ischaemic stoke whilst on warfarin, has shown that warfarin significantly reduces 30 day mortality if INR is between 2-3 (OR 0.38; 955 CI, 0. 2-0.7) but patients with INR>3 demonstrate increased odds of mortality due to intra-cranial haemorrhage 2.66 fold (95% CI, 1.21-5.86) [95].

Despite the obvious benefits of warfarin, the ATRIA study showed that it was being under-prescribed, particularly in those AF patients below 55 years and above 85 years, presumably due to physicians’ concerns regarding bleeding risk [96]. Interestingly, in contrast to this predominant view held by most physicians, patients are willing to accept the higher risk of bleeding associated with anti-coagulants in order to avoid disabling strokes which some even view as worse than death [97]. The search for more efficacious and potentially safer anti-thrombotics has heralded the era of novel anti-coagulants, as detailed below.

In the RELY study [98], dabigatran, a novel oral direct thrombin inhibitor, given at a dose of 110 mg to AF patients, was associated with rates of stroke and systemic embolism similar to warfarin, but with lower rates of major haemorrhage, whilst at doses of 150 mg, it was associated with lower rates of stroke and systemic embolism compared to warfarin, and similar rates of major haemorrhage. There was a trend towards reduction in all-cause mortality with the 150 mg dose (p=0.051) and a significant reduction in vascular mortality (p=0.04). The rates of death from any cause were 4.13% per year with warfarin, compared with 3.75% per year with 110 mg dabigatran (P=0.13), and 3.64% with 150 mg dabigatran (P=0.051). A meta-analysis of seven dabigatran studies (including 30514 patients) also showed a 11% reduction in all-cause mortality in comparison to warfarin [99].

Following this there has been the addition of the oral factor Xa inhibitors: rivaroxaban, assessed by the ROCKET-AF trial [100]; and apixaban, analysed by the AVERROES [16] and ARISTOTLE [101] trials. In the ROCKET-AF trial, in comparison with warfarin for non-valvular AF, rivaroxaban was shown to be non-inferior for prevention of stroke or systemic embolism. There was no significant difference in risk of major bleeding, though intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. There was no significant difference in mortality between the two groups. In the ARISTOTLE trial, apixaban was shown to be superior to warfarin by reducing the risk of stroke or systemic embolism by 21%, major bleeding by 31% and all-cause mortality by 11% [101].

The future for these novel anticoagulants is very promising, with significant progress being made in morbidity and mortality reduction compared to warfarin, mainly by way of further reduction in ischaemic strokes and less bleeding risks. However there are also several concerns regarding the use of the newer anticoagulants as detailed below. These include the lack of robust safety data in patients with creatinine clearance <30 ml/min, elderly patients and those with extremes of body weight. Whilst the lack of need to closely monitor anticoagulation whilst on newer anticoagulants can be viewed as an advantage by reducing patient inconvenience as well as the burden on healthcare resources, this feature can also be a disadvantage if patients miss one or more doses (due to the short offset time of these drugs leading to a rebound stroke risk). Additionally the lack of a specific antidote to these drugs is also of concern during major bleeding episodes. Thus there is a need for further studies in order to clarify the above concerns about these drugs before they can be incorporated into widespread clinical practice.

INTERVENTIONAL TREATMENTS

Catheter ablation is recommended in the management of symptomatic paroxysmal AF after failed AAD therapy and has not yet been demonstrated to confer mortality benefits possibly due to lack of long-term follow-up data. Being an invasive procedure, the procedure itself carries a mortality risk of up to 0.7% [2]. However, newer technological developments are consistently improving the safety and efficacy of catheter-based techniques. Left atrial appendage closure using occlusion devices has been suggested as an alternative for patients deemed unsuitable for oral anti-coagulation and again data on mortality benefits from this procedure is lacking currently.

CONCLUSIONS

AF and its associated co-morbidities continue to impose a significant mortality risk despite several new therapeutic advances. Indeed a proportion of the AF-related mortality is caused by side-effects due to attempts at restoring and maintaining sinus rhythm or major bleeding due to anti-coagulation. However effective anti-coagulation is the only therapeutic strategy that has been shown to reduce AF-related mortality and newer anticoagulants with improved efficacy and lesser bleeding side-effects, are only likely to improve the risk-benefit profile. Currently available AADs have limited efficacy and possess significant side-effects which seem to offset benefits of rhythm control; hence there is a pressing need to develop improved AADs in order to unmask the survival benefit that could accrue from maintenance of sinus rhythm. The impact of catheter ablation in the management of AF has currently been increasing and with improvements in safety and efficacy, is likely to reduce the use of AADs in the future.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

References

1. Feinberg W.M., Cornell E.S., Nightingale S.D., Pearce L.A., Tracy R.P., Hart R.G., Bovill E.G., et al. Stroke Prevention in Atrial Fibrillation Investigators. Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke. 1997;28(6):1101–1106. doi: 10.1161/01.STR.28.6.1101. [PubMed] [CrossRef] [Google Scholar]2. Camm A.J., Kirchhof P., Lip G.Y., Schotten U., Savelieva I., Ernst S., Van Gelder I.C., Al-Attar N., Hindricks G., Prendergast B., Heidbuchel H., Alfieri O., Angelini A., Atar D., Colonna P., De Caterina R., De Sutter J., Goette A., Gorenek B., Heldal M., Hohloser S.H., Kolh P., Le Heuzey J.Y., Ponikowski P., Rutten F.H., et al. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J. 2010;31(19):2369–2429. doi: 10.1093/eurheartj/ehq278. [PubMed] [CrossRef] [Google Scholar]3. Stewart S., Hart C.L., Hole D.J., McMurray J.J., et al. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am. J. Med. 2002;113(5):359–364. doi: 10.1016/S0002-9343(02)01236-6. [PubMed] [CrossRef] [Google Scholar]4. Kirchhof P., Auricchio A., Bax J., Crijns H., Camm J., Diener H.C., Goette A., Hindricks G., Hohnloser S., Kappenberger L., Kuck K.H., Lip G.Y., Olsson B., Meinertz T., Priori S., Ravens U., Steinbeck G., Svernhage E., Tijssen J., Vincent A., Breithardt G., et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur. Heart J. 2007;28(22):2803–2817. doi: 10.1093/eurheartj/ehm358. [PubMed] [CrossRef] [Google Scholar]5. Benjamin E.J., Wolf P.A., D’Agostino R.B., Silbershatz H., Kannel W.B., Levy D., et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946–952. doi: 10.1161/01.CIR.98.10.946. [PubMed] [CrossRef] [Google Scholar]6. Vidaillet H., Granada J.F., Chyou Po., Maassen K., Ortiz M., Pulido J.N., Sharma P., Smith P.N., Hayes J., et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am. J. Med. 2002;113(5):365–370. doi: 10.1016/S0002-9343(02)01253-6. [PubMed] [CrossRef] [Google Scholar]7. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A., et al. Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC Cardiovasc. Disord. 2002;2:5. doi: 10.1186/1471-2261-2-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]8. Miyasaka Y., Barnes M.E., Bailey K.R., Cha S.S., Gersh B.J., Seward J.B., Tsang T.S., et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J. Am. Coll. Cardiol. 2007;49(9):986–992. doi: 10.1016/j.jacc.2006.10.062. [PubMed] [CrossRef] [Google Scholar]9. Olsson S.B. Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691–1698. doi: 10.1016/S0140-6736(03)14841-6. [PubMed] [CrossRef] [Google Scholar]10. Wyse D.G., Waldo A.L., DiMarco J.P., Domanski M.J., Rosenberg Y., Schron E.B., Kellen J.C., Greene H.L., Mickel M.C., Dalquist J.E., Corley S.D., et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 2002;347(23):1825–1833. doi: 10.1056/NEJMoa021328. [PubMed] [CrossRef] [Google Scholar]11. Krahn A.D., Manfreda J., Tate R.B., Mathewson F.A., Cuddy T.E., et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am. J. Med. 1995;98(5):476–484. doi: 10.1016/S0002-9343(99)80348-9. [PubMed] [CrossRef] [Google Scholar]12. Gajewski J., Singer R.B. Mortality in an insured population with atrial fibrillation. JAMA. 1981;245(15):1540–1544. doi: 10.1001/jama.1981.03310400022019. [PubMed] [CrossRef] [Google Scholar]13. Piccini J.P., Hammill B.G., Sinner M.F., Jensen P.N., Hernandez A.F., Heckbert S.R., Benjamin E.J., Curtis L.H., et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5(1):85–93. doi: 10.1161/CIRCOUTCOMES.111.962688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]14. Hohnloser S.H., Crijns H.J., van Eickels M., Gaudin C., Page R.L., Torp-Pedersen C., Connolly S.J., et al. ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 2009;360(7):668–678. doi: 10.1056/NEJMoa0803778. [PubMed] [CrossRef] [Google Scholar]15. Go A.S., et al. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N. Engl. J. Med. 2009;360(20):2127–2129. doi: 10.1056/NEJMe0902676. [PubMed] [CrossRef] [Google Scholar]16. Connolly S.J., Eikelboom J., Joyner C., Diener H.C., Hart R., Golitsyn S., Flaker G., Avezum A., Hohnloser S.H., Diaz R., Talajic M., Zhu J., Pais P., Budaj A., Parkhomenko A., Jansky P., Commerford P., Tan R.S., Sim K.H., Lewis B.S., Van Mieghem W., Lip G.Y., Kim J.H., Lanas-Zanetti F., Gonzalez-Hermosillo A., Dans A.L., Munawar M., O’Donnell M., Lawrence J., Lewis G., Afzal R., Yusuf S., et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 2011;364(9):806–817. doi: 10.1056/NEJMoa1007432. [PubMed] [CrossRef] [Google Scholar]17. Arias E., et al. National vital statistics reports. Hyattsville, MD: National Centre for Health Statistics; 2010. United States Life Tables 2006. Report No. [Google Scholar]18. Miyasaka Y., Barnes M.E., Gersh B. J., Cha S.S., Seward J.B., Bailey K.R., Iwasaka T., Tsang T.S., et al. Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study. Stroke. 2005;36(11):2362–2366. doi: 10.1161/01.STR.0000185927.63746.23. [PubMed] [CrossRef] [Google Scholar]19. Turagam M.K., Velagapudi P., Visotcky A., Szabo A., Kocheril A.G., et al. African Americans have the highest risk of in-hospital mortality with atrial fibrillation related hospitalizations among all racial/ethnic groups: a nationwide analysis. Int. J. Cardiol. 2012;158(1):165–166. doi: 10.1016/j.ijcard.2012.04.090. [PubMed] [CrossRef] [Google Scholar]20. Rosiak M., Dziuba M., Chudzik M., Cygankiewicz I., Bartczak K., Drozdz J., Wranicz J.K., et al. Risk factors for atrial fibrillation: Not always severe heart disease, not always so ‘lonely’. Cardiol. J. 2010;17(5):437–442. [PubMed] [Google Scholar]21. Kopecky S.L., Gersh B.J., McGoon M.D., Whisnant J. P., Holmes D.R., Jr, Ilstrup D.M., Frye R.L., et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N. Engl. J. Med. 1987;317(11):669–674. doi: 10.1056/NEJM198709103171104. [PubMed] [CrossRef] [Google Scholar]22. Rostagno C., Bacci F., Martelli M., Naldoni A., Bertini G., Gensini G., et al. Clinical course of lone atrial fibrillation since first symptomatic arrhythmic episode. Am. J. Cardiol. 1995;76(11):837–839. doi: 10.1016/S0002-9149(99)80240-9. [PubMed] [CrossRef] [Google Scholar]23. Potpara T., Grujić M., Marinković J., Vujisić-Tesić B., Ostojić M., Polovina M., et al. Mortality of patients with lone and idiopathic atrial fibrillation is similar to mortality in general population of Serbia. Vojnosanit. Pregl. 2010;67(2):132–135. doi: 10.2298/VSP1002132P. [PubMed] [CrossRef] [Google Scholar]24. Botto G.L., Padeletti L., Santini M., Capucci A., Gulizia M., Zolezzi F., Favale S., Molon G., Ricci R., Biffi M., Russo G., Vimercati M., Corbucci G. , Boriani G., et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J. Cardiovasc. Electrophysiol. 2009;20(3):241–248. doi: 10.1111/j.1540-8167.2008.01320.x. [PubMed] [CrossRef] [Google Scholar]25. Lip G.Y., Hee F.L. Paroxysmal atrial fibrillation. QJM. 2001;94(12):665–678. doi: 10.1093/qjmed/94.12.665. [PubMed] [CrossRef] [Google Scholar]26. Keating R.J., Gersh B.J., Hodge D.O., Weivoda P.L., Patel P.J., Hammill S.C., Shen W.K., et al. Effect of atrial fibrillation pattern on survival in a community-based cohort. Am. J. Cardiol. 2005;96(10):1420–1424. doi: 10.1016/j.amjcard.2005.07.050. [PubMed] [CrossRef] [Google Scholar]27. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A. Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc. Disord. 2005;5:20. doi: 10.1186/1471-2261-5-20. [PMC free article] [PubMed] [CrossRef] [Google Scholar]28. Tuinenburg A.E., Van Gelder I.C., Van Den Berg M.P., Brügemann J., De Kam P.J., Crijns H.J., et al. Lack of prevention of heart failure by serial electrical cardioversion in patients with persistent atrial fibrillation. Heart. 1999;82(4):486–493. doi: 10.1136/hrt.82.4.486. [PMC free article] [PubMed] [CrossRef] [Google Scholar]29. Brown A.M., Sease K.L., Robey J.L., Shofer F.S., Hollander J.E., et al. The risk for acute coronary syndrome associated with atrial fibrillation among ED patients with chest pain syndromes. Am. J. Emerg. Med. 2007;25(5):523–528. doi: 10.1016/j.ajem.2006.09.015. [PubMed] [CrossRef] [Google Scholar]30. Sankaranarayanan R., et al. Mortality Risk Associated with AF in Myocardial Infarction Patients. J. Atr. Fibrillation. 2012;5(3):138–152. [PMC free article] [PubMed] [Google Scholar]31. Sankaranarayanan R., James M.A., Nuta B., Townsend M., Kesavan S., Burtchaell S., Holloway R., Ewings P., et al. Does atrial fibrillation beget ventricular fibrillation in patients with acute myocardial infarction? Pacing Clin. Electrophysiol. 2008;31(12):1612–1619. doi: 10.1111/j.1540-8159.2008.01234.x. [PubMed] [CrossRef] [Google Scholar]32. Lehto M., Snapinn S., Dickstein K., Swedberg K., Nieminen M.S., et al. OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience. Eur. Heart J. 2005;26(4):350–356. doi: 10.1093/eurheartj/ehi064. [PubMed] [CrossRef] [Google Scholar]33. Roy D., Talajic M., Nattel S., Wyse D.G., Dorian P., Lee K.L., Bourassa M.G., Arnold J.M., Buxton A.E., Camm A.J., Connolly S.J., Dubuc M., Ducharme A., Guerra P.G., Hohnloser S.H., Lambert J., Le Heuzey J.Y., O’Hara G., Pedersen O.D., Rouleau J.L., Singh B.N., Stevenson L.W., Stevenson W.G., Thibault B., Waldo A.L., et al. Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N. Engl. J. Med. 2008;358(25):2667–2677. doi: 10.1056/NEJMoa0708789. [PubMed] [CrossRef] [Google Scholar]34. Caldwell J.C., Contractor H., Petkar S., Ali R., Clarke B., Garratt C.J., Neyses L., Mamas M.A., et al. Atrial fibrillation is under-recognized in chronic heart failure: insights from a heart failure cohort treated with cardiac resynchronization therapy. Europace. 2009;11(10):1295–1300. doi: 10.1093/europace/eup201. [PubMed] [CrossRef] [Google Scholar]35. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Bailey K.R., Abhayaratna W., Seward J.B., Iwasaka T., Tsang T.S., et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: a community-based study over two decades. Eur. Heart J. 2006;27(8):936–941. doi: 10.1093/eurheartj/ehi694. [PubMed] [CrossRef] [Google Scholar]36. Wang T.J., Larson M.G., Levy D., Vasan R.S., Leip E.P., Wolf P.A., D’Agostino R.B., Murabito J.M., Kannel W.B., Benjamin E.J., et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920–2925. doi: 10.1161/01.CIR.0000072767.89944.6E. [PubMed] [CrossRef] [Google Scholar]37. Olsson L.G., Swedberg K., Ducharme A., Granger C.B., Michelson E.L., McMurray J.J., Puu M., Yusuf S., Pfeffer M.A., et al. CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J. Am. Coll. Cardiol. 2006;47(10):1997–2004. doi: 10.1016/j.jacc.2006.01.060. [PubMed] [CrossRef] [Google Scholar]38. Rivero-Ayerza M., Scholte Op Reimer W., Lenzen M., Theuns D.A., Jordaens L., Komajda M., Follath F., Swedberg K., Cleland J.G., et al. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalized heart failure patients: results of the EuroHeart Failure Survey. Eur. Heart J. 2008;29(13):1618–1624. doi: 10.1093/eurheartj/ehn217. [PubMed] [CrossRef] [Google Scholar]39. Dries D.L., Exner D.V., Gersh B.J., Domanski M.J., Waclawiw M.A., Stevenson L.W., et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J. Am. Coll. Cardiol. 1998;32(3):695–703. doi: 10.1016/S0735-1097(98)00297-6. [PubMed] [CrossRef] [Google Scholar]40. Mahoney P., Kimmel S., DeNofrio D., Wahl P., Loh E., et al. Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure. Am. J. Cardiol. 1999;83(11):1544–1547. doi: 10.1016/S0002-9149(99)00144-7. [PubMed] [CrossRef] [Google Scholar]41. Mamas M.A., Caldwell J.C., Chacko S., Garratt C.J., Fath-Ordoubadi F., Neyses L., et al. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur. J. Heart Fail. 2009;11(7):676–683. doi: 10.1093/eurjhf/hfp085. [PubMed] [CrossRef] [Google Scholar]42. Raunsø J., Pedersen O.D., Dominguez H., Hansen M.L., Møller J.E., Kjaergaard J., Hassager C., Torp-Pedersen C., Køber L., et al. EchoCardiography and Heart Outcome Study Investigators. Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease. Eur. J. Heart Fail. 2010;12(7):692–697. doi: 10.1093/eurjhf/hfq052. [PubMed] [CrossRef] [Google Scholar]43. Badheka A.O., Rathod A., Kizilbash M.A., Bhardwaj A., Ali O., Afonso L., Jacob S., et al. Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction. Am. J. Cardiol. 2011;108(9):1283–1288. doi: 10.1016/j.amjcard.2011.06.045. [PubMed] [CrossRef] [Google Scholar]44. Domanski M.J., et al. The epidemiology of atrial fibrillation. Coron. Artery Dis. 1995;6(2):95–100. doi: 10.1097/00019501-199502000-00002. [PubMed] [CrossRef] [Google Scholar]45. Cha Y.M., Redfield M.M., Shen W.K., Gersh B.J., et al. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation. 2004;109(23):2839–2843. doi: 10.1161/01.CIR.0000132470.78896.A8. [PubMed] [CrossRef] [Google Scholar]46. Daoud E.G., Weiss R., Bahu M., Knight B.P., Bogun F., Goyal R., Harvey M., Strickberger S.A., Man K.C., Morady F., et al. Effect of an irregular ventricular rhythm on cardiac output. Am. J. Cardiol. 1996;78(12):1433–1436. doi: 10.1016/S0002-9149(97)89297-1. [PubMed] [CrossRef] [Google Scholar]47. Shinbane J.S., Wood M.A., Jensen D.N., Ellenbogen K.A., Fitzpatrick A.P., Scheinman M.M., et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J. Am. Coll. Cardiol. 1997;29(4):709–715. doi: 10.1016/S0735-1097(96)00592-X. [PubMed] [CrossRef] [Google Scholar]48. Steinberg J.S., Sadaniantz A., Kron J., Krahn A., Denny D.M., Daubert J., Campbell W.B., Havranek E., Murray K., Olshansky B., O’Neill G., Sami M., Schmidt S., Storm R., Zabalgoitia M., Miller J., Chandler M., Nasco E.M., Greene H.L., et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation. 2004;109(16):1973–1980. doi: 10.1161/01.CIR.0000118472.77237.FA. [PubMed] [CrossRef] [Google Scholar]49. Fuster V., Rydén L.E., Cannom D.S., Crijns H.J., Curtis A.B., Ellenbogen K.A., Halperin J.L., Kay G.N., Le Huezey J.Y., Lowe J.E., Olsson S.B., Prystowsky E.N., Tamargo J.L., Wann L.S., et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2011;57(11):e101–e198. doi: 10.1016/j.jacc.2010.09.013. [PubMed] [CrossRef] [Google Scholar]50. Stein K.M., Euler D.E., Mehra R., Seidl K., Slotwiner D.J., Mittal S., Markowitz S.M., Lerman B.B. Jewel AF Worldwide Investigators. Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients? J. Am. Coll. Cardiol. 2002;40(2):335–340. doi: 10.1016/S0735-1097(02)01957-5. [PubMed] [CrossRef] [Google Scholar]51. Grau A.J., Weimar C., Buggle F., Heinrich A., Goertler M., Neumaier S., Glahn J., Brandt T., Hacke W., Diener H.C., et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559–2566. doi: 10.1161/hs1101.098524. [PubMed] [CrossRef] [Google Scholar]52. Kimura K., Minematsu K., Yamaguchi T., et al. Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC) Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with acute ischaemic stroke. J. Neurol. Neurosurg. Psychiatry. 2005;76(5):679–683. doi: 10.1136/jnnp.2004.048827. [PMC free article] [PubMed] [CrossRef] [Google Scholar]53. Jørgensen H.S., Nakayama H., Reith J., Raaschou H.O., Olsen T.S. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke. 1996;27(10):1765–1769. doi: 10.1161/01.STR.27.10.1765. [PubMed] [CrossRef] [Google Scholar]54. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255–1262. [PubMed] [Google Scholar]55. Akins P.T., Feldman H.A., Zoble R.G., Newman D., Spitzer S.G., Diener H.C., Albers G.W. Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials. Stroke. 2007;38(3):874–880. doi: 10.1161/01.STR.0000258004.64840.0b. [PubMed] [CrossRef] [Google Scholar]56. Watson T., Shantsila E., Lip G.Y. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373(9658):155–166. doi: 10.1016/S0140-6736(09)60040-4. [PubMed] [CrossRef] [Google Scholar]57. De Caterina R., Connolly S.J., Pogue J., Chrolavicius S., Budaj A., Morais J., Renda G., Yusuf S. ACTIVE Investigators. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur. Heart J. 2010;31(17):2133–2140. doi: 10.1093/eurheartj/ehq250. [PubMed] [CrossRef] [Google Scholar]58. Nattel S. Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Cardiovasc. Res. 1998;37(3):567–577. doi: 10.1016/S0008-6363(97)00293-9. [PubMed] [CrossRef] [Google Scholar]59. Freemantle N., Lafuente-Lafuente C., Mitchell S., Eckert L., Reynolds M. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace. 2011;13(3):329–345. doi: 10.1093/europace/euq450. [PubMed] [CrossRef] [Google Scholar]60. Gage B.F., Waterman A.D., Shannon W., Boechler M., Rich M.W., Radford M.J., et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–2870. doi: 10.1001/jama.285.22.2864. [PubMed] [CrossRef] [Google Scholar]61. Khumri T.M., Idupulapati M., Rader V.J., Nayyar S., Stoner C.N., Main M.L., et al. Clinical and echocardiographic markers of mortality risk in patients with atrial fibrillation. Am. J. Cardiol. 2007;99(12):1733–1736. doi: 10.1016/j.amjcard.2007.01.055. [PubMed] [CrossRef] [Google Scholar]62. Pisters R., Lane D.A., Nieuwlaat R., de Vos C.B., Crijns H.J., Lip G.Y., et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100. doi: 10.1378/chest.10-0134. [PubMed] [CrossRef] [Google Scholar]63. Gallego P., Roldán V., Torregrosa J.M., Gálvez J., Valdés M., Vicente V., Marín F., Lip G.Y., et al. Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation. Circ Arrhythm Electrophysiol. 2012;5(2):312–318. doi: 10.1161/CIRCEP.111.967000. [PubMed] [CrossRef] [Google Scholar]64. Gallego P., Roldán V., Marín F., Jover E., Manzano-Fernández S., Valdés M., Vicente V., Lip G.Y., et al. Ankle brachial index as an independent predictor of mortality in anticoagulated atrial fibrillation. Eur. J. Clin. Invest. 2012;42(12):1302–1308. doi: 10.1111/eci.12004. [PubMed] [CrossRef] [Google Scholar]65. Friberg L., Rosenqvist M., et al. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace. 2011;13(5):626–633. doi: 10.1093/europace/eur001. [PubMed] [CrossRef] [Google Scholar]66. Roldán V., Marín F., Díaz J., Gallego P., Jover E., Romera M., Manzano-Fernández S., Casas T., Valdés M., Vicente V., Lip G.Y., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation. J. Thromb. Haemost. 2012;10(8):1500–1507. doi: 10.1111/j.1538-7836.2012.04812.x. [PubMed] [CrossRef] [Google Scholar]67. Providencia R., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation: a rebuttal . J Thromb Haemost. 2012;10(11):2413–1507. author reply 2014-5. [PubMed] [Google Scholar]68. Roldán V., Marín F., Muiña B., Torregrosa J.M., Hernández-Romero D., Valdés M., Vicente V., Lip G.Y., et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J. Am. Coll. Cardiol. 2011;57(25):2496–2504. doi: 10.1016/j.jacc.2010.12.033. [PubMed] [CrossRef] [Google Scholar]69. Hermida J., Lopez F.L., Montes R., Matsushita K., Astor B.C., Alonso A., et al. Usefulness of high-sensitivity C-reactive protein to predict mortality in patients with atrial fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study). Am. J. Cardiol. 2012;109(1):95–99. doi: 10.1016/j.amjcard.2011.08.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]70. Go A.S., Fang M.C., Udaltsova N., Chang Y., Pomernacki N.K., Borowsky L., Singer D.E., et al. ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119(10):1363–1369. doi: 10.1161/CIRCULATIONAHA.108.816082. [PMC free article] [PubMed] [CrossRef] [Google Scholar]71. Potpara T.S., Vasiljevic Z.M., Vujisic-Tesic B.D., Marinkovic J.M., Polovina M.M., Stepanovic J.M., Stankovic G.R., Ostojic M.C., Lip G.Y., et al. Mitral annular calcification predicts cardiovascular morbidity and mortality in middle-aged patients with atrial fibrillation: the Belgrade Atrial Fibrillation Study. Chest. 2011;140(4):902–910. doi: 10.1378/chest.10-2963. [PubMed] [CrossRef] [Google Scholar]72. Echt D.S., Liebson P.R., Mitchell L.B., Peters R.W., Obias-Manno D., Barker A.H., Arensberg D., Baker A., Friedman L., Greene H.L., et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 1991;324(12):781–788. doi: 10.1056/NEJM199103213241201. [PubMed] [CrossRef] [Google Scholar]73. Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation. 1990;82(4):1106–1116. doi: 10.1161/01.CIR.82.4.1106. [PubMed] [CrossRef] [Google Scholar]74. Carlsson J., Miketic S., Windeler J., Cuneo A., Haun S., Micus S., Walter S., Tebbe U., et al. STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J. Am. Coll. Cardiol. 2003;41(10):1690–1696. doi: 10.1016/S0735-1097(03)00332-2. [PubMed] [CrossRef] [Google Scholar]75. Hohnloser S.H., Kuck K.H., Lilienthal J., et al. Rhythm or rate control in atrial fibrillation–Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356(9244):1789–1794. doi: 10.1016/S0140-6736(00)03230-X. [PubMed] [CrossRef] [Google Scholar]76. Van Gelder I.C., Hagens V.E., Bosker H.A., Kingma J.H., Kamp O., Kingma T., Said S.A., Darmanata J.I., Timmermans A.J., Tijssen J.G., Crijns H.J., et al. Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N. Engl. J. Med. 2002;347(23):1834–1840. doi: 10.1056/NEJMoa021375. [PubMed] [CrossRef] [Google Scholar]77. Opolski G., Torbicki A., Kosior D.A., Szulc M., Wozakowska-Kaplon B., Kolodziej P., Achremczyk P., et al. Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest. 2004;126(2):476–486. doi: 10.1378/chest.126.2.476. [PubMed] [CrossRef] [Google Scholar]78. Ogawa S., Yamashita T., Yamazaki T., Aizawa Y., Atarashi H., Inoue H., Ohe T., Ohtsu H., Okumura K., Katoh T., Kamakura S., Kumagai K., Kurachi Y., Kodama I., Koretsune Y., Saikawa T., Sakurai M., Sugi K., Tabuchi T., Nakaya H., Nakayama T., Hirai M., Fukatani M., Mitamura H., et al. J-RHYTHM Investigators. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ. J. 2009;73(2):242–248. doi: 10.1253/circj.CJ-08-0608. [PubMed] [CrossRef] [Google Scholar]79. Testa L., Biondi-Zoccai G.G., Dello Russo A., Bellocci F., Andreotti F., Crea F., et al. Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis. Eur. Heart J. 2005;26(19):2000–2006. doi: 10.1093/eurheartj/ehi306. [PubMed] [CrossRef] [Google Scholar]80. Corley S.D., Epstein A.E., DiMarco J.P., Domanski M.J., Geller N., Greene H.L., Josephson R.A., Kellen J.C., Klein R.C., Krahn A.D., Mickel M., Mitchell L.B., Nelson J.D., Rosenberg Y., Schron E., Shemanski L., Waldo A.L., Wyse D.G., et al. AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–1513. doi: 10.1161/01.CIR.0000121736.16643.11. [PubMed] [CrossRef] [Google Scholar]81. Pedersen O.D., Brendorp B., Elming H., Pehrson S., Køber L., Torp-Pedersen C., et al. Does conversion and prevention of atrial fibrillation enhance survival in patients with left ventricular dysfunction? Evidence from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide/(DIAMOND) study. Card. Electrophysiol. Rev. 2003;7(3):220–224. doi: 10.1023/B:CEPR.0000012386.82055.81. [PubMed] [CrossRef] [Google Scholar]82. Ionescu-Ittu R., Abrahamowicz M., Jackevicius C.A., Essebag V., Eisenberg M.J., Wynant W., Richard H., Pilote L., et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch. Intern. Med. 2012;172(13):997–1004. doi: 10.1001/archinternmed.2012.2266. [PubMed] [CrossRef] [Google Scholar]83. Bardy G.H., Lee K.L., Mark D.B., Poole J.E., Packer D.L., Boineau R., Domanski M., Troutman C., Anderson J., Johnson G., McNulty S.E., Clapp-Channing N., Davidson-Ray L.D., Fraulo E.S., Fishbein D.P., Luceri R.M., Ip J.H., et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 2005;352(3):225–237. doi: 10.1056/NEJMoa043399. [PubMed] [CrossRef] [Google Scholar]84. Julian D.G., Camm A.J., Frangin G., Janse M.J., Munoz A., Schwartz P.J., Simon P., et al. European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet. 1997;349(9053):667–674. doi: 10.1016/S0140-6736(96)09145-3. [PubMed] [CrossRef] [Google Scholar]85. Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J. Am. Coll. Cardiol. 1999;34(5):1552–1559. doi: 10.1016/S0735-1097(99)00376-9. [PubMed] [CrossRef] [Google Scholar]86. Singh S.N., Fletcher R.D., Fisher S.G., Singh B.N., Lewis H.D., Deedwania P.C., Massie B.M., Colling C., Lazzeri D., et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N. Engl. J. Med. 1995;333(2):77–82. doi: 10.1056/NEJM199507133330201. [PubMed] [CrossRef] [Google Scholar]87. Cairns J.A., Connolly S.J., Roberts R., Gent M., et al. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet. 1997;349(9053):675–682. doi: 10.1016/S0140-6736(96)08171-8. [PubMed] [CrossRef] [Google Scholar]88. Piccini J.P., Hasselblad V., Peterson E.D., Washam J.B., Califf R.M., Kong D.F., et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J. Am. Coll. Cardiol. 2009;54(12):1089–1095. doi: 10.1016/j.jacc.2009.04.085. [PubMed] [CrossRef] [Google Scholar]89. Duray G.Z., Torp-Pedersen C., Connolly S.J., Hohnloser S.H., et al. Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. J. Cardiovasc. Electrophysiol. 2011;22(7):770–776. doi: 10.1111/j.1540-8167.2010.02006.x. [PubMed] [CrossRef] [Google Scholar]90. Køber L., Torp-Pedersen C., McMurray J.J., Gøtzsche O., Lévy S., Crijns H., Amlie J., Carlsen J., et al. Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 2008;358(25):2678–2687. doi: 10.1056/NEJMoa0800456. [PubMed] [CrossRef] [Google Scholar]91. Connolly S.J., Camm A.J., Halperin J.L., Joyner C., Alings M., Amerena J., Atar D., Avezum Á., Blomström P., Borggrefe M., Budaj A., Chen S.A., Ching C.K., Commerford P., Dans A., Davy J.M., Delacrétaz E., Di Pasquale G., Diaz R., Dorian P., Flaker G., Golitsyn S., Gonzalez-Hermosillo A., Granger C.B., Heidbüchel H., Kautzner J., Kim J.S., Lanas F., Lewis B.S., Merino J.L., Morillo C., Murin J., Narasimhan C., Paolasso E., Parkhomenko A., Peters N.S., Sim K.H., Stiles M.K., Tanomsup S., Toivonen L., Tomcsányi J., Torp-Pedersen C., Tse H.F., Vardas P., Vinereanu D., Xavier D., Zhu J., Zhu J.R., Baret-Cormel L., Weinling E., Staiger C., Yusuf S., Chrolavicius S., Afzal R., Hohnloser S.H. PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med. 2011;365(24):2268–2276. doi: 10.1056/NEJMoa1109867. [PubMed] [CrossRef] [Google Scholar]92. Hylek E.M., Go A.S., Chang Y., Jensvold N.G., Henault L.E., Selby J.V., Singer D.E. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med. 2003;349(11):1019–1026. doi: 10.1056/NEJMoa022913. [PubMed] [CrossRef] [Google Scholar]93. Hart R.G., Pearce L.A., Aguilar M.I. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann. Intern. Med. 2007;147(8):590–592. doi: 10.7326/0003-4819-147-8-200710160-00018. [PubMed] [CrossRef] [Google Scholar]94. Gallagher A.M., Setakis E., Plumb J.M., Clemens A., van Staa T.P., et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb. Haemost. 2011;106(5):968–977. doi: 10.1160/Th21-05-0353. [PubMed] [CrossRef] [Google Scholar]95. Fang M.C., Go A.S., Chang Y., Borowsky L.H., Pomernacki N.K., Udaltsova N., Singer D.E., et al. Thirty-day mortality after ischemic stroke and intracranial hemorrhage in patients with atrial fibrillation on and off anticoagulants. Stroke. 2012;43(7):1795–1799. doi: 10.1161/STROKEAHA.111.630731. [PMC free article] [PubMed] [CrossRef] [Google Scholar]96. Go A.S., Hylek E.M., Borowsky L.H., Phillips K.A., Selby J.V., Singer D.E., et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann. Intern. Med. 1999;131(12):927–934. doi: 10.7326/0003-4819-131-12-199912210-00004. [PubMed] [CrossRef] [Google Scholar]97. Devereaux P.J., Anderson D.R., Gardner M.J., Putnam W., Flowerdew G.J., Brownell B.F., Nagpal S., Cox J.L., et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ. 2001;323(7323):1218–1222. doi: 10.1136/bmj.323.7323.1218. [PMC free article] [PubMed] [CrossRef] [Google Scholar]98. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., Pogue J., Reilly P.A., Themeles E., Varrone J., Wang S., Alings M., Xavier D., Zhu J., Diaz R., Lewis B.S., Darius H., Diener H.C., Joyner C.D., Wallentin L., et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009;361(12):1139–1151. doi: 10.1056/NEJMoa0905561. [PubMed] [CrossRef] [Google Scholar]99. Uchino K., Hernandez A.V., et al. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch. Intern. Med. 2012;172(5):397–402. doi: 10.1001/archinternmed.2011.1666. [PubMed] [CrossRef] [Google Scholar]100. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., Breithardt G., Halperin J.L., Hankey G.J., Piccini J.P., Becker R.C., Nessel C.C., Paolini J.F., Berkowitz S.D., Fox K.A., Califf R.M., et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011;365(10):883–891. doi: 10.1056/NEJMoa1009638. [PubMed] [CrossRef] [Google Scholar]101. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M., Al-Khalidi H.R., Ansell J., Atar D., Avezum A., Bahit M.C., Diaz R., Easton J.D., Ezekowitz J.A., Flaker G., Garcia D., Geraldes M., Gersh B.J., Golitsyn S., Goto S., Hermosillo A.G., Hohnloser S.H., Horowitz J., Mohan P., Jansky P., Lewis B.S., Lopez-Sendon J.L., Pais P., Parkhomenko A., Verheugt F.W., Zhu J., Wallentin L., et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011;365(11):981–992. doi: 10.1056/NEJMoa1107039. [PubMed] [CrossRef] [Google Scholar]

How does Chronic Atrial Fibrillation Influence Mortality in the Modern Treatment Era?

Curr Cardiol Rev. 2015 Aug; 11(3): 190–198.

Rajiv Sankaranarayanan

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Graeme Kirkwood

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Rajaverma Visweswariah

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

David J. Fox

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

^* Address correspondence to this author at the Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK; Tel: 00447525826672; Fax: 00441612751234; E-mail [email protected]

Received 2014 Apr 23; Revised 2014 Aug 22; Accepted 2014 Aug 27.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been cited by other articles in PMC.

Abstract

Atrial fibrillation (AF) continues to impose a significant burden upon healthcare resources. A sustained increase in the ageing population and better survival from conditions such as ischaemic heart disease have ensured that both the incidence and prevalence of AF continue to increase significantly. AF can lead to complications such as embolism and heart failure and these acting in concert with its associated co-morbidities portend increased mortality risk. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of various therapeutic strategies (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures). Despite several treatment advances including newer anti-arrhythmic drugs and developments in catheter ablation, anti-coagulation remains the only effective means to reduce the mortality due to AF. Warfarin has been used as the oral anticoagulant in the treatment of AF for many years but suffers from disadvantages such as unpredictable INR levels, bleeding risks and need for haematological monitoring. This has therefore spurred a renewed interest in research and clinical studies directed towards developing safer and more efficacious anti-coagulants. We shall review in this article the epidemiological features of AF-related mortality from several studies as well as the cardiovascular and non-cardiac mortality mechanisms. We shall also elucidate why a rhythm control strategy has appeared to be counter-productive and attempt to predict the likely future impact of novel anti-coagulants upon mortality reduction in AF.

Keywords: Atrial fibrillation, arrhythmia, mortality, anti-arrhythmic drugs.

INTRODUCTION

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. 2.2 million people in America and 4.5 million people in Europe are affected by either paroxysmal or persistent AF [1]. It is usually associated with cardiovascular co-morbidities such as hypertension, coronary artery disease, valvular heart disease and heart failure [2]. The presence of AF has been shown to independently increase the risk of death [3-7] and the mortality risk is highest during the first year after AF manifests [5-8]. The incidence of death due to AF has been shown to vary from 1.6-4.2% per annum in various controlled trials [9, 10]. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of the various therapeutic strategies for AF (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures).

EPIDEMIOLOGY

Large population studies both in North America and Europe have demonstrated incontrovertibly the impact of AFupon mortality. The landmark Framingham Heart Study analysed a cohort of 621 individuals who developed AF (out of a study population of over 5000) during 40 years of follow-up; the excess in all-cause mortality rates attributable to AF was 50% for men, and 90% for women, even when controlled for the presence of a wide range of cardiovascular co-morbidities [5]. This effect on mortality became apparent early, with 15% of deaths occurring within 30 days of diagnosis. Amongst the group of patients aged between 55-74 years, the 10 year mortality was 61.5% in men with AF compared to 30% in men without AF. Amongst women in a similar age group, the 10 year mortality was 57.6% in the AF group versus 20.9% in women without AF. Similar findings have been found from many other cohorts. The Renfrew-Paisley study followed-up 100 patients with AF for 20 years out of a cohort of over 15,000 men and women aged between 45-64 years in two Scottish towns and showed that AF increased all-cause mortality by 50% amongst men and 120% amongst women [3]. Ruigomez et al. followed a cohort of 1035 chronic AF patients in the UK for a mean duration of 2 years and reported a trebling of all cause mortality after matching for confounding factors [7]. The Olmsted County study was a community based study of 4618 patients with AF, followed-up for 5.3±5 years and demonstrated that relative to the general age and sex-matched population, AF significantly increased the mortality risk especially during the first four months following diagnosis (HR 9.62; 95% CI 8.93 to 10.32) and also thereafter (HR 1.66; 95% CI 1.59 to 1.73) [8]. The Manitoba study followed-up nearly 4000 young Canadian male air crew for 44 years and demonstrated that AF increased total mortality by 31% [11].

As might be expected, the annual mortality rates associated with AF vary substantially depending on the population demographics. Based on medical insurance claim data, values range from 2.6% in asymptomatic untreated individuals, to 24.2% amongst an elderly population with high rates of co-morbidities [12, 13]. There do not appear to have been significant reductions in AF-associated mortality between the years 1993 – 2007; this population-based data is supported by recent trials of novel anticoagulants and anti-arrhythmic therapies, which report annual mortality rates between 1.9 and 6.6% even with optimal contemporary treatment [14-16].

It is unambiguous from the epidemiological data that, although the presence of AF has a significant and dramatic effect to increase the mortality rate within a population, the effect on an individual is less clear-cut and is highly dependent on demographic risk factors and the presence of co-morbidities as discussed below.

AGE

Age is a major risk factor for developing AF, and older patients are more likely to have co-morbidities that might impact on survival. Nevertheless, patient age is the most powerful and consistent independent factor in determining the AF-associated mortality risk. Although the Framingham study found that all age groups demonstrated an excess mortality attributable to AF, the absolute risk increase seen in those aged over 75 years was approximately 3 times that seen in those under 65 years [5]. This was confirmed in the Paisley/Renfrew study, where the excess mortality was increased 3.5 times in the age group 60–64 years compared to 45–49 years [3]. Essentially, amongst all age groups, individuals with AF are more likely to die early than those without, and older patients with AF are substantially more at risk than younger patients. The annual mortality in 2007 amongst a large cohort of AF patients who were also Medicare beneficiaries aged >65 years was as high as 25% [13].

SEX

In developed societies, healthy females possess a survival advantage over males [17]. The mortality associated with AF is slightly but significantly higher in females than in males, such that this survival advantage is lost and the life expectancy of a woman with AF is similar to that of an age-matched man [5]. The Renfrew-Paisley study showed AF portends a higher all-cause and cardiovascular mortality amongst women [3]. There is also evidence that stroke-related mortality in AF is higher in women [18].

RACE /ETHNIC DIFFERENCES

During AF-related hospitalisations, in-hospital mortality has been shown to be highest amongst African-Americans in comparison to other ethnic groups [19].

LONE AF VS. CO-MORBIDITIES

‘Lone AF’ is defined as AF in the absence of structural heart disease or additional cardiovascular co-morbidities such as diabetes or hypertension. In reality, lone AF is an uncommon entity; 70% of patients with AF have additional risk factors at the time of diagnosis and of the remaining 30% many will have unrecognised co-morbidities such as sleep apnoea or obesity [20]. With a 15 year mortality of only 8%, survival amongst patients with lone AF has been shown to be not significantly different to that of age and sex-matched population control data [21-23]; this is in keeping with subgroup analysis from the Paisley/ Renfrew study which also did not identify a significant mortality excess attributable to lone AF [3].

In contrast, multivariate analysis from the afore-mentioned population studies indicates that cardiovascular and non-cardiovascular co-morbidities impact dramatically upon survival. Factors such as smoking, lung disease, hypertension, diabetes and obesity act to increase mortality by around 20 – 60% each, and the effects are additive with additional risk factors. These findings have led to the development of clinical scoring systems to aid therapeutic decisions.

TEMPORAL PROFILE OF AF

There is convincing evidence that AF burden may impact upon stroke rates [24], however the stroke risk due to paroxysmal AF is comparable to that of chronic AF [25]. In contrast, permanent AF is associated with higher mortality risk whereas paroxysmal AF has been shown to portend similar mortality risk as that of age and gender-matched general population [26, 27]. However, analysis of the mortality effect due to persistent AF in comparison to paroxysmal AF, has shown contrasting results [26, 28].

ISCHAEMIC HEART DISEASE (IHD) AND HEART FAILURE

AF and coronary artery disease share risk factors, but there is no clear evidence linking AF with increased risk of acute coronary syndromes [29]. Co-existing IHD has been shown to increase all-cause mortality due to AF three fold with up to 21% of deaths shown to be related to IHD [7]. Nevertheless, there is a clear association between AF and poor prognosis in myocardial infarction; multiple studies have shown that the development of AF following myocardial infarction is associated with a substantial increase in in-hospital as well as post-discharge mortality (reviewed in [30]). Many studies (including large-scale RCTs such as the OPTIMAAL trial, GUSTO-3 trial and TRACE study) have shown that chronic AF independently increases post-MI mortality (reviewed in [30]). A study by one of the authors of this paper (Sankaranarayanan et al. [31]) showed that chronic AF could increase post-MI mortality risk by increasing the risk of ventricular fibrillation in this setting [31]. The OPTIMAAL trial noted a significant increase in 30 day mortality only where new AF complicated acute MI, but that both acute and pre-existing AF were associated with reduced survival over the subsequent 3 years [32].

AF in congestive heart failure (CHF) has recently attracted substantial interest; AF can either exacerbate or complicate CHF [33], and in the modern era of device therapy it is becoming apparent that AF in CHF is under-recognised [34]. 24% out of 3288 individuals with AF in the Olmsted County study developed CHF over a mean follow-up of 6.1±5.2 years, leading to a significant increase in mortality (HR 3.4) [35]. The Framingham study illustrated the close relationship between these two pathologies showing that amongst 1470 participants who developed either or both these conditions, 382 individuals had both (36% of these developed AF first, 41% CHF first and 21% were diagnosed with both on the same day) [36]. The incidence of CHF amongst AF patients was 33 per 1000 person years, with 4 out of 10 AF subjects developing heart failure at some point during their lifetime and also significantly increasing mortality (men HR 1.6, women HR 2.7). Further analysis also demonstrated a significant mortality impact where AF complicated CHF, (incidence 54 per 1000 person years) with relative increases of 60% and 170% in men and women respectively compared to individuals with CHF in sinus rhythm. The Manitoba follow-up study showed that AF increases the risk of development of CHF by three-fold and increased cardiac mortality by 37% [11].

However, therapeutic CHF studies demonstrated conflicting results as to whether the presence of AF conferred an independent impact on mortality, or simply reflected disease state at baseline [37-40]. A recent meta-analysis of 16 studies including 53,969 patients appears to confirm that AF increases total mortality in CHF patients by around 40%, with an independent effect remaining after controlling for demographics and disease severity irrespective of impaired or preserved LV function [41]. Nevertheless, it remains controversial whether it is the arrhythmia or the co-morbidities that impacts upon mortality, with a recent analysis [42] suggesting that this effect is only seen where heart failure results from ischaemic heart disease. A post hoc analysis of the AFFIRM trial sub-set of patients with CHF and preserved ejection fraction showed a lower all-cause and cardiovascular mortality in comparison to patients with impaired systolic function [43].

In view of the strong association of AF with co-morbidities, several studies have attempted to analyse if the effects of AF upon mortality are truly independent or simply a risk marker for the cumulative pre-terminal effects of co-morbidities. The Olmsted County study for instance illustrated the very high 4 month and 1 year mortality following AF diagnosis, however there were no changes in early (<4 months) versus late mortality (after 4 months) in the whole cohort or within the sub-group of patients without pre-morbid cardiovascular disease [8]. These results and others showing that lone AF does not increase mortality, suggest that AF could simply represent a risk marker for mortality in a very sick population with multiple co-morbidities [3, 6, 8].

1. MECHANISMS OF AF-RELATED MORTALITY

Cardiac

Several large population-based studies have shown that AF independently increases cardiac mortality [3, 5, 11]. Increased cardiovascular mortality risk due to AF varies between 2 to 12 times [44]. The cardiac causes include heart failure, arrhythmia and possibly coronary heart disease.

AF has an intricate relationship with CHF whereby one can precipitate the other [45]. AF leads to a loss of atrial systole (which usually contributes up to 30% of pre-load in sinus rhythm). In addition to this, the loss of atrio-ventricular synchrony and irregular, uncontrolled ventricular rates contribute to development of CHF (“tachycardia-induced cardiomyopathy”) [46-48]. Uncontrolled ventricular rates during AF can also worsen mitral regurgitation and cause rate-related left bundle branch block, thereby reducing cardiac output [49].

AF can lead to arrhythmic sudden death by potentiating VT or VF in patients with ICDs [50], pre-excitation syndromes [49] and in the acute MI setting [31].

AF can also impair coronary perfusion and increase myocardial oxygen demand especially due to uncontrolled ventricular rates and this could worsen coronary ischaemia and thus increase mortality especially in the subset of patients with pre-existing ischaemic heart disease [48-50].

2. Vascular

AF contributes to 15-25% of all strokes and these contribute to a significant proportion of AF-related mortality [51, 52]. AF-related strokes tend to be associated with higher mortality, and more severe disability [52, 53]. The Olmsted County study followed up 4117 individuals with AF and reported a 11% incidence of stroke over a mean follow-up period of 5.5±5 years, with AF–related stroke significantly increasing the mortality hazard ratio to 3.03 for men and 3.8 for women in comparison to the general population [18]. The Manitoba follow-up study showed that AF increased cardiovascular mortality including fatal stroke by 41% [11]. Even amongst anti-coagulated patients with therapeutic INR, stroke risk due to AF can be up to 3% in high-risk individuals such as those with prior stroke [54, 55]. Un-coordinated atrial contraction leads to stasis of blood in the left atrium [56]. In addition to this, thrombogenesis is also perpetuated by haematological abnormalities such as platelet activation, inflammation and structural factors such as atrial dilatation, loss of endothelium and progressive fibrosis [56]. The left atrial appendage is the site responsible for the majority of thrombi in non-valvular AF [56]. However, it has been demonstrated that not all thrombo-embolic events necessarily predict mortality risk. For instance, the ACTIVE-W trial showed that only disabling strokes (both ischaemic and haemorrhagic with Rankin score ≥3) increase mortality risk whereas transient ischaemic attacks do not [57]. Major bleeding secondary to anti-coagulation can also contribute to mortality [57].

3. Non-cardiovascular Deaths

Most therapeutic strategies for AF such as anti-arrhythmic drugs, anti-thrombotics and catheter ablation can increase mortality risk in AF as a side-effect or serious adverse event. Anti-arrhythmic drugs can lead to potentially lethal pro-arrhythmic effects (such as torsade de pointes) but also cause multi-systemic side-effects and thus contribute to non-cardiovascular deaths [10, 58, 59]. A rhythm control strategy has also been shown to unmask non-cardiovascular co-morbidities such as malignancies or lung pathology, thus contributing to mortality burden (covered in greater detail in section on AADs) [10, 48]. Bleeding risk is inextricably linked to use of anti-thrombotics and can be fatal. Severe bleeding events (such as fatal events, drop in haemoglobin of at least 5 g/decilitre), need for inotropic agents, loss of vision due to intra-ocular bleeding, surgical intervention due to bleeding, symptomatic intra-cranial haemorrhage, need for transfusion of at least 4 units of blood) treble the mortality risk (HR. 3.35; 95% CI, 2.12-5.27) whilst non-severe major bleeding or minor bleeding events do not increase mortality.

RISK PREDICTION FOR AF-RELATED MORTALITY

In view of the significant mortality risk due to AF and the associated co-morbidities, several useful risk-predictors have been identified. The CHADS₂ Score (1 point each for Congestive Heart Failure, Hypertension, Age≥75 years, Diabetes Mellitus and 2 points for Stroke/TIA) was introduced over a decade back as a scoring system to assess thrombo-embolic risk due to AF [60] but can also predict mortality risk. Khumri et al. showed in a study that patients with CHADS₂ score of ≥5 have a 50 fold higher mortality risk in comparison to patients with a score of 0 [61]. Similarly, while the HAS-BLED score has been mainly used in clinical practice to predict risk of major haemorrhagic episodes due to anti-coagulation [62], this risk score has also been shown to predict adverse cardiovascular events as well as all-cause mortality, thus illustrating that thrombogenesis and haemorrhage are inextricably linked by sharing many common risk predictors [63]. Whilst the CHA₂DS₂Vasc score has been recommended in the latest guidelines to supersede CHADS₂ as a better risk predictor for thrombo-embolic risk, its role as a risk predictor for mortality remains to be established.

Abnormal ankle brachial index (ratio of ankle and brachial systolic blood pressure) has been shown to independently predict all-cause mortality after adjusting for CHADS2 score and also predict major haemorrhagic episodes irrespective of the HAS-BLED score [64]. Cardiovascular related hospitalisation in AF patients also significantly predicts risk of death (HR 2.69; 95% CI 1.96-3.68) and it has been suggested that this end-point could be used as a surrogate for mortality in trials [65].

Clinical investigations also help to identify patients at increased risk of AF-related averse events. Serum bio-markers such as interleukin-6, high sensitivity troponin T and von Willebrand factor have been shown to predict all-cause mortality independent of CHADS2 score in anti-coagulated AF patients, possibly reflecting coronary micro-vascular dysfunction, global endothelial dysfunction or athero-thrombosis [66-68]. High sensitivity CRP has also been shown to predict all-cause and cardiovascular mortality amongst AF patients [69]. Patients with renal failure (eGFR <45 ml/min and proteinuria) have been shown to have increased risk of AF-related thrombo-embolism, bleeding and mortality [70]. Echocardiographic markers such as mitral annular calcification, presence of spontaneous left atrial contrast, severe LV impairment and greater than moderate mitral regurgitation also help to predict increased mortality risk amongst chronic AF patients [61, 71].

TREATMENTS

Anti-arrhythmic Drugs (AADs)

Several AADs have been shown to cause pro-arrhythmic side-effects and thus increased mortality in patients [58]. The class I agent flecainide gained particular attention following the CAST trial [72] where increased mortality was observed in patients with history of myocardial infarction. These results have been extrapolated to extend its contraindication to patients with coronary artery disease, heart failure or left ventricular hypertrophy. Coplen, in a meta-analysis published in 1990, showed that treatment with quinidine was more effective than no anti-arrhythmic therapy in suppressing recurrences of atrial fibrillation but appeared to be associated with increased total mortality [73]. Class III medications such as amiodarone and sotalol, have also received similar attention, and are also well known for their risk of QT prolongation and Torsades de Pointes.

Indeed all AADs have the potential to have serious, pro-arrhythmic side effects [58]. This has implications when determining the optimal treatment strategy for atrial fibrillation (AF): the restoration and maintenance of sinus rhythm (rhythm control strategy) or control of heart rate alone (rate control strategy). Several studies have sought to answer this question, including the Strategies of Treatment of Atrial Fibrillation (STAF) [74], Pharmacological Intervention in Atrial Fibrillation (PIAF) [75], Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) [10], Rate Control vs. Electrical Cardioversion (RACE) [76], the HOT CAFÉ [77] and J-RHYTHM Study [78]. None of these studies has shown any significant difference in all-cause or cardiovascular mortality and stroke outcome between rate and rhythm control and in fact a meta-analysis of five major trials showed a trend towards reduced risk of death (rate vs. rhythm control; OR 0.87, 0.74-1.02- P=0.09) [79]. This has generally led to the adoption of rate control strategy as the pragmatic approach especially in the elderly or in presence of significant co-morbidities.

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) in particular showed a non-significant trend toward increased all-cause mortality in the rhythm control group (hazard ratio 1.14; 95% CI, 1-1.32) [10]. A retrospective analysis of the cause-specific mortality in the AFFIRM trial showed that the incidence of cardiac (including arrhythmic, heart failure and MI deaths) and vascular (including ischaemic and haemorrhagic strokes) deaths was not significantly different between the rhythm control and rate-control groups [48]. Thus the increased all-cause mortality in the rhythm-control group could be entirely accounted for by the significant difference between the incidences of non-cardiovascular deaths (47.5% in rhythm control group versus 36.5% in rate-control group; p=0.0008). These non-cardiovascular deaths were mainly due to malignancies and pneumonia. This was attributed to earlier discontinuation of warfarin and higher incidence of stroke rather than risk of the anti-arrhythmic itself which highlights the importance of anticoagulation in atrial fibrillation. Even in patients with heart failure (LVF<35%) complicated by AF, the AF-CHF trial did not demonstrate that rhythm control could lead to mortality benefit [33]. However, there has been some evidence demonstrating the benefits of rhythm control particularly in the longer term. For instance, a retrospective, “on-treatment analysis” of the AFFIRM study that analysed presence of sinus rhythm and use of anti-arrhythmic drugs as separate variables, showed a significant reduction in death due to presence of sinus rhythm [80]. Thus the mortality increase of 49% due to anti-arrhythmic drugs could have overshadowed the 53% mortality reduction due to maintenance of sinus rhythm [48]. The survival benefits of sinus rhythm were similar to that seen in the DIAMOND AF (dofetilide versus placebo in AF patients with LV dysfunction) study which did not show an all-cause mortality benefit; however, restoration and maintenance of sinus rhythm significantly reduced mortality (risk ratio 0.44; 95% CI 0.30-0.64) and risk of hospitalisation [81]. In a population-based study of rate versus rhythm control strategies among 26, 130 AF patients, showed that the rhythm control group demonstrated a small increase in mortality within six months of treatment initiation which then became similar to mortality in the rate-control group until year 4. In the longer term however (after year 5), the mortality was lower in the rhythm control group in comparison to that in the rate-control group (HR 0.89; 95% CI 0.81-0.96 after 5 years and HR 0.77; 95% CI 0.62-0.95 after 8 years) [82]. From the above studies, it is likely that the pro-arrhythmic effects and multi-systemic side-effects of existing AADs dilute and even offset the survival advantage provided by maintenance of sinus rhythm.

The most commonly used AAD for rhythm control in all these trials was amiodarone, which was shown in the studies to have a low pro-arrhythmic potential, with its adverse side effects being mainly extra-cardiac [59]. Amiodarone has been demonstrated to be the most efficacious drug in maintaining sinus rhythm [59, 79]. Some studies have found it to be associated with an increased risk of non-cardiac mortality (particularly cancer-related and pulmonary) [83-85] whilst this was not observed in other studies [86, 87]. Recently Freemantle et al. included thirty nine randomised controlled trials in a mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide and propafenone used for the management of AF and reported (from eighteen trials including about 10,000 patients) that sotalol in particular was associated with increased mortality whereas amiodarone (but not dronedarone) showed a trend towards increased all-cause mortality [59]. A meta-analysis by Piccini et al. also demonstrated an insignificant trend towards increased mortality due to amiodarone [88].

More recently, there has been the arrival of dronedarone, an AAD developed to have fewer side effects and improved safety profile compared to amiodarone [88]. The EURIDIS and ADONIS trials showed dronedarone was significantly more effective than placebo in maintaining sinus rhythm, and in reducing ventricular rate during recurrence of arrhythmia, with post hoc analysis also suggesting a 44% reduction in cardiovascular hospitalisation or death at 12 months [89]. Although dronedarone is less efficacious than amiodarone [88], a subsequent trial (ATHENA) showed that dronedarone reduces the composite endpoint of cardiovascular hospitalisation or death by 24% [14]. However, subsequent studies have shown that dronedarone can lead to increased early mortality in certain sub-sets of patients. For instance, in the ANDROMEDA trial (Anti-arrhythmic trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease), dronedarone (in comparison with placebo) led to a doubling of mortality (95%CI, 1.07-4.25) due to worsening heart failure after a median follow-up of only 2 months [90] Dronedarone also led to increased cardiovascular deaths (hazard ratio 2.11; 95% CI, 1-4.49), arrhythmic deaths (hazard ratio 3.26; 95% CI, 1.06-10) in addition to increased incidence of stroke and heart failure hospitalisations when used in patients with high-risk permanent AF (PALLAS) [91].

ANTI-COAGULATION

Effective anticoagulation is the most effective method of reducing mortality in AF patients [92]. In the absence of anti-coagulation, AF patients who develop a stroke have a 1 month mortality of nearly 25% [92]. In a meta-analysis of 29 trials of anti-thrombotic therapy for AF, compared to control, adjusted-dose warfarin reduced significantly stroke risk by 64% and all-cause mortality by 26%. Aspirin in contrast showed a non-significant 19% reduction in stroke risk and did not reduce mortality significantly [93]. In addition to anti-coagulation with warfarin, it is also important to closely monitor the therapeutic range of INR closely to both prevent thrombo-embolic complications as well as avoid major bleeding complications. Patients who spend at least 70% of the time with INR within therapeutic range demonstrate significantly lower mortality compared to patients whose INR is therapeutic <70% of the time [94]. Analysis of 30-day mortality due to ischaemic stoke whilst on warfarin, has shown that warfarin significantly reduces 30 day mortality if INR is between 2-3 (OR 0.38; 955 CI, 0.2-0.7) but patients with INR>3 demonstrate increased odds of mortality due to intra-cranial haemorrhage 2.66 fold (95% CI, 1.21-5.86) [95].

Despite the obvious benefits of warfarin, the ATRIA study showed that it was being under-prescribed, particularly in those AF patients below 55 years and above 85 years, presumably due to physicians’ concerns regarding bleeding risk [96]. Interestingly, in contrast to this predominant view held by most physicians, patients are willing to accept the higher risk of bleeding associated with anti-coagulants in order to avoid disabling strokes which some even view as worse than death [97]. The search for more efficacious and potentially safer anti-thrombotics has heralded the era of novel anti-coagulants, as detailed below.

In the RELY study [98], dabigatran, a novel oral direct thrombin inhibitor, given at a dose of 110 mg to AF patients, was associated with rates of stroke and systemic embolism similar to warfarin, but with lower rates of major haemorrhage, whilst at doses of 150 mg, it was associated with lower rates of stroke and systemic embolism compared to warfarin, and similar rates of major haemorrhage. There was a trend towards reduction in all-cause mortality with the 150 mg dose (p=0.051) and a significant reduction in vascular mortality (p=0.04). The rates of death from any cause were 4.13% per year with warfarin, compared with 3.75% per year with 110 mg dabigatran (P=0.13), and 3.64% with 150 mg dabigatran (P=0.051). A meta-analysis of seven dabigatran studies (including 30514 patients) also showed a 11% reduction in all-cause mortality in comparison to warfarin [99].

Following this there has been the addition of the oral factor Xa inhibitors: rivaroxaban, assessed by the ROCKET-AF trial [100]; and apixaban, analysed by the AVERROES [16] and ARISTOTLE [101] trials. In the ROCKET-AF trial, in comparison with warfarin for non-valvular AF, rivaroxaban was shown to be non-inferior for prevention of stroke or systemic embolism. There was no significant difference in risk of major bleeding, though intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. There was no significant difference in mortality between the two groups. In the ARISTOTLE trial, apixaban was shown to be superior to warfarin by reducing the risk of stroke or systemic embolism by 21%, major bleeding by 31% and all-cause mortality by 11% [101].

The future for these novel anticoagulants is very promising, with significant progress being made in morbidity and mortality reduction compared to warfarin, mainly by way of further reduction in ischaemic strokes and less bleeding risks. However there are also several concerns regarding the use of the newer anticoagulants as detailed below. These include the lack of robust safety data in patients with creatinine clearance <30 ml/min, elderly patients and those with extremes of body weight. Whilst the lack of need to closely monitor anticoagulation whilst on newer anticoagulants can be viewed as an advantage by reducing patient inconvenience as well as the burden on healthcare resources, this feature can also be a disadvantage if patients miss one or more doses (due to the short offset time of these drugs leading to a rebound stroke risk). Additionally the lack of a specific antidote to these drugs is also of concern during major bleeding episodes. Thus there is a need for further studies in order to clarify the above concerns about these drugs before they can be incorporated into widespread clinical practice.

INTERVENTIONAL TREATMENTS

Catheter ablation is recommended in the management of symptomatic paroxysmal AF after failed AAD therapy and has not yet been demonstrated to confer mortality benefits possibly due to lack of long-term follow-up data. Being an invasive procedure, the procedure itself carries a mortality risk of up to 0.7% [2]. However, newer technological developments are consistently improving the safety and efficacy of catheter-based techniques. Left atrial appendage closure using occlusion devices has been suggested as an alternative for patients deemed unsuitable for oral anti-coagulation and again data on mortality benefits from this procedure is lacking currently.

CONCLUSIONS

AF and its associated co-morbidities continue to impose a significant mortality risk despite several new therapeutic advances. Indeed a proportion of the AF-related mortality is caused by side-effects due to attempts at restoring and maintaining sinus rhythm or major bleeding due to anti-coagulation. However effective anti-coagulation is the only therapeutic strategy that has been shown to reduce AF-related mortality and newer anticoagulants with improved efficacy and lesser bleeding side-effects, are only likely to improve the risk-benefit profile. Currently available AADs have limited efficacy and possess significant side-effects which seem to offset benefits of rhythm control; hence there is a pressing need to develop improved AADs in order to unmask the survival benefit that could accrue from maintenance of sinus rhythm. The impact of catheter ablation in the management of AF has currently been increasing and with improvements in safety and efficacy, is likely to reduce the use of AADs in the future.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

References

1. Feinberg W.M., Cornell E.S., Nightingale S.D., Pearce L.A., Tracy R.P., Hart R.G., Bovill E.G., et al. Stroke Prevention in Atrial Fibrillation Investigators. Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke. 1997;28(6):1101–1106. doi: 10.1161/01.STR.28.6.1101. [PubMed] [CrossRef] [Google Scholar]2. Camm A.J., Kirchhof P., Lip G.Y., Schotten U., Savelieva I., Ernst S., Van Gelder I.C., Al-Attar N., Hindricks G., Prendergast B., Heidbuchel H., Alfieri O., Angelini A., Atar D., Colonna P., De Caterina R., De Sutter J., Goette A., Gorenek B., Heldal M., Hohloser S.H., Kolh P., Le Heuzey J.Y., Ponikowski P., Rutten F.H., et al. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J. 2010;31(19):2369–2429. doi: 10.1093/eurheartj/ehq278. [PubMed] [CrossRef] [Google Scholar]3. Stewart S., Hart C.L., Hole D.J., McMurray J.J., et al. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am. J. Med. 2002;113(5):359–364. doi: 10.1016/S0002-9343(02)01236-6. [PubMed] [CrossRef] [Google Scholar]4. Kirchhof P., Auricchio A., Bax J., Crijns H., Camm J., Diener H.C., Goette A., Hindricks G., Hohnloser S., Kappenberger L., Kuck K.H., Lip G.Y., Olsson B., Meinertz T., Priori S., Ravens U., Steinbeck G., Svernhage E., Tijssen J., Vincent A., Breithardt G., et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur. Heart J. 2007;28(22):2803–2817. doi: 10.1093/eurheartj/ehm358. [PubMed] [CrossRef] [Google Scholar]5. Benjamin E.J., Wolf P.A., D’Agostino R.B., Silbershatz H., Kannel W.B., Levy D., et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946–952. doi: 10.1161/01.CIR.98.10.946. [PubMed] [CrossRef] [Google Scholar]6. Vidaillet H., Granada J.F., Chyou Po., Maassen K., Ortiz M., Pulido J.N., Sharma P., Smith P.N., Hayes J., et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am. J. Med. 2002;113(5):365–370. doi: 10.1016/S0002-9343(02)01253-6. [PubMed] [CrossRef] [Google Scholar]7. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A., et al. Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC Cardiovasc. Disord. 2002;2:5. doi: 10.1186/1471-2261-2-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]8. Miyasaka Y., Barnes M.E., Bailey K.R., Cha S.S., Gersh B.J., Seward J.B., Tsang T.S., et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J. Am. Coll. Cardiol. 2007;49(9):986–992. doi: 10.1016/j.jacc.2006.10.062. [PubMed] [CrossRef] [Google Scholar]9. Olsson S.B. Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691–1698. doi: 10.1016/S0140-6736(03)14841-6. [PubMed] [CrossRef] [Google Scholar]10. Wyse D.G., Waldo A.L., DiMarco J.P., Domanski M.J., Rosenberg Y., Schron E.B., Kellen J.C., Greene H.L., Mickel M.C., Dalquist J.E., Corley S.D., et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 2002;347(23):1825–1833. doi: 10.1056/NEJMoa021328. [PubMed] [CrossRef] [Google Scholar]11. Krahn A.D., Manfreda J., Tate R.B., Mathewson F.A., Cuddy T.E., et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am. J. Med. 1995;98(5):476–484. doi: 10.1016/S0002-9343(99)80348-9. [PubMed] [CrossRef] [Google Scholar]12. Gajewski J., Singer R.B. Mortality in an insured population with atrial fibrillation. JAMA. 1981;245(15):1540–1544. doi: 10.1001/jama.1981.03310400022019. [PubMed] [CrossRef] [Google Scholar]13. Piccini J.P., Hammill B.G., Sinner M.F., Jensen P.N., Hernandez A.F., Heckbert S.R., Benjamin E.J., Curtis L.H., et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5(1):85–93. doi: 10.1161/CIRCOUTCOMES.111.962688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]14. Hohnloser S.H., Crijns H.J., van Eickels M., Gaudin C., Page R.L., Torp-Pedersen C., Connolly S.J., et al. ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 2009;360(7):668–678. doi: 10.1056/NEJMoa0803778. [PubMed] [CrossRef] [Google Scholar]15. Go A.S., et al. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N. Engl. J. Med. 2009;360(20):2127–2129. doi: 10.1056/NEJMe0902676. [PubMed] [CrossRef] [Google Scholar]16. Connolly S.J., Eikelboom J., Joyner C., Diener H.C., Hart R., Golitsyn S., Flaker G., Avezum A., Hohnloser S.H., Diaz R., Talajic M., Zhu J., Pais P., Budaj A., Parkhomenko A., Jansky P., Commerford P., Tan R.S., Sim K.H., Lewis B.S., Van Mieghem W., Lip G.Y., Kim J.H., Lanas-Zanetti F., Gonzalez-Hermosillo A., Dans A.L., Munawar M., O’Donnell M., Lawrence J., Lewis G., Afzal R., Yusuf S., et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 2011;364(9):806–817. doi: 10.1056/NEJMoa1007432. [PubMed] [CrossRef] [Google Scholar]17. Arias E., et al. National vital statistics reports. Hyattsville, MD: National Centre for Health Statistics; 2010. United States Life Tables 2006. Report No. [Google Scholar]18. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Seward J.B., Bailey K.R., Iwasaka T., Tsang T.S., et al. Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study. Stroke. 2005;36(11):2362–2366. doi: 10.1161/01.STR.0000185927.63746.23. [PubMed] [CrossRef] [Google Scholar]19. Turagam M.K., Velagapudi P., Visotcky A., Szabo A., Kocheril A.G., et al. African Americans have the highest risk of in-hospital mortality with atrial fibrillation related hospitalizations among all racial/ethnic groups: a nationwide analysis. Int. J. Cardiol. 2012;158(1):165–166. doi: 10.1016/j.ijcard.2012.04.090. [PubMed] [CrossRef] [Google Scholar]20. Rosiak M., Dziuba M., Chudzik M., Cygankiewicz I., Bartczak K., Drozdz J., Wranicz J.K., et al. Risk factors for atrial fibrillation: Not always severe heart disease, not always so ‘lonely’. Cardiol. J. 2010;17(5):437–442. [PubMed] [Google Scholar]21. Kopecky S.L., Gersh B.J., McGoon M.D., Whisnant J.P., Holmes D.R., Jr, Ilstrup D.M., Frye R.L., et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N. Engl. J. Med. 1987;317(11):669–674. doi: 10.1056/NEJM198709103171104. [PubMed] [CrossRef] [Google Scholar]22. Rostagno C., Bacci F., Martelli M., Naldoni A., Bertini G., Gensini G., et al. Clinical course of lone atrial fibrillation since first symptomatic arrhythmic episode. Am. J. Cardiol. 1995;76(11):837–839. doi: 10.1016/S0002-9149(99)80240-9. [PubMed] [CrossRef] [Google Scholar]23. Potpara T., Grujić M., Marinković J., Vujisić-Tesić B., Ostojić M., Polovina M., et al. Mortality of patients with lone and idiopathic atrial fibrillation is similar to mortality in general population of Serbia. Vojnosanit. Pregl. 2010;67(2):132–135. doi: 10.2298/VSP1002132P. [PubMed] [CrossRef] [Google Scholar]24. Botto G.L., Padeletti L., Santini M., Capucci A., Gulizia M., Zolezzi F., Favale S., Molon G., Ricci R., Biffi M., Russo G., Vimercati M., Corbucci G., Boriani G., et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J. Cardiovasc. Electrophysiol. 2009;20(3):241–248. doi: 10.1111/j.1540-8167.2008.01320.x. [PubMed] [CrossRef] [Google Scholar]25. Lip G.Y., Hee F.L. Paroxysmal atrial fibrillation. QJM. 2001;94(12):665–678. doi: 10.1093/qjmed/94.12.665. [PubMed] [CrossRef] [Google Scholar]26. Keating R.J., Gersh B.J., Hodge D.O., Weivoda P.L., Patel P.J., Hammill S.C., Shen W.K., et al. Effect of atrial fibrillation pattern on survival in a community-based cohort. Am. J. Cardiol. 2005;96(10):1420–1424. doi: 10.1016/j.amjcard.2005.07.050. [PubMed] [CrossRef] [Google Scholar]27. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A. Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc. Disord. 2005;5:20. doi: 10.1186/1471-2261-5-20. [PMC free article] [PubMed] [CrossRef] [Google Scholar]28. Tuinenburg A.E., Van Gelder I.C., Van Den Berg M.P., Brügemann J., De Kam P.J., Crijns H.J., et al. Lack of prevention of heart failure by serial electrical cardioversion in patients with persistent atrial fibrillation. Heart. 1999;82(4):486–493. doi: 10.1136/hrt.82.4.486. [PMC free article] [PubMed] [CrossRef] [Google Scholar]29. Brown A.M., Sease K.L., Robey J.L., Shofer F.S., Hollander J.E., et al. The risk for acute coronary syndrome associated with atrial fibrillation among ED patients with chest pain syndromes. Am. J. Emerg. Med. 2007;25(5):523–528. doi: 10.1016/j.ajem.2006.09.015. [PubMed] [CrossRef] [Google Scholar]30. Sankaranarayanan R., et al. Mortality Risk Associated with AF in Myocardial Infarction Patients. J. Atr. Fibrillation. 2012;5(3):138–152. [PMC free article] [PubMed] [Google Scholar]31. Sankaranarayanan R., James M.A., Nuta B., Townsend M., Kesavan S., Burtchaell S., Holloway R., Ewings P., et al. Does atrial fibrillation beget ventricular fibrillation in patients with acute myocardial infarction? Pacing Clin. Electrophysiol. 2008;31(12):1612–1619. doi: 10.1111/j.1540-8159.2008.01234.x. [PubMed] [CrossRef] [Google Scholar]32. Lehto M., Snapinn S., Dickstein K., Swedberg K., Nieminen M.S., et al. OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience. Eur. Heart J. 2005;26(4):350–356. doi: 10.1093/eurheartj/ehi064. [PubMed] [CrossRef] [Google Scholar]33. Roy D., Talajic M., Nattel S., Wyse D.G., Dorian P., Lee K.L., Bourassa M.G., Arnold J.M., Buxton A.E., Camm A.J., Connolly S.J., Dubuc M., Ducharme A., Guerra P.G., Hohnloser S.H., Lambert J., Le Heuzey J.Y., O’Hara G., Pedersen O.D., Rouleau J.L., Singh B.N., Stevenson L.W., Stevenson W.G., Thibault B., Waldo A.L., et al. Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N. Engl. J. Med. 2008;358(25):2667–2677. doi: 10.1056/NEJMoa0708789. [PubMed] [CrossRef] [Google Scholar]34. Caldwell J.C., Contractor H., Petkar S., Ali R., Clarke B., Garratt C.J., Neyses L., Mamas M.A., et al. Atrial fibrillation is under-recognized in chronic heart failure: insights from a heart failure cohort treated with cardiac resynchronization therapy. Europace. 2009;11(10):1295–1300. doi: 10.1093/europace/eup201. [PubMed] [CrossRef] [Google Scholar]35. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Bailey K.R., Abhayaratna W., Seward J.B., Iwasaka T., Tsang T.S., et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: a community-based study over two decades. Eur. Heart J. 2006;27(8):936–941. doi: 10.1093/eurheartj/ehi694. [PubMed] [CrossRef] [Google Scholar]36. Wang T.J., Larson M.G., Levy D., Vasan R.S., Leip E.P., Wolf P.A., D’Agostino R.B., Murabito J.M., Kannel W.B., Benjamin E.J., et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920–2925. doi: 10.1161/01.CIR.0000072767.89944.6E. [PubMed] [CrossRef] [Google Scholar]37. Olsson L.G., Swedberg K., Ducharme A., Granger C.B., Michelson E.L., McMurray J.J., Puu M., Yusuf S., Pfeffer M.A., et al. CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J. Am. Coll. Cardiol. 2006;47(10):1997–2004. doi: 10.1016/j.jacc.2006.01.060. [PubMed] [CrossRef] [Google Scholar]38. Rivero-Ayerza M., Scholte Op Reimer W., Lenzen M., Theuns D.A., Jordaens L., Komajda M., Follath F., Swedberg K., Cleland J.G., et al. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalized heart failure patients: results of the EuroHeart Failure Survey. Eur. Heart J. 2008;29(13):1618–1624. doi: 10.1093/eurheartj/ehn217. [PubMed] [CrossRef] [Google Scholar]39. Dries D.L., Exner D.V., Gersh B.J., Domanski M.J., Waclawiw M.A., Stevenson L.W., et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J. Am. Coll. Cardiol. 1998;32(3):695–703. doi: 10.1016/S0735-1097(98)00297-6. [PubMed] [CrossRef] [Google Scholar]40. Mahoney P., Kimmel S., DeNofrio D., Wahl P., Loh E., et al. Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure. Am. J. Cardiol. 1999;83(11):1544–1547. doi: 10.1016/S0002-9149(99)00144-7. [PubMed] [CrossRef] [Google Scholar]41. Mamas M.A., Caldwell J.C., Chacko S., Garratt C.J., Fath-Ordoubadi F., Neyses L., et al. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur. J. Heart Fail. 2009;11(7):676–683. doi: 10.1093/eurjhf/hfp085. [PubMed] [CrossRef] [Google Scholar]42. Raunsø J., Pedersen O.D., Dominguez H., Hansen M.L., Møller J.E., Kjaergaard J., Hassager C., Torp-Pedersen C., Køber L., et al. EchoCardiography and Heart Outcome Study Investigators. Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease. Eur. J. Heart Fail. 2010;12(7):692–697. doi: 10.1093/eurjhf/hfq052. [PubMed] [CrossRef] [Google Scholar]43. Badheka A.O., Rathod A., Kizilbash M.A., Bhardwaj A., Ali O., Afonso L., Jacob S., et al. Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction. Am. J. Cardiol. 2011;108(9):1283–1288. doi: 10.1016/j.amjcard.2011.06.045. [PubMed] [CrossRef] [Google Scholar]44. Domanski M.J., et al. The epidemiology of atrial fibrillation. Coron. Artery Dis. 1995;6(2):95–100. doi: 10.1097/00019501-199502000-00002. [PubMed] [CrossRef] [Google Scholar]45. Cha Y.M., Redfield M.M., Shen W.K., Gersh B.J., et al. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation. 2004;109(23):2839–2843. doi: 10.1161/01.CIR.0000132470.78896.A8. [PubMed] [CrossRef] [Google Scholar]46. Daoud E.G., Weiss R., Bahu M., Knight B.P., Bogun F., Goyal R., Harvey M., Strickberger S.A., Man K.C., Morady F., et al. Effect of an irregular ventricular rhythm on cardiac output. Am. J. Cardiol. 1996;78(12):1433–1436. doi: 10.1016/S0002-9149(97)89297-1. [PubMed] [CrossRef] [Google Scholar]47. Shinbane J.S., Wood M.A., Jensen D.N., Ellenbogen K.A., Fitzpatrick A.P., Scheinman M.M., et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J. Am. Coll. Cardiol. 1997;29(4):709–715. doi: 10.1016/S0735-1097(96)00592-X. [PubMed] [CrossRef] [Google Scholar]48. Steinberg J.S., Sadaniantz A., Kron J., Krahn A., Denny D.M., Daubert J., Campbell W.B., Havranek E., Murray K., Olshansky B., O’Neill G., Sami M., Schmidt S., Storm R., Zabalgoitia M., Miller J., Chandler M., Nasco E.M., Greene H.L., et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation. 2004;109(16):1973–1980. doi: 10.1161/01.CIR.0000118472.77237.FA. [PubMed] [CrossRef] [Google Scholar]49. Fuster V., Rydén L.E., Cannom D.S., Crijns H.J., Curtis A.B., Ellenbogen K.A., Halperin J.L., Kay G.N., Le Huezey J.Y., Lowe J.E., Olsson S.B., Prystowsky E.N., Tamargo J.L., Wann L.S., et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2011;57(11):e101–e198. doi: 10.1016/j.jacc.2010.09.013. [PubMed] [CrossRef] [Google Scholar]50. Stein K.M., Euler D.E., Mehra R., Seidl K., Slotwiner D.J., Mittal S., Markowitz S.M., Lerman B.B. Jewel AF Worldwide Investigators. Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients? J. Am. Coll. Cardiol. 2002;40(2):335–340. doi: 10.1016/S0735-1097(02)01957-5. [PubMed] [CrossRef] [Google Scholar]51. Grau A.J., Weimar C., Buggle F., Heinrich A., Goertler M., Neumaier S., Glahn J., Brandt T., Hacke W., Diener H.C., et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559–2566. doi: 10.1161/hs1101.098524. [PubMed] [CrossRef] [Google Scholar]52. Kimura K., Minematsu K., Yamaguchi T., et al. Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC) Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with acute ischaemic stroke. J. Neurol. Neurosurg. Psychiatry. 2005;76(5):679–683. doi: 10.1136/jnnp.2004.048827. [PMC free article] [PubMed] [CrossRef] [Google Scholar]53. Jørgensen H.S., Nakayama H., Reith J., Raaschou H.O., Olsen T.S. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke. 1996;27(10):1765–1769. doi: 10.1161/01.STR.27.10.1765. [PubMed] [CrossRef] [Google Scholar]54. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255–1262. [PubMed] [Google Scholar]55. Akins P.T., Feldman H.A., Zoble R.G., Newman D., Spitzer S.G., Diener H.C., Albers G.W. Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials. Stroke. 2007;38(3):874–880. doi: 10.1161/01.STR.0000258004.64840.0b. [PubMed] [CrossRef] [Google Scholar]56. Watson T., Shantsila E., Lip G.Y. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373(9658):155–166. doi: 10.1016/S0140-6736(09)60040-4. [PubMed] [CrossRef] [Google Scholar]57. De Caterina R., Connolly S.J., Pogue J., Chrolavicius S., Budaj A., Morais J., Renda G., Yusuf S. ACTIVE Investigators. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur. Heart J. 2010;31(17):2133–2140. doi: 10.1093/eurheartj/ehq250. [PubMed] [CrossRef] [Google Scholar]58. Nattel S. Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Cardiovasc. Res. 1998;37(3):567–577. doi: 10.1016/S0008-6363(97)00293-9. [PubMed] [CrossRef] [Google Scholar]59. Freemantle N., Lafuente-Lafuente C., Mitchell S., Eckert L., Reynolds M. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace. 2011;13(3):329–345. doi: 10.1093/europace/euq450. [PubMed] [CrossRef] [Google Scholar]60. Gage B.F., Waterman A.D., Shannon W., Boechler M., Rich M.W., Radford M.J., et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–2870. doi: 10.1001/jama.285.22.2864. [PubMed] [CrossRef] [Google Scholar]61. Khumri T.M., Idupulapati M., Rader V.J., Nayyar S., Stoner C.N., Main M.L., et al. Clinical and echocardiographic markers of mortality risk in patients with atrial fibrillation. Am. J. Cardiol. 2007;99(12):1733–1736. doi: 10.1016/j.amjcard.2007.01.055. [PubMed] [CrossRef] [Google Scholar]62. Pisters R., Lane D.A., Nieuwlaat R., de Vos C.B., Crijns H.J., Lip G.Y., et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100. doi: 10.1378/chest.10-0134. [PubMed] [CrossRef] [Google Scholar]63. Gallego P., Roldán V., Torregrosa J.M., Gálvez J., Valdés M., Vicente V., Marín F., Lip G.Y., et al. Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation. Circ Arrhythm Electrophysiol. 2012;5(2):312–318. doi: 10.1161/CIRCEP.111.967000. [PubMed] [CrossRef] [Google Scholar]64. Gallego P., Roldán V., Marín F., Jover E., Manzano-Fernández S., Valdés M., Vicente V., Lip G.Y., et al. Ankle brachial index as an independent predictor of mortality in anticoagulated atrial fibrillation. Eur. J. Clin. Invest. 2012;42(12):1302–1308. doi: 10.1111/eci.12004. [PubMed] [CrossRef] [Google Scholar]65. Friberg L., Rosenqvist M., et al. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace. 2011;13(5):626–633. doi: 10.1093/europace/eur001. [PubMed] [CrossRef] [Google Scholar]66. Roldán V., Marín F., Díaz J., Gallego P., Jover E., Romera M., Manzano-Fernández S., Casas T., Valdés M., Vicente V., Lip G.Y., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation. J. Thromb. Haemost. 2012;10(8):1500–1507. doi: 10.1111/j.1538-7836.2012.04812.x. [PubMed] [CrossRef] [Google Scholar]67. Providencia R., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation: a rebuttal . J Thromb Haemost. 2012;10(11):2413–1507. author reply 2014-5. [PubMed] [Google Scholar]68. Roldán V., Marín F., Muiña B., Torregrosa J.M., Hernández-Romero D., Valdés M., Vicente V., Lip G.Y., et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J. Am. Coll. Cardiol. 2011;57(25):2496–2504. doi: 10.1016/j.jacc.2010.12.033. [PubMed] [CrossRef] [Google Scholar]69. Hermida J., Lopez F.L., Montes R., Matsushita K., Astor B.C., Alonso A., et al. Usefulness of high-sensitivity C-reactive protein to predict mortality in patients with atrial fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study). Am. J. Cardiol. 2012;109(1):95–99. doi: 10.1016/j.amjcard.2011.08.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]70. Go A.S., Fang M.C., Udaltsova N., Chang Y., Pomernacki N.K., Borowsky L., Singer D.E., et al. ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119(10):1363–1369. doi: 10.1161/CIRCULATIONAHA.108.816082. [PMC free article] [PubMed] [CrossRef] [Google Scholar]71. Potpara T.S., Vasiljevic Z.M., Vujisic-Tesic B.D., Marinkovic J.M., Polovina M.M., Stepanovic J.M., Stankovic G.R., Ostojic M.C., Lip G.Y., et al. Mitral annular calcification predicts cardiovascular morbidity and mortality in middle-aged patients with atrial fibrillation: the Belgrade Atrial Fibrillation Study. Chest. 2011;140(4):902–910. doi: 10.1378/chest.10-2963. [PubMed] [CrossRef] [Google Scholar]72. Echt D.S., Liebson P.R., Mitchell L.B., Peters R.W., Obias-Manno D., Barker A.H., Arensberg D., Baker A., Friedman L., Greene H.L., et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 1991;324(12):781–788. doi: 10.1056/NEJM199103213241201. [PubMed] [CrossRef] [Google Scholar]73. Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation. 1990;82(4):1106–1116. doi: 10.1161/01.CIR.82.4.1106. [PubMed] [CrossRef] [Google Scholar]74. Carlsson J., Miketic S., Windeler J., Cuneo A., Haun S., Micus S., Walter S., Tebbe U., et al. STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J. Am. Coll. Cardiol. 2003;41(10):1690–1696. doi: 10.1016/S0735-1097(03)00332-2. [PubMed] [CrossRef] [Google Scholar]75. Hohnloser S.H., Kuck K.H., Lilienthal J., et al. Rhythm or rate control in atrial fibrillation–Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356(9244):1789–1794. doi: 10.1016/S0140-6736(00)03230-X. [PubMed] [CrossRef] [Google Scholar]76. Van Gelder I.C., Hagens V.E., Bosker H.A., Kingma J.H., Kamp O., Kingma T., Said S.A., Darmanata J.I., Timmermans A.J., Tijssen J.G., Crijns H.J., et al. Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N. Engl. J. Med. 2002;347(23):1834–1840. doi: 10.1056/NEJMoa021375. [PubMed] [CrossRef] [Google Scholar]77. Opolski G., Torbicki A., Kosior D.A., Szulc M., Wozakowska-Kaplon B., Kolodziej P., Achremczyk P., et al. Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest. 2004;126(2):476–486. doi: 10.1378/chest.126.2.476. [PubMed] [CrossRef] [Google Scholar]78. Ogawa S., Yamashita T., Yamazaki T., Aizawa Y., Atarashi H., Inoue H., Ohe T., Ohtsu H., Okumura K., Katoh T., Kamakura S., Kumagai K., Kurachi Y., Kodama I., Koretsune Y., Saikawa T., Sakurai M., Sugi K., Tabuchi T., Nakaya H., Nakayama T., Hirai M., Fukatani M., Mitamura H., et al. J-RHYTHM Investigators. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ. J. 2009;73(2):242–248. doi: 10.1253/circj.CJ-08-0608. [PubMed] [CrossRef] [Google Scholar]79. Testa L., Biondi-Zoccai G.G., Dello Russo A., Bellocci F., Andreotti F., Crea F., et al. Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis. Eur. Heart J. 2005;26(19):2000–2006. doi: 10.1093/eurheartj/ehi306. [PubMed] [CrossRef] [Google Scholar]80. Corley S.D., Epstein A.E., DiMarco J.P., Domanski M.J., Geller N., Greene H.L., Josephson R.A., Kellen J.C., Klein R.C., Krahn A.D., Mickel M., Mitchell L.B., Nelson J.D., Rosenberg Y., Schron E., Shemanski L., Waldo A.L., Wyse D.G., et al. AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–1513. doi: 10.1161/01.CIR.0000121736.16643.11. [PubMed] [CrossRef] [Google Scholar]81. Pedersen O.D., Brendorp B., Elming H., Pehrson S., Køber L., Torp-Pedersen C., et al. Does conversion and prevention of atrial fibrillation enhance survival in patients with left ventricular dysfunction? Evidence from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide/(DIAMOND) study. Card. Electrophysiol. Rev. 2003;7(3):220–224. doi: 10.1023/B:CEPR.0000012386.82055.81. [PubMed] [CrossRef] [Google Scholar]82. Ionescu-Ittu R., Abrahamowicz M., Jackevicius C.A., Essebag V., Eisenberg M.J., Wynant W., Richard H., Pilote L., et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch. Intern. Med. 2012;172(13):997–1004. doi: 10.1001/archinternmed.2012.2266. [PubMed] [CrossRef] [Google Scholar]83. Bardy G.H., Lee K.L., Mark D.B., Poole J.E., Packer D.L., Boineau R., Domanski M., Troutman C., Anderson J., Johnson G., McNulty S.E., Clapp-Channing N., Davidson-Ray L.D., Fraulo E.S., Fishbein D.P., Luceri R.M., Ip J.H., et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 2005;352(3):225–237. doi: 10.1056/NEJMoa043399. [PubMed] [CrossRef] [Google Scholar]84. Julian D.G., Camm A.J., Frangin G., Janse M.J., Munoz A., Schwartz P.J., Simon P., et al. European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet. 1997;349(9053):667–674. doi: 10.1016/S0140-6736(96)09145-3. [PubMed] [CrossRef] [Google Scholar]85. Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J. Am. Coll. Cardiol. 1999;34(5):1552–1559. doi: 10.1016/S0735-1097(99)00376-9. [PubMed] [CrossRef] [Google Scholar]86. Singh S.N., Fletcher R.D., Fisher S.G., Singh B.N., Lewis H.D., Deedwania P.C., Massie B.M., Colling C., Lazzeri D., et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N. Engl. J. Med. 1995;333(2):77–82. doi: 10.1056/NEJM199507133330201. [PubMed] [CrossRef] [Google Scholar]87. Cairns J.A., Connolly S.J., Roberts R., Gent M., et al. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet. 1997;349(9053):675–682. doi: 10.1016/S0140-6736(96)08171-8. [PubMed] [CrossRef] [Google Scholar]88. Piccini J.P., Hasselblad V., Peterson E.D., Washam J.B., Califf R.M., Kong D.F., et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J. Am. Coll. Cardiol. 2009;54(12):1089–1095. doi: 10.1016/j.jacc.2009.04.085. [PubMed] [CrossRef] [Google Scholar]89. Duray G.Z., Torp-Pedersen C., Connolly S.J., Hohnloser S.H., et al. Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. J. Cardiovasc. Electrophysiol. 2011;22(7):770–776. doi: 10.1111/j.1540-8167.2010.02006.x. [PubMed] [CrossRef] [Google Scholar]90. Køber L., Torp-Pedersen C., McMurray J.J., Gøtzsche O., Lévy S., Crijns H., Amlie J., Carlsen J., et al. Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 2008;358(25):2678–2687. doi: 10.1056/NEJMoa0800456. [PubMed] [CrossRef] [Google Scholar]91. Connolly S.J., Camm A.J., Halperin J.L., Joyner C., Alings M., Amerena J., Atar D., Avezum Á., Blomström P., Borggrefe M., Budaj A., Chen S.A., Ching C.K., Commerford P., Dans A., Davy J.M., Delacrétaz E., Di Pasquale G., Diaz R., Dorian P., Flaker G., Golitsyn S., Gonzalez-Hermosillo A., Granger C.B., Heidbüchel H., Kautzner J., Kim J.S., Lanas F., Lewis B.S., Merino J.L., Morillo C., Murin J., Narasimhan C., Paolasso E., Parkhomenko A., Peters N.S., Sim K.H., Stiles M.K., Tanomsup S., Toivonen L., Tomcsányi J., Torp-Pedersen C., Tse H.F., Vardas P., Vinereanu D., Xavier D., Zhu J., Zhu J.R., Baret-Cormel L., Weinling E., Staiger C., Yusuf S., Chrolavicius S., Afzal R., Hohnloser S.H. PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med. 2011;365(24):2268–2276. doi: 10.1056/NEJMoa1109867. [PubMed] [CrossRef] [Google Scholar]92. Hylek E.M., Go A.S., Chang Y., Jensvold N.G., Henault L.E., Selby J.V., Singer D.E. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med. 2003;349(11):1019–1026. doi: 10.1056/NEJMoa022913. [PubMed] [CrossRef] [Google Scholar]93. Hart R.G., Pearce L.A., Aguilar M.I. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann. Intern. Med. 2007;147(8):590–592. doi: 10.7326/0003-4819-147-8-200710160-00018. [PubMed] [CrossRef] [Google Scholar]94. Gallagher A.M., Setakis E., Plumb J.M., Clemens A., van Staa T.P., et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb. Haemost. 2011;106(5):968–977. doi: 10.1160/Th21-05-0353. [PubMed] [CrossRef] [Google Scholar]95. Fang M.C., Go A.S., Chang Y., Borowsky L.H., Pomernacki N.K., Udaltsova N., Singer D.E., et al. Thirty-day mortality after ischemic stroke and intracranial hemorrhage in patients with atrial fibrillation on and off anticoagulants. Stroke. 2012;43(7):1795–1799. doi: 10.1161/STROKEAHA.111.630731. [PMC free article] [PubMed] [CrossRef] [Google Scholar]96. Go A.S., Hylek E.M., Borowsky L.H., Phillips K.A., Selby J.V., Singer D.E., et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann. Intern. Med. 1999;131(12):927–934. doi: 10.7326/0003-4819-131-12-199912210-00004. [PubMed] [CrossRef] [Google Scholar]97. Devereaux P.J., Anderson D.R., Gardner M.J., Putnam W., Flowerdew G.J., Brownell B.F., Nagpal S., Cox J.L., et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ. 2001;323(7323):1218–1222. doi: 10.1136/bmj.323.7323.1218. [PMC free article] [PubMed] [CrossRef] [Google Scholar]98. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., Pogue J., Reilly P.A., Themeles E., Varrone J., Wang S., Alings M., Xavier D., Zhu J., Diaz R., Lewis B.S., Darius H., Diener H.C., Joyner C.D., Wallentin L., et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009;361(12):1139–1151. doi: 10.1056/NEJMoa0905561. [PubMed] [CrossRef] [Google Scholar]99. Uchino K., Hernandez A.V., et al. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch. Intern. Med. 2012;172(5):397–402. doi: 10.1001/archinternmed.2011.1666. [PubMed] [CrossRef] [Google Scholar]100. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., Breithardt G., Halperin J.L., Hankey G.J., Piccini J.P., Becker R.C., Nessel C.C., Paolini J.F., Berkowitz S.D., Fox K.A., Califf R.M., et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011;365(10):883–891. doi: 10.1056/NEJMoa1009638. [PubMed] [CrossRef] [Google Scholar]101. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M., Al-Khalidi H.R., Ansell J., Atar D., Avezum A., Bahit M.C., Diaz R., Easton J.D., Ezekowitz J.A., Flaker G., Garcia D., Geraldes M., Gersh B.J., Golitsyn S., Goto S., Hermosillo A.G., Hohnloser S.H., Horowitz J., Mohan P., Jansky P., Lewis B.S., Lopez-Sendon J.L., Pais P., Parkhomenko A., Verheugt F.W., Zhu J., Wallentin L., et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011;365(11):981–992. doi: 10.1056/NEJMoa1107039. [PubMed] [CrossRef] [Google Scholar]

How does Chronic Atrial Fibrillation Influence Mortality in the Modern Treatment Era?

Curr Cardiol Rev. 2015 Aug; 11(3): 190–198.

Rajiv Sankaranarayanan

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Graeme Kirkwood

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Rajaverma Visweswariah

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

David J. Fox

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

^* Address correspondence to this author at the Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK; Tel: 00447525826672; Fax: 00441612751234; E-mail [email protected]

Received 2014 Apr 23; Revised 2014 Aug 22; Accepted 2014 Aug 27.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been cited by other articles in PMC.

Abstract

Atrial fibrillation (AF) continues to impose a significant burden upon healthcare resources. A sustained increase in the ageing population and better survival from conditions such as ischaemic heart disease have ensured that both the incidence and prevalence of AF continue to increase significantly. AF can lead to complications such as embolism and heart failure and these acting in concert with its associated co-morbidities portend increased mortality risk. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of various therapeutic strategies (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures). Despite several treatment advances including newer anti-arrhythmic drugs and developments in catheter ablation, anti-coagulation remains the only effective means to reduce the mortality due to AF. Warfarin has been used as the oral anticoagulant in the treatment of AF for many years but suffers from disadvantages such as unpredictable INR levels, bleeding risks and need for haematological monitoring. This has therefore spurred a renewed interest in research and clinical studies directed towards developing safer and more efficacious anti-coagulants. We shall review in this article the epidemiological features of AF-related mortality from several studies as well as the cardiovascular and non-cardiac mortality mechanisms. We shall also elucidate why a rhythm control strategy has appeared to be counter-productive and attempt to predict the likely future impact of novel anti-coagulants upon mortality reduction in AF.

Keywords: Atrial fibrillation, arrhythmia, mortality, anti-arrhythmic drugs.

INTRODUCTION

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. 2.2 million people in America and 4.5 million people in Europe are affected by either paroxysmal or persistent AF [1]. It is usually associated with cardiovascular co-morbidities such as hypertension, coronary artery disease, valvular heart disease and heart failure [2]. The presence of AF has been shown to independently increase the risk of death [3-7] and the mortality risk is highest during the first year after AF manifests [5-8]. The incidence of death due to AF has been shown to vary from 1.6-4.2% per annum in various controlled trials [9, 10]. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of the various therapeutic strategies for AF (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures).

EPIDEMIOLOGY

Large population studies both in North America and Europe have demonstrated incontrovertibly the impact of AFupon mortality. The landmark Framingham Heart Study analysed a cohort of 621 individuals who developed AF (out of a study population of over 5000) during 40 years of follow-up; the excess in all-cause mortality rates attributable to AF was 50% for men, and 90% for women, even when controlled for the presence of a wide range of cardiovascular co-morbidities [5]. This effect on mortality became apparent early, with 15% of deaths occurring within 30 days of diagnosis. Amongst the group of patients aged between 55-74 years, the 10 year mortality was 61.5% in men with AF compared to 30% in men without AF. Amongst women in a similar age group, the 10 year mortality was 57.6% in the AF group versus 20.9% in women without AF. Similar findings have been found from many other cohorts. The Renfrew-Paisley study followed-up 100 patients with AF for 20 years out of a cohort of over 15,000 men and women aged between 45-64 years in two Scottish towns and showed that AF increased all-cause mortality by 50% amongst men and 120% amongst women [3]. Ruigomez et al. followed a cohort of 1035 chronic AF patients in the UK for a mean duration of 2 years and reported a trebling of all cause mortality after matching for confounding factors [7]. The Olmsted County study was a community based study of 4618 patients with AF, followed-up for 5.3±5 years and demonstrated that relative to the general age and sex-matched population, AF significantly increased the mortality risk especially during the first four months following diagnosis (HR 9.62; 95% CI 8.93 to 10.32) and also thereafter (HR 1.66; 95% CI 1.59 to 1.73) [8]. The Manitoba study followed-up nearly 4000 young Canadian male air crew for 44 years and demonstrated that AF increased total mortality by 31% [11].

As might be expected, the annual mortality rates associated with AF vary substantially depending on the population demographics. Based on medical insurance claim data, values range from 2.6% in asymptomatic untreated individuals, to 24.2% amongst an elderly population with high rates of co-morbidities [12, 13]. There do not appear to have been significant reductions in AF-associated mortality between the years 1993 – 2007; this population-based data is supported by recent trials of novel anticoagulants and anti-arrhythmic therapies, which report annual mortality rates between 1.9 and 6.6% even with optimal contemporary treatment [14-16].

It is unambiguous from the epidemiological data that, although the presence of AF has a significant and dramatic effect to increase the mortality rate within a population, the effect on an individual is less clear-cut and is highly dependent on demographic risk factors and the presence of co-morbidities as discussed below.

AGE

Age is a major risk factor for developing AF, and older patients are more likely to have co-morbidities that might impact on survival. Nevertheless, patient age is the most powerful and consistent independent factor in determining the AF-associated mortality risk. Although the Framingham study found that all age groups demonstrated an excess mortality attributable to AF, the absolute risk increase seen in those aged over 75 years was approximately 3 times that seen in those under 65 years [5]. This was confirmed in the Paisley/Renfrew study, where the excess mortality was increased 3.5 times in the age group 60–64 years compared to 45–49 years [3]. Essentially, amongst all age groups, individuals with AF are more likely to die early than those without, and older patients with AF are substantially more at risk than younger patients. The annual mortality in 2007 amongst a large cohort of AF patients who were also Medicare beneficiaries aged >65 years was as high as 25% [13].

SEX

In developed societies, healthy females possess a survival advantage over males [17]. The mortality associated with AF is slightly but significantly higher in females than in males, such that this survival advantage is lost and the life expectancy of a woman with AF is similar to that of an age-matched man [5]. The Renfrew-Paisley study showed AF portends a higher all-cause and cardiovascular mortality amongst women [3]. There is also evidence that stroke-related mortality in AF is higher in women [18].

RACE /ETHNIC DIFFERENCES

During AF-related hospitalisations, in-hospital mortality has been shown to be highest amongst African-Americans in comparison to other ethnic groups [19].

LONE AF VS. CO-MORBIDITIES

‘Lone AF’ is defined as AF in the absence of structural heart disease or additional cardiovascular co-morbidities such as diabetes or hypertension. In reality, lone AF is an uncommon entity; 70% of patients with AF have additional risk factors at the time of diagnosis and of the remaining 30% many will have unrecognised co-morbidities such as sleep apnoea or obesity [20]. With a 15 year mortality of only 8%, survival amongst patients with lone AF has been shown to be not significantly different to that of age and sex-matched population control data [21-23]; this is in keeping with subgroup analysis from the Paisley/ Renfrew study which also did not identify a significant mortality excess attributable to lone AF [3].

In contrast, multivariate analysis from the afore-mentioned population studies indicates that cardiovascular and non-cardiovascular co-morbidities impact dramatically upon survival. Factors such as smoking, lung disease, hypertension, diabetes and obesity act to increase mortality by around 20 – 60% each, and the effects are additive with additional risk factors. These findings have led to the development of clinical scoring systems to aid therapeutic decisions.

TEMPORAL PROFILE OF AF

There is convincing evidence that AF burden may impact upon stroke rates [24], however the stroke risk due to paroxysmal AF is comparable to that of chronic AF [25]. In contrast, permanent AF is associated with higher mortality risk whereas paroxysmal AF has been shown to portend similar mortality risk as that of age and gender-matched general population [26, 27]. However, analysis of the mortality effect due to persistent AF in comparison to paroxysmal AF, has shown contrasting results [26, 28].

ISCHAEMIC HEART DISEASE (IHD) AND HEART FAILURE

AF and coronary artery disease share risk factors, but there is no clear evidence linking AF with increased risk of acute coronary syndromes [29]. Co-existing IHD has been shown to increase all-cause mortality due to AF three fold with up to 21% of deaths shown to be related to IHD [7]. Nevertheless, there is a clear association between AF and poor prognosis in myocardial infarction; multiple studies have shown that the development of AF following myocardial infarction is associated with a substantial increase in in-hospital as well as post-discharge mortality (reviewed in [30]). Many studies (including large-scale RCTs such as the OPTIMAAL trial, GUSTO-3 trial and TRACE study) have shown that chronic AF independently increases post-MI mortality (reviewed in [30]). A study by one of the authors of this paper (Sankaranarayanan et al. [31]) showed that chronic AF could increase post-MI mortality risk by increasing the risk of ventricular fibrillation in this setting [31]. The OPTIMAAL trial noted a significant increase in 30 day mortality only where new AF complicated acute MI, but that both acute and pre-existing AF were associated with reduced survival over the subsequent 3 years [32].

AF in congestive heart failure (CHF) has recently attracted substantial interest; AF can either exacerbate or complicate CHF [33], and in the modern era of device therapy it is becoming apparent that AF in CHF is under-recognised [34]. 24% out of 3288 individuals with AF in the Olmsted County study developed CHF over a mean follow-up of 6.1±5.2 years, leading to a significant increase in mortality (HR 3.4) [35]. The Framingham study illustrated the close relationship between these two pathologies showing that amongst 1470 participants who developed either or both these conditions, 382 individuals had both (36% of these developed AF first, 41% CHF first and 21% were diagnosed with both on the same day) [36]. The incidence of CHF amongst AF patients was 33 per 1000 person years, with 4 out of 10 AF subjects developing heart failure at some point during their lifetime and also significantly increasing mortality (men HR 1.6, women HR 2.7). Further analysis also demonstrated a significant mortality impact where AF complicated CHF, (incidence 54 per 1000 person years) with relative increases of 60% and 170% in men and women respectively compared to individuals with CHF in sinus rhythm. The Manitoba follow-up study showed that AF increases the risk of development of CHF by three-fold and increased cardiac mortality by 37% [11].

However, therapeutic CHF studies demonstrated conflicting results as to whether the presence of AF conferred an independent impact on mortality, or simply reflected disease state at baseline [37-40]. A recent meta-analysis of 16 studies including 53,969 patients appears to confirm that AF increases total mortality in CHF patients by around 40%, with an independent effect remaining after controlling for demographics and disease severity irrespective of impaired or preserved LV function [41]. Nevertheless, it remains controversial whether it is the arrhythmia or the co-morbidities that impacts upon mortality, with a recent analysis [42] suggesting that this effect is only seen where heart failure results from ischaemic heart disease. A post hoc analysis of the AFFIRM trial sub-set of patients with CHF and preserved ejection fraction showed a lower all-cause and cardiovascular mortality in comparison to patients with impaired systolic function [43].

In view of the strong association of AF with co-morbidities, several studies have attempted to analyse if the effects of AF upon mortality are truly independent or simply a risk marker for the cumulative pre-terminal effects of co-morbidities. The Olmsted County study for instance illustrated the very high 4 month and 1 year mortality following AF diagnosis, however there were no changes in early (<4 months) versus late mortality (after 4 months) in the whole cohort or within the sub-group of patients without pre-morbid cardiovascular disease [8]. These results and others showing that lone AF does not increase mortality, suggest that AF could simply represent a risk marker for mortality in a very sick population with multiple co-morbidities [3, 6, 8].

1. MECHANISMS OF AF-RELATED MORTALITY

Cardiac

Several large population-based studies have shown that AF independently increases cardiac mortality [3, 5, 11]. Increased cardiovascular mortality risk due to AF varies between 2 to 12 times [44]. The cardiac causes include heart failure, arrhythmia and possibly coronary heart disease.

AF has an intricate relationship with CHF whereby one can precipitate the other [45]. AF leads to a loss of atrial systole (which usually contributes up to 30% of pre-load in sinus rhythm). In addition to this, the loss of atrio-ventricular synchrony and irregular, uncontrolled ventricular rates contribute to development of CHF (“tachycardia-induced cardiomyopathy”) [46-48]. Uncontrolled ventricular rates during AF can also worsen mitral regurgitation and cause rate-related left bundle branch block, thereby reducing cardiac output [49].

AF can lead to arrhythmic sudden death by potentiating VT or VF in patients with ICDs [50], pre-excitation syndromes [49] and in the acute MI setting [31].

AF can also impair coronary perfusion and increase myocardial oxygen demand especially due to uncontrolled ventricular rates and this could worsen coronary ischaemia and thus increase mortality especially in the subset of patients with pre-existing ischaemic heart disease [48-50].

2. Vascular

AF contributes to 15-25% of all strokes and these contribute to a significant proportion of AF-related mortality [51, 52]. AF-related strokes tend to be associated with higher mortality, and more severe disability [52, 53]. The Olmsted County study followed up 4117 individuals with AF and reported a 11% incidence of stroke over a mean follow-up period of 5.5±5 years, with AF–related stroke significantly increasing the mortality hazard ratio to 3.03 for men and 3.8 for women in comparison to the general population [18]. The Manitoba follow-up study showed that AF increased cardiovascular mortality including fatal stroke by 41% [11]. Even amongst anti-coagulated patients with therapeutic INR, stroke risk due to AF can be up to 3% in high-risk individuals such as those with prior stroke [54, 55]. Un-coordinated atrial contraction leads to stasis of blood in the left atrium [56]. In addition to this, thrombogenesis is also perpetuated by haematological abnormalities such as platelet activation, inflammation and structural factors such as atrial dilatation, loss of endothelium and progressive fibrosis [56]. The left atrial appendage is the site responsible for the majority of thrombi in non-valvular AF [56]. However, it has been demonstrated that not all thrombo-embolic events necessarily predict mortality risk. For instance, the ACTIVE-W trial showed that only disabling strokes (both ischaemic and haemorrhagic with Rankin score ≥3) increase mortality risk whereas transient ischaemic attacks do not [57]. Major bleeding secondary to anti-coagulation can also contribute to mortality [57].

3. Non-cardiovascular Deaths

Most therapeutic strategies for AF such as anti-arrhythmic drugs, anti-thrombotics and catheter ablation can increase mortality risk in AF as a side-effect or serious adverse event. Anti-arrhythmic drugs can lead to potentially lethal pro-arrhythmic effects (such as torsade de pointes) but also cause multi-systemic side-effects and thus contribute to non-cardiovascular deaths [10, 58, 59]. A rhythm control strategy has also been shown to unmask non-cardiovascular co-morbidities such as malignancies or lung pathology, thus contributing to mortality burden (covered in greater detail in section on AADs) [10, 48]. Bleeding risk is inextricably linked to use of anti-thrombotics and can be fatal. Severe bleeding events (such as fatal events, drop in haemoglobin of at least 5 g/decilitre), need for inotropic agents, loss of vision due to intra-ocular bleeding, surgical intervention due to bleeding, symptomatic intra-cranial haemorrhage, need for transfusion of at least 4 units of blood) treble the mortality risk (HR. 3.35; 95% CI, 2.12-5.27) whilst non-severe major bleeding or minor bleeding events do not increase mortality.

RISK PREDICTION FOR AF-RELATED MORTALITY

In view of the significant mortality risk due to AF and the associated co-morbidities, several useful risk-predictors have been identified. The CHADS₂ Score (1 point each for Congestive Heart Failure, Hypertension, Age≥75 years, Diabetes Mellitus and 2 points for Stroke/TIA) was introduced over a decade back as a scoring system to assess thrombo-embolic risk due to AF [60] but can also predict mortality risk. Khumri et al. showed in a study that patients with CHADS₂ score of ≥5 have a 50 fold higher mortality risk in comparison to patients with a score of 0 [61]. Similarly, while the HAS-BLED score has been mainly used in clinical practice to predict risk of major haemorrhagic episodes due to anti-coagulation [62], this risk score has also been shown to predict adverse cardiovascular events as well as all-cause mortality, thus illustrating that thrombogenesis and haemorrhage are inextricably linked by sharing many common risk predictors [63]. Whilst the CHA₂DS₂Vasc score has been recommended in the latest guidelines to supersede CHADS₂ as a better risk predictor for thrombo-embolic risk, its role as a risk predictor for mortality remains to be established.

Abnormal ankle brachial index (ratio of ankle and brachial systolic blood pressure) has been shown to independently predict all-cause mortality after adjusting for CHADS2 score and also predict major haemorrhagic episodes irrespective of the HAS-BLED score [64]. Cardiovascular related hospitalisation in AF patients also significantly predicts risk of death (HR 2.69; 95% CI 1.96-3.68) and it has been suggested that this end-point could be used as a surrogate for mortality in trials [65].

Clinical investigations also help to identify patients at increased risk of AF-related averse events. Serum bio-markers such as interleukin-6, high sensitivity troponin T and von Willebrand factor have been shown to predict all-cause mortality independent of CHADS2 score in anti-coagulated AF patients, possibly reflecting coronary micro-vascular dysfunction, global endothelial dysfunction or athero-thrombosis [66-68]. High sensitivity CRP has also been shown to predict all-cause and cardiovascular mortality amongst AF patients [69]. Patients with renal failure (eGFR <45 ml/min and proteinuria) have been shown to have increased risk of AF-related thrombo-embolism, bleeding and mortality [70]. Echocardiographic markers such as mitral annular calcification, presence of spontaneous left atrial contrast, severe LV impairment and greater than moderate mitral regurgitation also help to predict increased mortality risk amongst chronic AF patients [61, 71].

TREATMENTS

Anti-arrhythmic Drugs (AADs)

Several AADs have been shown to cause pro-arrhythmic side-effects and thus increased mortality in patients [58]. The class I agent flecainide gained particular attention following the CAST trial [72] where increased mortality was observed in patients with history of myocardial infarction. These results have been extrapolated to extend its contraindication to patients with coronary artery disease, heart failure or left ventricular hypertrophy. Coplen, in a meta-analysis published in 1990, showed that treatment with quinidine was more effective than no anti-arrhythmic therapy in suppressing recurrences of atrial fibrillation but appeared to be associated with increased total mortality [73]. Class III medications such as amiodarone and sotalol, have also received similar attention, and are also well known for their risk of QT prolongation and Torsades de Pointes.

Indeed all AADs have the potential to have serious, pro-arrhythmic side effects [58]. This has implications when determining the optimal treatment strategy for atrial fibrillation (AF): the restoration and maintenance of sinus rhythm (rhythm control strategy) or control of heart rate alone (rate control strategy). Several studies have sought to answer this question, including the Strategies of Treatment of Atrial Fibrillation (STAF) [74], Pharmacological Intervention in Atrial Fibrillation (PIAF) [75], Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) [10], Rate Control vs. Electrical Cardioversion (RACE) [76], the HOT CAFÉ [77] and J-RHYTHM Study [78]. None of these studies has shown any significant difference in all-cause or cardiovascular mortality and stroke outcome between rate and rhythm control and in fact a meta-analysis of five major trials showed a trend towards reduced risk of death (rate vs. rhythm control; OR 0.87, 0.74-1.02- P=0.09) [79]. This has generally led to the adoption of rate control strategy as the pragmatic approach especially in the elderly or in presence of significant co-morbidities.

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) in particular showed a non-significant trend toward increased all-cause mortality in the rhythm control group (hazard ratio 1.14; 95% CI, 1-1.32) [10]. A retrospective analysis of the cause-specific mortality in the AFFIRM trial showed that the incidence of cardiac (including arrhythmic, heart failure and MI deaths) and vascular (including ischaemic and haemorrhagic strokes) deaths was not significantly different between the rhythm control and rate-control groups [48]. Thus the increased all-cause mortality in the rhythm-control group could be entirely accounted for by the significant difference between the incidences of non-cardiovascular deaths (47.5% in rhythm control group versus 36.5% in rate-control group; p=0.0008). These non-cardiovascular deaths were mainly due to malignancies and pneumonia. This was attributed to earlier discontinuation of warfarin and higher incidence of stroke rather than risk of the anti-arrhythmic itself which highlights the importance of anticoagulation in atrial fibrillation. Even in patients with heart failure (LVF<35%) complicated by AF, the AF-CHF trial did not demonstrate that rhythm control could lead to mortality benefit [33]. However, there has been some evidence demonstrating the benefits of rhythm control particularly in the longer term. For instance, a retrospective, “on-treatment analysis” of the AFFIRM study that analysed presence of sinus rhythm and use of anti-arrhythmic drugs as separate variables, showed a significant reduction in death due to presence of sinus rhythm [80]. Thus the mortality increase of 49% due to anti-arrhythmic drugs could have overshadowed the 53% mortality reduction due to maintenance of sinus rhythm [48]. The survival benefits of sinus rhythm were similar to that seen in the DIAMOND AF (dofetilide versus placebo in AF patients with LV dysfunction) study which did not show an all-cause mortality benefit; however, restoration and maintenance of sinus rhythm significantly reduced mortality (risk ratio 0.44; 95% CI 0.30-0.64) and risk of hospitalisation [81]. In a population-based study of rate versus rhythm control strategies among 26, 130 AF patients, showed that the rhythm control group demonstrated a small increase in mortality within six months of treatment initiation which then became similar to mortality in the rate-control group until year 4. In the longer term however (after year 5), the mortality was lower in the rhythm control group in comparison to that in the rate-control group (HR 0.89; 95% CI 0.81-0.96 after 5 years and HR 0.77; 95% CI 0.62-0.95 after 8 years) [82]. From the above studies, it is likely that the pro-arrhythmic effects and multi-systemic side-effects of existing AADs dilute and even offset the survival advantage provided by maintenance of sinus rhythm.

The most commonly used AAD for rhythm control in all these trials was amiodarone, which was shown in the studies to have a low pro-arrhythmic potential, with its adverse side effects being mainly extra-cardiac [59]. Amiodarone has been demonstrated to be the most efficacious drug in maintaining sinus rhythm [59, 79]. Some studies have found it to be associated with an increased risk of non-cardiac mortality (particularly cancer-related and pulmonary) [83-85] whilst this was not observed in other studies [86, 87]. Recently Freemantle et al. included thirty nine randomised controlled trials in a mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide and propafenone used for the management of AF and reported (from eighteen trials including about 10,000 patients) that sotalol in particular was associated with increased mortality whereas amiodarone (but not dronedarone) showed a trend towards increased all-cause mortality [59]. A meta-analysis by Piccini et al. also demonstrated an insignificant trend towards increased mortality due to amiodarone [88].

More recently, there has been the arrival of dronedarone, an AAD developed to have fewer side effects and improved safety profile compared to amiodarone [88]. The EURIDIS and ADONIS trials showed dronedarone was significantly more effective than placebo in maintaining sinus rhythm, and in reducing ventricular rate during recurrence of arrhythmia, with post hoc analysis also suggesting a 44% reduction in cardiovascular hospitalisation or death at 12 months [89]. Although dronedarone is less efficacious than amiodarone [88], a subsequent trial (ATHENA) showed that dronedarone reduces the composite endpoint of cardiovascular hospitalisation or death by 24% [14]. However, subsequent studies have shown that dronedarone can lead to increased early mortality in certain sub-sets of patients. For instance, in the ANDROMEDA trial (Anti-arrhythmic trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease), dronedarone (in comparison with placebo) led to a doubling of mortality (95%CI, 1.07-4.25) due to worsening heart failure after a median follow-up of only 2 months [90] Dronedarone also led to increased cardiovascular deaths (hazard ratio 2.11; 95% CI, 1-4.49), arrhythmic deaths (hazard ratio 3.26; 95% CI, 1.06-10) in addition to increased incidence of stroke and heart failure hospitalisations when used in patients with high-risk permanent AF (PALLAS) [91].

ANTI-COAGULATION

Effective anticoagulation is the most effective method of reducing mortality in AF patients [92]. In the absence of anti-coagulation, AF patients who develop a stroke have a 1 month mortality of nearly 25% [92]. In a meta-analysis of 29 trials of anti-thrombotic therapy for AF, compared to control, adjusted-dose warfarin reduced significantly stroke risk by 64% and all-cause mortality by 26%. Aspirin in contrast showed a non-significant 19% reduction in stroke risk and did not reduce mortality significantly [93]. In addition to anti-coagulation with warfarin, it is also important to closely monitor the therapeutic range of INR closely to both prevent thrombo-embolic complications as well as avoid major bleeding complications. Patients who spend at least 70% of the time with INR within therapeutic range demonstrate significantly lower mortality compared to patients whose INR is therapeutic <70% of the time [94]. Analysis of 30-day mortality due to ischaemic stoke whilst on warfarin, has shown that warfarin significantly reduces 30 day mortality if INR is between 2-3 (OR 0.38; 955 CI, 0.2-0.7) but patients with INR>3 demonstrate increased odds of mortality due to intra-cranial haemorrhage 2.66 fold (95% CI, 1.21-5.86) [95].

Despite the obvious benefits of warfarin, the ATRIA study showed that it was being under-prescribed, particularly in those AF patients below 55 years and above 85 years, presumably due to physicians’ concerns regarding bleeding risk [96]. Interestingly, in contrast to this predominant view held by most physicians, patients are willing to accept the higher risk of bleeding associated with anti-coagulants in order to avoid disabling strokes which some even view as worse than death [97]. The search for more efficacious and potentially safer anti-thrombotics has heralded the era of novel anti-coagulants, as detailed below.

In the RELY study [98], dabigatran, a novel oral direct thrombin inhibitor, given at a dose of 110 mg to AF patients, was associated with rates of stroke and systemic embolism similar to warfarin, but with lower rates of major haemorrhage, whilst at doses of 150 mg, it was associated with lower rates of stroke and systemic embolism compared to warfarin, and similar rates of major haemorrhage. There was a trend towards reduction in all-cause mortality with the 150 mg dose (p=0.051) and a significant reduction in vascular mortality (p=0.04). The rates of death from any cause were 4.13% per year with warfarin, compared with 3.75% per year with 110 mg dabigatran (P=0.13), and 3.64% with 150 mg dabigatran (P=0.051). A meta-analysis of seven dabigatran studies (including 30514 patients) also showed a 11% reduction in all-cause mortality in comparison to warfarin [99].

Following this there has been the addition of the oral factor Xa inhibitors: rivaroxaban, assessed by the ROCKET-AF trial [100]; and apixaban, analysed by the AVERROES [16] and ARISTOTLE [101] trials. In the ROCKET-AF trial, in comparison with warfarin for non-valvular AF, rivaroxaban was shown to be non-inferior for prevention of stroke or systemic embolism. There was no significant difference in risk of major bleeding, though intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. There was no significant difference in mortality between the two groups. In the ARISTOTLE trial, apixaban was shown to be superior to warfarin by reducing the risk of stroke or systemic embolism by 21%, major bleeding by 31% and all-cause mortality by 11% [101].

The future for these novel anticoagulants is very promising, with significant progress being made in morbidity and mortality reduction compared to warfarin, mainly by way of further reduction in ischaemic strokes and less bleeding risks. However there are also several concerns regarding the use of the newer anticoagulants as detailed below. These include the lack of robust safety data in patients with creatinine clearance <30 ml/min, elderly patients and those with extremes of body weight. Whilst the lack of need to closely monitor anticoagulation whilst on newer anticoagulants can be viewed as an advantage by reducing patient inconvenience as well as the burden on healthcare resources, this feature can also be a disadvantage if patients miss one or more doses (due to the short offset time of these drugs leading to a rebound stroke risk). Additionally the lack of a specific antidote to these drugs is also of concern during major bleeding episodes. Thus there is a need for further studies in order to clarify the above concerns about these drugs before they can be incorporated into widespread clinical practice.

INTERVENTIONAL TREATMENTS

Catheter ablation is recommended in the management of symptomatic paroxysmal AF after failed AAD therapy and has not yet been demonstrated to confer mortality benefits possibly due to lack of long-term follow-up data. Being an invasive procedure, the procedure itself carries a mortality risk of up to 0.7% [2]. However, newer technological developments are consistently improving the safety and efficacy of catheter-based techniques. Left atrial appendage closure using occlusion devices has been suggested as an alternative for patients deemed unsuitable for oral anti-coagulation and again data on mortality benefits from this procedure is lacking currently.

CONCLUSIONS

AF and its associated co-morbidities continue to impose a significant mortality risk despite several new therapeutic advances. Indeed a proportion of the AF-related mortality is caused by side-effects due to attempts at restoring and maintaining sinus rhythm or major bleeding due to anti-coagulation. However effective anti-coagulation is the only therapeutic strategy that has been shown to reduce AF-related mortality and newer anticoagulants with improved efficacy and lesser bleeding side-effects, are only likely to improve the risk-benefit profile. Currently available AADs have limited efficacy and possess significant side-effects which seem to offset benefits of rhythm control; hence there is a pressing need to develop improved AADs in order to unmask the survival benefit that could accrue from maintenance of sinus rhythm. The impact of catheter ablation in the management of AF has currently been increasing and with improvements in safety and efficacy, is likely to reduce the use of AADs in the future.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

References

1. Feinberg W.M., Cornell E.S., Nightingale S.D., Pearce L.A., Tracy R.P., Hart R.G., Bovill E.G., et al. Stroke Prevention in Atrial Fibrillation Investigators. Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke. 1997;28(6):1101–1106. doi: 10.1161/01.STR.28.6.1101. [PubMed] [CrossRef] [Google Scholar]2. Camm A.J., Kirchhof P., Lip G.Y., Schotten U., Savelieva I., Ernst S., Van Gelder I.C., Al-Attar N., Hindricks G., Prendergast B., Heidbuchel H., Alfieri O., Angelini A., Atar D., Colonna P., De Caterina R., De Sutter J., Goette A., Gorenek B., Heldal M., Hohloser S.H., Kolh P., Le Heuzey J.Y., Ponikowski P., Rutten F.H., et al. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J. 2010;31(19):2369–2429. doi: 10.1093/eurheartj/ehq278. [PubMed] [CrossRef] [Google Scholar]3. Stewart S., Hart C.L., Hole D.J., McMurray J.J., et al. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am. J. Med. 2002;113(5):359–364. doi: 10.1016/S0002-9343(02)01236-6. [PubMed] [CrossRef] [Google Scholar]4. Kirchhof P., Auricchio A., Bax J., Crijns H., Camm J., Diener H.C., Goette A., Hindricks G., Hohnloser S., Kappenberger L., Kuck K.H., Lip G.Y., Olsson B., Meinertz T., Priori S., Ravens U., Steinbeck G., Svernhage E., Tijssen J., Vincent A., Breithardt G., et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur. Heart J. 2007;28(22):2803–2817. doi: 10.1093/eurheartj/ehm358. [PubMed] [CrossRef] [Google Scholar]5. Benjamin E.J., Wolf P.A., D’Agostino R.B., Silbershatz H., Kannel W.B., Levy D., et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946–952. doi: 10.1161/01.CIR.98.10.946. [PubMed] [CrossRef] [Google Scholar]6. Vidaillet H., Granada J.F., Chyou Po., Maassen K., Ortiz M., Pulido J.N., Sharma P., Smith P.N., Hayes J., et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am. J. Med. 2002;113(5):365–370. doi: 10.1016/S0002-9343(02)01253-6. [PubMed] [CrossRef] [Google Scholar]7. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A., et al. Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC Cardiovasc. Disord. 2002;2:5. doi: 10.1186/1471-2261-2-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]8. Miyasaka Y., Barnes M.E., Bailey K.R., Cha S.S., Gersh B.J., Seward J.B., Tsang T.S., et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J. Am. Coll. Cardiol. 2007;49(9):986–992. doi: 10.1016/j.jacc.2006.10.062. [PubMed] [CrossRef] [Google Scholar]9. Olsson S.B. Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691–1698. doi: 10.1016/S0140-6736(03)14841-6. [PubMed] [CrossRef] [Google Scholar]10. Wyse D.G., Waldo A.L., DiMarco J.P., Domanski M.J., Rosenberg Y., Schron E.B., Kellen J.C., Greene H.L., Mickel M.C., Dalquist J.E., Corley S.D., et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 2002;347(23):1825–1833. doi: 10.1056/NEJMoa021328. [PubMed] [CrossRef] [Google Scholar]11. Krahn A.D., Manfreda J., Tate R.B., Mathewson F.A., Cuddy T.E., et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am. J. Med. 1995;98(5):476–484. doi: 10.1016/S0002-9343(99)80348-9. [PubMed] [CrossRef] [Google Scholar]12. Gajewski J., Singer R.B. Mortality in an insured population with atrial fibrillation. JAMA. 1981;245(15):1540–1544. doi: 10.1001/jama.1981.03310400022019. [PubMed] [CrossRef] [Google Scholar]13. Piccini J.P., Hammill B.G., Sinner M.F., Jensen P.N., Hernandez A.F., Heckbert S.R., Benjamin E.J., Curtis L.H., et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5(1):85–93. doi: 10.1161/CIRCOUTCOMES.111.962688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]14. Hohnloser S.H., Crijns H.J., van Eickels M., Gaudin C., Page R.L., Torp-Pedersen C., Connolly S.J., et al. ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 2009;360(7):668–678. doi: 10.1056/NEJMoa0803778. [PubMed] [CrossRef] [Google Scholar]15. Go A.S., et al. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N. Engl. J. Med. 2009;360(20):2127–2129. doi: 10.1056/NEJMe0902676. [PubMed] [CrossRef] [Google Scholar]16. Connolly S.J., Eikelboom J., Joyner C., Diener H.C., Hart R., Golitsyn S., Flaker G., Avezum A., Hohnloser S.H., Diaz R., Talajic M., Zhu J., Pais P., Budaj A., Parkhomenko A., Jansky P., Commerford P., Tan R.S., Sim K.H., Lewis B.S., Van Mieghem W., Lip G.Y., Kim J.H., Lanas-Zanetti F., Gonzalez-Hermosillo A., Dans A.L., Munawar M., O’Donnell M., Lawrence J., Lewis G., Afzal R., Yusuf S., et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 2011;364(9):806–817. doi: 10.1056/NEJMoa1007432. [PubMed] [CrossRef] [Google Scholar]17. Arias E., et al. National vital statistics reports. Hyattsville, MD: National Centre for Health Statistics; 2010. United States Life Tables 2006. Report No. [Google Scholar]18. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Seward J.B., Bailey K.R., Iwasaka T., Tsang T.S., et al. Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study. Stroke. 2005;36(11):2362–2366. doi: 10.1161/01.STR.0000185927.63746.23. [PubMed] [CrossRef] [Google Scholar]19. Turagam M.K., Velagapudi P., Visotcky A., Szabo A., Kocheril A.G., et al. African Americans have the highest risk of in-hospital mortality with atrial fibrillation related hospitalizations among all racial/ethnic groups: a nationwide analysis. Int. J. Cardiol. 2012;158(1):165–166. doi: 10.1016/j.ijcard.2012.04.090. [PubMed] [CrossRef] [Google Scholar]20. Rosiak M., Dziuba M., Chudzik M., Cygankiewicz I., Bartczak K., Drozdz J., Wranicz J.K., et al. Risk factors for atrial fibrillation: Not always severe heart disease, not always so ‘lonely’. Cardiol. J. 2010;17(5):437–442. [PubMed] [Google Scholar]21. Kopecky S.L., Gersh B.J., McGoon M.D., Whisnant J.P., Holmes D.R., Jr, Ilstrup D.M., Frye R.L., et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N. Engl. J. Med. 1987;317(11):669–674. doi: 10.1056/NEJM198709103171104. [PubMed] [CrossRef] [Google Scholar]22. Rostagno C., Bacci F., Martelli M., Naldoni A., Bertini G., Gensini G., et al. Clinical course of lone atrial fibrillation since first symptomatic arrhythmic episode. Am. J. Cardiol. 1995;76(11):837–839. doi: 10.1016/S0002-9149(99)80240-9. [PubMed] [CrossRef] [Google Scholar]23. Potpara T., Grujić M., Marinković J., Vujisić-Tesić B., Ostojić M., Polovina M., et al. Mortality of patients with lone and idiopathic atrial fibrillation is similar to mortality in general population of Serbia. Vojnosanit. Pregl. 2010;67(2):132–135. doi: 10.2298/VSP1002132P. [PubMed] [CrossRef] [Google Scholar]24. Botto G.L., Padeletti L., Santini M., Capucci A., Gulizia M., Zolezzi F., Favale S., Molon G., Ricci R., Biffi M., Russo G., Vimercati M., Corbucci G., Boriani G., et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J. Cardiovasc. Electrophysiol. 2009;20(3):241–248. doi: 10.1111/j.1540-8167.2008.01320.x. [PubMed] [CrossRef] [Google Scholar]25. Lip G.Y., Hee F.L. Paroxysmal atrial fibrillation. QJM. 2001;94(12):665–678. doi: 10.1093/qjmed/94.12.665. [PubMed] [CrossRef] [Google Scholar]26. Keating R.J., Gersh B.J., Hodge D.O., Weivoda P.L., Patel P.J., Hammill S.C., Shen W.K., et al. Effect of atrial fibrillation pattern on survival in a community-based cohort. Am. J. Cardiol. 2005;96(10):1420–1424. doi: 10.1016/j.amjcard.2005.07.050. [PubMed] [CrossRef] [Google Scholar]27. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A. Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc. Disord. 2005;5:20. doi: 10.1186/1471-2261-5-20. [PMC free article] [PubMed] [CrossRef] [Google Scholar]28. Tuinenburg A.E., Van Gelder I.C., Van Den Berg M.P., Brügemann J., De Kam P.J., Crijns H.J., et al. Lack of prevention of heart failure by serial electrical cardioversion in patients with persistent atrial fibrillation. Heart. 1999;82(4):486–493. doi: 10.1136/hrt.82.4.486. [PMC free article] [PubMed] [CrossRef] [Google Scholar]29. Brown A.M., Sease K.L., Robey J.L., Shofer F.S., Hollander J.E., et al. The risk for acute coronary syndrome associated with atrial fibrillation among ED patients with chest pain syndromes. Am. J. Emerg. Med. 2007;25(5):523–528. doi: 10.1016/j.ajem.2006.09.015. [PubMed] [CrossRef] [Google Scholar]30. Sankaranarayanan R., et al. Mortality Risk Associated with AF in Myocardial Infarction Patients. J. Atr. Fibrillation. 2012;5(3):138–152. [PMC free article] [PubMed] [Google Scholar]31. Sankaranarayanan R., James M.A., Nuta B., Townsend M., Kesavan S., Burtchaell S., Holloway R., Ewings P., et al. Does atrial fibrillation beget ventricular fibrillation in patients with acute myocardial infarction? Pacing Clin. Electrophysiol. 2008;31(12):1612–1619. doi: 10.1111/j.1540-8159.2008.01234.x. [PubMed] [CrossRef] [Google Scholar]32. Lehto M., Snapinn S., Dickstein K., Swedberg K., Nieminen M.S., et al. OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience. Eur. Heart J. 2005;26(4):350–356. doi: 10.1093/eurheartj/ehi064. [PubMed] [CrossRef] [Google Scholar]33. Roy D., Talajic M., Nattel S., Wyse D.G., Dorian P., Lee K.L., Bourassa M.G., Arnold J.M., Buxton A.E., Camm A.J., Connolly S.J., Dubuc M., Ducharme A., Guerra P.G., Hohnloser S.H., Lambert J., Le Heuzey J.Y., O’Hara G., Pedersen O.D., Rouleau J.L., Singh B.N., Stevenson L.W., Stevenson W.G., Thibault B., Waldo A.L., et al. Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N. Engl. J. Med. 2008;358(25):2667–2677. doi: 10.1056/NEJMoa0708789. [PubMed] [CrossRef] [Google Scholar]34. Caldwell J.C., Contractor H., Petkar S., Ali R., Clarke B., Garratt C.J., Neyses L., Mamas M.A., et al. Atrial fibrillation is under-recognized in chronic heart failure: insights from a heart failure cohort treated with cardiac resynchronization therapy. Europace. 2009;11(10):1295–1300. doi: 10.1093/europace/eup201. [PubMed] [CrossRef] [Google Scholar]35. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Bailey K.R., Abhayaratna W., Seward J.B., Iwasaka T., Tsang T.S., et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: a community-based study over two decades. Eur. Heart J. 2006;27(8):936–941. doi: 10.1093/eurheartj/ehi694. [PubMed] [CrossRef] [Google Scholar]36. Wang T.J., Larson M.G., Levy D., Vasan R.S., Leip E.P., Wolf P.A., D’Agostino R.B., Murabito J.M., Kannel W.B., Benjamin E.J., et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920–2925. doi: 10.1161/01.CIR.0000072767.89944.6E. [PubMed] [CrossRef] [Google Scholar]37. Olsson L.G., Swedberg K., Ducharme A., Granger C.B., Michelson E.L., McMurray J.J., Puu M., Yusuf S., Pfeffer M.A., et al. CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J. Am. Coll. Cardiol. 2006;47(10):1997–2004. doi: 10.1016/j.jacc.2006.01.060. [PubMed] [CrossRef] [Google Scholar]38. Rivero-Ayerza M., Scholte Op Reimer W., Lenzen M., Theuns D.A., Jordaens L., Komajda M., Follath F., Swedberg K., Cleland J.G., et al. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalized heart failure patients: results of the EuroHeart Failure Survey. Eur. Heart J. 2008;29(13):1618–1624. doi: 10.1093/eurheartj/ehn217. [PubMed] [CrossRef] [Google Scholar]39. Dries D.L., Exner D.V., Gersh B.J., Domanski M.J., Waclawiw M.A., Stevenson L.W., et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J. Am. Coll. Cardiol. 1998;32(3):695–703. doi: 10.1016/S0735-1097(98)00297-6. [PubMed] [CrossRef] [Google Scholar]40. Mahoney P., Kimmel S., DeNofrio D., Wahl P., Loh E., et al. Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure. Am. J. Cardiol. 1999;83(11):1544–1547. doi: 10.1016/S0002-9149(99)00144-7. [PubMed] [CrossRef] [Google Scholar]41. Mamas M.A., Caldwell J.C., Chacko S., Garratt C.J., Fath-Ordoubadi F., Neyses L., et al. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur. J. Heart Fail. 2009;11(7):676–683. doi: 10.1093/eurjhf/hfp085. [PubMed] [CrossRef] [Google Scholar]42. Raunsø J., Pedersen O.D., Dominguez H., Hansen M.L., Møller J.E., Kjaergaard J., Hassager C., Torp-Pedersen C., Køber L., et al. EchoCardiography and Heart Outcome Study Investigators. Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease. Eur. J. Heart Fail. 2010;12(7):692–697. doi: 10.1093/eurjhf/hfq052. [PubMed] [CrossRef] [Google Scholar]43. Badheka A.O., Rathod A., Kizilbash M.A., Bhardwaj A., Ali O., Afonso L., Jacob S., et al. Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction. Am. J. Cardiol. 2011;108(9):1283–1288. doi: 10.1016/j.amjcard.2011.06.045. [PubMed] [CrossRef] [Google Scholar]44. Domanski M.J., et al. The epidemiology of atrial fibrillation. Coron. Artery Dis. 1995;6(2):95–100. doi: 10.1097/00019501-199502000-00002. [PubMed] [CrossRef] [Google Scholar]45. Cha Y.M., Redfield M.M., Shen W.K., Gersh B.J., et al. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation. 2004;109(23):2839–2843. doi: 10.1161/01.CIR.0000132470.78896.A8. [PubMed] [CrossRef] [Google Scholar]46. Daoud E.G., Weiss R., Bahu M., Knight B.P., Bogun F., Goyal R., Harvey M., Strickberger S.A., Man K.C., Morady F., et al. Effect of an irregular ventricular rhythm on cardiac output. Am. J. Cardiol. 1996;78(12):1433–1436. doi: 10.1016/S0002-9149(97)89297-1. [PubMed] [CrossRef] [Google Scholar]47. Shinbane J.S., Wood M.A., Jensen D.N., Ellenbogen K.A., Fitzpatrick A.P., Scheinman M.M., et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J. Am. Coll. Cardiol. 1997;29(4):709–715. doi: 10.1016/S0735-1097(96)00592-X. [PubMed] [CrossRef] [Google Scholar]48. Steinberg J.S., Sadaniantz A., Kron J., Krahn A., Denny D.M., Daubert J., Campbell W.B., Havranek E., Murray K., Olshansky B., O’Neill G., Sami M., Schmidt S., Storm R., Zabalgoitia M., Miller J., Chandler M., Nasco E.M., Greene H.L., et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation. 2004;109(16):1973–1980. doi: 10.1161/01.CIR.0000118472.77237.FA. [PubMed] [CrossRef] [Google Scholar]49. Fuster V., Rydén L.E., Cannom D.S., Crijns H.J., Curtis A.B., Ellenbogen K.A., Halperin J.L., Kay G.N., Le Huezey J.Y., Lowe J.E., Olsson S.B., Prystowsky E.N., Tamargo J.L., Wann L.S., et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2011;57(11):e101–e198. doi: 10.1016/j.jacc.2010.09.013. [PubMed] [CrossRef] [Google Scholar]50. Stein K.M., Euler D.E., Mehra R., Seidl K., Slotwiner D.J., Mittal S., Markowitz S.M., Lerman B.B. Jewel AF Worldwide Investigators. Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients? J. Am. Coll. Cardiol. 2002;40(2):335–340. doi: 10.1016/S0735-1097(02)01957-5. [PubMed] [CrossRef] [Google Scholar]51. Grau A.J., Weimar C., Buggle F., Heinrich A., Goertler M., Neumaier S., Glahn J., Brandt T., Hacke W., Diener H.C., et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559–2566. doi: 10.1161/hs1101.098524. [PubMed] [CrossRef] [Google Scholar]52. Kimura K., Minematsu K., Yamaguchi T., et al. Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC) Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with acute ischaemic stroke. J. Neurol. Neurosurg. Psychiatry. 2005;76(5):679–683. doi: 10.1136/jnnp.2004.048827. [PMC free article] [PubMed] [CrossRef] [Google Scholar]53. Jørgensen H.S., Nakayama H., Reith J., Raaschou H.O., Olsen T.S. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke. 1996;27(10):1765–1769. doi: 10.1161/01.STR.27.10.1765. [PubMed] [CrossRef] [Google Scholar]54. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255–1262. [PubMed] [Google Scholar]55. Akins P.T., Feldman H.A., Zoble R.G., Newman D., Spitzer S.G., Diener H.C., Albers G.W. Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials. Stroke. 2007;38(3):874–880. doi: 10.1161/01.STR.0000258004.64840.0b. [PubMed] [CrossRef] [Google Scholar]56. Watson T., Shantsila E., Lip G.Y. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373(9658):155–166. doi: 10.1016/S0140-6736(09)60040-4. [PubMed] [CrossRef] [Google Scholar]57. De Caterina R., Connolly S.J., Pogue J., Chrolavicius S., Budaj A., Morais J., Renda G., Yusuf S. ACTIVE Investigators. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur. Heart J. 2010;31(17):2133–2140. doi: 10.1093/eurheartj/ehq250. [PubMed] [CrossRef] [Google Scholar]58. Nattel S. Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Cardiovasc. Res. 1998;37(3):567–577. doi: 10.1016/S0008-6363(97)00293-9. [PubMed] [CrossRef] [Google Scholar]59. Freemantle N., Lafuente-Lafuente C., Mitchell S., Eckert L., Reynolds M. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace. 2011;13(3):329–345. doi: 10.1093/europace/euq450. [PubMed] [CrossRef] [Google Scholar]60. Gage B.F., Waterman A.D., Shannon W., Boechler M., Rich M.W., Radford M.J., et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–2870. doi: 10.1001/jama.285.22.2864. [PubMed] [CrossRef] [Google Scholar]61. Khumri T.M., Idupulapati M., Rader V.J., Nayyar S., Stoner C.N., Main M.L., et al. Clinical and echocardiographic markers of mortality risk in patients with atrial fibrillation. Am. J. Cardiol. 2007;99(12):1733–1736. doi: 10.1016/j.amjcard.2007.01.055. [PubMed] [CrossRef] [Google Scholar]62. Pisters R., Lane D.A., Nieuwlaat R., de Vos C.B., Crijns H.J., Lip G.Y., et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100. doi: 10.1378/chest.10-0134. [PubMed] [CrossRef] [Google Scholar]63. Gallego P., Roldán V., Torregrosa J.M., Gálvez J., Valdés M., Vicente V., Marín F., Lip G.Y., et al. Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation. Circ Arrhythm Electrophysiol. 2012;5(2):312–318. doi: 10.1161/CIRCEP.111.967000. [PubMed] [CrossRef] [Google Scholar]64. Gallego P., Roldán V., Marín F., Jover E., Manzano-Fernández S., Valdés M., Vicente V., Lip G.Y., et al. Ankle brachial index as an independent predictor of mortality in anticoagulated atrial fibrillation. Eur. J. Clin. Invest. 2012;42(12):1302–1308. doi: 10.1111/eci.12004. [PubMed] [CrossRef] [Google Scholar]65. Friberg L., Rosenqvist M., et al. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace. 2011;13(5):626–633. doi: 10.1093/europace/eur001. [PubMed] [CrossRef] [Google Scholar]66. Roldán V., Marín F., Díaz J., Gallego P., Jover E., Romera M., Manzano-Fernández S., Casas T., Valdés M., Vicente V., Lip G.Y., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation. J. Thromb. Haemost. 2012;10(8):1500–1507. doi: 10.1111/j.1538-7836.2012.04812.x. [PubMed] [CrossRef] [Google Scholar]67. Providencia R., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation: a rebuttal . J Thromb Haemost. 2012;10(11):2413–1507. author reply 2014-5. [PubMed] [Google Scholar]68. Roldán V., Marín F., Muiña B., Torregrosa J.M., Hernández-Romero D., Valdés M., Vicente V., Lip G.Y., et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J. Am. Coll. Cardiol. 2011;57(25):2496–2504. doi: 10.1016/j.jacc.2010.12.033. [PubMed] [CrossRef] [Google Scholar]69. Hermida J., Lopez F.L., Montes R., Matsushita K., Astor B.C., Alonso A., et al. Usefulness of high-sensitivity C-reactive protein to predict mortality in patients with atrial fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study). Am. J. Cardiol. 2012;109(1):95–99. doi: 10.1016/j.amjcard.2011.08.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]70. Go A.S., Fang M.C., Udaltsova N., Chang Y., Pomernacki N.K., Borowsky L., Singer D.E., et al. ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119(10):1363–1369. doi: 10.1161/CIRCULATIONAHA.108.816082. [PMC free article] [PubMed] [CrossRef] [Google Scholar]71. Potpara T.S., Vasiljevic Z.M., Vujisic-Tesic B.D., Marinkovic J.M., Polovina M.M., Stepanovic J.M., Stankovic G.R., Ostojic M.C., Lip G.Y., et al. Mitral annular calcification predicts cardiovascular morbidity and mortality in middle-aged patients with atrial fibrillation: the Belgrade Atrial Fibrillation Study. Chest. 2011;140(4):902–910. doi: 10.1378/chest.10-2963. [PubMed] [CrossRef] [Google Scholar]72. Echt D.S., Liebson P.R., Mitchell L.B., Peters R.W., Obias-Manno D., Barker A.H., Arensberg D., Baker A., Friedman L., Greene H.L., et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 1991;324(12):781–788. doi: 10.1056/NEJM199103213241201. [PubMed] [CrossRef] [Google Scholar]73. Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation. 1990;82(4):1106–1116. doi: 10.1161/01.CIR.82.4.1106. [PubMed] [CrossRef] [Google Scholar]74. Carlsson J., Miketic S., Windeler J., Cuneo A., Haun S., Micus S., Walter S., Tebbe U., et al. STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J. Am. Coll. Cardiol. 2003;41(10):1690–1696. doi: 10.1016/S0735-1097(03)00332-2. [PubMed] [CrossRef] [Google Scholar]75. Hohnloser S.H., Kuck K.H., Lilienthal J., et al. Rhythm or rate control in atrial fibrillation–Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356(9244):1789–1794. doi: 10.1016/S0140-6736(00)03230-X. [PubMed] [CrossRef] [Google Scholar]76. Van Gelder I.C., Hagens V.E., Bosker H.A., Kingma J.H., Kamp O., Kingma T., Said S.A., Darmanata J.I., Timmermans A.J., Tijssen J.G., Crijns H.J., et al. Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N. Engl. J. Med. 2002;347(23):1834–1840. doi: 10.1056/NEJMoa021375. [PubMed] [CrossRef] [Google Scholar]77. Opolski G., Torbicki A., Kosior D.A., Szulc M., Wozakowska-Kaplon B., Kolodziej P., Achremczyk P., et al. Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest. 2004;126(2):476–486. doi: 10.1378/chest.126.2.476. [PubMed] [CrossRef] [Google Scholar]78. Ogawa S., Yamashita T., Yamazaki T., Aizawa Y., Atarashi H., Inoue H., Ohe T., Ohtsu H., Okumura K., Katoh T., Kamakura S., Kumagai K., Kurachi Y., Kodama I., Koretsune Y., Saikawa T., Sakurai M., Sugi K., Tabuchi T., Nakaya H., Nakayama T., Hirai M., Fukatani M., Mitamura H., et al. J-RHYTHM Investigators. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ. J. 2009;73(2):242–248. doi: 10.1253/circj.CJ-08-0608. [PubMed] [CrossRef] [Google Scholar]79. Testa L., Biondi-Zoccai G.G., Dello Russo A., Bellocci F., Andreotti F., Crea F., et al. Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis. Eur. Heart J. 2005;26(19):2000–2006. doi: 10.1093/eurheartj/ehi306. [PubMed] [CrossRef] [Google Scholar]80. Corley S.D., Epstein A.E., DiMarco J.P., Domanski M.J., Geller N., Greene H.L., Josephson R.A., Kellen J.C., Klein R.C., Krahn A.D., Mickel M., Mitchell L.B., Nelson J.D., Rosenberg Y., Schron E., Shemanski L., Waldo A.L., Wyse D.G., et al. AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–1513. doi: 10.1161/01.CIR.0000121736.16643.11. [PubMed] [CrossRef] [Google Scholar]81. Pedersen O.D., Brendorp B., Elming H., Pehrson S., Køber L., Torp-Pedersen C., et al. Does conversion and prevention of atrial fibrillation enhance survival in patients with left ventricular dysfunction? Evidence from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide/(DIAMOND) study. Card. Electrophysiol. Rev. 2003;7(3):220–224. doi: 10.1023/B:CEPR.0000012386.82055.81. [PubMed] [CrossRef] [Google Scholar]82. Ionescu-Ittu R., Abrahamowicz M., Jackevicius C.A., Essebag V., Eisenberg M.J., Wynant W., Richard H., Pilote L., et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch. Intern. Med. 2012;172(13):997–1004. doi: 10.1001/archinternmed.2012.2266. [PubMed] [CrossRef] [Google Scholar]83. Bardy G.H., Lee K.L., Mark D.B., Poole J.E., Packer D.L., Boineau R., Domanski M., Troutman C., Anderson J., Johnson G., McNulty S.E., Clapp-Channing N., Davidson-Ray L.D., Fraulo E.S., Fishbein D.P., Luceri R.M., Ip J.H., et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 2005;352(3):225–237. doi: 10.1056/NEJMoa043399. [PubMed] [CrossRef] [Google Scholar]84. Julian D.G., Camm A.J., Frangin G., Janse M.J., Munoz A., Schwartz P.J., Simon P., et al. European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet. 1997;349(9053):667–674. doi: 10.1016/S0140-6736(96)09145-3. [PubMed] [CrossRef] [Google Scholar]85. Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J. Am. Coll. Cardiol. 1999;34(5):1552–1559. doi: 10.1016/S0735-1097(99)00376-9. [PubMed] [CrossRef] [Google Scholar]86. Singh S.N., Fletcher R.D., Fisher S.G., Singh B.N., Lewis H.D., Deedwania P.C., Massie B.M., Colling C., Lazzeri D., et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N. Engl. J. Med. 1995;333(2):77–82. doi: 10.1056/NEJM199507133330201. [PubMed] [CrossRef] [Google Scholar]87. Cairns J.A., Connolly S.J., Roberts R., Gent M., et al. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet. 1997;349(9053):675–682. doi: 10.1016/S0140-6736(96)08171-8. [PubMed] [CrossRef] [Google Scholar]88. Piccini J.P., Hasselblad V., Peterson E.D., Washam J.B., Califf R.M., Kong D.F., et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J. Am. Coll. Cardiol. 2009;54(12):1089–1095. doi: 10.1016/j.jacc.2009.04.085. [PubMed] [CrossRef] [Google Scholar]89. Duray G.Z., Torp-Pedersen C., Connolly S.J., Hohnloser S.H., et al. Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. J. Cardiovasc. Electrophysiol. 2011;22(7):770–776. doi: 10.1111/j.1540-8167.2010.02006.x. [PubMed] [CrossRef] [Google Scholar]90. Køber L., Torp-Pedersen C., McMurray J.J., Gøtzsche O., Lévy S., Crijns H., Amlie J., Carlsen J., et al. Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 2008;358(25):2678–2687. doi: 10.1056/NEJMoa0800456. [PubMed] [CrossRef] [Google Scholar]91. Connolly S.J., Camm A.J., Halperin J.L., Joyner C., Alings M., Amerena J., Atar D., Avezum Á., Blomström P., Borggrefe M., Budaj A., Chen S.A., Ching C.K., Commerford P., Dans A., Davy J.M., Delacrétaz E., Di Pasquale G., Diaz R., Dorian P., Flaker G., Golitsyn S., Gonzalez-Hermosillo A., Granger C.B., Heidbüchel H., Kautzner J., Kim J.S., Lanas F., Lewis B.S., Merino J.L., Morillo C., Murin J., Narasimhan C., Paolasso E., Parkhomenko A., Peters N.S., Sim K.H., Stiles M.K., Tanomsup S., Toivonen L., Tomcsányi J., Torp-Pedersen C., Tse H.F., Vardas P., Vinereanu D., Xavier D., Zhu J., Zhu J.R., Baret-Cormel L., Weinling E., Staiger C., Yusuf S., Chrolavicius S., Afzal R., Hohnloser S.H. PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med. 2011;365(24):2268–2276. doi: 10.1056/NEJMoa1109867. [PubMed] [CrossRef] [Google Scholar]92. Hylek E.M., Go A.S., Chang Y., Jensvold N.G., Henault L.E., Selby J.V., Singer D.E. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med. 2003;349(11):1019–1026. doi: 10.1056/NEJMoa022913. [PubMed] [CrossRef] [Google Scholar]93. Hart R.G., Pearce L.A., Aguilar M.I. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann. Intern. Med. 2007;147(8):590–592. doi: 10.7326/0003-4819-147-8-200710160-00018. [PubMed] [CrossRef] [Google Scholar]94. Gallagher A.M., Setakis E., Plumb J.M., Clemens A., van Staa T.P., et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb. Haemost. 2011;106(5):968–977. doi: 10.1160/Th21-05-0353. [PubMed] [CrossRef] [Google Scholar]95. Fang M.C., Go A.S., Chang Y., Borowsky L.H., Pomernacki N.K., Udaltsova N., Singer D.E., et al. Thirty-day mortality after ischemic stroke and intracranial hemorrhage in patients with atrial fibrillation on and off anticoagulants. Stroke. 2012;43(7):1795–1799. doi: 10.1161/STROKEAHA.111.630731. [PMC free article] [PubMed] [CrossRef] [Google Scholar]96. Go A.S., Hylek E.M., Borowsky L.H., Phillips K.A., Selby J.V., Singer D.E., et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann. Intern. Med. 1999;131(12):927–934. doi: 10.7326/0003-4819-131-12-199912210-00004. [PubMed] [CrossRef] [Google Scholar]97. Devereaux P.J., Anderson D.R., Gardner M.J., Putnam W., Flowerdew G.J., Brownell B.F., Nagpal S., Cox J.L., et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ. 2001;323(7323):1218–1222. doi: 10.1136/bmj.323.7323.1218. [PMC free article] [PubMed] [CrossRef] [Google Scholar]98. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., Pogue J., Reilly P.A., Themeles E., Varrone J., Wang S., Alings M., Xavier D., Zhu J., Diaz R., Lewis B.S., Darius H., Diener H.C., Joyner C.D., Wallentin L., et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009;361(12):1139–1151. doi: 10.1056/NEJMoa0905561. [PubMed] [CrossRef] [Google Scholar]99. Uchino K., Hernandez A.V., et al. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch. Intern. Med. 2012;172(5):397–402. doi: 10.1001/archinternmed.2011.1666. [PubMed] [CrossRef] [Google Scholar]100. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., Breithardt G., Halperin J.L., Hankey G.J., Piccini J.P., Becker R.C., Nessel C.C., Paolini J.F., Berkowitz S.D., Fox K.A., Califf R.M., et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011;365(10):883–891. doi: 10.1056/NEJMoa1009638. [PubMed] [CrossRef] [Google Scholar]101. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M., Al-Khalidi H.R., Ansell J., Atar D., Avezum A., Bahit M.C., Diaz R., Easton J.D., Ezekowitz J.A., Flaker G., Garcia D., Geraldes M., Gersh B.J., Golitsyn S., Goto S., Hermosillo A.G., Hohnloser S.H., Horowitz J., Mohan P., Jansky P., Lewis B.S., Lopez-Sendon J.L., Pais P., Parkhomenko A., Verheugt F.W., Zhu J., Wallentin L., et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011;365(11):981–992. doi: 10.1056/NEJMoa1107039. [PubMed] [CrossRef] [Google Scholar]

How does Chronic Atrial Fibrillation Influence Mortality in the Modern Treatment Era?

Curr Cardiol Rev. 2015 Aug; 11(3): 190–198.

Rajiv Sankaranarayanan

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Graeme Kirkwood

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Rajaverma Visweswariah

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

David J. Fox

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

^* Address correspondence to this author at the Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK; Tel: 00447525826672; Fax: 00441612751234; E-mail [email protected]

Received 2014 Apr 23; Revised 2014 Aug 22; Accepted 2014 Aug 27.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been cited by other articles in PMC.

Abstract

Atrial fibrillation (AF) continues to impose a significant burden upon healthcare resources. A sustained increase in the ageing population and better survival from conditions such as ischaemic heart disease have ensured that both the incidence and prevalence of AF continue to increase significantly. AF can lead to complications such as embolism and heart failure and these acting in concert with its associated co-morbidities portend increased mortality risk. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of various therapeutic strategies (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures). Despite several treatment advances including newer anti-arrhythmic drugs and developments in catheter ablation, anti-coagulation remains the only effective means to reduce the mortality due to AF. Warfarin has been used as the oral anticoagulant in the treatment of AF for many years but suffers from disadvantages such as unpredictable INR levels, bleeding risks and need for haematological monitoring. This has therefore spurred a renewed interest in research and clinical studies directed towards developing safer and more efficacious anti-coagulants. We shall review in this article the epidemiological features of AF-related mortality from several studies as well as the cardiovascular and non-cardiac mortality mechanisms. We shall also elucidate why a rhythm control strategy has appeared to be counter-productive and attempt to predict the likely future impact of novel anti-coagulants upon mortality reduction in AF.

Keywords: Atrial fibrillation, arrhythmia, mortality, anti-arrhythmic drugs.

INTRODUCTION

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. 2.2 million people in America and 4.5 million people in Europe are affected by either paroxysmal or persistent AF [1]. It is usually associated with cardiovascular co-morbidities such as hypertension, coronary artery disease, valvular heart disease and heart failure [2]. The presence of AF has been shown to independently increase the risk of death [3-7] and the mortality risk is highest during the first year after AF manifests [5-8]. The incidence of death due to AF has been shown to vary from 1.6-4.2% per annum in various controlled trials [9, 10]. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of the various therapeutic strategies for AF (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures).

EPIDEMIOLOGY

Large population studies both in North America and Europe have demonstrated incontrovertibly the impact of AFupon mortality. The landmark Framingham Heart Study analysed a cohort of 621 individuals who developed AF (out of a study population of over 5000) during 40 years of follow-up; the excess in all-cause mortality rates attributable to AF was 50% for men, and 90% for women, even when controlled for the presence of a wide range of cardiovascular co-morbidities [5]. This effect on mortality became apparent early, with 15% of deaths occurring within 30 days of diagnosis. Amongst the group of patients aged between 55-74 years, the 10 year mortality was 61.5% in men with AF compared to 30% in men without AF. Amongst women in a similar age group, the 10 year mortality was 57.6% in the AF group versus 20.9% in women without AF. Similar findings have been found from many other cohorts. The Renfrew-Paisley study followed-up 100 patients with AF for 20 years out of a cohort of over 15,000 men and women aged between 45-64 years in two Scottish towns and showed that AF increased all-cause mortality by 50% amongst men and 120% amongst women [3]. Ruigomez et al. followed a cohort of 1035 chronic AF patients in the UK for a mean duration of 2 years and reported a trebling of all cause mortality after matching for confounding factors [7]. The Olmsted County study was a community based study of 4618 patients with AF, followed-up for 5.3±5 years and demonstrated that relative to the general age and sex-matched population, AF significantly increased the mortality risk especially during the first four months following diagnosis (HR 9.62; 95% CI 8.93 to 10.32) and also thereafter (HR 1.66; 95% CI 1.59 to 1.73) [8]. The Manitoba study followed-up nearly 4000 young Canadian male air crew for 44 years and demonstrated that AF increased total mortality by 31% [11].

As might be expected, the annual mortality rates associated with AF vary substantially depending on the population demographics. Based on medical insurance claim data, values range from 2.6% in asymptomatic untreated individuals, to 24.2% amongst an elderly population with high rates of co-morbidities [12, 13]. There do not appear to have been significant reductions in AF-associated mortality between the years 1993 – 2007; this population-based data is supported by recent trials of novel anticoagulants and anti-arrhythmic therapies, which report annual mortality rates between 1.9 and 6.6% even with optimal contemporary treatment [14-16].

It is unambiguous from the epidemiological data that, although the presence of AF has a significant and dramatic effect to increase the mortality rate within a population, the effect on an individual is less clear-cut and is highly dependent on demographic risk factors and the presence of co-morbidities as discussed below.

AGE

Age is a major risk factor for developing AF, and older patients are more likely to have co-morbidities that might impact on survival. Nevertheless, patient age is the most powerful and consistent independent factor in determining the AF-associated mortality risk. Although the Framingham study found that all age groups demonstrated an excess mortality attributable to AF, the absolute risk increase seen in those aged over 75 years was approximately 3 times that seen in those under 65 years [5]. This was confirmed in the Paisley/Renfrew study, where the excess mortality was increased 3.5 times in the age group 60–64 years compared to 45–49 years [3]. Essentially, amongst all age groups, individuals with AF are more likely to die early than those without, and older patients with AF are substantially more at risk than younger patients. The annual mortality in 2007 amongst a large cohort of AF patients who were also Medicare beneficiaries aged >65 years was as high as 25% [13].

SEX

In developed societies, healthy females possess a survival advantage over males [17]. The mortality associated with AF is slightly but significantly higher in females than in males, such that this survival advantage is lost and the life expectancy of a woman with AF is similar to that of an age-matched man [5]. The Renfrew-Paisley study showed AF portends a higher all-cause and cardiovascular mortality amongst women [3]. There is also evidence that stroke-related mortality in AF is higher in women [18].

RACE /ETHNIC DIFFERENCES

During AF-related hospitalisations, in-hospital mortality has been shown to be highest amongst African-Americans in comparison to other ethnic groups [19].

LONE AF VS. CO-MORBIDITIES

‘Lone AF’ is defined as AF in the absence of structural heart disease or additional cardiovascular co-morbidities such as diabetes or hypertension. In reality, lone AF is an uncommon entity; 70% of patients with AF have additional risk factors at the time of diagnosis and of the remaining 30% many will have unrecognised co-morbidities such as sleep apnoea or obesity [20]. With a 15 year mortality of only 8%, survival amongst patients with lone AF has been shown to be not significantly different to that of age and sex-matched population control data [21-23]; this is in keeping with subgroup analysis from the Paisley/ Renfrew study which also did not identify a significant mortality excess attributable to lone AF [3].

In contrast, multivariate analysis from the afore-mentioned population studies indicates that cardiovascular and non-cardiovascular co-morbidities impact dramatically upon survival. Factors such as smoking, lung disease, hypertension, diabetes and obesity act to increase mortality by around 20 – 60% each, and the effects are additive with additional risk factors. These findings have led to the development of clinical scoring systems to aid therapeutic decisions.

TEMPORAL PROFILE OF AF

There is convincing evidence that AF burden may impact upon stroke rates [24], however the stroke risk due to paroxysmal AF is comparable to that of chronic AF [25]. In contrast, permanent AF is associated with higher mortality risk whereas paroxysmal AF has been shown to portend similar mortality risk as that of age and gender-matched general population [26, 27]. However, analysis of the mortality effect due to persistent AF in comparison to paroxysmal AF, has shown contrasting results [26, 28].

ISCHAEMIC HEART DISEASE (IHD) AND HEART FAILURE

AF and coronary artery disease share risk factors, but there is no clear evidence linking AF with increased risk of acute coronary syndromes [29]. Co-existing IHD has been shown to increase all-cause mortality due to AF three fold with up to 21% of deaths shown to be related to IHD [7]. Nevertheless, there is a clear association between AF and poor prognosis in myocardial infarction; multiple studies have shown that the development of AF following myocardial infarction is associated with a substantial increase in in-hospital as well as post-discharge mortality (reviewed in [30]). Many studies (including large-scale RCTs such as the OPTIMAAL trial, GUSTO-3 trial and TRACE study) have shown that chronic AF independently increases post-MI mortality (reviewed in [30]). A study by one of the authors of this paper (Sankaranarayanan et al. [31]) showed that chronic AF could increase post-MI mortality risk by increasing the risk of ventricular fibrillation in this setting [31]. The OPTIMAAL trial noted a significant increase in 30 day mortality only where new AF complicated acute MI, but that both acute and pre-existing AF were associated with reduced survival over the subsequent 3 years [32].

AF in congestive heart failure (CHF) has recently attracted substantial interest; AF can either exacerbate or complicate CHF [33], and in the modern era of device therapy it is becoming apparent that AF in CHF is under-recognised [34]. 24% out of 3288 individuals with AF in the Olmsted County study developed CHF over a mean follow-up of 6.1±5.2 years, leading to a significant increase in mortality (HR 3.4) [35]. The Framingham study illustrated the close relationship between these two pathologies showing that amongst 1470 participants who developed either or both these conditions, 382 individuals had both (36% of these developed AF first, 41% CHF first and 21% were diagnosed with both on the same day) [36]. The incidence of CHF amongst AF patients was 33 per 1000 person years, with 4 out of 10 AF subjects developing heart failure at some point during their lifetime and also significantly increasing mortality (men HR 1.6, women HR 2.7). Further analysis also demonstrated a significant mortality impact where AF complicated CHF, (incidence 54 per 1000 person years) with relative increases of 60% and 170% in men and women respectively compared to individuals with CHF in sinus rhythm. The Manitoba follow-up study showed that AF increases the risk of development of CHF by three-fold and increased cardiac mortality by 37% [11].

However, therapeutic CHF studies demonstrated conflicting results as to whether the presence of AF conferred an independent impact on mortality, or simply reflected disease state at baseline [37-40]. A recent meta-analysis of 16 studies including 53,969 patients appears to confirm that AF increases total mortality in CHF patients by around 40%, with an independent effect remaining after controlling for demographics and disease severity irrespective of impaired or preserved LV function [41]. Nevertheless, it remains controversial whether it is the arrhythmia or the co-morbidities that impacts upon mortality, with a recent analysis [42] suggesting that this effect is only seen where heart failure results from ischaemic heart disease. A post hoc analysis of the AFFIRM trial sub-set of patients with CHF and preserved ejection fraction showed a lower all-cause and cardiovascular mortality in comparison to patients with impaired systolic function [43].

In view of the strong association of AF with co-morbidities, several studies have attempted to analyse if the effects of AF upon mortality are truly independent or simply a risk marker for the cumulative pre-terminal effects of co-morbidities. The Olmsted County study for instance illustrated the very high 4 month and 1 year mortality following AF diagnosis, however there were no changes in early (<4 months) versus late mortality (after 4 months) in the whole cohort or within the sub-group of patients without pre-morbid cardiovascular disease [8]. These results and others showing that lone AF does not increase mortality, suggest that AF could simply represent a risk marker for mortality in a very sick population with multiple co-morbidities [3, 6, 8].

1. MECHANISMS OF AF-RELATED MORTALITY

Cardiac

Several large population-based studies have shown that AF independently increases cardiac mortality [3, 5, 11]. Increased cardiovascular mortality risk due to AF varies between 2 to 12 times [44]. The cardiac causes include heart failure, arrhythmia and possibly coronary heart disease.

AF has an intricate relationship with CHF whereby one can precipitate the other [45]. AF leads to a loss of atrial systole (which usually contributes up to 30% of pre-load in sinus rhythm). In addition to this, the loss of atrio-ventricular synchrony and irregular, uncontrolled ventricular rates contribute to development of CHF (“tachycardia-induced cardiomyopathy”) [46-48]. Uncontrolled ventricular rates during AF can also worsen mitral regurgitation and cause rate-related left bundle branch block, thereby reducing cardiac output [49].

AF can lead to arrhythmic sudden death by potentiating VT or VF in patients with ICDs [50], pre-excitation syndromes [49] and in the acute MI setting [31].

AF can also impair coronary perfusion and increase myocardial oxygen demand especially due to uncontrolled ventricular rates and this could worsen coronary ischaemia and thus increase mortality especially in the subset of patients with pre-existing ischaemic heart disease [48-50].

2. Vascular

AF contributes to 15-25% of all strokes and these contribute to a significant proportion of AF-related mortality [51, 52]. AF-related strokes tend to be associated with higher mortality, and more severe disability [52, 53]. The Olmsted County study followed up 4117 individuals with AF and reported a 11% incidence of stroke over a mean follow-up period of 5.5±5 years, with AF–related stroke significantly increasing the mortality hazard ratio to 3.03 for men and 3.8 for women in comparison to the general population [18]. The Manitoba follow-up study showed that AF increased cardiovascular mortality including fatal stroke by 41% [11]. Even amongst anti-coagulated patients with therapeutic INR, stroke risk due to AF can be up to 3% in high-risk individuals such as those with prior stroke [54, 55]. Un-coordinated atrial contraction leads to stasis of blood in the left atrium [56]. In addition to this, thrombogenesis is also perpetuated by haematological abnormalities such as platelet activation, inflammation and structural factors such as atrial dilatation, loss of endothelium and progressive fibrosis [56]. The left atrial appendage is the site responsible for the majority of thrombi in non-valvular AF [56]. However, it has been demonstrated that not all thrombo-embolic events necessarily predict mortality risk. For instance, the ACTIVE-W trial showed that only disabling strokes (both ischaemic and haemorrhagic with Rankin score ≥3) increase mortality risk whereas transient ischaemic attacks do not [57]. Major bleeding secondary to anti-coagulation can also contribute to mortality [57].

3. Non-cardiovascular Deaths

Most therapeutic strategies for AF such as anti-arrhythmic drugs, anti-thrombotics and catheter ablation can increase mortality risk in AF as a side-effect or serious adverse event. Anti-arrhythmic drugs can lead to potentially lethal pro-arrhythmic effects (such as torsade de pointes) but also cause multi-systemic side-effects and thus contribute to non-cardiovascular deaths [10, 58, 59]. A rhythm control strategy has also been shown to unmask non-cardiovascular co-morbidities such as malignancies or lung pathology, thus contributing to mortality burden (covered in greater detail in section on AADs) [10, 48]. Bleeding risk is inextricably linked to use of anti-thrombotics and can be fatal. Severe bleeding events (such as fatal events, drop in haemoglobin of at least 5 g/decilitre), need for inotropic agents, loss of vision due to intra-ocular bleeding, surgical intervention due to bleeding, symptomatic intra-cranial haemorrhage, need for transfusion of at least 4 units of blood) treble the mortality risk (HR. 3.35; 95% CI, 2.12-5.27) whilst non-severe major bleeding or minor bleeding events do not increase mortality.

RISK PREDICTION FOR AF-RELATED MORTALITY

In view of the significant mortality risk due to AF and the associated co-morbidities, several useful risk-predictors have been identified. The CHADS₂ Score (1 point each for Congestive Heart Failure, Hypertension, Age≥75 years, Diabetes Mellitus and 2 points for Stroke/TIA) was introduced over a decade back as a scoring system to assess thrombo-embolic risk due to AF [60] but can also predict mortality risk. Khumri et al. showed in a study that patients with CHADS₂ score of ≥5 have a 50 fold higher mortality risk in comparison to patients with a score of 0 [61]. Similarly, while the HAS-BLED score has been mainly used in clinical practice to predict risk of major haemorrhagic episodes due to anti-coagulation [62], this risk score has also been shown to predict adverse cardiovascular events as well as all-cause mortality, thus illustrating that thrombogenesis and haemorrhage are inextricably linked by sharing many common risk predictors [63]. Whilst the CHA₂DS₂Vasc score has been recommended in the latest guidelines to supersede CHADS₂ as a better risk predictor for thrombo-embolic risk, its role as a risk predictor for mortality remains to be established.

Abnormal ankle brachial index (ratio of ankle and brachial systolic blood pressure) has been shown to independently predict all-cause mortality after adjusting for CHADS2 score and also predict major haemorrhagic episodes irrespective of the HAS-BLED score [64]. Cardiovascular related hospitalisation in AF patients also significantly predicts risk of death (HR 2.69; 95% CI 1.96-3.68) and it has been suggested that this end-point could be used as a surrogate for mortality in trials [65].

Clinical investigations also help to identify patients at increased risk of AF-related averse events. Serum bio-markers such as interleukin-6, high sensitivity troponin T and von Willebrand factor have been shown to predict all-cause mortality independent of CHADS2 score in anti-coagulated AF patients, possibly reflecting coronary micro-vascular dysfunction, global endothelial dysfunction or athero-thrombosis [66-68]. High sensitivity CRP has also been shown to predict all-cause and cardiovascular mortality amongst AF patients [69]. Patients with renal failure (eGFR <45 ml/min and proteinuria) have been shown to have increased risk of AF-related thrombo-embolism, bleeding and mortality [70]. Echocardiographic markers such as mitral annular calcification, presence of spontaneous left atrial contrast, severe LV impairment and greater than moderate mitral regurgitation also help to predict increased mortality risk amongst chronic AF patients [61, 71].

TREATMENTS

Anti-arrhythmic Drugs (AADs)

Several AADs have been shown to cause pro-arrhythmic side-effects and thus increased mortality in patients [58]. The class I agent flecainide gained particular attention following the CAST trial [72] where increased mortality was observed in patients with history of myocardial infarction. These results have been extrapolated to extend its contraindication to patients with coronary artery disease, heart failure or left ventricular hypertrophy. Coplen, in a meta-analysis published in 1990, showed that treatment with quinidine was more effective than no anti-arrhythmic therapy in suppressing recurrences of atrial fibrillation but appeared to be associated with increased total mortality [73]. Class III medications such as amiodarone and sotalol, have also received similar attention, and are also well known for their risk of QT prolongation and Torsades de Pointes.

Indeed all AADs have the potential to have serious, pro-arrhythmic side effects [58]. This has implications when determining the optimal treatment strategy for atrial fibrillation (AF): the restoration and maintenance of sinus rhythm (rhythm control strategy) or control of heart rate alone (rate control strategy). Several studies have sought to answer this question, including the Strategies of Treatment of Atrial Fibrillation (STAF) [74], Pharmacological Intervention in Atrial Fibrillation (PIAF) [75], Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) [10], Rate Control vs. Electrical Cardioversion (RACE) [76], the HOT CAFÉ [77] and J-RHYTHM Study [78]. None of these studies has shown any significant difference in all-cause or cardiovascular mortality and stroke outcome between rate and rhythm control and in fact a meta-analysis of five major trials showed a trend towards reduced risk of death (rate vs. rhythm control; OR 0.87, 0.74-1.02- P=0.09) [79]. This has generally led to the adoption of rate control strategy as the pragmatic approach especially in the elderly or in presence of significant co-morbidities.

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) in particular showed a non-significant trend toward increased all-cause mortality in the rhythm control group (hazard ratio 1.14; 95% CI, 1-1.32) [10]. A retrospective analysis of the cause-specific mortality in the AFFIRM trial showed that the incidence of cardiac (including arrhythmic, heart failure and MI deaths) and vascular (including ischaemic and haemorrhagic strokes) deaths was not significantly different between the rhythm control and rate-control groups [48]. Thus the increased all-cause mortality in the rhythm-control group could be entirely accounted for by the significant difference between the incidences of non-cardiovascular deaths (47.5% in rhythm control group versus 36.5% in rate-control group; p=0.0008). These non-cardiovascular deaths were mainly due to malignancies and pneumonia. This was attributed to earlier discontinuation of warfarin and higher incidence of stroke rather than risk of the anti-arrhythmic itself which highlights the importance of anticoagulation in atrial fibrillation. Even in patients with heart failure (LVF<35%) complicated by AF, the AF-CHF trial did not demonstrate that rhythm control could lead to mortality benefit [33]. However, there has been some evidence demonstrating the benefits of rhythm control particularly in the longer term. For instance, a retrospective, “on-treatment analysis” of the AFFIRM study that analysed presence of sinus rhythm and use of anti-arrhythmic drugs as separate variables, showed a significant reduction in death due to presence of sinus rhythm [80]. Thus the mortality increase of 49% due to anti-arrhythmic drugs could have overshadowed the 53% mortality reduction due to maintenance of sinus rhythm [48]. The survival benefits of sinus rhythm were similar to that seen in the DIAMOND AF (dofetilide versus placebo in AF patients with LV dysfunction) study which did not show an all-cause mortality benefit; however, restoration and maintenance of sinus rhythm significantly reduced mortality (risk ratio 0.44; 95% CI 0.30-0.64) and risk of hospitalisation [81]. In a population-based study of rate versus rhythm control strategies among 26, 130 AF patients, showed that the rhythm control group demonstrated a small increase in mortality within six months of treatment initiation which then became similar to mortality in the rate-control group until year 4. In the longer term however (after year 5), the mortality was lower in the rhythm control group in comparison to that in the rate-control group (HR 0.89; 95% CI 0.81-0.96 after 5 years and HR 0.77; 95% CI 0.62-0.95 after 8 years) [82]. From the above studies, it is likely that the pro-arrhythmic effects and multi-systemic side-effects of existing AADs dilute and even offset the survival advantage provided by maintenance of sinus rhythm.

The most commonly used AAD for rhythm control in all these trials was amiodarone, which was shown in the studies to have a low pro-arrhythmic potential, with its adverse side effects being mainly extra-cardiac [59]. Amiodarone has been demonstrated to be the most efficacious drug in maintaining sinus rhythm [59, 79]. Some studies have found it to be associated with an increased risk of non-cardiac mortality (particularly cancer-related and pulmonary) [83-85] whilst this was not observed in other studies [86, 87]. Recently Freemantle et al. included thirty nine randomised controlled trials in a mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide and propafenone used for the management of AF and reported (from eighteen trials including about 10,000 patients) that sotalol in particular was associated with increased mortality whereas amiodarone (but not dronedarone) showed a trend towards increased all-cause mortality [59]. A meta-analysis by Piccini et al. also demonstrated an insignificant trend towards increased mortality due to amiodarone [88].

More recently, there has been the arrival of dronedarone, an AAD developed to have fewer side effects and improved safety profile compared to amiodarone [88]. The EURIDIS and ADONIS trials showed dronedarone was significantly more effective than placebo in maintaining sinus rhythm, and in reducing ventricular rate during recurrence of arrhythmia, with post hoc analysis also suggesting a 44% reduction in cardiovascular hospitalisation or death at 12 months [89]. Although dronedarone is less efficacious than amiodarone [88], a subsequent trial (ATHENA) showed that dronedarone reduces the composite endpoint of cardiovascular hospitalisation or death by 24% [14]. However, subsequent studies have shown that dronedarone can lead to increased early mortality in certain sub-sets of patients. For instance, in the ANDROMEDA trial (Anti-arrhythmic trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease), dronedarone (in comparison with placebo) led to a doubling of mortality (95%CI, 1.07-4.25) due to worsening heart failure after a median follow-up of only 2 months [90] Dronedarone also led to increased cardiovascular deaths (hazard ratio 2.11; 95% CI, 1-4.49), arrhythmic deaths (hazard ratio 3.26; 95% CI, 1.06-10) in addition to increased incidence of stroke and heart failure hospitalisations when used in patients with high-risk permanent AF (PALLAS) [91].

ANTI-COAGULATION

Effective anticoagulation is the most effective method of reducing mortality in AF patients [92]. In the absence of anti-coagulation, AF patients who develop a stroke have a 1 month mortality of nearly 25% [92]. In a meta-analysis of 29 trials of anti-thrombotic therapy for AF, compared to control, adjusted-dose warfarin reduced significantly stroke risk by 64% and all-cause mortality by 26%. Aspirin in contrast showed a non-significant 19% reduction in stroke risk and did not reduce mortality significantly [93]. In addition to anti-coagulation with warfarin, it is also important to closely monitor the therapeutic range of INR closely to both prevent thrombo-embolic complications as well as avoid major bleeding complications. Patients who spend at least 70% of the time with INR within therapeutic range demonstrate significantly lower mortality compared to patients whose INR is therapeutic <70% of the time [94]. Analysis of 30-day mortality due to ischaemic stoke whilst on warfarin, has shown that warfarin significantly reduces 30 day mortality if INR is between 2-3 (OR 0.38; 955 CI, 0.2-0.7) but patients with INR>3 demonstrate increased odds of mortality due to intra-cranial haemorrhage 2.66 fold (95% CI, 1.21-5.86) [95].

Despite the obvious benefits of warfarin, the ATRIA study showed that it was being under-prescribed, particularly in those AF patients below 55 years and above 85 years, presumably due to physicians’ concerns regarding bleeding risk [96]. Interestingly, in contrast to this predominant view held by most physicians, patients are willing to accept the higher risk of bleeding associated with anti-coagulants in order to avoid disabling strokes which some even view as worse than death [97]. The search for more efficacious and potentially safer anti-thrombotics has heralded the era of novel anti-coagulants, as detailed below.

In the RELY study [98], dabigatran, a novel oral direct thrombin inhibitor, given at a dose of 110 mg to AF patients, was associated with rates of stroke and systemic embolism similar to warfarin, but with lower rates of major haemorrhage, whilst at doses of 150 mg, it was associated with lower rates of stroke and systemic embolism compared to warfarin, and similar rates of major haemorrhage. There was a trend towards reduction in all-cause mortality with the 150 mg dose (p=0.051) and a significant reduction in vascular mortality (p=0.04). The rates of death from any cause were 4.13% per year with warfarin, compared with 3.75% per year with 110 mg dabigatran (P=0.13), and 3.64% with 150 mg dabigatran (P=0.051). A meta-analysis of seven dabigatran studies (including 30514 patients) also showed a 11% reduction in all-cause mortality in comparison to warfarin [99].

Following this there has been the addition of the oral factor Xa inhibitors: rivaroxaban, assessed by the ROCKET-AF trial [100]; and apixaban, analysed by the AVERROES [16] and ARISTOTLE [101] trials. In the ROCKET-AF trial, in comparison with warfarin for non-valvular AF, rivaroxaban was shown to be non-inferior for prevention of stroke or systemic embolism. There was no significant difference in risk of major bleeding, though intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. There was no significant difference in mortality between the two groups. In the ARISTOTLE trial, apixaban was shown to be superior to warfarin by reducing the risk of stroke or systemic embolism by 21%, major bleeding by 31% and all-cause mortality by 11% [101].

The future for these novel anticoagulants is very promising, with significant progress being made in morbidity and mortality reduction compared to warfarin, mainly by way of further reduction in ischaemic strokes and less bleeding risks. However there are also several concerns regarding the use of the newer anticoagulants as detailed below. These include the lack of robust safety data in patients with creatinine clearance <30 ml/min, elderly patients and those with extremes of body weight. Whilst the lack of need to closely monitor anticoagulation whilst on newer anticoagulants can be viewed as an advantage by reducing patient inconvenience as well as the burden on healthcare resources, this feature can also be a disadvantage if patients miss one or more doses (due to the short offset time of these drugs leading to a rebound stroke risk). Additionally the lack of a specific antidote to these drugs is also of concern during major bleeding episodes. Thus there is a need for further studies in order to clarify the above concerns about these drugs before they can be incorporated into widespread clinical practice.

INTERVENTIONAL TREATMENTS

Catheter ablation is recommended in the management of symptomatic paroxysmal AF after failed AAD therapy and has not yet been demonstrated to confer mortality benefits possibly due to lack of long-term follow-up data. Being an invasive procedure, the procedure itself carries a mortality risk of up to 0.7% [2]. However, newer technological developments are consistently improving the safety and efficacy of catheter-based techniques. Left atrial appendage closure using occlusion devices has been suggested as an alternative for patients deemed unsuitable for oral anti-coagulation and again data on mortality benefits from this procedure is lacking currently.

CONCLUSIONS

AF and its associated co-morbidities continue to impose a significant mortality risk despite several new therapeutic advances. Indeed a proportion of the AF-related mortality is caused by side-effects due to attempts at restoring and maintaining sinus rhythm or major bleeding due to anti-coagulation. However effective anti-coagulation is the only therapeutic strategy that has been shown to reduce AF-related mortality and newer anticoagulants with improved efficacy and lesser bleeding side-effects, are only likely to improve the risk-benefit profile. Currently available AADs have limited efficacy and possess significant side-effects which seem to offset benefits of rhythm control; hence there is a pressing need to develop improved AADs in order to unmask the survival benefit that could accrue from maintenance of sinus rhythm. The impact of catheter ablation in the management of AF has currently been increasing and with improvements in safety and efficacy, is likely to reduce the use of AADs in the future.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

References

1. Feinberg W.M., Cornell E.S., Nightingale S.D., Pearce L.A., Tracy R.P., Hart R.G., Bovill E.G., et al. Stroke Prevention in Atrial Fibrillation Investigators. Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke. 1997;28(6):1101–1106. doi: 10.1161/01.STR.28.6.1101. [PubMed] [CrossRef] [Google Scholar]2. Camm A.J., Kirchhof P., Lip G.Y., Schotten U., Savelieva I., Ernst S., Van Gelder I.C., Al-Attar N., Hindricks G., Prendergast B., Heidbuchel H., Alfieri O., Angelini A., Atar D., Colonna P., De Caterina R., De Sutter J., Goette A., Gorenek B., Heldal M., Hohloser S.H., Kolh P., Le Heuzey J.Y., Ponikowski P., Rutten F.H., et al. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J. 2010;31(19):2369–2429. doi: 10.1093/eurheartj/ehq278. [PubMed] [CrossRef] [Google Scholar]3. Stewart S., Hart C.L., Hole D.J., McMurray J.J., et al. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am. J. Med. 2002;113(5):359–364. doi: 10.1016/S0002-9343(02)01236-6. [PubMed] [CrossRef] [Google Scholar]4. Kirchhof P., Auricchio A., Bax J., Crijns H., Camm J., Diener H.C., Goette A., Hindricks G., Hohnloser S., Kappenberger L., Kuck K.H., Lip G.Y., Olsson B., Meinertz T., Priori S., Ravens U., Steinbeck G., Svernhage E., Tijssen J., Vincent A., Breithardt G., et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur. Heart J. 2007;28(22):2803–2817. doi: 10.1093/eurheartj/ehm358. [PubMed] [CrossRef] [Google Scholar]5. Benjamin E.J., Wolf P.A., D’Agostino R.B., Silbershatz H., Kannel W.B., Levy D., et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946–952. doi: 10.1161/01.CIR.98.10.946. [PubMed] [CrossRef] [Google Scholar]6. Vidaillet H., Granada J.F., Chyou Po., Maassen K., Ortiz M., Pulido J.N., Sharma P., Smith P.N., Hayes J., et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am. J. Med. 2002;113(5):365–370. doi: 10.1016/S0002-9343(02)01253-6. [PubMed] [CrossRef] [Google Scholar]7. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A., et al. Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC Cardiovasc. Disord. 2002;2:5. doi: 10.1186/1471-2261-2-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]8. Miyasaka Y., Barnes M.E., Bailey K.R., Cha S.S., Gersh B.J., Seward J.B., Tsang T.S., et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J. Am. Coll. Cardiol. 2007;49(9):986–992. doi: 10.1016/j.jacc.2006.10.062. [PubMed] [CrossRef] [Google Scholar]9. Olsson S.B. Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691–1698. doi: 10.1016/S0140-6736(03)14841-6. [PubMed] [CrossRef] [Google Scholar]10. Wyse D.G., Waldo A.L., DiMarco J.P., Domanski M.J., Rosenberg Y., Schron E.B., Kellen J.C., Greene H.L., Mickel M.C., Dalquist J.E., Corley S.D., et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 2002;347(23):1825–1833. doi: 10.1056/NEJMoa021328. [PubMed] [CrossRef] [Google Scholar]11. Krahn A.D., Manfreda J., Tate R.B., Mathewson F.A., Cuddy T.E., et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am. J. Med. 1995;98(5):476–484. doi: 10.1016/S0002-9343(99)80348-9. [PubMed] [CrossRef] [Google Scholar]12. Gajewski J., Singer R.B. Mortality in an insured population with atrial fibrillation. JAMA. 1981;245(15):1540–1544. doi: 10.1001/jama.1981.03310400022019. [PubMed] [CrossRef] [Google Scholar]13. Piccini J.P., Hammill B.G., Sinner M.F., Jensen P.N., Hernandez A.F., Heckbert S.R., Benjamin E.J., Curtis L.H., et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5(1):85–93. doi: 10.1161/CIRCOUTCOMES.111.962688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]14. Hohnloser S.H., Crijns H.J., van Eickels M., Gaudin C., Page R.L., Torp-Pedersen C., Connolly S.J., et al. ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 2009;360(7):668–678. doi: 10.1056/NEJMoa0803778. [PubMed] [CrossRef] [Google Scholar]15. Go A.S., et al. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N. Engl. J. Med. 2009;360(20):2127–2129. doi: 10.1056/NEJMe0902676. [PubMed] [CrossRef] [Google Scholar]16. Connolly S.J., Eikelboom J., Joyner C., Diener H.C., Hart R., Golitsyn S., Flaker G., Avezum A., Hohnloser S.H., Diaz R., Talajic M., Zhu J., Pais P., Budaj A., Parkhomenko A., Jansky P., Commerford P., Tan R.S., Sim K.H., Lewis B.S., Van Mieghem W., Lip G.Y., Kim J.H., Lanas-Zanetti F., Gonzalez-Hermosillo A., Dans A.L., Munawar M., O’Donnell M., Lawrence J., Lewis G., Afzal R., Yusuf S., et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 2011;364(9):806–817. doi: 10.1056/NEJMoa1007432. [PubMed] [CrossRef] [Google Scholar]17. Arias E., et al. National vital statistics reports. Hyattsville, MD: National Centre for Health Statistics; 2010. United States Life Tables 2006. Report No. [Google Scholar]18. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Seward J.B., Bailey K.R., Iwasaka T., Tsang T.S., et al. Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study. Stroke. 2005;36(11):2362–2366. doi: 10.1161/01.STR.0000185927.63746.23. [PubMed] [CrossRef] [Google Scholar]19. Turagam M.K., Velagapudi P., Visotcky A., Szabo A., Kocheril A.G., et al. African Americans have the highest risk of in-hospital mortality with atrial fibrillation related hospitalizations among all racial/ethnic groups: a nationwide analysis. Int. J. Cardiol. 2012;158(1):165–166. doi: 10.1016/j.ijcard.2012.04.090. [PubMed] [CrossRef] [Google Scholar]20. Rosiak M., Dziuba M., Chudzik M., Cygankiewicz I., Bartczak K., Drozdz J., Wranicz J.K., et al. Risk factors for atrial fibrillation: Not always severe heart disease, not always so ‘lonely’. Cardiol. J. 2010;17(5):437–442. [PubMed] [Google Scholar]21. Kopecky S.L., Gersh B.J., McGoon M.D., Whisnant J.P., Holmes D.R., Jr, Ilstrup D.M., Frye R.L., et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N. Engl. J. Med. 1987;317(11):669–674. doi: 10.1056/NEJM198709103171104. [PubMed] [CrossRef] [Google Scholar]22. Rostagno C., Bacci F., Martelli M., Naldoni A., Bertini G., Gensini G., et al. Clinical course of lone atrial fibrillation since first symptomatic arrhythmic episode. Am. J. Cardiol. 1995;76(11):837–839. doi: 10.1016/S0002-9149(99)80240-9. [PubMed] [CrossRef] [Google Scholar]23. Potpara T., Grujić M., Marinković J., Vujisić-Tesić B., Ostojić M., Polovina M., et al. Mortality of patients with lone and idiopathic atrial fibrillation is similar to mortality in general population of Serbia. Vojnosanit. Pregl. 2010;67(2):132–135. doi: 10.2298/VSP1002132P. [PubMed] [CrossRef] [Google Scholar]24. Botto G.L., Padeletti L., Santini M., Capucci A., Gulizia M., Zolezzi F., Favale S., Molon G., Ricci R., Biffi M., Russo G., Vimercati M., Corbucci G., Boriani G., et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J. Cardiovasc. Electrophysiol. 2009;20(3):241–248. doi: 10.1111/j.1540-8167.2008.01320.x. [PubMed] [CrossRef] [Google Scholar]25. Lip G.Y., Hee F.L. Paroxysmal atrial fibrillation. QJM. 2001;94(12):665–678. doi: 10.1093/qjmed/94.12.665. [PubMed] [CrossRef] [Google Scholar]26. Keating R.J., Gersh B.J., Hodge D.O., Weivoda P.L., Patel P.J., Hammill S.C., Shen W.K., et al. Effect of atrial fibrillation pattern on survival in a community-based cohort. Am. J. Cardiol. 2005;96(10):1420–1424. doi: 10.1016/j.amjcard.2005.07.050. [PubMed] [CrossRef] [Google Scholar]27. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A. Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc. Disord. 2005;5:20. doi: 10.1186/1471-2261-5-20. [PMC free article] [PubMed] [CrossRef] [Google Scholar]28. Tuinenburg A.E., Van Gelder I.C., Van Den Berg M.P., Brügemann J., De Kam P.J., Crijns H.J., et al. Lack of prevention of heart failure by serial electrical cardioversion in patients with persistent atrial fibrillation. Heart. 1999;82(4):486–493. doi: 10.1136/hrt.82.4.486. [PMC free article] [PubMed] [CrossRef] [Google Scholar]29. Brown A.M., Sease K.L., Robey J.L., Shofer F.S., Hollander J.E., et al. The risk for acute coronary syndrome associated with atrial fibrillation among ED patients with chest pain syndromes. Am. J. Emerg. Med. 2007;25(5):523–528. doi: 10.1016/j.ajem.2006.09.015. [PubMed] [CrossRef] [Google Scholar]30. Sankaranarayanan R., et al. Mortality Risk Associated with AF in Myocardial Infarction Patients. J. Atr. Fibrillation. 2012;5(3):138–152. [PMC free article] [PubMed] [Google Scholar]31. Sankaranarayanan R., James M.A., Nuta B., Townsend M., Kesavan S., Burtchaell S., Holloway R., Ewings P., et al. Does atrial fibrillation beget ventricular fibrillation in patients with acute myocardial infarction? Pacing Clin. Electrophysiol. 2008;31(12):1612–1619. doi: 10.1111/j.1540-8159.2008.01234.x. [PubMed] [CrossRef] [Google Scholar]32. Lehto M., Snapinn S., Dickstein K., Swedberg K., Nieminen M.S., et al. OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience. Eur. Heart J. 2005;26(4):350–356. doi: 10.1093/eurheartj/ehi064. [PubMed] [CrossRef] [Google Scholar]33. Roy D., Talajic M., Nattel S., Wyse D.G., Dorian P., Lee K.L., Bourassa M.G., Arnold J.M., Buxton A.E., Camm A.J., Connolly S.J., Dubuc M., Ducharme A., Guerra P.G., Hohnloser S.H., Lambert J., Le Heuzey J.Y., O’Hara G., Pedersen O.D., Rouleau J.L., Singh B.N., Stevenson L.W., Stevenson W.G., Thibault B., Waldo A.L., et al. Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N. Engl. J. Med. 2008;358(25):2667–2677. doi: 10.1056/NEJMoa0708789. [PubMed] [CrossRef] [Google Scholar]34. Caldwell J.C., Contractor H., Petkar S., Ali R., Clarke B., Garratt C.J., Neyses L., Mamas M.A., et al. Atrial fibrillation is under-recognized in chronic heart failure: insights from a heart failure cohort treated with cardiac resynchronization therapy. Europace. 2009;11(10):1295–1300. doi: 10.1093/europace/eup201. [PubMed] [CrossRef] [Google Scholar]35. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Bailey K.R., Abhayaratna W., Seward J.B., Iwasaka T., Tsang T.S., et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: a community-based study over two decades. Eur. Heart J. 2006;27(8):936–941. doi: 10.1093/eurheartj/ehi694. [PubMed] [CrossRef] [Google Scholar]36. Wang T.J., Larson M.G., Levy D., Vasan R.S., Leip E.P., Wolf P.A., D’Agostino R.B., Murabito J.M., Kannel W.B., Benjamin E.J., et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920–2925. doi: 10.1161/01.CIR.0000072767.89944.6E. [PubMed] [CrossRef] [Google Scholar]37. Olsson L.G., Swedberg K., Ducharme A., Granger C.B., Michelson E.L., McMurray J.J., Puu M., Yusuf S., Pfeffer M.A., et al. CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J. Am. Coll. Cardiol. 2006;47(10):1997–2004. doi: 10.1016/j.jacc.2006.01.060. [PubMed] [CrossRef] [Google Scholar]38. Rivero-Ayerza M., Scholte Op Reimer W., Lenzen M., Theuns D.A., Jordaens L., Komajda M., Follath F., Swedberg K., Cleland J.G., et al. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalized heart failure patients: results of the EuroHeart Failure Survey. Eur. Heart J. 2008;29(13):1618–1624. doi: 10.1093/eurheartj/ehn217. [PubMed] [CrossRef] [Google Scholar]39. Dries D.L., Exner D.V., Gersh B.J., Domanski M.J., Waclawiw M.A., Stevenson L.W., et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J. Am. Coll. Cardiol. 1998;32(3):695–703. doi: 10.1016/S0735-1097(98)00297-6. [PubMed] [CrossRef] [Google Scholar]40. Mahoney P., Kimmel S., DeNofrio D., Wahl P., Loh E., et al. Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure. Am. J. Cardiol. 1999;83(11):1544–1547. doi: 10.1016/S0002-9149(99)00144-7. [PubMed] [CrossRef] [Google Scholar]41. Mamas M.A., Caldwell J.C., Chacko S., Garratt C.J., Fath-Ordoubadi F., Neyses L., et al. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur. J. Heart Fail. 2009;11(7):676–683. doi: 10.1093/eurjhf/hfp085. [PubMed] [CrossRef] [Google Scholar]42. Raunsø J., Pedersen O.D., Dominguez H., Hansen M.L., Møller J.E., Kjaergaard J., Hassager C., Torp-Pedersen C., Køber L., et al. EchoCardiography and Heart Outcome Study Investigators. Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease. Eur. J. Heart Fail. 2010;12(7):692–697. doi: 10.1093/eurjhf/hfq052. [PubMed] [CrossRef] [Google Scholar]43. Badheka A.O., Rathod A., Kizilbash M.A., Bhardwaj A., Ali O., Afonso L., Jacob S., et al. Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction. Am. J. Cardiol. 2011;108(9):1283–1288. doi: 10.1016/j.amjcard.2011.06.045. [PubMed] [CrossRef] [Google Scholar]44. Domanski M.J., et al. The epidemiology of atrial fibrillation. Coron. Artery Dis. 1995;6(2):95–100. doi: 10.1097/00019501-199502000-00002. [PubMed] [CrossRef] [Google Scholar]45. Cha Y.M., Redfield M.M., Shen W.K., Gersh B.J., et al. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation. 2004;109(23):2839–2843. doi: 10.1161/01.CIR.0000132470.78896.A8. [PubMed] [CrossRef] [Google Scholar]46. Daoud E.G., Weiss R., Bahu M., Knight B.P., Bogun F., Goyal R., Harvey M., Strickberger S.A., Man K.C., Morady F., et al. Effect of an irregular ventricular rhythm on cardiac output. Am. J. Cardiol. 1996;78(12):1433–1436. doi: 10.1016/S0002-9149(97)89297-1. [PubMed] [CrossRef] [Google Scholar]47. Shinbane J.S., Wood M.A., Jensen D.N., Ellenbogen K.A., Fitzpatrick A.P., Scheinman M.M., et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J. Am. Coll. Cardiol. 1997;29(4):709–715. doi: 10.1016/S0735-1097(96)00592-X. [PubMed] [CrossRef] [Google Scholar]48. Steinberg J.S., Sadaniantz A., Kron J., Krahn A., Denny D.M., Daubert J., Campbell W.B., Havranek E., Murray K., Olshansky B., O’Neill G., Sami M., Schmidt S., Storm R., Zabalgoitia M., Miller J., Chandler M., Nasco E.M., Greene H.L., et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation. 2004;109(16):1973–1980. doi: 10.1161/01.CIR.0000118472.77237.FA. [PubMed] [CrossRef] [Google Scholar]49. Fuster V., Rydén L.E., Cannom D.S., Crijns H.J., Curtis A.B., Ellenbogen K.A., Halperin J.L., Kay G.N., Le Huezey J.Y., Lowe J.E., Olsson S.B., Prystowsky E.N., Tamargo J.L., Wann L.S., et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2011;57(11):e101–e198. doi: 10.1016/j.jacc.2010.09.013. [PubMed] [CrossRef] [Google Scholar]50. Stein K.M., Euler D.E., Mehra R., Seidl K., Slotwiner D.J., Mittal S., Markowitz S.M., Lerman B.B. Jewel AF Worldwide Investigators. Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients? J. Am. Coll. Cardiol. 2002;40(2):335–340. doi: 10.1016/S0735-1097(02)01957-5. [PubMed] [CrossRef] [Google Scholar]51. Grau A.J., Weimar C., Buggle F., Heinrich A., Goertler M., Neumaier S., Glahn J., Brandt T., Hacke W., Diener H.C., et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559–2566. doi: 10.1161/hs1101.098524. [PubMed] [CrossRef] [Google Scholar]52. Kimura K., Minematsu K., Yamaguchi T., et al. Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC) Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with acute ischaemic stroke. J. Neurol. Neurosurg. Psychiatry. 2005;76(5):679–683. doi: 10.1136/jnnp.2004.048827. [PMC free article] [PubMed] [CrossRef] [Google Scholar]53. Jørgensen H.S., Nakayama H., Reith J., Raaschou H.O., Olsen T.S. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke. 1996;27(10):1765–1769. doi: 10.1161/01.STR.27.10.1765. [PubMed] [CrossRef] [Google Scholar]54. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255–1262. [PubMed] [Google Scholar]55. Akins P.T., Feldman H.A., Zoble R.G., Newman D., Spitzer S.G., Diener H.C., Albers G.W. Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials. Stroke. 2007;38(3):874–880. doi: 10.1161/01.STR.0000258004.64840.0b. [PubMed] [CrossRef] [Google Scholar]56. Watson T., Shantsila E., Lip G.Y. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373(9658):155–166. doi: 10.1016/S0140-6736(09)60040-4. [PubMed] [CrossRef] [Google Scholar]57. De Caterina R., Connolly S.J., Pogue J., Chrolavicius S., Budaj A., Morais J., Renda G., Yusuf S. ACTIVE Investigators. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur. Heart J. 2010;31(17):2133–2140. doi: 10.1093/eurheartj/ehq250. [PubMed] [CrossRef] [Google Scholar]58. Nattel S. Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Cardiovasc. Res. 1998;37(3):567–577. doi: 10.1016/S0008-6363(97)00293-9. [PubMed] [CrossRef] [Google Scholar]59. Freemantle N., Lafuente-Lafuente C., Mitchell S., Eckert L., Reynolds M. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace. 2011;13(3):329–345. doi: 10.1093/europace/euq450. [PubMed] [CrossRef] [Google Scholar]60. Gage B.F., Waterman A.D., Shannon W., Boechler M., Rich M.W., Radford M.J., et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–2870. doi: 10.1001/jama.285.22.2864. [PubMed] [CrossRef] [Google Scholar]61. Khumri T.M., Idupulapati M., Rader V.J., Nayyar S., Stoner C.N., Main M.L., et al. Clinical and echocardiographic markers of mortality risk in patients with atrial fibrillation. Am. J. Cardiol. 2007;99(12):1733–1736. doi: 10.1016/j.amjcard.2007.01.055. [PubMed] [CrossRef] [Google Scholar]62. Pisters R., Lane D.A., Nieuwlaat R., de Vos C.B., Crijns H.J., Lip G.Y., et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100. doi: 10.1378/chest.10-0134. [PubMed] [CrossRef] [Google Scholar]63. Gallego P., Roldán V., Torregrosa J.M., Gálvez J., Valdés M., Vicente V., Marín F., Lip G.Y., et al. Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation. Circ Arrhythm Electrophysiol. 2012;5(2):312–318. doi: 10.1161/CIRCEP.111.967000. [PubMed] [CrossRef] [Google Scholar]64. Gallego P., Roldán V., Marín F., Jover E., Manzano-Fernández S., Valdés M., Vicente V., Lip G.Y., et al. Ankle brachial index as an independent predictor of mortality in anticoagulated atrial fibrillation. Eur. J. Clin. Invest. 2012;42(12):1302–1308. doi: 10.1111/eci.12004. [PubMed] [CrossRef] [Google Scholar]65. Friberg L., Rosenqvist M., et al. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace. 2011;13(5):626–633. doi: 10.1093/europace/eur001. [PubMed] [CrossRef] [Google Scholar]66. Roldán V., Marín F., Díaz J., Gallego P., Jover E., Romera M., Manzano-Fernández S., Casas T., Valdés M., Vicente V., Lip G.Y., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation. J. Thromb. Haemost. 2012;10(8):1500–1507. doi: 10.1111/j.1538-7836.2012.04812.x. [PubMed] [CrossRef] [Google Scholar]67. Providencia R., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation: a rebuttal . J Thromb Haemost. 2012;10(11):2413–1507. author reply 2014-5. [PubMed] [Google Scholar]68. Roldán V., Marín F., Muiña B., Torregrosa J.M., Hernández-Romero D., Valdés M., Vicente V., Lip G.Y., et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J. Am. Coll. Cardiol. 2011;57(25):2496–2504. doi: 10.1016/j.jacc.2010.12.033. [PubMed] [CrossRef] [Google Scholar]69. Hermida J., Lopez F.L., Montes R., Matsushita K., Astor B.C., Alonso A., et al. Usefulness of high-sensitivity C-reactive protein to predict mortality in patients with atrial fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study). Am. J. Cardiol. 2012;109(1):95–99. doi: 10.1016/j.amjcard.2011.08.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]70. Go A.S., Fang M.C., Udaltsova N., Chang Y., Pomernacki N.K., Borowsky L., Singer D.E., et al. ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119(10):1363–1369. doi: 10.1161/CIRCULATIONAHA.108.816082. [PMC free article] [PubMed] [CrossRef] [Google Scholar]71. Potpara T.S., Vasiljevic Z.M., Vujisic-Tesic B.D., Marinkovic J.M., Polovina M.M., Stepanovic J.M., Stankovic G.R., Ostojic M.C., Lip G.Y., et al. Mitral annular calcification predicts cardiovascular morbidity and mortality in middle-aged patients with atrial fibrillation: the Belgrade Atrial Fibrillation Study. Chest. 2011;140(4):902–910. doi: 10.1378/chest.10-2963. [PubMed] [CrossRef] [Google Scholar]72. Echt D.S., Liebson P.R., Mitchell L.B., Peters R.W., Obias-Manno D., Barker A.H., Arensberg D., Baker A., Friedman L., Greene H.L., et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 1991;324(12):781–788. doi: 10.1056/NEJM199103213241201. [PubMed] [CrossRef] [Google Scholar]73. Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation. 1990;82(4):1106–1116. doi: 10.1161/01.CIR.82.4.1106. [PubMed] [CrossRef] [Google Scholar]74. Carlsson J., Miketic S., Windeler J., Cuneo A., Haun S., Micus S., Walter S., Tebbe U., et al. STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J. Am. Coll. Cardiol. 2003;41(10):1690–1696. doi: 10.1016/S0735-1097(03)00332-2. [PubMed] [CrossRef] [Google Scholar]75. Hohnloser S.H., Kuck K.H., Lilienthal J., et al. Rhythm or rate control in atrial fibrillation–Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356(9244):1789–1794. doi: 10.1016/S0140-6736(00)03230-X. [PubMed] [CrossRef] [Google Scholar]76. Van Gelder I.C., Hagens V.E., Bosker H.A., Kingma J.H., Kamp O., Kingma T., Said S.A., Darmanata J.I., Timmermans A.J., Tijssen J.G., Crijns H.J., et al. Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N. Engl. J. Med. 2002;347(23):1834–1840. doi: 10.1056/NEJMoa021375. [PubMed] [CrossRef] [Google Scholar]77. Opolski G., Torbicki A., Kosior D.A., Szulc M., Wozakowska-Kaplon B., Kolodziej P., Achremczyk P., et al. Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest. 2004;126(2):476–486. doi: 10.1378/chest.126.2.476. [PubMed] [CrossRef] [Google Scholar]78. Ogawa S., Yamashita T., Yamazaki T., Aizawa Y., Atarashi H., Inoue H., Ohe T., Ohtsu H., Okumura K., Katoh T., Kamakura S., Kumagai K., Kurachi Y., Kodama I., Koretsune Y., Saikawa T., Sakurai M., Sugi K., Tabuchi T., Nakaya H., Nakayama T., Hirai M., Fukatani M., Mitamura H., et al. J-RHYTHM Investigators. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ. J. 2009;73(2):242–248. doi: 10.1253/circj.CJ-08-0608. [PubMed] [CrossRef] [Google Scholar]79. Testa L., Biondi-Zoccai G.G., Dello Russo A., Bellocci F., Andreotti F., Crea F., et al. Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis. Eur. Heart J. 2005;26(19):2000–2006. doi: 10.1093/eurheartj/ehi306. [PubMed] [CrossRef] [Google Scholar]80. Corley S.D., Epstein A.E., DiMarco J.P., Domanski M.J., Geller N., Greene H.L., Josephson R.A., Kellen J.C., Klein R.C., Krahn A.D., Mickel M., Mitchell L.B., Nelson J.D., Rosenberg Y., Schron E., Shemanski L., Waldo A.L., Wyse D.G., et al. AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–1513. doi: 10.1161/01.CIR.0000121736.16643.11. [PubMed] [CrossRef] [Google Scholar]81. Pedersen O.D., Brendorp B., Elming H., Pehrson S., Køber L., Torp-Pedersen C., et al. Does conversion and prevention of atrial fibrillation enhance survival in patients with left ventricular dysfunction? Evidence from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide/(DIAMOND) study. Card. Electrophysiol. Rev. 2003;7(3):220–224. doi: 10.1023/B:CEPR.0000012386.82055.81. [PubMed] [CrossRef] [Google Scholar]82. Ionescu-Ittu R., Abrahamowicz M., Jackevicius C.A., Essebag V., Eisenberg M.J., Wynant W., Richard H., Pilote L., et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch. Intern. Med. 2012;172(13):997–1004. doi: 10.1001/archinternmed.2012.2266. [PubMed] [CrossRef] [Google Scholar]83. Bardy G.H., Lee K.L., Mark D.B., Poole J.E., Packer D.L., Boineau R., Domanski M., Troutman C., Anderson J., Johnson G., McNulty S.E., Clapp-Channing N., Davidson-Ray L.D., Fraulo E.S., Fishbein D.P., Luceri R.M., Ip J.H., et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 2005;352(3):225–237. doi: 10.1056/NEJMoa043399. [PubMed] [CrossRef] [Google Scholar]84. Julian D.G., Camm A.J., Frangin G., Janse M.J., Munoz A., Schwartz P.J., Simon P., et al. European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet. 1997;349(9053):667–674. doi: 10.1016/S0140-6736(96)09145-3. [PubMed] [CrossRef] [Google Scholar]85. Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J. Am. Coll. Cardiol. 1999;34(5):1552–1559. doi: 10.1016/S0735-1097(99)00376-9. [PubMed] [CrossRef] [Google Scholar]86. Singh S.N., Fletcher R.D., Fisher S.G., Singh B.N., Lewis H.D., Deedwania P.C., Massie B.M., Colling C., Lazzeri D., et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N. Engl. J. Med. 1995;333(2):77–82. doi: 10.1056/NEJM199507133330201. [PubMed] [CrossRef] [Google Scholar]87. Cairns J.A., Connolly S.J., Roberts R., Gent M., et al. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet. 1997;349(9053):675–682. doi: 10.1016/S0140-6736(96)08171-8. [PubMed] [CrossRef] [Google Scholar]88. Piccini J.P., Hasselblad V., Peterson E.D., Washam J.B., Califf R.M., Kong D.F., et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J. Am. Coll. Cardiol. 2009;54(12):1089–1095. doi: 10.1016/j.jacc.2009.04.085. [PubMed] [CrossRef] [Google Scholar]89. Duray G.Z., Torp-Pedersen C., Connolly S.J., Hohnloser S.H., et al. Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. J. Cardiovasc. Electrophysiol. 2011;22(7):770–776. doi: 10.1111/j.1540-8167.2010.02006.x. [PubMed] [CrossRef] [Google Scholar]90. Køber L., Torp-Pedersen C., McMurray J.J., Gøtzsche O., Lévy S., Crijns H., Amlie J., Carlsen J., et al. Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 2008;358(25):2678–2687. doi: 10.1056/NEJMoa0800456. [PubMed] [CrossRef] [Google Scholar]91. Connolly S.J., Camm A.J., Halperin J.L., Joyner C., Alings M., Amerena J., Atar D., Avezum Á., Blomström P., Borggrefe M., Budaj A., Chen S.A., Ching C.K., Commerford P., Dans A., Davy J.M., Delacrétaz E., Di Pasquale G., Diaz R., Dorian P., Flaker G., Golitsyn S., Gonzalez-Hermosillo A., Granger C.B., Heidbüchel H., Kautzner J., Kim J.S., Lanas F., Lewis B.S., Merino J.L., Morillo C., Murin J., Narasimhan C., Paolasso E., Parkhomenko A., Peters N.S., Sim K.H., Stiles M.K., Tanomsup S., Toivonen L., Tomcsányi J., Torp-Pedersen C., Tse H.F., Vardas P., Vinereanu D., Xavier D., Zhu J., Zhu J.R., Baret-Cormel L., Weinling E., Staiger C., Yusuf S., Chrolavicius S., Afzal R., Hohnloser S.H. PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med. 2011;365(24):2268–2276. doi: 10.1056/NEJMoa1109867. [PubMed] [CrossRef] [Google Scholar]92. Hylek E.M., Go A.S., Chang Y., Jensvold N.G., Henault L.E., Selby J.V., Singer D.E. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med. 2003;349(11):1019–1026. doi: 10.1056/NEJMoa022913. [PubMed] [CrossRef] [Google Scholar]93. Hart R.G., Pearce L.A., Aguilar M.I. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann. Intern. Med. 2007;147(8):590–592. doi: 10.7326/0003-4819-147-8-200710160-00018. [PubMed] [CrossRef] [Google Scholar]94. Gallagher A.M., Setakis E., Plumb J.M., Clemens A., van Staa T.P., et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb. Haemost. 2011;106(5):968–977. doi: 10.1160/Th21-05-0353. [PubMed] [CrossRef] [Google Scholar]95. Fang M.C., Go A.S., Chang Y., Borowsky L.H., Pomernacki N.K., Udaltsova N., Singer D.E., et al. Thirty-day mortality after ischemic stroke and intracranial hemorrhage in patients with atrial fibrillation on and off anticoagulants. Stroke. 2012;43(7):1795–1799. doi: 10.1161/STROKEAHA.111.630731. [PMC free article] [PubMed] [CrossRef] [Google Scholar]96. Go A.S., Hylek E.M., Borowsky L.H., Phillips K.A., Selby J.V., Singer D.E., et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann. Intern. Med. 1999;131(12):927–934. doi: 10.7326/0003-4819-131-12-199912210-00004. [PubMed] [CrossRef] [Google Scholar]97. Devereaux P.J., Anderson D.R., Gardner M.J., Putnam W., Flowerdew G.J., Brownell B.F., Nagpal S., Cox J.L., et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ. 2001;323(7323):1218–1222. doi: 10.1136/bmj.323.7323.1218. [PMC free article] [PubMed] [CrossRef] [Google Scholar]98. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., Pogue J., Reilly P.A., Themeles E., Varrone J., Wang S., Alings M., Xavier D., Zhu J., Diaz R., Lewis B.S., Darius H., Diener H.C., Joyner C.D., Wallentin L., et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009;361(12):1139–1151. doi: 10.1056/NEJMoa0905561. [PubMed] [CrossRef] [Google Scholar]99. Uchino K., Hernandez A.V., et al. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch. Intern. Med. 2012;172(5):397–402. doi: 10.1001/archinternmed.2011.1666. [PubMed] [CrossRef] [Google Scholar]100. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., Breithardt G., Halperin J.L., Hankey G.J., Piccini J.P., Becker R.C., Nessel C.C., Paolini J.F., Berkowitz S.D., Fox K.A., Califf R.M., et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011;365(10):883–891. doi: 10.1056/NEJMoa1009638. [PubMed] [CrossRef] [Google Scholar]101. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M., Al-Khalidi H.R., Ansell J., Atar D., Avezum A., Bahit M.C., Diaz R., Easton J.D., Ezekowitz J.A., Flaker G., Garcia D., Geraldes M., Gersh B.J., Golitsyn S., Goto S., Hermosillo A.G., Hohnloser S.H., Horowitz J., Mohan P., Jansky P., Lewis B.S., Lopez-Sendon J.L., Pais P., Parkhomenko A., Verheugt F.W., Zhu J., Wallentin L., et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011;365(11):981–992. doi: 10.1056/NEJMoa1107039. [PubMed] [CrossRef] [Google Scholar]

How does Chronic Atrial Fibrillation Influence Mortality in the Modern Treatment Era?

Curr Cardiol Rev. 2015 Aug; 11(3): 190–198.

Rajiv Sankaranarayanan

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Graeme Kirkwood

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

Rajaverma Visweswariah

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

David J. Fox

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

¹ Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK

² Cardiology Specialist Registrar in Devices, Manchester Heart Centre, Manchester Royal Infirmary

³ Consultant Cardiologist and Electrophysiologist, Department of Cardiology, University Hospital South Manchester, Manchester, UK

^* Address correspondence to this author at the Cardiology Specialist Registrar in Electrophysiology and British Heart Foundation Clinical Research Fellow, University Hospital South Manchester and University of Manchester, Manchester, UK; Tel: 00447525826672; Fax: 00441612751234; E-mail [email protected]

Received 2014 Apr 23; Revised 2014 Aug 22; Accepted 2014 Aug 27.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been cited by other articles in PMC.

Abstract

Atrial fibrillation (AF) continues to impose a significant burden upon healthcare resources. A sustained increase in the ageing population and better survival from conditions such as ischaemic heart disease have ensured that both the incidence and prevalence of AF continue to increase significantly. AF can lead to complications such as embolism and heart failure and these acting in concert with its associated co-morbidities portend increased mortality risk. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of various therapeutic strategies (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures). Despite several treatment advances including newer anti-arrhythmic drugs and developments in catheter ablation, anti-coagulation remains the only effective means to reduce the mortality due to AF. Warfarin has been used as the oral anticoagulant in the treatment of AF for many years but suffers from disadvantages such as unpredictable INR levels, bleeding risks and need for haematological monitoring. This has therefore spurred a renewed interest in research and clinical studies directed towards developing safer and more efficacious anti-coagulants. We shall review in this article the epidemiological features of AF-related mortality from several studies as well as the cardiovascular and non-cardiac mortality mechanisms. We shall also elucidate why a rhythm control strategy has appeared to be counter-productive and attempt to predict the likely future impact of novel anti-coagulants upon mortality reduction in AF.

Keywords: Atrial fibrillation, arrhythmia, mortality, anti-arrhythmic drugs.

INTRODUCTION

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. 2.2 million people in America and 4.5 million people in Europe are affected by either paroxysmal or persistent AF [1]. It is usually associated with cardiovascular co-morbidities such as hypertension, coronary artery disease, valvular heart disease and heart failure [2]. The presence of AF has been shown to independently increase the risk of death [3-7] and the mortality risk is highest during the first year after AF manifests [5-8]. The incidence of death due to AF has been shown to vary from 1.6-4.2% per annum in various controlled trials [9, 10]. Whilst some studies suggest that the mortality risk from AF is due to the “bad company it keeps” i.e. the associated co-morbidities rather than AF itself; undoubtedly some of the mortality is also due to the side-effects of the various therapeutic strategies for AF (anti-arrhythmic drugs, bleeding side-effects due to anti-coagulants or invasive procedures).

EPIDEMIOLOGY

Large population studies both in North America and Europe have demonstrated incontrovertibly the impact of AFupon mortality. The landmark Framingham Heart Study analysed a cohort of 621 individuals who developed AF (out of a study population of over 5000) during 40 years of follow-up; the excess in all-cause mortality rates attributable to AF was 50% for men, and 90% for women, even when controlled for the presence of a wide range of cardiovascular co-morbidities [5]. This effect on mortality became apparent early, with 15% of deaths occurring within 30 days of diagnosis. Amongst the group of patients aged between 55-74 years, the 10 year mortality was 61.5% in men with AF compared to 30% in men without AF. Amongst women in a similar age group, the 10 year mortality was 57.6% in the AF group versus 20.9% in women without AF. Similar findings have been found from many other cohorts. The Renfrew-Paisley study followed-up 100 patients with AF for 20 years out of a cohort of over 15,000 men and women aged between 45-64 years in two Scottish towns and showed that AF increased all-cause mortality by 50% amongst men and 120% amongst women [3]. Ruigomez et al. followed a cohort of 1035 chronic AF patients in the UK for a mean duration of 2 years and reported a trebling of all cause mortality after matching for confounding factors [7]. The Olmsted County study was a community based study of 4618 patients with AF, followed-up for 5.3±5 years and demonstrated that relative to the general age and sex-matched population, AF significantly increased the mortality risk especially during the first four months following diagnosis (HR 9.62; 95% CI 8.93 to 10.32) and also thereafter (HR 1.66; 95% CI 1.59 to 1.73) [8]. The Manitoba study followed-up nearly 4000 young Canadian male air crew for 44 years and demonstrated that AF increased total mortality by 31% [11].

As might be expected, the annual mortality rates associated with AF vary substantially depending on the population demographics. Based on medical insurance claim data, values range from 2.6% in asymptomatic untreated individuals, to 24.2% amongst an elderly population with high rates of co-morbidities [12, 13]. There do not appear to have been significant reductions in AF-associated mortality between the years 1993 – 2007; this population-based data is supported by recent trials of novel anticoagulants and anti-arrhythmic therapies, which report annual mortality rates between 1.9 and 6.6% even with optimal contemporary treatment [14-16].

It is unambiguous from the epidemiological data that, although the presence of AF has a significant and dramatic effect to increase the mortality rate within a population, the effect on an individual is less clear-cut and is highly dependent on demographic risk factors and the presence of co-morbidities as discussed below.

AGE

Age is a major risk factor for developing AF, and older patients are more likely to have co-morbidities that might impact on survival. Nevertheless, patient age is the most powerful and consistent independent factor in determining the AF-associated mortality risk. Although the Framingham study found that all age groups demonstrated an excess mortality attributable to AF, the absolute risk increase seen in those aged over 75 years was approximately 3 times that seen in those under 65 years [5]. This was confirmed in the Paisley/Renfrew study, where the excess mortality was increased 3.5 times in the age group 60–64 years compared to 45–49 years [3]. Essentially, amongst all age groups, individuals with AF are more likely to die early than those without, and older patients with AF are substantially more at risk than younger patients. The annual mortality in 2007 amongst a large cohort of AF patients who were also Medicare beneficiaries aged >65 years was as high as 25% [13].

SEX

In developed societies, healthy females possess a survival advantage over males [17]. The mortality associated with AF is slightly but significantly higher in females than in males, such that this survival advantage is lost and the life expectancy of a woman with AF is similar to that of an age-matched man [5]. The Renfrew-Paisley study showed AF portends a higher all-cause and cardiovascular mortality amongst women [3]. There is also evidence that stroke-related mortality in AF is higher in women [18].

RACE /ETHNIC DIFFERENCES

During AF-related hospitalisations, in-hospital mortality has been shown to be highest amongst African-Americans in comparison to other ethnic groups [19].

LONE AF VS. CO-MORBIDITIES

‘Lone AF’ is defined as AF in the absence of structural heart disease or additional cardiovascular co-morbidities such as diabetes or hypertension. In reality, lone AF is an uncommon entity; 70% of patients with AF have additional risk factors at the time of diagnosis and of the remaining 30% many will have unrecognised co-morbidities such as sleep apnoea or obesity [20]. With a 15 year mortality of only 8%, survival amongst patients with lone AF has been shown to be not significantly different to that of age and sex-matched population control data [21-23]; this is in keeping with subgroup analysis from the Paisley/ Renfrew study which also did not identify a significant mortality excess attributable to lone AF [3].

In contrast, multivariate analysis from the afore-mentioned population studies indicates that cardiovascular and non-cardiovascular co-morbidities impact dramatically upon survival. Factors such as smoking, lung disease, hypertension, diabetes and obesity act to increase mortality by around 20 – 60% each, and the effects are additive with additional risk factors. These findings have led to the development of clinical scoring systems to aid therapeutic decisions.

TEMPORAL PROFILE OF AF

There is convincing evidence that AF burden may impact upon stroke rates [24], however the stroke risk due to paroxysmal AF is comparable to that of chronic AF [25]. In contrast, permanent AF is associated with higher mortality risk whereas paroxysmal AF has been shown to portend similar mortality risk as that of age and gender-matched general population [26, 27]. However, analysis of the mortality effect due to persistent AF in comparison to paroxysmal AF, has shown contrasting results [26, 28].

ISCHAEMIC HEART DISEASE (IHD) AND HEART FAILURE

AF and coronary artery disease share risk factors, but there is no clear evidence linking AF with increased risk of acute coronary syndromes [29]. Co-existing IHD has been shown to increase all-cause mortality due to AF three fold with up to 21% of deaths shown to be related to IHD [7]. Nevertheless, there is a clear association between AF and poor prognosis in myocardial infarction; multiple studies have shown that the development of AF following myocardial infarction is associated with a substantial increase in in-hospital as well as post-discharge mortality (reviewed in [30]). Many studies (including large-scale RCTs such as the OPTIMAAL trial, GUSTO-3 trial and TRACE study) have shown that chronic AF independently increases post-MI mortality (reviewed in [30]). A study by one of the authors of this paper (Sankaranarayanan et al. [31]) showed that chronic AF could increase post-MI mortality risk by increasing the risk of ventricular fibrillation in this setting [31]. The OPTIMAAL trial noted a significant increase in 30 day mortality only where new AF complicated acute MI, but that both acute and pre-existing AF were associated with reduced survival over the subsequent 3 years [32].

AF in congestive heart failure (CHF) has recently attracted substantial interest; AF can either exacerbate or complicate CHF [33], and in the modern era of device therapy it is becoming apparent that AF in CHF is under-recognised [34]. 24% out of 3288 individuals with AF in the Olmsted County study developed CHF over a mean follow-up of 6.1±5.2 years, leading to a significant increase in mortality (HR 3.4) [35]. The Framingham study illustrated the close relationship between these two pathologies showing that amongst 1470 participants who developed either or both these conditions, 382 individuals had both (36% of these developed AF first, 41% CHF first and 21% were diagnosed with both on the same day) [36]. The incidence of CHF amongst AF patients was 33 per 1000 person years, with 4 out of 10 AF subjects developing heart failure at some point during their lifetime and also significantly increasing mortality (men HR 1.6, women HR 2.7). Further analysis also demonstrated a significant mortality impact where AF complicated CHF, (incidence 54 per 1000 person years) with relative increases of 60% and 170% in men and women respectively compared to individuals with CHF in sinus rhythm. The Manitoba follow-up study showed that AF increases the risk of development of CHF by three-fold and increased cardiac mortality by 37% [11].

However, therapeutic CHF studies demonstrated conflicting results as to whether the presence of AF conferred an independent impact on mortality, or simply reflected disease state at baseline [37-40]. A recent meta-analysis of 16 studies including 53,969 patients appears to confirm that AF increases total mortality in CHF patients by around 40%, with an independent effect remaining after controlling for demographics and disease severity irrespective of impaired or preserved LV function [41]. Nevertheless, it remains controversial whether it is the arrhythmia or the co-morbidities that impacts upon mortality, with a recent analysis [42] suggesting that this effect is only seen where heart failure results from ischaemic heart disease. A post hoc analysis of the AFFIRM trial sub-set of patients with CHF and preserved ejection fraction showed a lower all-cause and cardiovascular mortality in comparison to patients with impaired systolic function [43].

In view of the strong association of AF with co-morbidities, several studies have attempted to analyse if the effects of AF upon mortality are truly independent or simply a risk marker for the cumulative pre-terminal effects of co-morbidities. The Olmsted County study for instance illustrated the very high 4 month and 1 year mortality following AF diagnosis, however there were no changes in early (<4 months) versus late mortality (after 4 months) in the whole cohort or within the sub-group of patients without pre-morbid cardiovascular disease [8]. These results and others showing that lone AF does not increase mortality, suggest that AF could simply represent a risk marker for mortality in a very sick population with multiple co-morbidities [3, 6, 8].

1. MECHANISMS OF AF-RELATED MORTALITY

Cardiac

Several large population-based studies have shown that AF independently increases cardiac mortality [3, 5, 11]. Increased cardiovascular mortality risk due to AF varies between 2 to 12 times [44]. The cardiac causes include heart failure, arrhythmia and possibly coronary heart disease.

AF has an intricate relationship with CHF whereby one can precipitate the other [45]. AF leads to a loss of atrial systole (which usually contributes up to 30% of pre-load in sinus rhythm). In addition to this, the loss of atrio-ventricular synchrony and irregular, uncontrolled ventricular rates contribute to development of CHF (“tachycardia-induced cardiomyopathy”) [46-48]. Uncontrolled ventricular rates during AF can also worsen mitral regurgitation and cause rate-related left bundle branch block, thereby reducing cardiac output [49].

AF can lead to arrhythmic sudden death by potentiating VT or VF in patients with ICDs [50], pre-excitation syndromes [49] and in the acute MI setting [31].

AF can also impair coronary perfusion and increase myocardial oxygen demand especially due to uncontrolled ventricular rates and this could worsen coronary ischaemia and thus increase mortality especially in the subset of patients with pre-existing ischaemic heart disease [48-50].

2. Vascular

AF contributes to 15-25% of all strokes and these contribute to a significant proportion of AF-related mortality [51, 52]. AF-related strokes tend to be associated with higher mortality, and more severe disability [52, 53]. The Olmsted County study followed up 4117 individuals with AF and reported a 11% incidence of stroke over a mean follow-up period of 5.5±5 years, with AF–related stroke significantly increasing the mortality hazard ratio to 3.03 for men and 3.8 for women in comparison to the general population [18]. The Manitoba follow-up study showed that AF increased cardiovascular mortality including fatal stroke by 41% [11]. Even amongst anti-coagulated patients with therapeutic INR, stroke risk due to AF can be up to 3% in high-risk individuals such as those with prior stroke [54, 55]. Un-coordinated atrial contraction leads to stasis of blood in the left atrium [56]. In addition to this, thrombogenesis is also perpetuated by haematological abnormalities such as platelet activation, inflammation and structural factors such as atrial dilatation, loss of endothelium and progressive fibrosis [56]. The left atrial appendage is the site responsible for the majority of thrombi in non-valvular AF [56]. However, it has been demonstrated that not all thrombo-embolic events necessarily predict mortality risk. For instance, the ACTIVE-W trial showed that only disabling strokes (both ischaemic and haemorrhagic with Rankin score ≥3) increase mortality risk whereas transient ischaemic attacks do not [57]. Major bleeding secondary to anti-coagulation can also contribute to mortality [57].

3. Non-cardiovascular Deaths

Most therapeutic strategies for AF such as anti-arrhythmic drugs, anti-thrombotics and catheter ablation can increase mortality risk in AF as a side-effect or serious adverse event. Anti-arrhythmic drugs can lead to potentially lethal pro-arrhythmic effects (such as torsade de pointes) but also cause multi-systemic side-effects and thus contribute to non-cardiovascular deaths [10, 58, 59]. A rhythm control strategy has also been shown to unmask non-cardiovascular co-morbidities such as malignancies or lung pathology, thus contributing to mortality burden (covered in greater detail in section on AADs) [10, 48]. Bleeding risk is inextricably linked to use of anti-thrombotics and can be fatal. Severe bleeding events (such as fatal events, drop in haemoglobin of at least 5 g/decilitre), need for inotropic agents, loss of vision due to intra-ocular bleeding, surgical intervention due to bleeding, symptomatic intra-cranial haemorrhage, need for transfusion of at least 4 units of blood) treble the mortality risk (HR. 3.35; 95% CI, 2.12-5.27) whilst non-severe major bleeding or minor bleeding events do not increase mortality.

RISK PREDICTION FOR AF-RELATED MORTALITY

In view of the significant mortality risk due to AF and the associated co-morbidities, several useful risk-predictors have been identified. The CHADS₂ Score (1 point each for Congestive Heart Failure, Hypertension, Age≥75 years, Diabetes Mellitus and 2 points for Stroke/TIA) was introduced over a decade back as a scoring system to assess thrombo-embolic risk due to AF [60] but can also predict mortality risk. Khumri et al. showed in a study that patients with CHADS₂ score of ≥5 have a 50 fold higher mortality risk in comparison to patients with a score of 0 [61]. Similarly, while the HAS-BLED score has been mainly used in clinical practice to predict risk of major haemorrhagic episodes due to anti-coagulation [62], this risk score has also been shown to predict adverse cardiovascular events as well as all-cause mortality, thus illustrating that thrombogenesis and haemorrhage are inextricably linked by sharing many common risk predictors [63]. Whilst the CHA₂DS₂Vasc score has been recommended in the latest guidelines to supersede CHADS₂ as a better risk predictor for thrombo-embolic risk, its role as a risk predictor for mortality remains to be established.

Abnormal ankle brachial index (ratio of ankle and brachial systolic blood pressure) has been shown to independently predict all-cause mortality after adjusting for CHADS2 score and also predict major haemorrhagic episodes irrespective of the HAS-BLED score [64]. Cardiovascular related hospitalisation in AF patients also significantly predicts risk of death (HR 2.69; 95% CI 1.96-3.68) and it has been suggested that this end-point could be used as a surrogate for mortality in trials [65].

Clinical investigations also help to identify patients at increased risk of AF-related averse events. Serum bio-markers such as interleukin-6, high sensitivity troponin T and von Willebrand factor have been shown to predict all-cause mortality independent of CHADS2 score in anti-coagulated AF patients, possibly reflecting coronary micro-vascular dysfunction, global endothelial dysfunction or athero-thrombosis [66-68]. High sensitivity CRP has also been shown to predict all-cause and cardiovascular mortality amongst AF patients [69]. Patients with renal failure (eGFR <45 ml/min and proteinuria) have been shown to have increased risk of AF-related thrombo-embolism, bleeding and mortality [70]. Echocardiographic markers such as mitral annular calcification, presence of spontaneous left atrial contrast, severe LV impairment and greater than moderate mitral regurgitation also help to predict increased mortality risk amongst chronic AF patients [61, 71].

TREATMENTS

Anti-arrhythmic Drugs (AADs)

Several AADs have been shown to cause pro-arrhythmic side-effects and thus increased mortality in patients [58]. The class I agent flecainide gained particular attention following the CAST trial [72] where increased mortality was observed in patients with history of myocardial infarction. These results have been extrapolated to extend its contraindication to patients with coronary artery disease, heart failure or left ventricular hypertrophy. Coplen, in a meta-analysis published in 1990, showed that treatment with quinidine was more effective than no anti-arrhythmic therapy in suppressing recurrences of atrial fibrillation but appeared to be associated with increased total mortality [73]. Class III medications such as amiodarone and sotalol, have also received similar attention, and are also well known for their risk of QT prolongation and Torsades de Pointes.

Indeed all AADs have the potential to have serious, pro-arrhythmic side effects [58]. This has implications when determining the optimal treatment strategy for atrial fibrillation (AF): the restoration and maintenance of sinus rhythm (rhythm control strategy) or control of heart rate alone (rate control strategy). Several studies have sought to answer this question, including the Strategies of Treatment of Atrial Fibrillation (STAF) [74], Pharmacological Intervention in Atrial Fibrillation (PIAF) [75], Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) [10], Rate Control vs. Electrical Cardioversion (RACE) [76], the HOT CAFÉ [77] and J-RHYTHM Study [78]. None of these studies has shown any significant difference in all-cause or cardiovascular mortality and stroke outcome between rate and rhythm control and in fact a meta-analysis of five major trials showed a trend towards reduced risk of death (rate vs. rhythm control; OR 0.87, 0.74-1.02- P=0.09) [79]. This has generally led to the adoption of rate control strategy as the pragmatic approach especially in the elderly or in presence of significant co-morbidities.

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) in particular showed a non-significant trend toward increased all-cause mortality in the rhythm control group (hazard ratio 1.14; 95% CI, 1-1.32) [10]. A retrospective analysis of the cause-specific mortality in the AFFIRM trial showed that the incidence of cardiac (including arrhythmic, heart failure and MI deaths) and vascular (including ischaemic and haemorrhagic strokes) deaths was not significantly different between the rhythm control and rate-control groups [48]. Thus the increased all-cause mortality in the rhythm-control group could be entirely accounted for by the significant difference between the incidences of non-cardiovascular deaths (47.5% in rhythm control group versus 36.5% in rate-control group; p=0.0008). These non-cardiovascular deaths were mainly due to malignancies and pneumonia. This was attributed to earlier discontinuation of warfarin and higher incidence of stroke rather than risk of the anti-arrhythmic itself which highlights the importance of anticoagulation in atrial fibrillation. Even in patients with heart failure (LVF<35%) complicated by AF, the AF-CHF trial did not demonstrate that rhythm control could lead to mortality benefit [33]. However, there has been some evidence demonstrating the benefits of rhythm control particularly in the longer term. For instance, a retrospective, “on-treatment analysis” of the AFFIRM study that analysed presence of sinus rhythm and use of anti-arrhythmic drugs as separate variables, showed a significant reduction in death due to presence of sinus rhythm [80]. Thus the mortality increase of 49% due to anti-arrhythmic drugs could have overshadowed the 53% mortality reduction due to maintenance of sinus rhythm [48]. The survival benefits of sinus rhythm were similar to that seen in the DIAMOND AF (dofetilide versus placebo in AF patients with LV dysfunction) study which did not show an all-cause mortality benefit; however, restoration and maintenance of sinus rhythm significantly reduced mortality (risk ratio 0.44; 95% CI 0.30-0.64) and risk of hospitalisation [81]. In a population-based study of rate versus rhythm control strategies among 26, 130 AF patients, showed that the rhythm control group demonstrated a small increase in mortality within six months of treatment initiation which then became similar to mortality in the rate-control group until year 4. In the longer term however (after year 5), the mortality was lower in the rhythm control group in comparison to that in the rate-control group (HR 0.89; 95% CI 0.81-0.96 after 5 years and HR 0.77; 95% CI 0.62-0.95 after 8 years) [82]. From the above studies, it is likely that the pro-arrhythmic effects and multi-systemic side-effects of existing AADs dilute and even offset the survival advantage provided by maintenance of sinus rhythm.

The most commonly used AAD for rhythm control in all these trials was amiodarone, which was shown in the studies to have a low pro-arrhythmic potential, with its adverse side effects being mainly extra-cardiac [59]. Amiodarone has been demonstrated to be the most efficacious drug in maintaining sinus rhythm [59, 79]. Some studies have found it to be associated with an increased risk of non-cardiac mortality (particularly cancer-related and pulmonary) [83-85] whilst this was not observed in other studies [86, 87]. Recently Freemantle et al. included thirty nine randomised controlled trials in a mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide and propafenone used for the management of AF and reported (from eighteen trials including about 10,000 patients) that sotalol in particular was associated with increased mortality whereas amiodarone (but not dronedarone) showed a trend towards increased all-cause mortality [59]. A meta-analysis by Piccini et al. also demonstrated an insignificant trend towards increased mortality due to amiodarone [88].

More recently, there has been the arrival of dronedarone, an AAD developed to have fewer side effects and improved safety profile compared to amiodarone [88]. The EURIDIS and ADONIS trials showed dronedarone was significantly more effective than placebo in maintaining sinus rhythm, and in reducing ventricular rate during recurrence of arrhythmia, with post hoc analysis also suggesting a 44% reduction in cardiovascular hospitalisation or death at 12 months [89]. Although dronedarone is less efficacious than amiodarone [88], a subsequent trial (ATHENA) showed that dronedarone reduces the composite endpoint of cardiovascular hospitalisation or death by 24% [14]. However, subsequent studies have shown that dronedarone can lead to increased early mortality in certain sub-sets of patients. For instance, in the ANDROMEDA trial (Anti-arrhythmic trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease), dronedarone (in comparison with placebo) led to a doubling of mortality (95%CI, 1.07-4.25) due to worsening heart failure after a median follow-up of only 2 months [90] Dronedarone also led to increased cardiovascular deaths (hazard ratio 2.11; 95% CI, 1-4.49), arrhythmic deaths (hazard ratio 3.26; 95% CI, 1.06-10) in addition to increased incidence of stroke and heart failure hospitalisations when used in patients with high-risk permanent AF (PALLAS) [91].

ANTI-COAGULATION

Effective anticoagulation is the most effective method of reducing mortality in AF patients [92]. In the absence of anti-coagulation, AF patients who develop a stroke have a 1 month mortality of nearly 25% [92]. In a meta-analysis of 29 trials of anti-thrombotic therapy for AF, compared to control, adjusted-dose warfarin reduced significantly stroke risk by 64% and all-cause mortality by 26%. Aspirin in contrast showed a non-significant 19% reduction in stroke risk and did not reduce mortality significantly [93]. In addition to anti-coagulation with warfarin, it is also important to closely monitor the therapeutic range of INR closely to both prevent thrombo-embolic complications as well as avoid major bleeding complications. Patients who spend at least 70% of the time with INR within therapeutic range demonstrate significantly lower mortality compared to patients whose INR is therapeutic <70% of the time [94]. Analysis of 30-day mortality due to ischaemic stoke whilst on warfarin, has shown that warfarin significantly reduces 30 day mortality if INR is between 2-3 (OR 0.38; 955 CI, 0.2-0.7) but patients with INR>3 demonstrate increased odds of mortality due to intra-cranial haemorrhage 2.66 fold (95% CI, 1.21-5.86) [95].

Despite the obvious benefits of warfarin, the ATRIA study showed that it was being under-prescribed, particularly in those AF patients below 55 years and above 85 years, presumably due to physicians’ concerns regarding bleeding risk [96]. Interestingly, in contrast to this predominant view held by most physicians, patients are willing to accept the higher risk of bleeding associated with anti-coagulants in order to avoid disabling strokes which some even view as worse than death [97]. The search for more efficacious and potentially safer anti-thrombotics has heralded the era of novel anti-coagulants, as detailed below.

In the RELY study [98], dabigatran, a novel oral direct thrombin inhibitor, given at a dose of 110 mg to AF patients, was associated with rates of stroke and systemic embolism similar to warfarin, but with lower rates of major haemorrhage, whilst at doses of 150 mg, it was associated with lower rates of stroke and systemic embolism compared to warfarin, and similar rates of major haemorrhage. There was a trend towards reduction in all-cause mortality with the 150 mg dose (p=0.051) and a significant reduction in vascular mortality (p=0.04). The rates of death from any cause were 4.13% per year with warfarin, compared with 3.75% per year with 110 mg dabigatran (P=0.13), and 3.64% with 150 mg dabigatran (P=0.051). A meta-analysis of seven dabigatran studies (including 30514 patients) also showed a 11% reduction in all-cause mortality in comparison to warfarin [99].

Following this there has been the addition of the oral factor Xa inhibitors: rivaroxaban, assessed by the ROCKET-AF trial [100]; and apixaban, analysed by the AVERROES [16] and ARISTOTLE [101] trials. In the ROCKET-AF trial, in comparison with warfarin for non-valvular AF, rivaroxaban was shown to be non-inferior for prevention of stroke or systemic embolism. There was no significant difference in risk of major bleeding, though intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. There was no significant difference in mortality between the two groups. In the ARISTOTLE trial, apixaban was shown to be superior to warfarin by reducing the risk of stroke or systemic embolism by 21%, major bleeding by 31% and all-cause mortality by 11% [101].

The future for these novel anticoagulants is very promising, with significant progress being made in morbidity and mortality reduction compared to warfarin, mainly by way of further reduction in ischaemic strokes and less bleeding risks. However there are also several concerns regarding the use of the newer anticoagulants as detailed below. These include the lack of robust safety data in patients with creatinine clearance <30 ml/min, elderly patients and those with extremes of body weight. Whilst the lack of need to closely monitor anticoagulation whilst on newer anticoagulants can be viewed as an advantage by reducing patient inconvenience as well as the burden on healthcare resources, this feature can also be a disadvantage if patients miss one or more doses (due to the short offset time of these drugs leading to a rebound stroke risk). Additionally the lack of a specific antidote to these drugs is also of concern during major bleeding episodes. Thus there is a need for further studies in order to clarify the above concerns about these drugs before they can be incorporated into widespread clinical practice.

INTERVENTIONAL TREATMENTS

Catheter ablation is recommended in the management of symptomatic paroxysmal AF after failed AAD therapy and has not yet been demonstrated to confer mortality benefits possibly due to lack of long-term follow-up data. Being an invasive procedure, the procedure itself carries a mortality risk of up to 0.7% [2]. However, newer technological developments are consistently improving the safety and efficacy of catheter-based techniques. Left atrial appendage closure using occlusion devices has been suggested as an alternative for patients deemed unsuitable for oral anti-coagulation and again data on mortality benefits from this procedure is lacking currently.

CONCLUSIONS

AF and its associated co-morbidities continue to impose a significant mortality risk despite several new therapeutic advances. Indeed a proportion of the AF-related mortality is caused by side-effects due to attempts at restoring and maintaining sinus rhythm or major bleeding due to anti-coagulation. However effective anti-coagulation is the only therapeutic strategy that has been shown to reduce AF-related mortality and newer anticoagulants with improved efficacy and lesser bleeding side-effects, are only likely to improve the risk-benefit profile. Currently available AADs have limited efficacy and possess significant side-effects which seem to offset benefits of rhythm control; hence there is a pressing need to develop improved AADs in order to unmask the survival benefit that could accrue from maintenance of sinus rhythm. The impact of catheter ablation in the management of AF has currently been increasing and with improvements in safety and efficacy, is likely to reduce the use of AADs in the future.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

References

1. Feinberg W.M., Cornell E.S., Nightingale S.D., Pearce L.A., Tracy R.P., Hart R.G., Bovill E.G., et al. Stroke Prevention in Atrial Fibrillation Investigators. Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke. 1997;28(6):1101–1106. doi: 10.1161/01.STR.28.6.1101. [PubMed] [CrossRef] [Google Scholar]2. Camm A.J., Kirchhof P., Lip G.Y., Schotten U., Savelieva I., Ernst S., Van Gelder I.C., Al-Attar N., Hindricks G., Prendergast B., Heidbuchel H., Alfieri O., Angelini A., Atar D., Colonna P., De Caterina R., De Sutter J., Goette A., Gorenek B., Heldal M., Hohloser S.H., Kolh P., Le Heuzey J.Y., Ponikowski P., Rutten F.H., et al. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J. 2010;31(19):2369–2429. doi: 10.1093/eurheartj/ehq278. [PubMed] [CrossRef] [Google Scholar]3. Stewart S., Hart C.L., Hole D.J., McMurray J.J., et al. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am. J. Med. 2002;113(5):359–364. doi: 10.1016/S0002-9343(02)01236-6. [PubMed] [CrossRef] [Google Scholar]4. Kirchhof P., Auricchio A., Bax J., Crijns H., Camm J., Diener H.C., Goette A., Hindricks G., Hohnloser S., Kappenberger L., Kuck K.H., Lip G.Y., Olsson B., Meinertz T., Priori S., Ravens U., Steinbeck G., Svernhage E., Tijssen J., Vincent A., Breithardt G., et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur. Heart J. 2007;28(22):2803–2817. doi: 10.1093/eurheartj/ehm358. [PubMed] [CrossRef] [Google Scholar]5. Benjamin E.J., Wolf P.A., D’Agostino R.B., Silbershatz H., Kannel W.B., Levy D., et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946–952. doi: 10.1161/01.CIR.98.10.946. [PubMed] [CrossRef] [Google Scholar]6. Vidaillet H., Granada J.F., Chyou Po., Maassen K., Ortiz M., Pulido J.N., Sharma P., Smith P.N., Hayes J., et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am. J. Med. 2002;113(5):365–370. doi: 10.1016/S0002-9343(02)01253-6. [PubMed] [CrossRef] [Google Scholar]7. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A., et al. Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC Cardiovasc. Disord. 2002;2:5. doi: 10.1186/1471-2261-2-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]8. Miyasaka Y., Barnes M.E., Bailey K.R., Cha S.S., Gersh B.J., Seward J.B., Tsang T.S., et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J. Am. Coll. Cardiol. 2007;49(9):986–992. doi: 10.1016/j.jacc.2006.10.062. [PubMed] [CrossRef] [Google Scholar]9. Olsson S.B. Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691–1698. doi: 10.1016/S0140-6736(03)14841-6. [PubMed] [CrossRef] [Google Scholar]10. Wyse D.G., Waldo A.L., DiMarco J.P., Domanski M.J., Rosenberg Y., Schron E.B., Kellen J.C., Greene H.L., Mickel M.C., Dalquist J.E., Corley S.D., et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 2002;347(23):1825–1833. doi: 10.1056/NEJMoa021328. [PubMed] [CrossRef] [Google Scholar]11. Krahn A.D., Manfreda J., Tate R.B., Mathewson F.A., Cuddy T.E., et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am. J. Med. 1995;98(5):476–484. doi: 10.1016/S0002-9343(99)80348-9. [PubMed] [CrossRef] [Google Scholar]12. Gajewski J., Singer R.B. Mortality in an insured population with atrial fibrillation. JAMA. 1981;245(15):1540–1544. doi: 10.1001/jama.1981.03310400022019. [PubMed] [CrossRef] [Google Scholar]13. Piccini J.P., Hammill B.G., Sinner M.F., Jensen P.N., Hernandez A.F., Heckbert S.R., Benjamin E.J., Curtis L.H., et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5(1):85–93. doi: 10.1161/CIRCOUTCOMES.111.962688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]14. Hohnloser S.H., Crijns H.J., van Eickels M., Gaudin C., Page R.L., Torp-Pedersen C., Connolly S.J., et al. ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 2009;360(7):668–678. doi: 10.1056/NEJMoa0803778. [PubMed] [CrossRef] [Google Scholar]15. Go A.S., et al. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N. Engl. J. Med. 2009;360(20):2127–2129. doi: 10.1056/NEJMe0902676. [PubMed] [CrossRef] [Google Scholar]16. Connolly S.J., Eikelboom J., Joyner C., Diener H.C., Hart R., Golitsyn S., Flaker G., Avezum A., Hohnloser S.H., Diaz R., Talajic M., Zhu J., Pais P., Budaj A., Parkhomenko A., Jansky P., Commerford P., Tan R.S., Sim K.H., Lewis B.S., Van Mieghem W., Lip G.Y., Kim J.H., Lanas-Zanetti F., Gonzalez-Hermosillo A., Dans A.L., Munawar M., O’Donnell M., Lawrence J., Lewis G., Afzal R., Yusuf S., et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 2011;364(9):806–817. doi: 10.1056/NEJMoa1007432. [PubMed] [CrossRef] [Google Scholar]17. Arias E., et al. National vital statistics reports. Hyattsville, MD: National Centre for Health Statistics; 2010. United States Life Tables 2006. Report No. [Google Scholar]18. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Seward J.B., Bailey K.R., Iwasaka T., Tsang T.S., et al. Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study. Stroke. 2005;36(11):2362–2366. doi: 10.1161/01.STR.0000185927.63746.23. [PubMed] [CrossRef] [Google Scholar]19. Turagam M.K., Velagapudi P., Visotcky A., Szabo A., Kocheril A.G., et al. African Americans have the highest risk of in-hospital mortality with atrial fibrillation related hospitalizations among all racial/ethnic groups: a nationwide analysis. Int. J. Cardiol. 2012;158(1):165–166. doi: 10.1016/j.ijcard.2012.04.090. [PubMed] [CrossRef] [Google Scholar]20. Rosiak M., Dziuba M., Chudzik M., Cygankiewicz I., Bartczak K., Drozdz J., Wranicz J.K., et al. Risk factors for atrial fibrillation: Not always severe heart disease, not always so ‘lonely’. Cardiol. J. 2010;17(5):437–442. [PubMed] [Google Scholar]21. Kopecky S.L., Gersh B.J., McGoon M.D., Whisnant J.P., Holmes D.R., Jr, Ilstrup D.M., Frye R.L., et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N. Engl. J. Med. 1987;317(11):669–674. doi: 10.1056/NEJM198709103171104. [PubMed] [CrossRef] [Google Scholar]22. Rostagno C., Bacci F., Martelli M., Naldoni A., Bertini G., Gensini G., et al. Clinical course of lone atrial fibrillation since first symptomatic arrhythmic episode. Am. J. Cardiol. 1995;76(11):837–839. doi: 10.1016/S0002-9149(99)80240-9. [PubMed] [CrossRef] [Google Scholar]23. Potpara T., Grujić M., Marinković J., Vujisić-Tesić B., Ostojić M., Polovina M., et al. Mortality of patients with lone and idiopathic atrial fibrillation is similar to mortality in general population of Serbia. Vojnosanit. Pregl. 2010;67(2):132–135. doi: 10.2298/VSP1002132P. [PubMed] [CrossRef] [Google Scholar]24. Botto G.L., Padeletti L., Santini M., Capucci A., Gulizia M., Zolezzi F., Favale S., Molon G., Ricci R., Biffi M., Russo G., Vimercati M., Corbucci G., Boriani G., et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J. Cardiovasc. Electrophysiol. 2009;20(3):241–248. doi: 10.1111/j.1540-8167.2008.01320.x. [PubMed] [CrossRef] [Google Scholar]25. Lip G.Y., Hee F.L. Paroxysmal atrial fibrillation. QJM. 2001;94(12):665–678. doi: 10.1093/qjmed/94.12.665. [PubMed] [CrossRef] [Google Scholar]26. Keating R.J., Gersh B.J., Hodge D.O., Weivoda P.L., Patel P.J., Hammill S.C., Shen W.K., et al. Effect of atrial fibrillation pattern on survival in a community-based cohort. Am. J. Cardiol. 2005;96(10):1420–1424. doi: 10.1016/j.amjcard.2005.07.050. [PubMed] [CrossRef] [Google Scholar]27. Ruigómez A., Johansson S., Wallander M.A., García Rodríguez L.A. Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc. Disord. 2005;5:20. doi: 10.1186/1471-2261-5-20. [PMC free article] [PubMed] [CrossRef] [Google Scholar]28. Tuinenburg A.E., Van Gelder I.C., Van Den Berg M.P., Brügemann J., De Kam P.J., Crijns H.J., et al. Lack of prevention of heart failure by serial electrical cardioversion in patients with persistent atrial fibrillation. Heart. 1999;82(4):486–493. doi: 10.1136/hrt.82.4.486. [PMC free article] [PubMed] [CrossRef] [Google Scholar]29. Brown A.M., Sease K.L., Robey J.L., Shofer F.S., Hollander J.E., et al. The risk for acute coronary syndrome associated with atrial fibrillation among ED patients with chest pain syndromes. Am. J. Emerg. Med. 2007;25(5):523–528. doi: 10.1016/j.ajem.2006.09.015. [PubMed] [CrossRef] [Google Scholar]30. Sankaranarayanan R., et al. Mortality Risk Associated with AF in Myocardial Infarction Patients. J. Atr. Fibrillation. 2012;5(3):138–152. [PMC free article] [PubMed] [Google Scholar]31. Sankaranarayanan R., James M.A., Nuta B., Townsend M., Kesavan S., Burtchaell S., Holloway R., Ewings P., et al. Does atrial fibrillation beget ventricular fibrillation in patients with acute myocardial infarction? Pacing Clin. Electrophysiol. 2008;31(12):1612–1619. doi: 10.1111/j.1540-8159.2008.01234.x. [PubMed] [CrossRef] [Google Scholar]32. Lehto M., Snapinn S., Dickstein K., Swedberg K., Nieminen M.S., et al. OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience. Eur. Heart J. 2005;26(4):350–356. doi: 10.1093/eurheartj/ehi064. [PubMed] [CrossRef] [Google Scholar]33. Roy D., Talajic M., Nattel S., Wyse D.G., Dorian P., Lee K.L., Bourassa M.G., Arnold J.M., Buxton A.E., Camm A.J., Connolly S.J., Dubuc M., Ducharme A., Guerra P.G., Hohnloser S.H., Lambert J., Le Heuzey J.Y., O’Hara G., Pedersen O.D., Rouleau J.L., Singh B.N., Stevenson L.W., Stevenson W.G., Thibault B., Waldo A.L., et al. Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N. Engl. J. Med. 2008;358(25):2667–2677. doi: 10.1056/NEJMoa0708789. [PubMed] [CrossRef] [Google Scholar]34. Caldwell J.C., Contractor H., Petkar S., Ali R., Clarke B., Garratt C.J., Neyses L., Mamas M.A., et al. Atrial fibrillation is under-recognized in chronic heart failure: insights from a heart failure cohort treated with cardiac resynchronization therapy. Europace. 2009;11(10):1295–1300. doi: 10.1093/europace/eup201. [PubMed] [CrossRef] [Google Scholar]35. Miyasaka Y., Barnes M.E., Gersh B.J., Cha S.S., Bailey K.R., Abhayaratna W., Seward J.B., Iwasaka T., Tsang T.S., et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: a community-based study over two decades. Eur. Heart J. 2006;27(8):936–941. doi: 10.1093/eurheartj/ehi694. [PubMed] [CrossRef] [Google Scholar]36. Wang T.J., Larson M.G., Levy D., Vasan R.S., Leip E.P., Wolf P.A., D’Agostino R.B., Murabito J.M., Kannel W.B., Benjamin E.J., et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920–2925. doi: 10.1161/01.CIR.0000072767.89944.6E. [PubMed] [CrossRef] [Google Scholar]37. Olsson L.G., Swedberg K., Ducharme A., Granger C.B., Michelson E.L., McMurray J.J., Puu M., Yusuf S., Pfeffer M.A., et al. CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J. Am. Coll. Cardiol. 2006;47(10):1997–2004. doi: 10.1016/j.jacc.2006.01.060. [PubMed] [CrossRef] [Google Scholar]38. Rivero-Ayerza M., Scholte Op Reimer W., Lenzen M., Theuns D.A., Jordaens L., Komajda M., Follath F., Swedberg K., Cleland J.G., et al. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalized heart failure patients: results of the EuroHeart Failure Survey. Eur. Heart J. 2008;29(13):1618–1624. doi: 10.1093/eurheartj/ehn217. [PubMed] [CrossRef] [Google Scholar]39. Dries D.L., Exner D.V., Gersh B.J., Domanski M.J., Waclawiw M.A., Stevenson L.W., et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J. Am. Coll. Cardiol. 1998;32(3):695–703. doi: 10.1016/S0735-1097(98)00297-6. [PubMed] [CrossRef] [Google Scholar]40. Mahoney P., Kimmel S., DeNofrio D., Wahl P., Loh E., et al. Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure. Am. J. Cardiol. 1999;83(11):1544–1547. doi: 10.1016/S0002-9149(99)00144-7. [PubMed] [CrossRef] [Google Scholar]41. Mamas M.A., Caldwell J.C., Chacko S., Garratt C.J., Fath-Ordoubadi F., Neyses L., et al. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur. J. Heart Fail. 2009;11(7):676–683. doi: 10.1093/eurjhf/hfp085. [PubMed] [CrossRef] [Google Scholar]42. Raunsø J., Pedersen O.D., Dominguez H., Hansen M.L., Møller J.E., Kjaergaard J., Hassager C., Torp-Pedersen C., Køber L., et al. EchoCardiography and Heart Outcome Study Investigators. Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease. Eur. J. Heart Fail. 2010;12(7):692–697. doi: 10.1093/eurjhf/hfq052. [PubMed] [CrossRef] [Google Scholar]43. Badheka A.O., Rathod A., Kizilbash M.A., Bhardwaj A., Ali O., Afonso L., Jacob S., et al. Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction. Am. J. Cardiol. 2011;108(9):1283–1288. doi: 10.1016/j.amjcard.2011.06.045. [PubMed] [CrossRef] [Google Scholar]44. Domanski M.J., et al. The epidemiology of atrial fibrillation. Coron. Artery Dis. 1995;6(2):95–100. doi: 10.1097/00019501-199502000-00002. [PubMed] [CrossRef] [Google Scholar]45. Cha Y.M., Redfield M.M., Shen W.K., Gersh B.J., et al. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation. 2004;109(23):2839–2843. doi: 10.1161/01.CIR.0000132470.78896.A8. [PubMed] [CrossRef] [Google Scholar]46. Daoud E.G., Weiss R., Bahu M., Knight B.P., Bogun F., Goyal R., Harvey M., Strickberger S.A., Man K.C., Morady F., et al. Effect of an irregular ventricular rhythm on cardiac output. Am. J. Cardiol. 1996;78(12):1433–1436. doi: 10.1016/S0002-9149(97)89297-1. [PubMed] [CrossRef] [Google Scholar]47. Shinbane J.S., Wood M.A., Jensen D.N., Ellenbogen K.A., Fitzpatrick A.P., Scheinman M.M., et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J. Am. Coll. Cardiol. 1997;29(4):709–715. doi: 10.1016/S0735-1097(96)00592-X. [PubMed] [CrossRef] [Google Scholar]48. Steinberg J.S., Sadaniantz A., Kron J., Krahn A., Denny D.M., Daubert J., Campbell W.B., Havranek E., Murray K., Olshansky B., O’Neill G., Sami M., Schmidt S., Storm R., Zabalgoitia M., Miller J., Chandler M., Nasco E.M., Greene H.L., et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation. 2004;109(16):1973–1980. doi: 10.1161/01.CIR.0000118472.77237.FA. [PubMed] [CrossRef] [Google Scholar]49. Fuster V., Rydén L.E., Cannom D.S., Crijns H.J., Curtis A.B., Ellenbogen K.A., Halperin J.L., Kay G.N., Le Huezey J.Y., Lowe J.E., Olsson S.B., Prystowsky E.N., Tamargo J.L., Wann L.S., et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2011;57(11):e101–e198. doi: 10.1016/j.jacc.2010.09.013. [PubMed] [CrossRef] [Google Scholar]50. Stein K.M., Euler D.E., Mehra R., Seidl K., Slotwiner D.J., Mittal S., Markowitz S.M., Lerman B.B. Jewel AF Worldwide Investigators. Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients? J. Am. Coll. Cardiol. 2002;40(2):335–340. doi: 10.1016/S0735-1097(02)01957-5. [PubMed] [CrossRef] [Google Scholar]51. Grau A.J., Weimar C., Buggle F., Heinrich A., Goertler M., Neumaier S., Glahn J., Brandt T., Hacke W., Diener H.C., et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559–2566. doi: 10.1161/hs1101.098524. [PubMed] [CrossRef] [Google Scholar]52. Kimura K., Minematsu K., Yamaguchi T., et al. Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC) Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with acute ischaemic stroke. J. Neurol. Neurosurg. Psychiatry. 2005;76(5):679–683. doi: 10.1136/jnnp.2004.048827. [PMC free article] [PubMed] [CrossRef] [Google Scholar]53. Jørgensen H.S., Nakayama H., Reith J., Raaschou H.O., Olsen T.S. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke. 1996;27(10):1765–1769. doi: 10.1161/01.STR.27.10.1765. [PubMed] [CrossRef] [Google Scholar]54. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255–1262. [PubMed] [Google Scholar]55. Akins P.T., Feldman H.A., Zoble R.G., Newman D., Spitzer S.G., Diener H.C., Albers G.W. Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials. Stroke. 2007;38(3):874–880. doi: 10.1161/01.STR.0000258004.64840.0b. [PubMed] [CrossRef] [Google Scholar]56. Watson T., Shantsila E., Lip G.Y. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373(9658):155–166. doi: 10.1016/S0140-6736(09)60040-4. [PubMed] [CrossRef] [Google Scholar]57. De Caterina R., Connolly S.J., Pogue J., Chrolavicius S., Budaj A., Morais J., Renda G., Yusuf S. ACTIVE Investigators. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur. Heart J. 2010;31(17):2133–2140. doi: 10.1093/eurheartj/ehq250. [PubMed] [CrossRef] [Google Scholar]58. Nattel S. Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Cardiovasc. Res. 1998;37(3):567–577. doi: 10.1016/S0008-6363(97)00293-9. [PubMed] [CrossRef] [Google Scholar]59. Freemantle N., Lafuente-Lafuente C., Mitchell S., Eckert L., Reynolds M. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace. 2011;13(3):329–345. doi: 10.1093/europace/euq450. [PubMed] [CrossRef] [Google Scholar]60. Gage B.F., Waterman A.D., Shannon W., Boechler M., Rich M.W., Radford M.J., et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–2870. doi: 10.1001/jama.285.22.2864. [PubMed] [CrossRef] [Google Scholar]61. Khumri T.M., Idupulapati M., Rader V.J., Nayyar S., Stoner C.N., Main M.L., et al. Clinical and echocardiographic markers of mortality risk in patients with atrial fibrillation. Am. J. Cardiol. 2007;99(12):1733–1736. doi: 10.1016/j.amjcard.2007.01.055. [PubMed] [CrossRef] [Google Scholar]62. Pisters R., Lane D.A., Nieuwlaat R., de Vos C.B., Crijns H.J., Lip G.Y., et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100. doi: 10.1378/chest.10-0134. [PubMed] [CrossRef] [Google Scholar]63. Gallego P., Roldán V., Torregrosa J.M., Gálvez J., Valdés M., Vicente V., Marín F., Lip G.Y., et al. Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation. Circ Arrhythm Electrophysiol. 2012;5(2):312–318. doi: 10.1161/CIRCEP.111.967000. [PubMed] [CrossRef] [Google Scholar]64. Gallego P., Roldán V., Marín F., Jover E., Manzano-Fernández S., Valdés M., Vicente V., Lip G.Y., et al. Ankle brachial index as an independent predictor of mortality in anticoagulated atrial fibrillation. Eur. J. Clin. Invest. 2012;42(12):1302–1308. doi: 10.1111/eci.12004. [PubMed] [CrossRef] [Google Scholar]65. Friberg L., Rosenqvist M., et al. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace. 2011;13(5):626–633. doi: 10.1093/europace/eur001. [PubMed] [CrossRef] [Google Scholar]66. Roldán V., Marín F., Díaz J., Gallego P., Jover E., Romera M., Manzano-Fernández S., Casas T., Valdés M., Vicente V., Lip G.Y., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation. J. Thromb. Haemost. 2012;10(8):1500–1507. doi: 10.1111/j.1538-7836.2012.04812.x. [PubMed] [CrossRef] [Google Scholar]67. Providencia R., et al. High sensitivity cardiac troponin T and interleukin-6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation: a rebuttal . J Thromb Haemost. 2012;10(11):2413–1507. author reply 2014-5. [PubMed] [Google Scholar]68. Roldán V., Marín F., Muiña B., Torregrosa J.M., Hernández-Romero D., Valdés M., Vicente V., Lip G.Y., et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J. Am. Coll. Cardiol. 2011;57(25):2496–2504. doi: 10.1016/j.jacc.2010.12.033. [PubMed] [CrossRef] [Google Scholar]69. Hermida J., Lopez F.L., Montes R., Matsushita K., Astor B.C., Alonso A., et al. Usefulness of high-sensitivity C-reactive protein to predict mortality in patients with atrial fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study). Am. J. Cardiol. 2012;109(1):95–99. doi: 10.1016/j.amjcard.2011.08.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]70. Go A.S., Fang M.C., Udaltsova N., Chang Y., Pomernacki N.K., Borowsky L., Singer D.E., et al. ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119(10):1363–1369. doi: 10.1161/CIRCULATIONAHA.108.816082. [PMC free article] [PubMed] [CrossRef] [Google Scholar]71. Potpara T.S., Vasiljevic Z.M., Vujisic-Tesic B.D., Marinkovic J.M., Polovina M.M., Stepanovic J.M., Stankovic G.R., Ostojic M.C., Lip G.Y., et al. Mitral annular calcification predicts cardiovascular morbidity and mortality in middle-aged patients with atrial fibrillation: the Belgrade Atrial Fibrillation Study. Chest. 2011;140(4):902–910. doi: 10.1378/chest.10-2963. [PubMed] [CrossRef] [Google Scholar]72. Echt D.S., Liebson P.R., Mitchell L.B., Peters R.W., Obias-Manno D., Barker A.H., Arensberg D., Baker A., Friedman L., Greene H.L., et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 1991;324(12):781–788. doi: 10.1056/NEJM199103213241201. [PubMed] [CrossRef] [Google Scholar]73. Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation. 1990;82(4):1106–1116. doi: 10.1161/01.CIR.82.4.1106. [PubMed] [CrossRef] [Google Scholar]74. Carlsson J., Miketic S., Windeler J., Cuneo A., Haun S., Micus S., Walter S., Tebbe U., et al. STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J. Am. Coll. Cardiol. 2003;41(10):1690–1696. doi: 10.1016/S0735-1097(03)00332-2. [PubMed] [CrossRef] [Google Scholar]75. Hohnloser S.H., Kuck K.H., Lilienthal J., et al. Rhythm or rate control in atrial fibrillation–Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356(9244):1789–1794. doi: 10.1016/S0140-6736(00)03230-X. [PubMed] [CrossRef] [Google Scholar]76. Van Gelder I.C., Hagens V.E., Bosker H.A., Kingma J.H., Kamp O., Kingma T., Said S.A., Darmanata J.I., Timmermans A.J., Tijssen J.G., Crijns H.J., et al. Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N. Engl. J. Med. 2002;347(23):1834–1840. doi: 10.1056/NEJMoa021375. [PubMed] [CrossRef] [Google Scholar]77. Opolski G., Torbicki A., Kosior D.A., Szulc M., Wozakowska-Kaplon B., Kolodziej P., Achremczyk P., et al. Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest. 2004;126(2):476–486. doi: 10.1378/chest.126.2.476. [PubMed] [CrossRef] [Google Scholar]78. Ogawa S., Yamashita T., Yamazaki T., Aizawa Y., Atarashi H., Inoue H., Ohe T., Ohtsu H., Okumura K., Katoh T., Kamakura S., Kumagai K., Kurachi Y., Kodama I., Koretsune Y., Saikawa T., Sakurai M., Sugi K., Tabuchi T., Nakaya H., Nakayama T., Hirai M., Fukatani M., Mitamura H., et al. J-RHYTHM Investigators. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ. J. 2009;73(2):242–248. doi: 10.1253/circj.CJ-08-0608. [PubMed] [CrossRef] [Google Scholar]79. Testa L., Biondi-Zoccai G.G., Dello Russo A., Bellocci F., Andreotti F., Crea F., et al. Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis. Eur. Heart J. 2005;26(19):2000–2006. doi: 10.1093/eurheartj/ehi306. [PubMed] [CrossRef] [Google Scholar]80. Corley S.D., Epstein A.E., DiMarco J.P., Domanski M.J., Geller N., Greene H.L., Josephson R.A., Kellen J.C., Klein R.C., Krahn A.D., Mickel M., Mitchell L.B., Nelson J.D., Rosenberg Y., Schron E., Shemanski L., Waldo A.L., Wyse D.G., et al. AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–1513. doi: 10.1161/01.CIR.0000121736.16643.11. [PubMed] [CrossRef] [Google Scholar]81. Pedersen O.D., Brendorp B., Elming H., Pehrson S., Køber L., Torp-Pedersen C., et al. Does conversion and prevention of atrial fibrillation enhance survival in patients with left ventricular dysfunction? Evidence from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide/(DIAMOND) study. Card. Electrophysiol. Rev. 2003;7(3):220–224. doi: 10.1023/B:CEPR.0000012386.82055.81. [PubMed] [CrossRef] [Google Scholar]82. Ionescu-Ittu R., Abrahamowicz M., Jackevicius C.A., Essebag V., Eisenberg M.J., Wynant W., Richard H., Pilote L., et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch. Intern. Med. 2012;172(13):997–1004. doi: 10.1001/archinternmed.2012.2266. [PubMed] [CrossRef] [Google Scholar]83. Bardy G.H., Lee K.L., Mark D.B., Poole J.E., Packer D.L., Boineau R., Domanski M., Troutman C., Anderson J., Johnson G., McNulty S.E., Clapp-Channing N., Davidson-Ray L.D., Fraulo E.S., Fishbein D.P., Luceri R.M., Ip J.H., et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 2005;352(3):225–237. doi: 10.1056/NEJMoa043399. [PubMed] [CrossRef] [Google Scholar]84. Julian D.G., Camm A.J., Frangin G., Janse M.J., Munoz A., Schwartz P.J., Simon P., et al. European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet. 1997;349(9053):667–674. doi: 10.1016/S0140-6736(96)09145-3. [PubMed] [CrossRef] [Google Scholar]85. Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J. Am. Coll. Cardiol. 1999;34(5):1552–1559. doi: 10.1016/S0735-1097(99)00376-9. [PubMed] [CrossRef] [Google Scholar]86. Singh S.N., Fletcher R.D., Fisher S.G., Singh B.N., Lewis H.D., Deedwania P.C., Massie B.M., Colling C., Lazzeri D., et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N. Engl. J. Med. 1995;333(2):77–82. doi: 10.1056/NEJM199507133330201. [PubMed] [CrossRef] [Google Scholar]87. Cairns J.A., Connolly S.J., Roberts R., Gent M., et al. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet. 1997;349(9053):675–682. doi: 10.1016/S0140-6736(96)08171-8. [PubMed] [CrossRef] [Google Scholar]88. Piccini J.P., Hasselblad V., Peterson E.D., Washam J.B., Califf R.M., Kong D.F., et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J. Am. Coll. Cardiol. 2009;54(12):1089–1095. doi: 10.1016/j.jacc.2009.04.085. [PubMed] [CrossRef] [Google Scholar]89. Duray G.Z., Torp-Pedersen C., Connolly S.J., Hohnloser S.H., et al. Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. J. Cardiovasc. Electrophysiol. 2011;22(7):770–776. doi: 10.1111/j.1540-8167.2010.02006.x. [PubMed] [CrossRef] [Google Scholar]90. Køber L., Torp-Pedersen C., McMurray J.J., Gøtzsche O., Lévy S., Crijns H., Amlie J., Carlsen J., et al. Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 2008;358(25):2678–2687. doi: 10.1056/NEJMoa0800456. [PubMed] [CrossRef] [Google Scholar]91. Connolly S.J., Camm A.J., Halperin J.L., Joyner C., Alings M., Amerena J., Atar D., Avezum Á., Blomström P., Borggrefe M., Budaj A., Chen S.A., Ching C.K., Commerford P., Dans A., Davy J.M., Delacrétaz E., Di Pasquale G., Diaz R., Dorian P., Flaker G., Golitsyn S., Gonzalez-Hermosillo A., Granger C.B., Heidbüchel H., Kautzner J., Kim J.S., Lanas F., Lewis B.S., Merino J.L., Morillo C., Murin J., Narasimhan C., Paolasso E., Parkhomenko A., Peters N.S., Sim K.H., Stiles M.K., Tanomsup S., Toivonen L., Tomcsányi J., Torp-Pedersen C., Tse H.F., Vardas P., Vinereanu D., Xavier D., Zhu J., Zhu J.R., Baret-Cormel L., Weinling E., Staiger C., Yusuf S., Chrolavicius S., Afzal R., Hohnloser S.H. PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med. 2011;365(24):2268–2276. doi: 10.1056/NEJMoa1109867. [PubMed] [CrossRef] [Google Scholar]92. Hylek E.M., Go A.S., Chang Y., Jensvold N.G., Henault L.E., Selby J.V., Singer D.E. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med. 2003;349(11):1019–1026. doi: 10.1056/NEJMoa022913. [PubMed] [CrossRef] [Google Scholar]93. Hart R.G., Pearce L.A., Aguilar M.I. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann. Intern. Med. 2007;147(8):590–592. doi: 10.7326/0003-4819-147-8-200710160-00018. [PubMed] [CrossRef] [Google Scholar]94. Gallagher A.M., Setakis E., Plumb J.M., Clemens A., van Staa T.P., et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb. Haemost. 2011;106(5):968–977. doi: 10.1160/Th21-05-0353. [PubMed] [CrossRef] [Google Scholar]95. Fang M.C., Go A.S., Chang Y., Borowsky L.H., Pomernacki N.K., Udaltsova N., Singer D.E., et al. Thirty-day mortality after ischemic stroke and intracranial hemorrhage in patients with atrial fibrillation on and off anticoagulants. Stroke. 2012;43(7):1795–1799. doi: 10.1161/STROKEAHA.111.630731. [PMC free article] [PubMed] [CrossRef] [Google Scholar]96. Go A.S., Hylek E.M., Borowsky L.H., Phillips K.A., Selby J.V., Singer D.E., et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann. Intern. Med. 1999;131(12):927–934. doi: 10.7326/0003-4819-131-12-199912210-00004. [PubMed] [CrossRef] [Google Scholar]97. Devereaux P.J., Anderson D.R., Gardner M.J., Putnam W., Flowerdew G.J., Brownell B.F., Nagpal S., Cox J.L., et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ. 2001;323(7323):1218–1222. doi: 10.1136/bmj.323.7323.1218. [PMC free article] [PubMed] [CrossRef] [Google Scholar]98. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., Pogue J., Reilly P.A., Themeles E., Varrone J., Wang S., Alings M., Xavier D., Zhu J., Diaz R., Lewis B.S., Darius H., Diener H.C., Joyner C.D., Wallentin L., et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009;361(12):1139–1151. doi: 10.1056/NEJMoa0905561. [PubMed] [CrossRef] [Google Scholar]99. Uchino K., Hernandez A.V., et al. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch. Intern. Med. 2012;172(5):397–402. doi: 10.1001/archinternmed.2011.1666. [PubMed] [CrossRef] [Google Scholar]100. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., Breithardt G., Halperin J.L., Hankey G.J., Piccini J.P., Becker R.C., Nessel C.C., Paolini J.F., Berkowitz S.D., Fox K.A., Califf R.M., et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011;365(10):883–891. doi: 10.1056/NEJMoa1009638. [PubMed] [CrossRef] [Google Scholar]101. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M., Al-Khalidi H.R., Ansell J., Atar D., Avezum A., Bahit M.C., Diaz R., Easton J.D., Ezekowitz J.A., Flaker G., Garcia D., Geraldes M., Gersh B.J., Golitsyn S., Goto S., Hermosillo A.G., Hohnloser S.H., Horowitz J., Mohan P., Jansky P., Lewis B.S., Lopez-Sendon J.L., Pais P., Parkhomenko A., Verheugt F.W., Zhu J., Wallentin L., et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011;365(11):981–992. doi: 10.1056/NEJMoa1107039. [PubMed] [CrossRef] [Google Scholar]

Life expectancy with AFib | Atrial Fibrillation Centers of America

It is common to have an irregular heartbeat. Research shows that over three million people in America are diagnosed with heart rhythm disorders. And if the disorder is in the upper chamber of the heart that can make the heart quiver, the condition is called Atrial Fibrillation (AFib). There’s an electrical system in our heart that makes it beat. The system gives a signal to the heart. However, if the signal does not reach the heart correctly, the heartbeat becomes irregular. AFib is a serious heart problem as it affects the routine life of a person. Therefore, life expectancy with AFib also becomes a major concern for people.

Does AFib shorten life expectancy?

Despite being a heart disorder, AFib is not life-threatening. However, if left untreated, the irregular heartbeat may cause problems. The following are some of the problems that a person might face:
1. Chances of blood clot increase which may be a cause of stroke
2. Heart function damages
3. Heart failure in extreme cases

Therefore, it becomes vital to manage and treat AFib so that a person may live a healthy life.

Risk factors of AFib

Several factors increase the risk of AFib. Some of them are genetic, and a person is born with them, like heart defects. Other factors may include high blood pressure and obesity. A person when manages these conditions by adjusting the lifestyle can manage AFib.

Consulting a doctor

AFib can lead to heart failure in certain patients. Therefore, it is essential to consult a doctor at the Atrial Fibrillation Centers of America. The doctors would know the best course of the treatment depending upon the individual needs of the patients. Furthermore, the patients must also take their medicines on time as the chances of a lower life expectancy increase if a person leaves AFib untreated. You can also call on (832) 478-5067 for knowing the ways to manage AFib before it starts affecting your healthy life.

8 Atrial Fibrillation Myths, Debunked

Atrial fibrillation, also known as Afib, is the most common type of arrhythmia, and it currently affects almost 2.5 million Americans. And, as with many health issues, there’s a lot of misinformation circulating about Afib. Get the truth behind these common atrial fibrillation myths so you can better understand this form of irregular heartbeat.

Myth: Atrial fibrillation only affects the elderly.

Fact: Yes, Afib is more common in people over 70, and the greatest number of cases is in people 80 and older — but it can occur at any age. Among adults younger than 55, fewer than one in 1,000 have atrial fibrillation. However, the risk of developing Afib over a person’s entire life is considered to be between 18 and 25 percent. The causes vary, and can include everything from trauma to medications to heart attack.

Myth: You can tell when you’re having atrial fibrillation symptoms.

Fact: The symptoms of Afib may be barely noticeable or even nonexistent. Atrial fibrillation symptoms are not always noticeable because the chamber that is fibrillating, or quivering, is the small upper chamber, which doesn’t do the bulk of the work in pumping blood. “If a healthy or near-normal heart goes into Afib, there’s still normal pump function from the lower chamber, which helps the blood flow passively through the upper chamber that is fibrillating,” says Thomas Togioka, MD, a cardiologist at Marina Del Rey Hospital in Marina del Rey, Calif. “There is a small loss of efficiency that, in a normal heart, may not be noticed.”

Myth: You can’t exercise when you have atrial fibrillation.

Fact: For most people, this is false. “Exercise is typically fine for people with atrial fibrillation, as long as their heart rate does not get too fast,” says Sarah Samaan, MD, a cardiologist at Legacy Heart Center; a physician partner at the Baylor Heart Hospital in Plano, Texas; and author of Best Practices for a Healthy Heart: How to Stop Heart Disease Before or After It Starts. “Some people who are in atrial fibrillation may notice poor endurance and shortness of breath while exercising. And exercise may provoke an Afib episode in people with paroxysmal atrial fibrillation (meaning the symptoms start and stop on their own). But generally, instead of discouraging people from working out, we work to find a treatment that controls the problem and allows them to stay active.”

Before you start exercising, it’s important to talk to your doctor or cardiologist about which exercises are best for you, and whether or not you should use a heart rate monitor during your workouts.

Myth: Diet doesn’t affect atrial fibrillation.

Fact: Caffeine and alcohol, along with other stimulants, can trigger atrial fibrillation symptoms. In addition, very rich foods may be a problem for some people. And salty foods can raise blood pressure, which in turn could provoke an Afib episode.

Myth: The biggest risk of atrial fibrillation is having a heart attack.

Fact: With atrial fibrillation symptoms like heart palpitations, it’s easy to see why people think this. In reality, the largest risk of atrial fibrillation is an embolic stroke, which occurs when a blood clot forms, commonly in the heart, and is swept through the bloodstreams to the brain. “Not everyone with Afib is at a high risk of a stroke, but many are,” says Dr. Togioka. However, certain types of atrial fibrillation treatment such as anti-clotting drugs, can help prevent stroke.

Myth: Atrial fibrillation affects life expectancy.

Fact: It depends. Younger, generally healthy people who keep symptoms under control and take medications to prevent stroke typically do not have an increased risk of death from Afib. However, the underlying cause is usually the determining factor. Someone who developed atrial fibrillation after a heart attack that caused significant heart muscle damage may have a worse prognosis than someone with treatable high blood pressure and a normal heart.

Myth: Electrically shocking the heart fixes atrial fibrillation.

Fact: “Although an electrical cardioversion procedure resets the heart rhythm back to normal for most people, it has no impact on whether or not atrial fibrillation will return,” says Dr. Samaan. The low-energy shocks of electrical cardioversion succeed about 75 percent of the time, but the procedure often has to be repeated because the arrhythmia returns.

Myth: Atrial fibrillation can be cured.

Fact: It depends on the cause. Thyroid disorders and binge drinking, for example, can both lead to Afib, but if those conditions are treated, the Afib should resolve. On the other hand, causes such as high blood pressure and coronary artery disease generally result in cases of Afib that are not curable — but they are manageable.

If you have questions about Afib and the best ways to manage it, talk to your doctor.

Catheter ablation of atrial fibrillation

1. What is Atrial Fibrillation?

Normally, the regular work of our heart is supported by electrical impulses that are generated by a group of special cells. These cells are formed into a compact formation – the sinus node, located in the upper part of the right atrium [Fig. 1].

At atrial fibrillation (atrial fibrillation) instead of a regular heart rate, multiple electrical waves appear in the atria, leading to chaotic contractions of both atria with a very high frequency [Fig.2].

Atrial fibrillation (atrial fibrillation) , as a rule, is manifested by an increased irregular heart rate, shortness of breath, poor exercise tolerance. Often, atrial fibrillation is asymptomatic and is detected by chance during ECG registration. Often in patients with atrial fibrillation (atrial fibrillation), another type of cardiac arrhythmia is found – atrial flutter [Fig. 3]. Symptoms of atrial flutter differ little from atrial fibrillation.Accurate diagnosis of these rhythm disturbances and determination of treatment tactics should be determined by a cardiologist-arrhythmologist.

2. Why and how to treat atrial fibrillation?

Treatment of atrial fibrillation aims at:

1. Elimination of arrhythmia symptoms, i.e. improving the quality of life of patients;
2. elimination of the threat of developing heart failure;
3. prevention of thromboembolic complications.

According to world medical statistics, atrial fibrillation (atrial fibrillation) is the most common (1-2% in the population) heart rhythm disorder.In a significant proportion of patients (up to 40%), AF is asymptomatic. In this category of patients, antiarrhythmic drug or non-drug treatment (catheter ablation) of AF is usually not performed. Treatment for these patients consists of monitoring heart rate and prescribing anticoagulants to prevent thromboembolic complications. Patients in whom atrial fibrillation is accompanied by the symptoms described above are prescribed continuous antiarrhythmic therapy aimed at preventing recurrence of AF.In about one third of all AF patients, it is possible to find an effective antiarrhythmic drug or a combination of both.

In 30% of patients with symptomatic, poorly tolerated atrial fibrillation, it is not possible to find an effective antiarrhythmic therapy, or antiarrhythmic drugs are contraindicated, accompanied by the development of side effects, or patients do not want to adhere to the tactics of long-term conservative drug treatment. Catheter ablation is recommended for this category of patients in accordance with modern international and Russian recommendations.

It should be emphasized that the choice of treatment options in each specific case is the task of the cardiologist-arrhythmologist, taking into account the patient’s opinion and objective medical data.

3. Catheter and surgical ablation

Depending on the form of atrial fibrillation (paroxysmal, persistent or permanent), the presence of other pathology on the part of the cardiovascular system and concomitant diseases, 3 types of catheter (or surgical) ablation are used:

• intracardiac catheter ablation is the most widely used non-pharmacological treatment of AF.Catheter ablation is performed in an X-ray operating room using guided catheters moved into the heart chambers through the vascular access (femoral and subclavian veins). The goal of catheter ablation is to radically eliminate the “sources” of arrhythmia in the left and (with atrial flutter) right atrium. Currently, 2 types of catheter ablation have found wide clinical use: radiofrequency catheter ablation and balloon cryoablation.

• catheter ablation (destruction) of the AV node – a type of intracardiac catheter ablation, which is used in cases when AF is accompanied by a persistently high heart rate when drug control or radical elimination of AF is impossible.Ablation of the AV node is performed only after the implantation of an artificial pacemaker (pacemaker).

• Operation “Labyrinth” – surgical ablation of AF. Labyrinth surgery (MAZE) is used when an open heart surgery is indicated for a patient with AF due to the presence of an underlying heart disease: coronary artery bypass grafting, valve replacement, etc. As an independent intervention in AF, the “labyrinth” operation is used in the form of modified minimally invasive operations with thoracoscopic access and only if the earlier attempts of catheter ablation are ineffective.

4. Radiofrequency or balloon cryoablation?

According to modern concepts, the key role in the development of AF belongs to the so-called “arrhythmogenic” pulmonary veins (the so-called triggers of AF) – large vessels that flow into the left atrium [Fig. 4]. That is why the majority of patients with paroxysmal and persistent forms of atrial fibrillation are shown to perform catheter ablation (isolation) of the pulmonary veins.

How does it work?

In radiofrequency catheter ablation, pulmonary vein isolation is achieved by applying a large number of point treatments using high frequency current.These influences should form a continuous chain of many successive coagulative necrosis around each of the veins [Fig. 5A]. When using another technology – balloon cryoablation , a zone of necrosis around the veins is created due to the effect of low temperature (up to -60 ° C) in a cryoballoon located sequentially in each of the orifices of the pulmonary veins [Fig. 5B]. In most cases, complete isolation is achieved with a single cryotherapy for several minutes, which is an absolute advantage over radiofrequency ablation.Both types of catheter ablation are performed in the X-ray operating room under general anesthesia or under conditions of deep sedation. These interventions are high-tech types of medical care and should be performed by qualified professionals with sufficient experience in interventional interventions.

Video 1. Balloon cryoablation

Efficiency and safety

The generally accepted definition of the effectiveness of catheter ablation in AF is the absence of any atrial arrhythmias after ablation without the use of antiarrhythmics.Efficiency monitoring is carried out clinically (self-monitoring of patients) or using long-term ECG recording systems (HM ECG or special implantable heart rate recorders).

One of the main factors determining the effectiveness of catheter ablation in AF is the duration of the episodes of atrial fibrillation. In cases where arrhythmia attacks do not exceed several hours or days (the so-called paroxysmal form) and, as a rule, are pumped on their own, surgical treatment is most effective.In comparative studies (international study “Fire and Ice”), recurrence of AF during the first year was not observed in 65% of patients both after radiofrequency and after balloon cryoablation. At the same time, there are observations that in persons without concomitant cardiac pathology, the efficiency of balloon cryoablation can reach 80-90%.

In patients with persistent AF, i.e. with arrhythmias lasting more than 7 days, as well as requiring medical or electrical cardioversion to restore sinus rhythm, the expected efficiency of catheter ablation is about 50-60%.

If AF recurs with the same frequency and duration after catheter ablation, reoperation is warranted.

Complications of catheter ablation of AF can manifest as vascular damage at the puncture site, perforation of the heart wall with the development of tamponade, the formation of blood clots in the heart cavity and thromboembolic complications, thermal damage to the esophagus, the development of phrenic nerve paresis, and a number of others. The use of modern high-tech methods of control during intracardiac interventions, sufficient experience and qualifications of doctors allows performing these interventions effectively and without a significant risk of complications.At the same time, it is necessary to clearly understand that the decision to conduct an interventional treatment of AF should be made by a physician with sufficient experience in treating this category of patients, objectively taking into account the pros and cons.

5. Catheter ablation of AF in the Department of Clinical Electrophysiology and X-ray Surgery of Rhythm Disorders

Interventional arrhythmology has been one of the main directions in the scientific and clinical work of the Department of Clinical Electrophysiology since its foundation in 1990.He has almost 20 years of experience in the treatment of various cardiac arrhythmias using catheter ablation technology.

Since 2012, the department has introduced the method of catheter ablation for AF. Today, the priority method used in the clinical practice of the Department of Clinical Electrophysiology in the non-drug treatment of AF is the method of balloon cryoablation. This choice is based on the fact that cryoablation in AF is not inferior in efficiency to radiofrequency, being at the same time the safest method of interventional treatment of AF, which was proved by analyzing the long-term experience of the world’s leading centers in the treatment of AF.

Specialists of the Department of Clinical Electrophysiology conduct a full preoperative examination of patients, perform interventional interventions and provide outpatient monitoring of all patients for at least 1 year after catheter cryoablation of AF. In cases where patients have complex concomitant cardiac arrhythmias, complex (one-step) interventional treatment is used, or the so-called. “Hybrid therapy”, combining catheter intervention and subsequent drug treatment.If AF recurs, repeat balloon cryoablation or radiofrequency catheter ablation may be performed.

Clinical Research Atrial Fibrillation: Decision Support, Educational Intervention Only – Clinical Research Register

Possibilities and prospects of atrial fibrillation surgical treatment

Authors:

Vaskovskiy VA, Serguladze S.Yu.

Summary:

Surgical treatment of patients with atrial fibrillation (AF) represents a huge scientific
and practical interest for modern cardiac surgeons.From the moment of the first successful operation on
more than a quarter of a century has passed since the surgical removal of AF. During this time, in everyday practice, a certain experience has been accumulated in the surgical treatment of patients with this arrhythmia, and attempts have been made to study the electrophysiological substrate of its occurrence and maintenance. To date, the possible causes of atrial fibrillation are already known,
the schemes of prevention of this disease and methods of its surgical correction were determined. The problem lies in the variety of mechanisms of this arrhythmia and the practical impossibility of their
accurate identification in each individual patient.Recently, there has been a trend
to improve the results of treatment of patients with this pathology due to the improvement
complex of electrophysiological diagnostics, methods of operational manual, artificial
circulation, anesthetic and resuscitation approaches, as well as the emergence of new ablation technologies that can replace surgical incisions. Global practice shows that the use of this approach for planned cardiac surgery and in the absence of contraindications, along with the restoration of sinus rhythm, can help reduce hospital mortality, as well as improve the quality of life.
patients and an increase in life expectancy at a later date.It was noted that
criteria such as the ability of the operation to ensure freedom from AF for a long time, influence on the functional state of the sinus node, eliminate the causes of early and late
recurrences of atrial arrhythmias, the absence of thromboembolic complications, as well as the restoration of the mechanical function of the atria, are also of great importance for the assessment and further selection of a particular procedure in the surgical treatment of atrial fibrillation. In general, the unresolved problems of AF treatment remain primarily tactical issues, such as the procedure
and the correct selection of patients for surgical treatment.To date, to eliminate
atrial fibrillation, cardiac surgeons have various options for procedures that involve the use of alternative energy sources to create transmural atrial injury, the following concepts of the operation “Labyrinth III” and demonstrating comparable
results with the classic version of the operation. Unfortunately, some of the surgical procedures that are described in the literature are based on limited experience and technical feasibility rather than true science.

Quote as:

Vaskovsky V.A., Serguladze S.Yu. Possibilities and prospects of atrial fibrillation surgical treatment. Annals of Arrhythmology. 2016; 13 (2): 64-72. DOI: 10.15275 / annaritmol.2016.2.1

DOI:

10.15275 / annaritmol.2016.2.1

Pages:

complex cases from the practice of a cardiologist uMEDp

The Russian National Congress of Cardiology was held in Moscow from 6 to 8 October 2009 in the building of the Russian Academy of Sciences.Within the framework of the congress, with the support of Dr. Reddy`s, a scientific symposium was held on the problems of modern clinical cardiology.

ON. Mazur, MD, DSc, Professor, RMAPO

Table 1. Tactics of management and treatment of patients with arrhythmia

Table 2. Thromboembolic risk groups

WITH.F. Sokolov, Leading Researcher at the Institute of Cardiology. A.L. Myasnikov RKNPK Roszdrav

Table 3. The most important studies to study the strategy of heart rate control in AF

Figure 1. Deviations of rhythm frequencies in the group of examined patients from the average hourly heart rate values ​​for healthy individuals with sinus rhythm in control and under the influence of Corbis

O.L. Barbarash, Professor, Kuzbass Cardiology Center

Figure 2. Heart rate dynamics during operation

A.I. Martynov, MD, DSc, Professor, Academician of the Russian Academy of Medical Sciences

Figure 3. Study design of drugs Corbis and Concor

Management strategy for patients with atrial fibrillation

The most common form of arrhythmias is atrial fibrillation (AF), with a prevalence of 3% to 12% in people over 60 years of age.

The average life expectancy of patients after atrial fibrillation does not exceed 6 years. It is especially important that these patients, in addition to heart rhythm disturbances and the development of heart failure, have a threat of thromboembolism. Practice shows that when diagnosing a stroke, the percentage of errors is minimal, while thromboembolism is sometimes difficult to determine. The risk of thromboembolism is especially high in the presence of rheumatic heart disease. However, at present, the main causes of AF are arterial hypertension, heart failure of various etiologies, and diabetes mellitus.It was found that predictors of its development among patients are 3 indicators: the size of the left atrium, hypertrophy of the walls of the left ventricle and a decrease in myocardial contractility of the left ventricle, the value of which has a close correlation with the risk of AF. With minimal deviations from the norm of these indicators, the risk of its development is 4% per year, with maximum – 17% per year.

The treatment strategy for patients with AF should include relief and prevention of seizures, and, due to the high risk of thrombosis and thromboembolism, also their prevention.In addition, if this is possible, etiological treatment is carried out, for example, surgical correction of a heart defect.

Currently, there are no agreed approaches in the treatment of patients with arterial hypertension with atrial fibrillation. Therefore, the staff of the Department of Cardiology of the Russian Medical Academy of Postgraduate Education conducted a study in which the effect of certain drugs belonging to different groups on blood pressure and cardiac arrhythmias was studied. In particular, the efficacy of Verapamil, a calcium antagonist, which is used to treat arterial hypertension, coronary heart disease, and to slow the heart rate during an AF attack or in patients with atrial fibrillation tachyform, has been studied.Its effectiveness in the prevention of AF paroxysms of various etiologies has not been proven.

In our study, patients were treated with an individually selected dose of Verapamil (from 240 to 480 mg per day). Therapy for 3 months led to a significant decrease in the frequency of paroxysms (before the use of the drug in this group of patients, there were from 3 to 12 paroxysms per month). In four patients, in order to achieve the target blood pressure level (below 140/90 mm Hg.) ACE inhibitors were added to Verapamil therapy. A more detailed analysis showed that in the subgroup of patients in whom Verapamil provided a decrease in systolic blood pressure to a level below 130-120 mm Hg. Art., there was a complete disappearance of paroxysms during the observation period. In cases where systolic blood pressure remained above 130 mm Hg. Art., the number of attacks decreased and during paroxysms, the heart rate was less frequent, the patients tolerated them more easily. In addition, seizures in most cases were short-lived and self-limited.When monitoring the effectiveness of treatment, it was found that in patients in whom the complete disappearance of clinically felt paroxysms was recorded, when recording a Holter ECG, paired or burst extrasystoles were detected, which were significantly less in patients in whom AF paroxysms did not recur. Therefore, they should be considered as indicators of the presence of electrical atrial instability in this group of patients. Prevention of the onset of AF paroxysms in the subgroup of patients who had systolic blood pressure below 130 mm Hg.Art., there was an increase in the content of metalloproteinase-1 in the blood and a decrease in the content of its inhibitor, which was accompanied by an improvement in the diastolic function of the left ventricle. The latter can be explained by the degradation of collagen present in the walls of the ventricles, which leads to a decrease in the rigidity of the myocardial walls and end-diastolic pressure in the left ventricle, to a decrease in resistance during atrial systole, which could not but affect the state of the left atrium. It is likely that in such cases, reverse remodeling of the left atrium occurs, which is one of the possible mechanisms of the positive effect of Verapamil on the risk of developing atrial fibrillation.

In the recommendations of the European Society of Cardiology in the presented last classification, it is emphasized that the paroxysmal form of AF resolves itself within the first day. While in the persistent form, self-relief does not occur for at least 7 days. With a paroxysmal form, the tactics of patient management depends on the severity of the seizure course (Table 1).

If the paroxysm proceeds easily, then you can limit yourself to a drug that lowers the heart rate or which accelerates its relief.In cases where the paroxysm is severe, then, in addition to relief, treatment with antiarrhythmic drugs is necessary in order to prevent recurrence of arrhythmia. With a persistent form, it is possible to adhere to the tactics of restoring the sinus rhythm or only decreasing the ventricular rate, since there were no differences in long-term outcomes with one or another tactic of their management. But in both cases, antithrombotic therapy is shown to prevent thrombus formation.

When stopping paroxysm with the help of drugs that do not slow down the time of impulses in the AV node, it is necessary to prescribe a drug that reduces heart rate.According to our data, in patients with paroxysmal AF with an initial heart rate of more than 75 per minute. preference for slowing down the heart rate should be given to a β-blocker, and with an initial rhythm of 60 or less, it is better to reduce the heart rate during paroxysm with the help of Verapamil.

When choosing antithrombotic therapy, one should take into account which thromboembolic risk group the patient belongs to (Table 2).

Patients from the low-risk group can be prevented from thromboembolism with aspirin (preferably at a dose of about 325 mg), in the moderate-risk group – with the help of aspirin or a vitamin K antagonist (Warfarin) or a direct thrombin antagonist – Dabigatran, and in the high-risk group – with using one of the last two drugs.

Effect of bisoprolol (Corbis) on heart rate slowdown in patients with atrial fibrillation

Atrial fibrillation has four main immediate consequences:

• disappearance of atrial contractions;
• irregular heartbeat;
• violation of coronary blood flow;
• development of tachycardia.

Medicines that are used to slow down the rhythm primarily affect the function of the atrioventricular node.Consideration should be given to the consequences of high heart rate in atrial fibrillation. First, painful subjective feelings in the patient. Secondly, a violation of the diastolic function of the left ventricle, which can lead to very serious consequences: stagnation in the small circle, up to cardiac asthma and pulmonary edema. Over time, with the prolonged existence of atrial fibrillation, a violation of the contractile function of the left ventricle inevitably occurs and, ultimately, the development of the so-called tachycardic cardiomyopathy, when the cause of dilatation of the heart cavities is directly tachycardia, and not concomitant diseases.Ultimately, the high heart rate associated with atrial fibrillation significantly affects the quality of life of patients.

Thus, in the treatment of these patients, it is necessary to eliminate the high heart rate associated with atrial fibrillation. There are guidelines published by the American College of Cardiology and the American Heart Association. According to the document, patients with persistent or permanent AF are recommended to measure the rhythm frequency at rest and during exercise, as well as to control the frequency using pharmacological drugs (in most cases, β-blockers and calcium antagonists).Another important point in the recommendation is that for patients who develop symptoms associated with AF during activity, the adequacy of heart rate control should be assessed during exercise. In addition, drug treatment should be adjusted, if necessary, so that the frequency is kept within physiological limits. This concept for atrial fibrillation has not yet been defined. But the following considerations can be considered. If the frequency of the ventricular rhythm during atrial fibrillation at rest and with moderate physical activity differs little from the frequency of the restored sinus rhythm, then the cardiac output practically does not change in these two conditions.This means that if at atrial fibrillation the heart rate does not differ from the sinus frequency, then hemodynamically it will be practically equivalent, which gives reason to rely on the frequency of the sinus rhythm as a reference point for the physiological frequency limits.

Nevertheless, the question of the criteria for an adequate decrease in the heart rate in atrial fibrillation has not been finally resolved. At the moment, there are 5 main studies that allow analyzing the adequacy of the criteria for slowing the rhythm (Table 3).It should be noted that in two of the studies presented in the table, the criteria are not indicated, only the value of the decrease in heart rate on average was assessed. However, three studies provide quite definite criteria.

To identify the most optimal methods for slowing down the heart rate in patients with AF, a retrospective comparison of two studies was undertaken (see table): RACE and AFFIRM. Based on comparisons of these works, a new study was initiated in 2005, called RACE-2, the purpose of which was to compare two approaches: the one based on lenient criteria and the approach based on strict criteria.

Now you can determine the drugs to slow down the heart rate. For patients with AF, oral digoxin is an effective means of resting heart rate control and is indicated for patients with heart failure, left ventricular dysfunction, or sedentary patients. For patients with AF, it is prudent to prescribe Digoxin in combination with either a beta-blocker or a calcium antagonist to control heart rate both at rest and during exercise. The choice of drugs should be individualized and bradycardia should be avoided when choosing dosages.Summarizing the results of multiple scattered studies, oral pharmacological agents have been identified to control heart rate in AF. In mild conditions and chronic maintenance therapy, it is recommended: Metoprolol, Propranolol, Diltiazem, Verapamil. For heart failure: Digoxin, Amiodarone.

To determine the effectiveness of β-blockers in the treatment of patients with AF, we started a study aimed at studying the effectiveness of bisoprolol in the form of Corbis in the control of heart rate in persistent and permanent AF.This study was supposed to include 20 patients. The initial dose of the drug, 5 mg, could be increased in the absence of effect or insufficient decrease in the rhythm. The effect was assessed by measuring resting heart rate. And also based on the results of Holter monitoring, during which a 6-minute walk test was carried out. Patients were selected with persistent and permanent AF with one or more of the following signs, the elimination of which during treatment was considered an efficacy criterion:

• Resting heart rate more than 80 / min.;
• average heart rate per day more than 100 / min;
• maximum heart rate per day over (220 – age) + 10%;
• Maximum heart rate during the test with a 6-minute walk of more than 140 / min.

This research is not yet completed. According to the current results, 8 patients (5 men and 3 women) aged 41-71 with organic heart diseases, thyrotoxicosis and idiopathic arrhythmia were examined. The drug Corbis was prescribed to 5 patients at a dose of 5 mg / day., 3 patients – at a dose of 10 mg / day. The drug significantly reduced the average heart rate per day according to the results of Holter monitoring. The effectiveness of therapy was 62.5% (5 of 8).

In the course of the study, the dynamics of hourly values ​​of the average heart rate during the day was noted in control and under the influence of Corbis. The frequencies are quite high in the daytime, and against the background of taking Corbis (a single dose at 8:00), there is a significant and reliable decrease in heart rate and reliable changes persist from the 8th to the 20th hour of the day.Moreover, the drug is purposefully focused on action in the daytime, exactly when the action of β-blockers is required.

In addition, the result of the deviation of the rhythm frequencies in the group of examined patients from the average hourly heart rate values ​​for healthy individuals with sinus rhythm in control and under the influence of Corbis was analyzed. Against the background of drug treatment in the daytime, a significant decrease in frequencies is noted (Figure 1).

Thus, a preliminary conclusion of this study can be made.Bisoprolol (Corbis) has the ability to reduce heart rate in atrial fibrillation mainly during daytime activity. The drug has pharmacokinetic properties that make it convenient for use in conditions of long-term maintenance therapy (long-term, uniform effect after a single oral administration).

Cardiovascular complications in patients undergoing non-cardiac surgery. Place of β-blockers

Advances in anesthesiology and surgery have led to a steady increase in the number of surgical interventions, and therefore therapists, general practitioners and cardiologists increasingly have to address the issue of patient tolerance to surgery.Myocardial infarction (MI), unstable angina pectoris are the main causes of death after surgery. Thus, in a patient over 50 years of age, the likelihood of developing perioperative MI approaches 1%, and if the patient has a known history of coronary heart disease (IHD), the risk of developing perioperative MI increases by 5 times.

Perioperative cardiovascular events increase the likelihood of subsequent complications and dramatically increase hospital mortality.

In many countries of the world, the procedure for preoperative examination is quite clearly regulated and based on the principles of evidence-based medicine. In Russia, unfortunately, little attention is paid to this issue, which, along with a number of other problems, leads to an increase in the duration of hospitalization, the cost of treatment and a high frequency of refusal to perform operations in high-risk categories.

In 2009, the European guidelines for risk assessment and prevention of cardiovascular complications in non-cardiological surgeries were published.These recommendations require an assessment from the standpoint of the reality of implementation in Russian conditions, however, they are valuable from the standpoint of evidence-based medicine to substantiate the need for certain diagnostic and therapeutic procedures in surgical patients.

Preoperative treatment – preparing patients for surgical trauma-stress has been the subject of a very serious debate over the past decade. The operation, with its trauma, anesthesia, analgesia, intubation and extubation, pain, hypothermia, bleeding and anemia, fasting, is an analogue of a stress test.It is known that the classic attribute of stress is an increase in blood pressure and heart rate (HR). These hemodynamic parameters increase in parallel with the increase in blood adrenaline, norepinephrine, cortisol and reflect the intensity of the surgical trauma. Thus, conditions are created under which the existing atherosclerotic plaque is destabilized and myocardial oxygen demand increases, which naturally increases the risk of developing acute coronary syndrome.

The DECREASE II study demonstrated the relationship between heart rate and the risk of myocardial infarction (MI) in patients undergoing noncardiac surgery.It has been proven that the higher the heart rate before surgery, the higher the risk of myocardial infarction. The relative risk of developing myocardial infarction increases 1.5 times with an increase in heart rate for every 5 beats per minute. With this in mind, β-blockers are an important component of the patient’s preoperative preparation. For a patient on preoperative preparation, not only the known hemodynamic effects of this class of drugs are important, but also a decrease in myocardial oxygen demand, an increase in the duration of diastole and the time of myocardial perfusion, as well as an antiarrhythmic effect.It is known that β-blockers have a lot of metabolic positive effects, which are very important for patients undergoing noncardiological operations, they reduce the production of free radicals, metalloproteinase activity and inflammation processes; reduce the expression of receptors responsible for cell apoptosis, etc.

The study, which was conducted at the Kuzbass Cardiology Center, analyzed the frequency of detection of arterial hypertension syndrome in a surgical clinic: retrospectively, 554 patients who underwent elective laparoscopic cholecystectomy with unified approaches in anesthesia were assessed.It turned out that 47% of patients came to the clinic with a previously diagnosed arterial hypertension; 28% in the clinic were diagnosed with arterial hypertension for the first time. Interestingly, patients with arterial hypertension demonstrated not only cardiovascular complications during the postoperative period, but also a higher frequency of purulent-septic complications. This analysis was carried out in age-adjusted, body mass index groups of patients. The next stage of the study was aimed at assessing the possibility of bisoprolol to reduce the risk of developing perioperative hemodynamic disorders.Two groups of patients with arterial hypertension were identified. Group I was prescribed therapy by an outpatient physician, and it was standard (angiotensin-converting enzyme inhibitors, diuretics, calcium antagonists). Group II patients were prescribed antihypertensive therapy based on the intake of a β-blocker, bisoprolol. Both groups were absolutely identical in terms of hemodynamic parameters. Corbis was chosen from bisoprolol preparations. Within 14 days, the dose of bisoprolol was carefully titrated, and subsequently this therapy was continued for 30 days.

Bisoprolol has indeed been shown to be effective and safe. During treatment, patients demonstrated stability in hemodynamic parameters, in particular during intubation (the most traumatic period). Patients taking bisoprolol entered the operation for relative normocardia, this indicator did not change during the surgical intervention (Figure 2). While in patients who received standard therapy, tachycardia was recorded.

Thus, arterial hypertension in a surgical clinic is a big problem that is associated with a high risk of complications, therefore, according to the results of the study, it can be stated that bisoprolol therapy, in particular with Corbis, is effective and safe.

Case study

Signs of an excessive pulse response to exercise and a significant increase in blood pressure (BP) are not only dangerous from the point of view of the development of cardiovascular pathology, but also from the point of view of the development of rhythm disturbances, and in particular, such as atrial fibrillation. Given the frequent presence of concomitant pathology in patients, β-blockers have recently acquired particular importance in violation of the heart rhythm, and, in particular, atrial fibrillation.Of the β-blockers on the pharmaceutical market, many specialists opted for bisoprolol. Previously, metoprolol was widely used in clinical practice, because this drug was the most studied in Russia, well-proven. However, with the advent of bisoprolol, studies of this drug began to be actively carried out. Bisoprolol is a highly selective β-blocker without its own sympathomimetic activity. The bioavailability of the drug is 85-90%, Cmax in blood plasma is achieved in 1-3 hours.

Several foreign and domestic generics are represented on our pharmaceutical market. In particular, you can consider a generic drug such as Corbis. We present a clinical case. A 58-year-old patient was admitted to the intensive care unit with atrial fibrillation for 3 days. The patient tolerated rhythm disturbance relatively favorably, but noted a gradual increase in shortness of breath. Six months before the last hospitalization, he suffered subendocardial myocardial infarction against the background of hypertension, after which angina pectoris and the initial manifestations of circulatory failure in the form of shortness of breath during exertion appeared.In the postinfarction period, the patient took Corbis 5 mg / day. and Noliprel forte 1 tablet daily. Paroxysm of rhythm disturbances arose against the background of emotional stress and an increase in blood pressure. The daily dose of Corbis was doubled (10 mg / day). In 2.5 hours after taking the medication, the sinus rhythm was restored and the blood pressure returned to normal. Thus, the restoration of the heart rhythm with a high degree of probability can be associated with an increase in the dose of Corbis.

We conducted a study that analyzed the effect of 2 drugs: the generic Corbis and the original drug Concor.The study involved 12 patients with coronary heart disease, who were divided into 2 randomized groups of 6 people. In group I, Corbis was prescribed 5-10 mg once a day, in group II – Concor in the same dose for 14 days. After 2 weeks of treatment, the drugs were changed. As a result, after analyzing a number of indicators (decrease in heart rate, decrease in angina pectoris and extrasystole), we came to the conclusion that Corbis is identical in clinical effect to Concor (Figure 3). It is noted that Corbis has an antiarrhythmic effect mainly in patients with signs of sympathicotonia.

It should be noted that Korbis and Konkor are included in all state programs: DLO, ZhVNLS, SMPA, SMPS. The annotation notes the following indications for the appointment of bisoprolol: arterial hypertension, ischemic heart disease (prevention of angina pectoris attacks, CHF). National clinical guidelines include: postponed MI, CHF, rhythm disturbances, migraine, preoperative hypertension, hyperthyroidism, essential tremor. Research on bisoprolol is ongoing. However, already at this stage, we can say that Corbis (bisoprolol) has shown good clinical efficacy and is comparable to Concor.

90,000 Life expectancy in Russia during the pandemic decreased by 2 years :: Economy :: RBC

In March 2020, Rosstat published a demographic forecast until 2035, which did not yet take into account the impact of the COVID-19 pandemic. According to the baseline scenario, life expectancy at birth was to increase in 2020 to almost 73.9 years.

Read on RBK Pro

A decrease in life expectancy against the background of coronavirus occurs in other countries. For example, in the United States, in the first half of 2020, the indicator fell by one year (from 78.8 to 77.8 years) – this is the largest decline since 1943, the US Center for Disease Control and Prevention (CDC) reported in February.

“The spread of the new coronavirus infection objectively deviated the Russian Federation from the development trajectory aimed at achieving the national goals set in 2018,” the government’s draft unified plan says.But the implementation of the measures outlined in the document is designed to ensure a return to economic growth and growth in incomes of the population, as well as the achievement of national development goals. In particular, in 2030, life expectancy in Russia should be 78 years, as required by a decree signed by President Vladimir Putin in July 2020.

The next five years, Russia will continue to lose population, follows from the draft government plan. This indicator is influenced by both natural population decline and migration processes.According to preliminary estimates, in 2020 the population decline will be 583.4 thousand people compared to 99.7 thousand in 2019 and 32.1 thousand in 2018.

The estimate in the draft government plan is more pessimistic than the preliminary estimate of Rosstat for 2020, published at the end of January. According to the department, over the year, the resident population of Russia decreased by 510 thousand people – from 146.75 million to 146.24 million.The decline in the country’s population in the pandemic 2020 set a record in 15 years: in 2005, the population decline was 564.5 thous.human.

In 2021, according to the draft government plan, the population decline will continue and amount to 522.1 thousand people, in 2022 – 451.5 thousand, in 2023 – 344.6 thousand, in 2024 – 270 , 6 thousand people. The total population of the country, according to the document, in 2020-2024 will decrease by more than 2.2 million people. In the previous forecast, it was about a decrease in the population by 1.2 million people.

Alexander Shirov, Deputy Director of the Institute for Economic Forecasting of the Russian Academy of Sciences, considers the new forecast for 2020–2021 too pessimistic.On the other hand, he believes, the indicators of population decline in 2022–2025 are getting significantly better. “This will largely be associated with a decrease in the potential for mortality, since some of the citizens who could have died during this period died during the pandemic,” Shirov added.

In 2030, the government expects to achieve a population growth of 54.7 thousand people. According to the July presidential decree, it is by 2030 that a sustainable population growth should be ensured in Russia, taking into account the effect of migration.

RBC sent inquiries to the government press service and the representative of Deputy Prime Minister Tatyana Golikova, who oversees demography. The Rosstat press service did not comment on the demographic figures from the project.

In accordance with the target forecast of Rosstat, after 2030, an increase in the population of Russia can be expected, the press service of the Ministry of Labor told RBC. Measures to improve the health of Russians and improve the demographic situation became a key area of ​​government activity in the post-period period.In 2020, a significant reduction in the infant mortality rate was achieved, the department stressed. As specified in the Ministry of Health, the infant mortality rate in Russia decreased in 2020 to 4.52 per 1,000 births against 4.92 in 2019. This level was planned to be reached only by 2024, but it has been achieved now, the ministry said.

Atrial fibrillation – treatment of atrial fibrillation in St. Petersburg, price

Atrial fibrillation (AF), or atrial fibrillation, is a heart rhythm disorder characterized by frequent and irregular heartbeats.

This is the most common arrhythmia in the world. It is estimated that atrial fibrillation affects up to 3% of the world’s adult population. With age, the prevalence of atrial fibrillation increases and among people over 60 years of age can reach 60%. The disease causes a decrease in quality of life due to repetitive heartbeat attacks and is associated with increased mortality.

The disunity of the work of the atria and ventricles during atrial fibrillation leads to a decrease in cardiac output by 20-30% due to the absence of an atrial contribution to cardiac output and inadequate filling of the left ventricle with blood.Thus, long-term atrial fibrillation leads to an expansion of the heart cavities, a pronounced decrease in the pumping function of the heart, the occurrence of insufficiency of the mitral and tricuspid valves, which leads to an increase in heart failure.

One of the most serious complications of atrial fibrillation is stroke. This is due to the fact that with atrial fibrillation in the heart, extremely favorable conditions arise for the formation of blood clots: the atria cease to contract normally, which, in turn, leads to stagnation of blood and thrombus formation in the heart.Blood clots leave the heart with the flow of blood and can block blood flow in the arteries of the brain or other organs.

Atrial fibrillation increases the risk of stroke by 5 times, and among patients with dysfunction of the heart valves – 20 times, in comparison with patients without arrhythmias.

Causes of atrial fibrillation

Diseases of the cardiovascular system:

• Pathology of the mitral valve of the heart (congenital and acquired defects).
• Arterial hypertension (systolic blood pressure more than 140 mm Hg).
• Rapid heart rate (eg in athletes after exercise).
• Ischemic heart disease, myocardial infarction (atherosclerotic coronary artery disease).
• Pericarditis (inflammation of the bursa – pericardium).
• Myocarditis (inflammatory lesion of the heart muscle – myocardium).

Others:

• Thyrotoxicosis (hyperfunction of the thyroid gland).
• Diabetes mellitus (high blood glucose).
• Infectious diseases.
• Genetic predisposition.
• Nervous shock or stressful situation.
• Intense strenuous physical activity.
• Alcohol, nicotine and drug abuse.
• Intoxication with various drugs.

Symptoms of atrial fibrillation

The most common symptoms of atrial fibrillation are:

• heart failure,
• heart sink,
• rapid irregular heartbeat,
• chest pain,
• dizziness,
• fainting or short-term loss of consciousness,
• shortness of breath, shortness of breath,
• shortness of breath,
• increased fatigue,
• general weakness.

Often, atrial fibrillation is asymptomatic and is detected by chance on an ECG or during Holter monitoring.

Classification of atrial fibrillation (ESCGuidlines):

• Paroxysmal form – a sudden onset of AF, lasting from several minutes to 7 days, recovers on its own (more often within 24-48 hours).
• Persistent form – atrial fibrillation lasting from 7 days to 1 month.It does not recover on its own, but there are indications and the possibility of cardioversion.
• Long-term persistent form – atrial fibrillation lasting more than 1 month, persisting or recurrent, despite attempts at cardioversion.
• Permanent form – atrial fibrillation in which cardioversion is contraindicated, was not performed, or was unsuccessful.

The prevalence of atrial fibrillation is 6% in elderly and senile people and about 2% in the entire population.In 6-10% of patients with coronary artery disease, the disease is complicated by atrial fibrillation, and in patients with mitral heart disease requiring surgical treatment, atrial fibrillation develops in 60-80% of cases. Observations indicate a significant increase in the incidence of this arrhythmia.

In patients with atrial fibrillation, mortality is approximately 2 times higher than in patients with sinus rhythm. Dissociation of the work of the atria and ventricles leads to a decrease in cardiac output by 20-30% due to the lack of an atrial contribution to cardiac output, as well as inadequate filling of the left ventricle with blood.Thus, long-term atrial fibrillation leads to the development of dilated cardiomyopathy, which is accompanied by expansion of the heart cavities, pronounced systolic dysfunction of the left ventricle (decreased ejection fraction), the occurrence of mitral and tricuspid regurgitation (reverse flow of blood), which leads to an increase in heart failure.

The presence of atrial fibrillation leads to stagnation of blood and thrombus formation in the left atrial appendage with a high risk of blockage of the cerebral arteries, the great arteries of the upper and lower extremities (systemic circulation), and blood vessels supplying internal organs.Every sixth stroke occurs in a patient with atrial fibrillation. The risk of such a complication in patients with atrial fibrillation is 5 to 7 times higher than in people without arrhythmia. In patients with heart defects of rheumatic etiology complicated by atrial fibrillation, the risk of developing acute cerebrovascular accident (ACVA) is 17 times higher than in patients without atrial fibrillation.

Diagnostics

The main method for diagnosing atrial fibrillation is electrocardiography (ECG) and Holter monitoring – continuous long-term (for 1 – 7 days) ECG recording.

If the diagnosis of AF is confirmed and the indications for endovascular catheter ablation of AF are determined, the patient undergoes an electrophysiological study (EPI) with the identification of zones of ectopic foci and the construction of a map of these zones.

Treatment

1. Conservative treatment of atrial fibrillation (atrial fibrillation)

Atrial fibrillation is a risk factor for ischemic stroke resulting from the formation of blood clots in the left atrial cavity.The primary agents in the treatment of atrial fibrillation are drugs that prevent blood clots. They are prescribed by a doctor, tk. monitoring of the blood coagulation system is required. These funds are indicated for almost all patients who suffer from atrial fibrillation, regardless of whether arrhythmia is constantly present or seizures occur (paroxysmal arrhythmia). The risk of stroke is the same both in the presence of a chronic form of arrhythmia and in a paroxysmal form of arrhythmia.

In patients with a paroxysmal form of atrial fibrillation, the issue of preventing the onset of arrhythmia attacks is resolved.If an attack occurs for the first time, antiarrhythmic drugs are not prescribed. Drugs may be recommended to control heart rate and improve the tolerance of recurrent paroxysms of arrhythmias. Antiarrhythmic drugs are also not prescribed if the patient’s arrhythmia attacks are asymptomatic and do not reduce his quality of life. In case of recurrence of rhythm disturbances and deterioration of the tolerance of paroxysms, the cardiologist-arrhythmologist, together with the patient, decides on the appointment of antiarrhythmic drugs or surgical treatment of arrhythmia (catheter ablation).

With the development of a protracted attack of atrial fibrillation, which did not go away on its own, it is necessary to consult a specialist cardiologist-arrhythmologist who will choose the most appropriate method for arrhythmia relief for the patient. The technique of medicamentous restoration of normal heart rhythm has been worked out, as well as the procedure for restoring the rhythm by the method of electrical cardioversion. To restore the rhythm, a certain drug preparation is required, the scheme of which will be determined by the doctor, based on the individual characteristics of the course of the disease.With the advent of the latest highly effective antiarrhythmic drugs, preference is given to medication-assisted rhythm restoration.

When the paroxysmal form of atrial fibrillation is transformed into a chronic form, the main task is to control the heart rate. In the presence of tachysystole (high heart rate), drugs are prescribed that reduce the heart rate, the primary of which are beta-blockers. An integral part of the treatment of atrial fibrillation is the treatment of the disease that provoked the rhythm disturbance – ischemic heart disease, heart failure, arterial hypertension, thyroid disorders and others.

It is necessary to consult a cardiologist-arrhythmologist in case:

• development of an attack of atrial fibrillation for the first time in life,
• development of the next attack of arrhythmia, which cannot be stopped by usual means,
• ineffectiveness of previously prescribed antiarrhythmic therapy.

2. Radiofrequency catheter ablation

In the event of symptomatic paroxysms of atrial fibrillation, according to modern recommendations, surgical treatment (catheter ablation) can be offered to patients even before antiarrhythmic drugs are prescribed as an alternative to drug treatment.

The efficiency of catheter ablation of atrial fibrillation in most centers around the world is 60-80%. The effectiveness of the intervention is significantly increased by eliminating factors contributing to the development of arrhythmias, such as high blood pressure, overweight, alcohol consumption, etc.

During the procedure, special catheters are inserted into the heart through large vessels (subclavian and femoral veins), through which radiofrequency current is supplied, affecting the source of arrhythmia.

The operation is electrophysiologically grounded and anatomically oriented. Based on the theory of multiple circles of macro re-entry (circulation of impulse), formed around anatomical structures: the mouths of the pulmonary veins and coronary sinus, superior and inferior vena cava, appendages of the left and right atria, openings of atrioventricular valves. The operation involves the isolation of these formations and the interruption of the pathways.

The procedure is performed under X-ray control.The intervention is performed under intravenous (general) anesthesia. The duration of the procedure is 2-3 hours, depending on the clinical situation.

The main goal of the intervention is to eliminate atrial fibrillation. However, it is not possible to achieve a complete cure in all cases, especially with long-term arrhythmia or its chronic forms. The use of a hybrid approach – surgical treatment in combination with the intake of antiarrhythmic drugs – can significantly improve the quality of life of patients by reducing the number of attacks and the severity of arrhythmia symptoms.

In the postoperative period, for 3 months, patients are shown the use of drugs that prevent the formation of blood clots, for the prevention of ischemic strokes and antiarrhythmic drugs. The need for further drug treatment is determined by the attending arrhythmologist.

However, catheter ablation of atrial fibrillation may not always be performed. The procedure is contraindicated in the presence of blood clots in the cavities of the heart, as this contributes to the occurrence of ischemic stroke.

To determine the indications and contraindications for surgical treatment, it is necessary to consult an arrhythmologist.

Since October 2015, at the Clinic of High Medical Technologies named after I. N.I. Pirogov, at the Department of Cardiovascular Surgery, radiofrequency catheter ablation of atrial fibrillation is performed.

Catheter ablation is nearly 10 times more effective in preventing the progression of atrial fibrillation compared to drug therapy, but millions of patients around the world still lack access to this life-changing treatment.

Media contact:
Maria Medvedeva
[email protected]
+7 495 580 7777

New company report Biosense Webster , corporate divisions Johnson & Johnson , highlights the need for early diagnosis and comprehensive treatment approaches atrial fibrillation (AF) is one of the most important public health problems in the world.

Moscow, Russia, November 18, 2019. Biosense Webster, a division of Johnson & Johnson Corporation, a leader in the treatment of atrial fibrillation (AF), has published a report on the Treatment of Atrial Fibrillation, which reviews available treatment options and long-term clinical, patient and the economic impact of these treatments for AF in Europe.

In Europe, 11 million people suffer from AF, a condition characterized by an irregular and fast heart rate ^1.2 .The prevalence of atrial fibrillation in Russia is also high, about 2.3 million people suffer from the disease ³² . An irregular heart rhythm (arrhythmia) can lead to serious health complications, including blood clots, a 5-fold and 2.4-fold increase in the risk of heart failure and stroke, respectively ³ .

Early detection of AF and early treatment can change the progression of the disease, potentially improving the quality and overall life expectancy of patients.

The published report on the Treatment of Atrial Fibrillation includes the results of the independent study ATTEST, which compares two treatments for patients with AF — antiarrhythmic drug therapy and catheter ablation.

Only in half of patients (52%) ⁵ therapy with antiarrhythmic drugs is effective. The ATTEST study proves that catheter ablation is nearly 10 times more effective than drug therapy in preventing disease progression ⁷ .Despite this, catheter ablation is performed in only 4% of patients who meet the referral criteria for this treatment ⁶ .

In addition, this study found that catheter ablation is a highly effective and cost-effective treatment option for the following parameters:

• Significant improvement in the quality of life of patients (37% versus 18% with antiarrhythmic drug therapy) ^8.9 .
• Stable results in 94% of patients without arrhythmia recurrence 1 year after surgery and in 48% without arrhythmia recurrence after 4 years ^10-20 .
• 46% reduction in mortality, stroke, cardiac arrest and hospitalizations for cardiovascular disease compared with antiarrhythmic drug therapy ^20.21 .
• Reduced the need for unplanned doctor visits (up to 80%) and long-term cost savings by 35% ^22.23 .

Many patients with atrial fibrillation do not receive the medical care they need. The European Society of Cardiology (ESC) guidelines set out internationally recommended treatments for patients with different types of AF.To date, the long-term impact of the chosen treatment method has not been clearly defined 90,513 20.21. . The results of the ATTEST study provide a timely reminder of the potential for life-changing patients with AF with current therapies for cardiac arrhythmias such as catheter ablation, including reducing the risk of serious AF-related consequences such as stroke, dementia, heart failure and death ^8,9,20,21 .

AF is a growing epidemic and poses a significant financial burden on health systems, with funding of up to US $ 3.2 billion in some European countries.euro per year ²⁴ . By 2030, the number of people with AF is projected to increase to 70%, and by 2050 Europe will have the largest increase in the number of patients with AF compared to other regions in the world, thanks to factors such as economic growth, aging populations and an increase in the prevalence of risk factors for FP in Western countries ^25.26 .

“The number of people with cardiac arrhythmias is on the rise. It is important for healthcare professionals to understand how they can most effectively reduce the burden on hospital resources, avoid unnecessary emergency costs, and improve the lives of millions of people living with the condition.This issue is relevant in Russia as well. In our country, such major scientific centers as the National Medical Research Center named after V.I. V. A. Almazov (St. Petersburg), National Medical Research Center named after Academician E. N. Meshalkin (Novosibirsk), Federal State Budgetary Institution “National Medical Research Center for Preventive Medicine” of the Ministry of Health of Russia (Moscow), Tomsk National Research medical center of the Russian Academy of Sciences (g.Tomsk). In turn, at our Biosense Webster division, we are committed to continuing to develop innovative technology solutions by investing in research and publications to improve clinical understanding and awareness of AF among physicians and the general public. ” equipment Johnson & Johnson Julia Markova .

NOTES TO EDITORS

About Atrial Fibrillation ( AF, AF)

Atrial fibrillation, sometimes called AF ( AF, AFib ) or atrial fibrillation, is the most common cardiac arrhythmia (irregular heart rate) ^.1 This occurs when the two upper chambers of the heart (atria) contract too quickly or in an uncontrolled manner ² .

The heart rate is controlled by electrical impulses that coordinate the contractions of the heart ²⁷ . In AF, these electrical impulses become irregular, resulting in an inconsistent contraction of the two chambers of the heart (atrium). This results in an irregular and fast heart rate that can sometimes feel like a flutter.When the heart beats erratically, it doesn’t pump blood as efficiently as it should.

This can make the patient feel unwell or other symptoms of AF because oxygen is not being delivered properly to all parts of your body. AF is not life threatening by itself. However, it is important to consult a doctor to access the correct treatment, not only to control symptoms, but also because AF can lead to more serious conditions such as stroke ³ .

AF is a common health problem affecting 11 million people in Europe and becoming more prevalent with age. In 1 in 4 people over the age of 40, AF can develop in their lifetime ^{1, 28} . The causes of AF are not always clear and can be complex ^4.29.30 . Possible causes vary widely depending on comorbid heart disease, age, family history, blood pressure levels, alcohol consumption, obesity, and other chronic conditions – all contributing to risk factors for AF ^4.31 .

O Biosense Webster

Biosense Webster, Inc., a division of Johnson & Johnson Medical Devices, is a global leader in the diagnosis and treatment of cardiac arrhythmias. The company partners with clinicians to develop innovative technologies that improve the quality of care for patients with arrhythmias around the world.

Visit www.biosensewebster.com for more information.

Sources

1. Global Burden of Disease Collaborating Network (2016).Global Burden of Disease Study 2016 (GBD 2016)., Results. Seattle, USA, Institute of Heart Metrics and Evaluation (IHME), 2017. Accessed 2018-04-20. Available from http://ghdx.healthdata.org/gbd-results-tool.
2. Iaizzo PA (2015). Handbook of anatomy, cardiac physiology and equipment. Handbook of Cardiac Anatomy, Physiology, and Devices. Springer Science + Business Media, LLC: Switzerland
3. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG et al. (2016). Atrial fibrillation and the risks of cardiovascular disease, kidney disease, and death: a systematic review and meta-analysis.BMJ 354 i4482
4. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D et al. (2016) 2016 European Society of Cardiology Guidelines for the Management of Atrial Fibrillation, co-created with the European Association for Cardiothoracic Surgery. Eur Heart J 37 (38): 2893-2962.
5. Calkins H, Reynolds MR, Spector P, Sondhi M, Xu Y et al. (2009) Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and a meta-analysis.Circ Arrhythm Electrophysiol 2 (4): 349-361
6. Pillarisetti J, Lakkireddy D. Atrial fibrillation in Europe: the state of disease control. Bloch Heart Rhythm Center, Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Hospital & Medical Center, Kansas City, KS. European Heart Journal (2014) 35, 3326–3327
7. Kuck KH, Lebedev, D., Mikaylov, E., Romanov, A., Geller, L., Kalejs, O., Neumann, T., Davtyan, K., On, Y.K., Popov, S., Ouyang, F. (2019) Catheter ablation slows the progression of atrial fibrillation from paroxysmal to persistent. ESC Late-breaking Science 2019. Paris, France. August 31, 2019.
8. Mark DB, Anstrom KJ, Sheng S, Piccini JP, Baloch KN et al. (2019) Impact of catheter ablation and drug therapy on quality of life in patients with atrial fibrillation: a randomized clinical trial CABANA. JAMA
9. Jais P, Cauchemez B, Macle L, Daoud E, Khairy P et al.(2008) Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: a study A4. Circulation 118 (24): 2498-2505.
10. Hussein A, Das M, Chaturvedi V, Asfour IK, Daryanani N et al. (2017) Using the Ablation Index improves clinical outcomes after ablation in atrial fibrillation. J Cardiovasc Electrophysiol 28 (9): 1037-1047.
11. Taghji P, El Haddad M, Phlips T, Wolf M, Knecht S et al. (2018) Evaluation of a strategy for isolation of pulmonary veins with a continuous line of optimized radiofrequency exposures in paroxysmal atrial fibrillation: a pilot study.JACC Clin Electrophysiol 4 (1): 99-108.
12. Phlips T, Taghji P, El Haddad M, Wolf M, Knecht S et al. (2018) Improving the effectiveness of pulmonary vein isolation procedure using contact force control technology after 1 year follow-up: the role of the distance between RF exposures, ablation index and variability of contact force in the CLOSE protocol. Europace 20 (FI_3): f419-f427.
13. Solimene F, Schillaci V, Shopova G, Urraro F, Arestia A et al. (2019) Safety and efficacy of ablation using the ablation index in patients with atrial fibrillation.J Interv Card Electrophysiol 54 (1): 9-15.
14. Di Giovanni G, Wauters K, Chierchia GB, Sieira J, Levinstein M et al. (2014) One-year follow-up after a single cryo-balloon ablation procedure: comparison between a first and second generation balloon. J Cardiovasc Electrophysiol 25 (8): 834-839.
15. Jourda F, Providencia R, Marijon E, Bouzeman A, Hireche H et al. (2015) Radiofrequency ablation using contact force control technology versus cryotherapy using a second-generation balloon to isolate the pulmonary veins in patients with paroxysmal atrial fibrillation – a prospective evaluation.Europace 17 (2): 225-231.
16. Lemes C, Wissner E, Lin T, Mathew S, Deiss S et al. (2016) Clinical results within one year after pulmonary vein isolation in persistent atrial fibrillation using a second-generation 28 mm cryoballoon: a retrospective analysis. Europace 18 (2): 201-205.
17. Guhl EN, Siddoway D, Adelstein E, Voigt A, Saba S et al. (2016) The effectiveness of pulmonary vein isolation in patients with persistent atrial fibrillation using a cryoballoon.J Cardiovasc Electrophysiol 27 (4): 423-427.
18. Irfan G, de Asmundis C, Mugnai G, Poelaert J, Verborgh C et al. (2016) Follow-up for one year after ablation with a second-generation cryoballoon in a large group of patients with atrial fibrillation: a single-center experience. One-year follow-up after second-generation cryoballoon ablation for atrial fibrillation in a large cohort of patients: a single-center experience. Europace 18 (7): 987-993.
19. Boveda S, Metzner A, Nguyen DQ, Chun KRJ, Goehl K et al.(2018) Results of a single procedure and improvement in the quality of life of patients 12 months after cryoablation in persistent atrial fibrillation: results of the multicenter study CRYO4PERSISTENT AF. JACC Clin Electrophysiol 4 (11): 1440-1447.
20. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD et al. (2019) Effect of catheter ablation and antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest in patients with atrial fibrillation: a randomized clinical trial of CABANA.JAMA
21. Noseworthy PA, Gersh BJ, Kent DM, Piccini JP, Packer DL et al. (2019) Atrial fibrillation ablation in practice: assessing CABANA generalizability. Eur Heart J 40 (16): 1257-1264.
22. Samuel M, Avgil Tsadok M, Joza J, Behlouli H, Verma A et al. (2017) Catheter ablation for the treatment of atrial fibrillation is associated with reduced use of health care resources. J Cardiovasc Electrophysiol 28 (7): 733-741.
23. Weerasooriya R, Jais P, Le Heuzey JY, Scavee C, Choi KJ et al. (2003) Cost analysis of catheter ablation for paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 26 (1 Pt 2): 292-294.
24. Ball J, Carrington MJ, McMurray JJ, Stewart S (2013) Atrial fibrillation: the profile and burden of an evolving epidemic in the 21st century. Int J Cardiol 167 (5): 1807-1824.
25. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S (2014) Epidemiology of atrial fibrillation: a European perspective.Clin Epidemiol 6 213-220.
26. Rahman F, Kwan GF, Benjamin EJ (2014) Global epidemiology of atrial fibrillation. Nat Rev Cardiol 11 (11): 639-654.
27. Waktare EP (2002). Atrial fibrillation. 106: 14-16
28. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D et al. (2004). Atrial fibrillation risk: Framingham Heart Institute Circulation 110 (9): 1042-1046
29. Cedars-Sinai. Atrial Fibrilation. 2019-06-12. Available at https: // www.cedars-sinai.org/health-library/diseases-and-conditions/a/atrial-fibrillation.html.
30. Naser N, Dilic M, Durak A, Kulic M, Pepic E et al.