Are Pacerone and Amiodarone the same medication. What are the primary uses of Pacerone. How does Amiodarone work to treat irregular heartbeats. What are the potential side effects of taking Amiodarone.

The Relationship Between Pacerone and Amiodarone

Pacerone and Amiodarone are indeed the same medication. Amiodarone hydrochloride is the generic name for the drug, while Pacerone and Cordarone are brand names under which it is marketed. This anti-arrhythmic medication is primarily used to treat serious irregular heartbeats, also known as arrhythmias.

Why is this medication known by different names? Pharmaceutical companies often create brand names for generic drugs to market them more effectively. In this case, Amiodarone is the active ingredient, while Pacerone and Cordarone are simply different brand names for the same medication.

Understanding the Uses of Amiodarone (Pacerone)

Amiodarone, whether prescribed as Pacerone or under another brand name, serves a crucial role in cardiac care. Its primary uses include:

• Treating recurrent ventricular fibrillation
• Managing ventricular tachycardia
• Restoring normal heart rhythm
• Maintaining a regular, steady heartbeat

How effective is Amiodarone in treating these conditions? Clinical studies have shown that Amiodarone is highly effective in managing life-threatening arrhythmias, particularly in cases where other medications have failed. Its unique properties make it a valuable tool in the cardiologist’s arsenal.

The Mechanism of Action: How Amiodarone Works

Amiodarone’s effectiveness in treating irregular heartbeats stems from its unique mechanism of action. As an anti-arrhythmic drug, it works by:

1. Blocking certain electrical signals in the heart
2. Slowing the transmission of electrical impulses
3. Prolonging the heart’s action potential
4. Reducing the heart’s sensitivity to catecholamines

These actions collectively help to restore and maintain a normal heart rhythm. But how exactly does Amiodarone achieve these effects at the cellular level?

At its core, Amiodarone primarily acts as a potassium channel blocker. By inhibiting the potassium efflux from cardiac cells, it prolongs the action potential duration and effective refractory period. This mechanism helps prevent the rapid, uncontrolled electrical activity that characterizes many arrhythmias.

Multi-Channel Blocking Properties

Unlike many other anti-arrhythmic drugs, Amiodarone exhibits multi-channel blocking properties. It affects not only potassium channels but also sodium and calcium channels, as well as beta-adrenergic receptors. This broad spectrum of activity contributes to its efficacy in treating various types of arrhythmias.

Proper Administration of Pacerone (Amiodarone)

Proper administration of Pacerone is crucial for its effectiveness and safety. Here are the key points to remember:

• Take the medication as directed by your doctor, usually once or twice daily
• It can be taken with or without food, but consistency is important
• Avoid grapefruit and grapefruit juice while on this medication
• Do not stop taking the medication or change the dose without consulting your doctor

Why is consistency in taking Amiodarone so important? The drug has a long half-life and takes time to build up to therapeutic levels in the body. Consistent dosing helps maintain these levels and ensures the medication’s effectiveness in controlling arrhythmias.

The Role of Grapefruit Interactions

The warning against consuming grapefruit while taking Amiodarone is not arbitrary. Grapefruit contains compounds that can interfere with the enzymes responsible for metabolizing Amiodarone in the body. This interaction can lead to increased levels of the drug in the bloodstream, potentially exacerbating side effects or altering its efficacy.

Potential Side Effects and Precautions

While Amiodarone (Pacerone) is effective in treating arrhythmias, it’s associated with a range of potential side effects. Some common side effects include:

• Nausea and vomiting
• Constipation
• Loss of appetite
• Fatigue
• Tremors

More serious side effects that require immediate medical attention include:

• Shortness of breath
• Chest pain
• Irregular heartbeat
• Severe dizziness or fainting
• Vision changes

How common are these side effects? While many patients tolerate Amiodarone well, studies suggest that up to 15% of patients may experience significant side effects requiring discontinuation of the drug. The likelihood of side effects often increases with higher doses and longer duration of use.

Long-Term Effects and Monitoring

Long-term use of Amiodarone requires careful monitoring due to its potential to affect various organ systems. Regular check-ups typically include:

1. Liver function tests
2. Thyroid function tests
3. Pulmonary function tests
4. Eye examinations
5. ECG monitoring

Why is such extensive monitoring necessary? Amiodarone can accumulate in various tissues over time, potentially leading to toxicity. By closely monitoring organ function, healthcare providers can detect any adverse effects early and adjust treatment as needed.

Amiodarone’s Impact on Thyroid Function

One of the unique aspects of Amiodarone is its significant impact on thyroid function. The drug contains a high amount of iodine, which can affect thyroid hormone production and metabolism. As a result, Amiodarone can cause both hypothyroidism (underactive thyroid) and hyperthyroidism (overactive thyroid).

What are the signs of thyroid dysfunction in patients taking Amiodarone? Symptoms of hypothyroidism may include fatigue, weight gain, and cold intolerance. Conversely, hyperthyroidism can manifest as weight loss, heat intolerance, and increased heart rate. Regular thyroid function tests are crucial for early detection and management of these issues.

Amiodarone-Induced Thyrotoxicosis

Amiodarone-induced thyrotoxicosis (AIT) is a particularly challenging condition that can occur in patients taking the drug. There are two types of AIT:

• Type 1 AIT: Occurs in patients with underlying thyroid disorders
• Type 2 AIT: Develops due to a destructive thyroiditis caused by Amiodarone

Management of AIT often requires collaboration between cardiologists and endocrinologists to balance the need for anti-arrhythmic treatment with thyroid management.

Pulmonary Toxicity: A Serious Concern

Amiodarone-induced pulmonary toxicity is one of the most serious potential side effects of the drug. It can manifest in various forms, including:

• Interstitial pneumonitis
• Organizing pneumonia
• Acute respiratory distress syndrome (ARDS)
• Pulmonary fibrosis

How common is Amiodarone-induced pulmonary toxicity? Studies suggest that it occurs in approximately 5-10% of patients taking the drug, with the risk increasing with higher doses and longer duration of use.

Monitoring and Early Detection

Early detection of pulmonary toxicity is crucial for preventing irreversible lung damage. Patients on Amiodarone should be monitored for:

1. New or worsening shortness of breath
2. Persistent cough
3. Chest pain
4. Fever

Regular pulmonary function tests and chest X-rays are often part of the monitoring protocol for patients on long-term Amiodarone therapy.

Drug Interactions and Precautions

Amiodarone has a complex pharmacokinetic profile and can interact with numerous other medications. Some important drug interactions include:

• Warfarin: Amiodarone can increase the anticoagulant effect of warfarin
• Digoxin: Amiodarone can increase digoxin levels
• Beta-blockers: Combining these with Amiodarone can increase the risk of bradycardia
• Statins: Amiodarone can increase the risk of statin-induced myopathy

Why are these interactions so significant? Many patients with heart rhythm disorders are on multiple medications, increasing the risk of potentially harmful drug interactions. Careful medication management and regular monitoring are essential to mitigate these risks.

Special Populations and Precautions

Certain populations require special consideration when being prescribed Amiodarone:

1. Elderly patients: May be more susceptible to side effects
2. Pregnant women: Amiodarone can cross the placenta and affect fetal thyroid function
3. Breastfeeding mothers: The drug can be excreted in breast milk
4. Patients with liver or lung disease: May be at higher risk for toxicity

In these populations, the benefits of Amiodarone therapy must be carefully weighed against the potential risks, and alternative treatments may be considered when appropriate.

Long-Term Management and Patient Education

Successful long-term management of patients on Amiodarone requires a comprehensive approach that includes:

• Regular follow-up appointments
• Ongoing patient education
• Monitoring for side effects and complications
• Adjusting dosage as needed
• Considering drug holidays or discontinuation when appropriate

What role does patient education play in the successful use of Amiodarone? Informed patients are better equipped to recognize potential side effects early, adhere to their medication regimen, and communicate effectively with their healthcare providers. This collaboration between patient and provider is crucial for optimizing the benefits of Amiodarone therapy while minimizing risks.

The Importance of Lifestyle Modifications

In addition to medication management, patients on Amiodarone often benefit from lifestyle modifications to support heart health:

1. Maintaining a heart-healthy diet
2. Engaging in regular, appropriate exercise
3. Managing stress
4. Avoiding alcohol and tobacco
5. Getting adequate sleep

These lifestyle changes can complement the effects of Amiodarone, potentially allowing for lower doses and reducing the risk of side effects.

Future Directions in Anti-Arrhythmic Therapy

While Amiodarone remains a cornerstone of anti-arrhythmic therapy, ongoing research is exploring new treatments and refining existing ones. Some areas of focus include:

• Development of new anti-arrhythmic drugs with improved safety profiles
• Advances in catheter ablation techniques for arrhythmia treatment
• Personalized medicine approaches to optimize drug selection and dosing
• Exploration of gene therapies for inherited arrhythmia syndromes

How might these advancements impact the use of Amiodarone in the future? As new treatments emerge, Amiodarone may be reserved for more specific indications or used in combination with newer therapies to enhance efficacy and reduce side effects.

The Role of Artificial Intelligence in Arrhythmia Management

Artificial intelligence (AI) is increasingly being applied to various aspects of cardiac care, including arrhythmia management. Potential applications include:

1. AI-assisted ECG interpretation for early arrhythmia detection
2. Predictive models for identifying patients at high risk of arrhythmias
3. Optimization of anti-arrhythmic drug selection and dosing
4. Real-time monitoring and alert systems for patients on medications like Amiodarone

These technological advancements may help improve the safety and efficacy of anti-arrhythmic therapy, including the use of drugs like Amiodarone.

Pacerone Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing

Uses

This medication is used to treat certain types of serious (possibly fatal) irregular heartbeat (such as recurrent ventricular fibrillation/tachycardia). It is used to restore normal heart rhythm and maintain a regular, steady heartbeat. Amiodarone is known as an anti-arrhythmic drug. It works by blocking certain electrical signals in the heart that can cause an irregular heartbeat.

How to use Pacerone

Read the Medication Guide provided by your pharmacist before you start using amiodarone and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth as directed by your doctor, usually once or twice daily. You may take this medication with or without food, but it is important to choose one way and take this medication the same way with every dose.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

The dosage is based on your medical condition and response to treatment. Your doctor may direct you to start this medication at a higher dose and gradually decrease your dose. Follow your doctor’s instructions carefully. Do not stop taking this medication or change the dose without first consulting your doctor.

Tell your doctor if your condition does not improve or if it worsens.

Side Effects

See also Warning section.

Nausea, vomiting, constipation, loss of appetite, shaking, or tiredness may occur. If any of these effects last or get worse, tell your doctor promptly.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: easy bruising/bleeding, loss of coordination, tingling/numbness of the hands or feet, uncontrolled movements, new or worsening symptoms of heart failure (such as shortness of breath, swelling ankles/feet, unusual tiredness, unusual/sudden weight gain).

Get medical help right away if you have any very serious side effects, including: faster/slower/more irregular heartbeat, severe dizziness, fainting.

Amiodarone may rarely cause thyroid problems. Either low thyroid function or overactive thyroid function may occur. Tell your doctor right away if you develop any symptoms of low or overactive thyroid, including cold or heat intolerance, unexplained weight loss/gain, thinning hair, unusual sweating, nervousness, irritability, restlessness, or lump/growth in the front of the neck (goiter).

This drug may cause your skin to be more sensitive to the sun. With long-term treatment, you may rarely develop blue-gray color of the skin. This effect is not harmful and color may return to normal after the drug is stopped. To help prevent skin effects, limit your time in the sun. Avoid tanning booths and sunlamps. Use sunscreen and wear protective clothing when outdoors. Tell your doctor right away if you get sunburned or have skin blisters/redness.

This drug may rarely cause vision changes. Very rarely, cases of permanent blindness have been reported. Tell your doctor right away if you develop any vision changes (such as seeing halos or blurred vision).

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US – Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

See also Side Effects section.

Before taking amiodarone, tell your doctor or pharmacist if you are allergic to it; or to iodine; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, lung disease, thyroid problems.

This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

Before having surgery, tell your doctors or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Amiodarone may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can rarely cause serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that need medical attention right away.

The risk of QT prolongation may be increased if you have certain medical conditions or are taking other drugs that may cause QT prolongation. Before using amiodarone, tell your doctor or pharmacist of all the drugs you take and if you have any of the following conditions: certain heart problems (heart failure, slow heartbeat, QT prolongation in the EKG), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).

Low levels of potassium or magnesium in the blood may also increase your risk of QT prolongation. This risk may increase if you use certain drugs (such as diuretics/”water pills”) or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using amiodarone safely.

Older adults may be more sensitive to the side effects of this drug, especially QT prolongation (see above), thyroid problems (see Side Effects section), lung problems (see Warning section).

Tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while using amiodarone. Amiodarone may harm an unborn baby. If you become pregnant, talk to your doctor right away about the risks and benefits of this medication.

Amiodarone passes into breast milk and may have undesirable effects on a nursing infant. Breast-feeding is not recommended while using this drug.

Interactions

See also How to Use section.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: fingolimod, certain drugs to treat hepatitis C (ledipasvir/sofosbuvir, sofosbuvir).

Many drugs besides amiodarone may affect the heart rhythm (QT prolongation), including dofetilide, pimozide, procainamide, quinidine, sotalol, macrolide antibiotics (such as clarithromycin, erythromycin), quinolone antibiotics (such as levofloxacin), among others. (See also Precautions section.)

Other medications can affect the removal of amiodarone from your body, which may affect how amiodarone works. Examples include azole antifungals (such as itraconazole), cimetidine, cobicistat, protease inhibitors (such as fosamprenavir, indinavir), rifamycins (such as rifampin), saquinavir, St. John’s wort, among others.

Amiodarone can slow down the removal of other medications from your body, which may affect how they work. Examples of affected drugs include clopidogrel, macitentan, phenytoin, certain “statin” drugs (atorvastatin, lovastatin), trazodone, warfarin, among others.

Does Pacerone interact with other drugs you are taking?

Enter your medication into the WebMD interaction checker

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: weakness, severe dizziness, very slow heartbeat, fainting.

Do not share this medication with others.

Lab and/or medical tests (such as EKG, chest X-rays, lung/liver/thyroid function, eye exams) should be done while you are taking this medication. Keep all medical and lab appointments. Consult your doctor for more details.

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Images

Pacerone 400 mg tablet

Color: whiteShape: roundImprint: U-S 1645 P400

This medicine is a white, round, scored, tablet imprinted with “U-S 1645” and “P400”.

Pacerone 100 mg tablet

Color: peachShape: roundImprint: P U-S 144

This medicine is a white, round, scored, tablet imprinted with “U-S 1645” and “P400”.

Pacerone 200 mg tablet

Color: pinkShape: roundImprint: P 200 U-S 0147

This medicine is a white, round, scored, tablet imprinted with “U-S 1645” and “P400”.

Pacerone 400 mg tablet

Color: light yellowShape: ovalImprint: P 400 01 45

This medicine is a white, round, scored, tablet imprinted with “U-S 1645” and “P400”.

Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use.

CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

Amiodarone vs Pacerone Comparison – Drugs.com

Amiodarone vs Pacerone Comparison – Drugs.com
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View side-by-side comparisons of medication uses, ratings, cost, side effects and interactions.

Amiodarone does not appear to increase life expectancy and can be difficult to manage, with a high risk of potentially fatal toxicities. Every effort should be made to use alternative agents first.</p> <p> Prescribed for Ventricular Tachycardia, Arrhythmia, Ventricular Fibrillation, Supraventricular Tachycardia. </p> <p> amiodarone may also be used for purposes not listed in this comparison guide. </p> ”> Prescription only Amiodarone should ONLY be used in the treatment of life-threatening ventricular arrhythmias that have not responded to other treatments. Amiodarone does not appear to increase life expectancy and can… View more	Prescription only Prescribed for Ventricular Tachycardia, Arrhythmia, Ventricular Fibrillation, Supraventricular Tachycardia. Pacerone may also be used for purposes not listed in this medication guide.	Related suggestions Supraventricular Tachycardia Metoprolol Atenolol Diltiazem Verapamil Bisoprolol Toprol-XL Arrhythmia Propranolol Verapamil Tikosyn Dofetilide Lidocaine Mexiletine Ventricular Tachycardia Atenolol Propranolol Flecainide Tenormin Mexiletine Propafenone Ventricular Fibrillation Lidocaine Vasopressin Nexterone Xylocaine-MPF Xylocaine HCl DentiPatch Popular comparisons Amiodarone vs atenolol
More about Amiodarone	More about Pacerone (amiodarone)
Generic Status
Lower-cost generic is available	Lower-cost generic is available
Ratings & Reviews
Amiodarone has an average rating of 4. 7 out of 10 from a total of 95 ratings on Drugs.com. 38% of reviewers reported a positive effect, while 51% reported a negative effect.	Pacerone has an average rating of 9.7 out of 10 from a total of 4 ratings on Drugs.com. 100% of reviewers reported a positive effect, while 0% reported a negative effect.
View all 95 reviews	View all 4 reviews
Drug Class
Group III antiarrhythmics	Group III antiarrhythmics
Side Effects
Commonly reported side effects include: hypersensitivity pneumonitis interstitial pneumonitis pulmonary toxicity pulmonary alveolitis hypotension corneal deposits ataxia blurred vision decreased visual acuity dermatological reaction gastrointestinal signs and symptoms peripheral neuropathy photophobia phototoxicity skin photosensitivity visual halos around lights xerophthalmia ddc-list-cropped” data-toggle-hide=””>show all 17 See also: amiodarone side effects in more detail.	Common side effects include: hypersensitivity pneumonitis interstitial pneumonitis pulmonary toxicity blurred vision peripheral neuropathy phototoxicity visual halos around lights See also: Pacerone side effects in more detail.
Pricing and Coupons * Prices are without insurance
Quantity 100 each Dosage 200 mg Per Unit* $0.31 – $0.61 Cost* $31.18 – $61.04 View all amiodarone prices	Quantity 60 tablet Dosage 200 mg Per Unit* $1. 04 Cost* $62.17 View all Pacerone prices and generic prices
Get free Discount Card	Get free Discount Card
Dosage Form(s) Available
Intravenous solution Oral tablet	Oral tablet
Half Life The half-life of a drug is the time taken for the plasma concentration of a drug to reduce to half its original value.
240 hours	240 hours
CSA Schedule ** View glossary of terms
Is not subject to the Controlled Substances Act.	Is not subject to the Controlled Substances Act.
Pregnancy Category
See the full pregnancy warnings document.	See the full pregnancy warnings document.
Drug Interactions
A total of 689 drugs are known to interact with amiodarone: 297 major drug interactions (1011 brand and generic names) 360 moderate drug interactions (1384 brand and generic names) 32 minor drug interactions (88 brand and generic names)	A total of 689 drugs are known to interact with Pacerone: 297 major drug interactions (1011 brand and generic names) 360 moderate drug interactions (1384 brand and generic names) 32 minor drug interactions (88 brand and generic names)
Alcohol/Food/Lifestyle Interactions
Amiodarone may be taken with or without food but should be taken at the same way each time. You… View more	Amiodarone may be taken with or without food but should be taken at the same way each time. You… View more
Disease Interactions
Dialysis Pulmonary dysfunction Sinus node dysfunction Visual impairment Cardiovascular dysfunction Proarrhythmic effects QT prolongation Hepatic impairment Neurologic dysfunction Thyroid dysfunction Electrolyte imbalance	Dialysis Pulmonary dysfunction Sinus node dysfunction Visual impairment Cardiovascular dysfunction Proarrhythmic effects QT prolongation Hepatic impairment Neurologic dysfunction Thyroid dysfunction Electrolyte imbalance
First Approval Date
December 24, 1985	April 30, 1998
WADA Class View World Anti-Doping Agency classifications.
N/A	N/A
More Information
Side effects Pregnancy warnings Breastfeeding warnings Dosage information Drug images Drug interactions Support group Pricing and coupons	Side effects Pregnancy warnings Breastfeeding warnings Dosage information Drug images Drug interactions Pricing and coupons En Español
Patient resources
Overview Advanced reading	Overview Advanced reading
Professional Resources
Monograph (AHFS) Prescribing information	Prescribing information

** The Controlled Substances Act (CSA) schedule information displayed applies to substances regulated under federal law. There may be variations in CSA schedules between individual states.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

Amiodarone: between originator and generics | Shubik Yu.V.

Perhaps the economic crisis is not the best time to compare original and generic drugs (GPs). Everyone is well aware that one must live within one’s means: generic replacement is one of the most obvious ways to reduce the cost of treatment and increase the availability of therapy, which is actively used all over the world. In the United States, for example, the share of HP in 1984 was 18.6% of all prescriptions for prescription drugs, and in 2007 it was already 63% [1]. Obviously, the ratio of original drugs and GP most significantly depends on the class of drugs. Thus, in the Medicare system (the state program of health care costs, focused mainly on the elderly in the United States), generics of b-blockers and thiazide diuretics clearly dominate (86. 6 and 92% of appointments, respectively), while in the group of ACE inhibitors they account for only 59%, and in the group of calcium antagonists – 55.5% of the total number of appointments [2].

It should be noted right away that in “civilized” countries, in addition to the original drugs, there are, as a rule, 5–6 GPs on the market, no more. But even such a small number of SOEs in the United States, for example, are divided into groups “A” and “B”. Group “A” – these are GPs that have passed clinical studies for therapeutic equivalence and have no more than 3-4% differences in bioequivalence from the original drug. Group “B” – GPs that have not passed such clinical trials [3]. Information about the “status” of drugs is contained in the Orange Book and is available to everyone (www.fda.gov/cder/ob). In a pharmacy, it is impossible to replace drugs with one trade name with another by a pharmacist.
In Russia, the situation is different. A favorite example of colleagues in pharmacoeconomics is diclofenac: in addition to the original drug with the trade name Voltaren, there are more than 100 different GPs on the Russian market. It’s no secret to any of us that their effectiveness is not the same.
There is no doubt that when deciding on the choice of an original drug or GP for a patient, we should be guided by two considerations – economic feasibility and clinical efficiency. It makes no sense to hide that for a practicing physician, the second of them will always be a priority. Even with a quite favorable situation with the control of the effectiveness of GPs in Western countries, the attitude towards their use can hardly be called positive. There are constantly publications that cast doubt on the conformity of the GP with the original drugs.
Thus, in the United States, in the Medicare system, with an increase in the proportion of HP, the frequency of hospitalizations of patients significantly increased [4]. In Japan, when comparing the ability of the original omeprazole and three GPs to provide acid suppression, there were significant differences, manifested both in a decrease in the proportion of time with a pH> 4, and in a greater pH variability in patients receiving generic drugs [5].
There are also publications on antiarrhythmic drugs. For example, an expert assessment of the consequences of generic substitution of antiarrhythmic drugs showed that it can lead to an increase in the frequency of arrhythmia episodes, and in isolated cases it is the cause of death [6]. Perhaps, in some cases, this is due to a change in the concentration of active metabolites, characterized by a higher level of toxicity (in the case of amiodarone, deethylamiodarone) [7].
It must be said that amiodarone tablet GPs in Russia and the United States are quantitatively represented approximately the same – there are about 10 of them. But in the United States, such studies were carried out. One may recall the study by Sauro S. et al. in 2002 [8]. It showed that the transition from the original Cordarone to one of the GPs does not lead to a change in the concentration of amiodarone and its active metabolite in the blood plasma. At the same time, individual fluctuations in the concentration of amiodarone in plasma are higher with the use of GP. The authors conclude that to ensure the safety of patients, it is advisable to monitor the concentration of the drug in blood plasma for 1–3 months after switching from one analogue to another. A recommendation that is hardly feasible in the conditions of the Russian Federation.
And yet, one cannot but agree that the quality of SOEs in Western countries (with the indispensable strict control) does not cause much criticism. An illustration can be the data of a meta-analysis of a large number (38) of comparative studies of the effectiveness of cardiovascular original drugs and HP. The results of this meta-analysis were the most favorable for generics. But this is not interesting: the publication reports that, nevertheless, more than half of the editorial articles of medical journals (23 out of 43) express a negative attitude towards HP [9]!
In Russia, at present, the problem of generic replacement is given quite a lot of attention. It is covered in great detail in the 80-page report of the Formulary Committee published this year [10].
One can only regret that this remarkable document in many respects has not yet been widely disseminated. We will try to at least partly fill this gap.
Some of the figures cited by the report’s authors may be quite impressive for practitioners of public health. So, for example, it is indicated that 60–70% of drugs registered in Russia belong to drugs whose effectiveness has not been proven in well-organized studies or is not obvious as a result of the practice of using drugs.
The report states that currently all drugs are subject to a single registration procedure, but for GPs, instead of clinical trials, bioequivalence studies are being conducted. It was noted that when using HP, a large number of complaints about the effectiveness of drugs arise, but there is no system for assessing comparative clinical effectiveness in the Russian Federation.
According to the authors of the publication, of the drugs available on the market, the state buys the cheapest GP without taking into account their quality, efficiency and cost-effectiveness. However, they are not tested for therapeutic equivalence with the original drugs. This practice makes the fears of patients very substantiated that the replacement of the original drug with a HP will lead to a decrease in the effectiveness of treatment. Unfortunately, cases when GPs differ in their therapeutic efficacy from the original drugs are indeed not uncommon. The situation with public procurement of drugs is regarded by a group of experts as catastrophic.
Particular attention in the report is given to post-registration (post-marketing) research. Their necessity is due to the very frequent lack of pre-registration clinical trials in accordance with the requirements of the GCP, the lack of data on the clinical efficacy and safety of drugs. Often, post-marketing studies are of extremely poor quality and are a veiled mechanism for paying doctors and health officials. Even firms that comply with all the requirements for conducting such studies in developed countries use simplified research protocols in Russia. These large-scale post-marketing studies carried out in Russia have nothing to do with GCP requirements. But it is their results that are presented as scientific evidence of the effectiveness of drugs.
A special section of the report is devoted to drug provision for cardiac patients. It was noted that the Russian market has a full range of original cardiological drugs and a large number of their generics. However, the real availability of drugs and the quality of treatment are still assessed as low.
Among the most important reasons for poor-quality treatment is, in particular, the presence of a large number of generic forms of drugs, including low, according to doctors and patients, quality. First of all, this applies to domestic and Southeast Asian drugs. It is their bioequivalence with the original drugs that is especially doubtful and needs more careful monitoring. The authors point out that drug provision within the framework of the DLO is more social than medical assistance, and this assistance is based on cheap drugs of dubious quality.
Mentioned in the report and antiarrhythmic drugs. In particular, they talk about their limited range and high cost, including domestically produced drugs. Generic antiarrhythmics are said to be affordable both in price and quality. At the same time, it is obvious that sotalol and propafenone GP are meant, since, unfortunately, amiodarone is not even mentioned in the report.
As a practicing cardiologist-arrhythmologist, I am ready to subscribe to almost every word of this document. As the head of the clinical division, representatives of pharmaceutical companies come to me every day. If the subject of discussion is the emergence of a new GP on the market, then I am primarily interested in the presence of studies on bioequivalence and therapeutic equivalence with the original drug. As an example, I am ready to describe a meeting that took place relatively recently. A representative of a well-known Russian pharmaceutical company first came to me with samples of the new GP amiodarone. In response to a request to present the results of studies on bioequivalence with the original drug, I was assured that such studies were absolutely accurately carried out, and I would be acquainted with their results at the next visit. The document was indeed submitted, but it had nothing to do with comparison for bioequivalence. It was a conclusion on the therapeutic efficacy of GP amiodarone in ventricular extrasystole, presented on the letterhead of a highly respected medical institution in St. Petersburg, equipped with a round seal and signed by a well-known professor of cardiology. In this document, several lines in length, it was said that the effectiveness of GP was evaluated when it was prescribed to 20 patients with ventricular extrasystole against the background of various diseases of the cardiovascular system, for a period of 3 months. A positive effect was achieved in all 20 patients, while no side effects and complications were noted in any case.
I think it’s hard to do more damage to a pharmaceutical company by “promoting” a new drug in this way. Even if you do not refer to the GCP requirements: the “document” does not say a word about the causes and nature of extrasystole, the doses of GP used in the treatment, the method for assessing the effectiveness of treatment … Not to mention the fact that the effectiveness of the original amiodarone, in accordance with the publications of the latter, is almost 50 years is still much lower. I would like to end the story here. But, unfortunately, it doesn’t work! A few months later, I was surprised to find that my home hospital had purchased this particular amiodarone HP. The reason for this, of course, was the difference in the cost of the original drug and HP.
Not being a specialist in the field of pharmacoeconomics, I will allow myself a small study that can be done in 10 minutes without leaving your computer. So:
1. We go to the site with the name www.webapteka.ru (dated March 18, 2009): here you can find out about the cost of drugs in different (not all, but only some!) pharmacies in Moscow and St. Petersburg.
2. We choose the original amiodarone preparation (Cordarone Sanofi Aventis) and the 3 most common amiodarone GPs in Russia: amiocordin, amiodarone and cardiodarone.
3. We determine the minimum and maximum cost of 30 tablets (1 package) of each of the drugs in different pharmacies, after which we calculate the average cost as half of the sum of the minimum and maximum prices.
It turns out that the difference in the cost of the original amiodarone and the cheapest GP is fivefold! With such differences, the “preferences” of the administration of any medical institution are quite understandable. In addition, the financial responsibility of health care leaders is as great as the responsibility for outcomes is speculative.
But representatives of practical health care should be primarily interested in the results. And here we have to take into account absolutely not a “pharmacoeconomic” concept, which can be called the “price of a mistake”. So, from the point of view of a cardiologist-arrhythmologist, the cost of a mistake may be the death of a patient. In most cases, by prescribing a GP instead of the original drug, we risk the patient’s quality of life. But if we treat heart rhythm disorders (especially ventricular arrhythmias), we risk the patient’s life. As an illustration, I would like to cite the following clinical observation.

Patient G., 44 years old. He was admitted to the clinic of the North-West Center for Diagnosis and Treatment of Arrhythmias due to the fact that the cardioverter-defibrillator implanted in him 4 years ago worked 8 times during the previous two days of hospitalization. From the anamnesis it is known that a patient with metabolic syndrome (arterial hypertension, obesity, impaired glucose tolerance, hyperlipidemia, gout), who did not receive adequate treatment, without previous angina pectoris, at the age of 39 suffered a widespread anterior transmural myocardial infarction complicated by acute left ventricular failure. During the first day of myocardial infarction, in addition, paroxysms of spindle-shaped ventricular tachycardia occurred twice with transformation into ventricular fibrillation. Subsequently, an aneurysm of the anterior wall of the left ventricle was formed with a decrease in the ejection fraction to 42%.
Six months later, the patient was operated on in one of the clinics in Germany: aortocoronary bypass grafting with plastic aneurysm of the left ventricle. The postoperative period was complicated by polymorphic ventricular tachycardia with transformation into ventricular fibrillation. In the first two days after the operation, tachycardia acquired a constantly relapsing character (“storm”), in connection with which electrical cardioversion was performed more than 80 (!) times. The patient’s condition was regarded as critical, the patient’s relatives were informed that the chances of a successful outcome are minimal. Nevertheless, the condition was stabilized by immersing the patient in a narcotic sleep for three days and parenteral administration of large (more than 1000 mg per day) doses of amiodarone. In the following days, the patient was implanted with a cardioverter-defibrillator with the appointment of Kordaron (Sanofi Aventis) at a loading dose of 800 mg per day, followed by a transfer to a maintenance dose of first 600 and then 400 mg per day.
After discharge from the hospital, the cardioverter-defibrillator worked for the first time after 1.5 years three times in a row (within one day). The patient associated the deterioration with an attempt to cancel Kordaron on the recommendation of the attending physician. The cause of cardioversion in all three cases was paroxysms of polymorphic ventricular tachycardia. The antiarrhythmic was resumed, and in the next 2.5 years there were no life-threatening arrhythmias. Holter monitoring revealed only a single polymorphic ventricular extrasystole in a relatively small amount. In addition to Kordaron, the patient received systematically selective lipophilic
β-blockers (bisoprolol), statins (simvastatin), angiotensin-converting enzyme inhibitors (perindopril), antiplatelet agents (acetylsalicylic acid), antidiabetic drugs (metformin), periodically – allopurinol. Outpatient observation of the patient with a frequency of 1 time in 3-6 months, in accordance with his desire, was carried out in the German clinic in which aortocoronary bypass grafting was performed. In the same place, in Germany, he purchased all the medicines.
Before the last hospitalization for about 5 days, the patient paid attention to the fact that he had interruptions in the work of the heart.
Holter monitoring, performed on the first day after the patient’s admission to the hospital, revealed a fivefold increase in the number, as well as the appearance of paired and group polymorphic ventricular extrasystoles. When programming the cardioverter-defibrillator, it turned out that the battery charge was sufficient, and the operation of the device all 8 times was associated with the appearance of paroxysms of polymorphic ventricular tachycardia lasting 30 seconds (in accordance with the programmed defibrillation parameters). It was suggested that amiodarone had lost its effectiveness, but as a first step, to finally make sure of this, it was decided to replace oral administration of the drug with parenteral (intravenous drip) administration at a dose of 7 mg per 1 kg of body weight. The very next day of Holter monitoring showed the almost complete disappearance of paired and group ventricular extrasystoles. It was after receiving such results of treatment that it was first suggested that the amiodarone that the patient received was ineffective.
Indeed, upon repeated questioning, it was possible to find out that during the last visit of the patient to Germany, for the first time, due to the absence of the original drug in the pharmacy, he purchased on the recommendation of the pharmacist (!) GP.
Since it was possible to find out about the viability of the above assumption only by determining the concentration of amiodarone in the plasma (in our clinic there is no such possibility), the patient, of his own free will and contrary to our recommendations, the next day flew to the German clinic where he was systematically observed. A few days later, he gratefully reported that, despite the intravenous drip of the drug in St. Petersburg, the content of amiodarone in the plasma was indeed very low.
It seems that the above clinical observation is quite correct in the sense that a GP of non-Russian production turned out to be insolvent (for unknown reasons).
Another question that I would like to briefly highlight: is treatment with the original amiodarone so expensive in comparison with other antiarrhythmics? It is easy to answer it by turning back to the site www.webapteka.ru and conducting another simple 10-minute study. So:
1. Let’s determine which antiarrhythmic drugs are most often used in Russia. It must be assumed that, in addition to amiodarone, these are (in alphabetical order) allapinin, propafenone, sotalol, etatsizin. At the same time, allapinin and etatsizin are original drugs. Propafenone in Russia is known as ritmonorm and propanorm, sotalol – as sotalex (original drug) and sotahexal (GP).
2. Determine the average therapeutic doses for each of the antiarrhythmics. It seems that for allapinin it is 75 mg per day, for amiodarone – 400 mg per day (given that it is prescribed first in a loading dose), for propafenone – 450 mg per day, for sotalol – 240 mg per day, for ethacizine – 150 mg per day.
3. We determine the minimum, maximum and average cost of each drug package, calculate the cost of one tablet and the cost of treatment for 30 days.
The results are presented in Table 1. Note that we included in the study tablets of Pronorm 150 (but not 300) mg, Sotahexal – 160 (but not 80) mg. In addition, it was taken into account that the number of tablets in the packages is different: sotahexal – 20, allapinin, Cordaron and Sotalex – 30, propanorm, ritmonorm and ethacizin – 50.
As you can see, the results obtained are very interesting. The most “expensive” was the treatment with the original drugs Allapinin and Rimonorm, one of which is Russian-made. Treatment of HP with sotahexal turned out to be more “expensive” than the original drug with sotalex. The use of the original drug Kordaron, along with sotalol preparations, is the least expensive.
The above does not mean at all that amiodarone should be used instead of allapinin and propafenone for the treatment of cardiac arrhythmias. It is quite obvious that the choice of an antiarrhythmic agent is determined primarily by the clinical feasibility of its use, and only secondarily by the cost of drugs.
However, when prescribing drugs for the purpose, for example, of treating life-threatening ventricular arrhythmias and preventing sudden cardiac death, we would like to be sure that the therapeutic efficacy of the recommended drug corresponds to our ideas about it.
Therefore, on the one hand, we must strive to tighten the drug registration system so that generic substitution in Russia does not entail a deterioration in the quality of treatment. On the other hand, in cases where the patient’s life may be at the cost of an error, we must prescribe drugs whose effectiveness is beyond doubt.

Literature
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3. Tarlovskaya E.I. Generics and original drugs: the view of a practical doctor.//RMJ 2008;16(5):333.
4. Christian–Herman J., Emons M., George D. Effects of generic–only drug coverage in a Medicare HMO.//Health Affairs 2004; W4-45 5; DOI 10.1377/hlthaff.W4.455.
5. Shimatani T., Inoue M., Kuroiwa T. et al. Acid-suppressive effects of generic omeprazole: comparison of three brands of generic omeprazole with original omeprazole.//Dig. LiverDis. 2006; 38(8): 554–559.
6. Reiffel J., Kowey P. Generic antiarrhythmics are not therapeutically equivalent for the treatment of tachyarrhythmias.//Am. J. Cardiol. 2000; 85(9): 1151–1153, A10.
7. Pollak P. Altered metabolite concentrations with amiodarone generic substitution cannot be observed without monitoring.//Can. J. Cardiol. 2001; 17(11): 1159–1163.
8. Sauro S., DeCarolis D., Pierpont G., Gornick C. Comparison of plasma concentrations for two amiodarone products.//The Annals of Pharmacotherapy 2002; 36(11): 1682–1685.
9. Kesselheim A., Misono A. Lee J. et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease. A systematic review and meta-analysis.//JAMA. 2008; 300(21): 2514–2526.
10. Formulary Committee of the Russian Academy of Medical Sciences. Report on the state of drug provision of the population in the Russian Federation (2008).// M.: NYUDIAMED, 2009. 80 p.

Some controversial issues of atrial fibrillation pharmacotherapy.

Yuri Andreevich Bunin , Professor:

– Good afternoon, dear colleagues. Today I would like to discuss some issues in the treatment of atrial fibrillation, and debatable issues. Firstly, in my report I would like to dwell on the issues of the effectiveness and safety of antiarrhythmic drugs, the advisability of using one or another antiarrhythmic drug, given the ratio, efficacy and safety of this particular antiarrhythmic. In addition, I would like to talk about combined antiarrhythmic therapy in the same message, because there are some disagreements and misunderstandings among doctors. It seems to me that an important problem in the treatment of atrial fibrillation is the treatment of this type of heart rhythm disturbance in patients with chronic heart failure. Finally, I would like to dwell on some analysis or evaluation of some of the meta-analyses on the effect of beta-blockers and cardiac glycosides on prognosis in patients with atrial fibrillation.

This slide presents the algorithm of the European Society of Cardiology from 2010 with clarifications from 2012, which shows the advisability of taking one or another antiarrhythmic drug depending on concomitant cardiovascular disease. In Europe, only five antiarrhythmic drugs are recommended for the prevention of atrial fibrillation. Of these, two antiarrhythmics are class 1C drugs – propafenone and flecainide. Flecainide, unfortunately, is not registered in our country. And the three class 3 antiarrhythmic drugs are sotalol, amiodarone and dronedarone. As can be seen from these recommendations, from this algorithm, in the first place, if there is no severe heart failure or severe myocardial hypertrophy, class 1C antiarrhythmics and sotalol are in the first place. At the same time, amiodarone, despite the fact that it is the most effective antiarrhythmic drug in the prevention of atrial fibrillation, due to its organotoxic effects, it is in many algorithms, in particular the European algorithm, in most situations in last place, when it is no longer effective. the above drugs are class 1C.

I want to focus on Dronedarone. It is registered in Europe, in 17 countries of the European Union, in Canada, in the United States, and in Israel. But the latest research shows that this drug is highly toxic and has many side effects. Compared with placebo in the PALLAS study, patients with permanent atrial fibrillation experienced a three-fold increase in sudden death, a two-fold increase in total mortality, and almost a two-fold increase in hospitalization. Adding to this study, I would like to point out that the effectiveness of the drug dronedarone is very low. This is the most ineffective drug currently available on the pharmaceutical market. Therefore, I am satisfied that although it is registered on the Russian market, it does not exist for sale. And I do not advise using it for the prevention of paroxysms of atrial fibrillation. That’s exactly what we talked about, in terms of efficiency / safety ratio – this is the most unsuccessful drug on the pharmaceutical market in Europe and Russia at the present time.

If we talk about class 1C antiarrhythmics, their significance in the treatment of atrial fibrillation, I would like to note that only two class 1C antiarrhythmics, propafenone and flecainide, have the largest clinical evidence base of these drugs. The effectiveness of domestic class 1C antiarrhythmics has been studied only in small and uncontrolled studies, so there is much less reliable data on their effectiveness. In addition, in the recommendations of the European Society of Cardiology, the American College of Cardiology, the American Heart Association, these two class 1C drugs – propafenone and flecainide – are the only drugs that are recommended for oral relief of atrial fibrillation. It is very convenient for the patient and economically very beneficial for health care.

This slide shows the RAFT study, which evaluated the efficacy of extended release formulations of propafenone. And here we see that compared with placebo – this is a green bar – the effectiveness of various doses of propafenone can reduce the risk of recurrent atrial fibrillation by an average of 50% to 60% of cases. At the same time, one can refer to another study. This is a large Cochrane review, including twelve and a half thousand patients with atrial fibrillation of any type and duration. And we see that class 1C and class 3 drugs are the most effective in preventing recurrence of atrial fibrillation. All other drugs – drugs of class 1A, class 1B are significantly inferior in their effectiveness in preventing recurrence of atrial fibrillation.

I want to dwell on the results of my own research. With our colleagues, we conducted a placebo-controlled study, one of the few in Russia, which evaluated the effectiveness of the class 1C antiarrhythmic propafenone (propanorm) by PRO. MED CS.Praha. We compared this efficacy with that of placebo. And if you look at the right side of the slide, we see that with very severe paroxysms of arrhythmia, and here we included in the study patients who had more than ten paroxysms of atrial fibrillation during the week, the effectiveness of propafenone, propanorm, compared with placebo, exceeded 50%. And also this class 1C drug, propafenone, was effective in other types of supraventricular tachycardia. We see that in atrioventricular nodal reciprocal tachycardia its effectiveness is significant, and in atrioventricular reciprocal tachycardia in the presence of additional pathways of the atrial ventricle and focal atrial tachycardia, this drug is highly effective.

We will touch on the issue of combined antiarrhythmic therapy. Unfortunately, the latest recommendations of the European Society of Cardiology, and to my even greater regret, and the national recommendations, which are the actual analogue of the recommendations of the European Society of Cardiology, do not indicate the advisability of combined antiarrhythmic therapy. I think this is wrong, because when I asked those who created the European guidelines for atrial fibrillation, they replied that they themselves treat with a combination of antiarrhythmic drugs. In the recommendations of the American Heart Association, the American College of Cardiology, this item is retained – on the advisability of combined antiarrhythmic therapy. It is recommended to combine the following drugs for the prevention of recurrence of atrial fibrillation – class 1C drugs with a beta-blocker, verapamil, cordaron and sotalol. It is already known that the combination of cordarone with beta-blockers has a good preventive effect in atrial fibrillation and is somewhat inferior to this, but the combination of cordarone with verapamil also has a fairly high efficiency. Here is a fragment of our study, also placebo-controlled, where we can see that if we add to cordarone, which may be ineffective in some patient, an antiarrhythmic – and propranolol, and half doses of propafenone (propanorm), then it becomes effective, and this the effect may even become complete. And this is all statistically significant data. Therefore, I confirm and insist that combined antiarrhythmic therapy, which requires certain skills, makes it possible not only to increase the effectiveness of monotherapy, but also to reduce the number of adverse reactions. Because you can start with half daily doses of antiarrhythmics in combination antiarrhythmic therapy.

The European and American Heart Association guidelines suggest that occasional atrial fibrillation be treated with oral propafenone or flecainide. We also conducted our own placebo-controlled study, one of the few in Russia, where we evaluated the effectiveness of oral administration of 600 milligrams of propafenone (propanorm) in stopping atrial fibrillation. The stopping effect of oral administration of 600 milligrams of pronorm is high – more than 70%, which is in line with other studies conducted in Europe and the United States of America. This effect occurs on average three hours after the start of the drug. Who can recommend oral atrial fibrillation relief? Certainly not for patients with severe atrial fibrillation. These patients should be treated intravenously with drugs for relief or, in severe hemodynamic disorders, electrical cardioversion. The group of patients who are indicated for oral stopping therapy are patients with not very severe, but debilitating, prolonged attacks of atrial fibrillation. You must first work out this dose and see the absence or presence of side effects from oral stopping therapy – they are not pronounced, but they can be – in a hospital, and then prescribe atrial fibrillation for oral stopping at home. It is economically very beneficial and psychologically also very beneficial for patients, because there is no need to call an ambulance and stop it with intravenous administration of the drug.

The pharmacological treatment of atrial fibrillation has now stagnated. Looking for new drugs. I have already noted one drug – dronedarone is ineffective. And many doctors in Europe stop prescribing it. And there is a search for new antiarrhythmic drugs. One of the new studies and attempts to find a new antiarrhythmic drug is the drug ranolazine. It is well known to cardiologists as a late sodium current blocker. This drug is used to treat coronary heart disease. RAFFAELLO is being studied to evaluate its antiarrhythmic effect in patients with persistent atrial fibrillation who have been restored to sinus rhythm by electrical cardioversion. Let’s see the final results, how this drug will be suitable for the prevention of atrial fibrillation. An important issue in the treatment of atrial fibrillation and not fully understood is the treatment of atrial fibrillation in patients with chronic systolic heart failure.

European guidelines emphasize that only one antiarrhythmic drug, amiodarone, is recommended for the treatment of atrial fibrillation in patients with chronic systolic heart failure. But everyone forgets, on purpose or for some other reason, this SCD-HeFT study. What are the results of this study? It turns out that if amiodarone is used as a prophylactic therapy in patients with severe heart failure – these are patients of the third and fourth functional class, the right side of the slide, then it can be seen that mortality in patients who are prescribed amiodarone – this is the red line – is reliable and significantly higher than placebo mortality is the blue line. To be objective, I want to say that in patients with severe heart failure of the third or fourth functional class, implantation of a cardioverter-defibrillator also does not increase survival.

Why is this happening? And how to approach the treatment of atrial fibrillation in patients with heart failure? This is another study, it may be less significant, but still this is the VALIANT study, which also shows that patients with postinfarction cardiosclerosis who took amiodarone had a lower survival rate than patients who did not take amiodarone. I think that the explanation must be sought in severe myocardial damage in patients with postinfarction cardiosclerosis or in general with any non-ischemic theology of heart failure. On the right side of the slide, we see that sudden death, that is, arrhythmic death, in which antiarrhythmics or implantable cardioverter-defibrillators can help, with an increase in the functional class of heart failure – the red part of these columns – it is decreasing. And in the third or fourth functional class, mortality occurs not mainly arrhythmic, but more than half – this is mortality from heart failure itself. What does death from heart failure mean? This is death from bradyarrhythmia. Naturally, antiarrhythmics will not help in this case. And therefore, the appointment of antiarrhythmics may not be indicated in patients with severe heart failure.

Our reasoning is supported by the guidelines for the treatment of heart failure and the 2012 European guidelines. At the top of these recommendations, it is written that restoration of sinus rhythm by electrical impulse therapy or pharmacological cardioversion is Class II B if rate control is present. Even amiodarone will not maintain sinus rhythm in patients with heart failure class II B indications. And, of course, the use of dronedarone and first-class antiarrhythmics, which increase mortality in these patients, is not recommended for the treatment of atrial fibrillation in patients with heart failure.

What approach to the treatment of atrial fibrillation in patients with heart failure, depending on the severity of heart failure, we offer? If not severe heart failure – the first or second functional class, we can choose any drug treatment strategy. Either the “rhythm-control” strategy, that is, stopping the arrhythmia and prescribing anti-arrhythmic antiarrhythmic therapy with amiodarone, and dofetilide, which can also be used for heart failure, is still registered in North America, or choose “frequency control”. If the patient has severe heart failure of the third or fourth functional class, taking into account the SCD-HeFT studies, it is not necessary to carry out classical antiarrhythmic therapy and not even prescribe amiodarone to prevent recurrence of atrial fibrillation, but to carry out the “frequency-control” strategy. That is, to prescribe beta-blockers in the first place, those three blockers that reduce mortality in patients with heart failure – metoprolol succinate, bisoprolol (Concor) and carvedilol, and to slow down the heart rate, thereby not exposing the patient to any dangers in terms of worsening prognosis when prescribing an antiarrhythmic drug.

In conclusion, I would like to review two reviews on the use of digoxin and beta-blockers in patients with atrial fibrillation. In 2012, an article “Increased mortality among patients treated with digoxin” appeared. This is a large study, more than four thousand patients. And just here two strategies were compared – the strategy of reducing the frequency of gastric contraction and the strategy of preventing the retention of sinus rhythm, the prevention of recurrence of atrial fibrillation. And it turned out that in the group of patients in whom the frequency of gastric contractions decreased during atrial fibrillation with digoxin, mortality was increased. Of course, many analyzes of this study and the DIG study immediately appeared – this is a classic study on the use of cardiac glucosides in heart failure. What did they show? It turns out that if you very carefully observe patients with heart failure, those who were prescribed cardiac glucosides – this is the right side of the slide, then there is no increase in mortality, hospitalization, or arrhythmia compared to placebo. At the same time, if we look at the left side of the slide, then if patients who received digoxin are not included in the study or their follow-up is not very good, then the prognosis may worsen, and mortality may also increase. And here the red bars are higher than the placebo, than the little blue bars. What is the way out? Can digoxin be used to treat atrial fibrillation? Let’s look further. This is very important. This is an analysis of the DIG study, this is the only and largest, outstanding study on cardiac glycosides, their use in patients on sinus rhythm, atrial fibrillation, it turned out that if the concentration of digoxin is low – no more than one nanogram per milliliter in blood plasma, then mortality decreases . And if the concentration of digoxin increases – more than one nanogram per milliliter, then mortality can also be increased. What conclusion can be drawn from this analysis? I think that cardiac glycosides should be used to treat atrial fibrillation, but digoxin should be treated carefully, know that if this is an elderly patient or a patient with renal insufficiency – and it is known that digoxin is excreted by the kidneys in unchanged form, – or the patient takes drugs that can increase the concentration of digoxin in the blood plasma, I mean primarily amiodarone, verapamil and propafenone, then these patients should have a very low dose – no more than 0. 25 milligrams, that is, one a tablet, but it is better if it is an elderly patient, and in combination with those drugs, half a tablet and even a quarter of a tablet. And then, if you look at the left side of the slide, there will be no deterioration in the prognosis of morbidity in these patients. Therefore, my suggestion is to continue using digoxin, but to treat it more carefully, not to assume that this drug is absolutely safe for long-term use.

And I would like to review, review another meta-analysis. This is a meta-analysis on the effect of a beta-blocker on survival in patients with atrial fibrillation and chronic heart failure. A meta-analysis was conducted, it was published in 2013, where they took four studies with carvedilol, metoprolol, bisoprolol and nebivolol and looked at whether the survival of patients with the use of beta-blockers in heart failure in sinus rhythm and in atrial fibrillation increases. On sinus rhythm, the survival of these patients – the prognosis improves – the total mortality is reduced by 46%. At the same time, this analysis showed that mortality does not change with atrial fibrillation. The difference in mortality is not statistically significant. Such statements and such meta-analyses require very careful consideration. Because sometimes a meta-analysis, the average temperature in a hospital, is worse than a well-conducted single controlled study. We conducted this analysis, and it turned out that the conclusions are incorrect in this meta-analysis. Why? And we wrote that “In three of the four studies analyzed, digoxin was twice as likely to be used in atrial fibrillation than in sinus rhythm. That is, the groups of comparisons were different. We just said that there is a risk on digoxin and at the same time we do not take this into account. In the CIBIS study, which evaluated the efficacy of bisoprolol, Concor in heart failure, along with beta-blockers in patients with atrial fibrillation, amiodarone was used as the only agent. But we also just saw that amiodarone in patients with severe heart failure can worsen the prognosis.