Side effects of plavix long term: Side effects and what to do about them
Side effects and what to do about them
Plavix (clopidogrel) is a brand-name prescription medication. The Food and Drug Administration (FDA) has approved it to decrease the risk of heart attack and stroke in people with:
- peripheral arterial disease or who have had a recent heart attack or stroke
- acute coronary syndrome,* which includes unstable angina and certain types of heart attack called non-ST-elevation myocardial infarction or ST-elevation myocardial infarction
Plavix is typically taken long term. Unlike Coumadin (warfarin), Plavix is not an anticoagulant. Instead, it stops platelets from sticking together to form blood clots.
Here are some fast facts about Plavix:
- Active ingredient: clopidogrel
- Drug class: platelet inhibitor
- Drug form: oral tablet
As with other drugs, Plavix can cause side effects (also known as adverse effects). Read on to learn about potential common, mild, and serious side effects. For a general overview of Plavix, including details about its uses, see this article.
* For acute coronary syndrome, Plavix is given in combination with aspirin.
Plavix can cause certain side effects, some of which are more common than others. These side effects may be temporary, lasting a few days to weeks. However, if the side effects last longer than that, bother you, or become severe, be sure to talk with your doctor or pharmacist.
These are just a few of the more common side effects reported by people who took Plavix in clinical trials:
- bleeding, such as nosebleeds
For more information about these side effects, see “Side effect specifics” below.
Mild side effects can occur with Plavix. This list doesn’t include all possible mild side effects of the drug. For more information, you can refer to Plavix’s prescribing information.
Mild side effects that have been reported with Plavix include:
- mild allergic reaction*
These side effects may be temporary, lasting a few days to weeks. However, if the side effects last longer than that, bother you, or become severe, be sure to talk with your doctor or pharmacist.
Note: After the Food and Drug Administration (FDA) approves a drug, it tracks side effects of the medication. If you develop a side effect while taking Plavix and want to tell the FDA about it, visit MedWatch.
* For more information about this side effect, see “Side effect specifics” below.
Plavix may cause serious side effects. The list below may not include all possible serious side effects of the drug. For more information, you can refer to Plavix’s prescribing information.
If you develop serious side effects while taking Plavix, call your doctor right away. If the side effects seem life threatening or you think you’re having a medical emergency, immediately call 911 or your local emergency number.
Serious side effects that have been reported and their symptoms include:
- Serious bleeding problems. Symptoms can include:
- blood in your urine
- unexplained bleeding that lasts a long time
- bleeding in the brain, also called a stroke
- coughing up blood
- blood in your stool
- Thrombotic thrombocytopenic purpura.*
- Severe allergic reaction.†
* For more information about this side effect, see “Side effect specifics” below.
† An allergic reaction is possible after taking Plavix. However, this side effect wasn’t reported in clinical trials. To learn more, see the “Side effect specifics” section below.
Plavix may cause several side effects. Here are some frequently asked questions about the drug’s side effects and their answers.
Does Plavix cause any different side effects in older adults?
No, it’s not likely. In clinical trials of Plavix, older adults (ages 65 years and over) reported the same side effects as other age groups. These side effects can include bruising and bleeding problems.
If you are an older adult and you have questions about side effects from Plavix, talk with your doctor or pharmacist.
If I stop taking Plavix 75 mg, will I experience withdrawal symptoms?
No, withdrawal symptoms were not a reported side effect in Plavix’s clinical trials. Withdrawal symptoms are side effects that happen after you stop taking a drug that your body has become dependent on.
However, stopping Plavix can increase your risk of heart attack and stroke.
Talk with your doctor before stopping Plavix. If you need to stop the drug for any reason, follow their instructions for doing so.
Can Plavix cause fatigue, hallucinations, or constipation?
Fatigue, hallucinations, and constipation were not reported in clinical trials of Plavix.
However, after the drug was available on the market, some people reported having hallucinations while taking Plavix. It’s not known whether this side effect was caused by Plavix or something else.
If you have fatigue, hallucinations, or constipation while taking Plavix, talk with your doctor. They can help determine what may be causing these symptoms.
Learn more about some of the side effects that Plavix may cause. To find out how often side effects occurred in clinical trials, see the prescribing information for Plavix.
In clinical trials, bruising was a common side effect reported with Plavix.
Bruising happens when small blood vessels under the skin break and release blood. A bruise may appear discolored at first and then change in color and appearance as it heals. The bruised area may be painful or tender.
What you can do
Most bruises are small and will heal quickly. If a bruise is painful, you can apply an ice pack for 20 minutes at a time.
However, bruising can sometimes be serious. Talk with your doctor if you have concerns about bruising, such as large bruises that don’t seem to be healing or getting better.
It’s possible to have nosebleeds during treatment with Plavix. In clinical trials, this side effect was common. Symptoms can include tasting blood, needing to swallow frequently, and bleeding from either nostril.
What you can do
Tell your doctor about any nosebleeds that won’t stop on their own or become severe.
To stop a nosebleed, you should:
- sit down, lean forward, and breathe through your mouth
- pinch the soft part of your nose shut for 10 to 15 minutes
- after 15 minutes, let go of your nose and see if it starts bleeding again
- place an ice pack or cold cloth against your nose and face to reduce bleeding
- avoid exercise or heavy lifting after a nosebleed
Call your doctor or go to the nearest emergency room for a nosebleed that continues for more than 15 minutes or makes you feel lightheaded (as if you’re going to pass out). You should also talk with your doctor if your nosebleed is very heavy, with blood rushing out your nostrils and down your throat.
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TPP) is a side effect that was reported after Plavix was released on the market.
TTP is a serious condition that can be life threatening. It happens when tiny blood clots form throughout your body. Symptoms can include:
- feeling tired and weak
- being unable to catch your breath
- increased heart rate
- change in skin tone
- small red or purple rash all over your body
What you can do
If you have symptoms of TPP, call your doctor right away. If the symptoms seem life threatening or you think you are having a medical emergency, immediately call 911 or your local emergency number.
In clinical trials of Plavix, itching was a common side effect. Itching may go away on its own or may be a sign of an allergic reaction.
What you can do
Tell your doctor about any itching you develop while taking Plavix. They may be able to offer ways to manage this side effect, such as taking an over-the-counter antihistamine such as Benadryl (diphenhydramine).
If the itching occurs with any symptoms of an allergic reaction, call 911 or go to the nearest emergency room right away. See “Allergic reaction” below for more details.
As with most drugs, Plavix can cause an allergic reaction in some people. However, this side effect wasn’t reported in clinical trials.
Symptoms can be mild or serious and can include:
- skin rash
- swelling under your skin, typically in your eyelids, lips, hands, or feet
- swelling of your mouth, tongue, or throat, which can make it hard to breathe
What you can do
For mild symptoms of an allergic reaction, call your doctor right away. They may be able to recommend ways to ease your symptoms and determine whether you should keep taking Plavix. However, if your symptoms are serious and you think you’re having a medical emergency, immediately call 911 or your local emergency number.
Plavix comes with several precautions. Read on for more details.
Boxed warning: Drug metabolism problem in certain people
This drug has a boxed warning for a risk of drug metabolism problems in certain people. This is a serious warning from the Food and Drug Administration (FDA).
In your body, Plavix is metabolized (processed) by the liver to its active form. This happens through an enzyme (protein) called CYP2C19. However, if you’re missing this enzyme, you may not be able to metabolize Plavix. Because of this, the drug may not work as it should. Your doctor may check your CYP2C19 function before prescribing Plavix to check whether your body is able to metabolize the drug.
Be sure to talk with your doctor about your health history before you take Plavix. This drug may not be the right treatment option for you if you have certain medical conditions or other factors that affect your health. These are known as drug-condition or drug-factor interactions. The conditions and factors to consider include:
Risk of bleeding. Plavix increases your risk of bleeding. If you take other medications that affect your platelets, you may be at an increased risk of this side effect. Tell your doctor about all of the medications you take, including any over-the-counter medications such as Motrin (ibuprofen) or Aleve (naproxen).
If you’re bleeding from an injury or recent surgery, talk with your doctor before taking Plavix. They’ll likely recommend that you give your body time to heal before taking this drug. If you have any health conditions that increase your risk of bleeding, such as hemophilia, tell your doctor. They may decide Plavix is not the best treatment option for you.
Surgery. If you’re planning on having surgery, your doctor may advise you to stop taking Plavix beforehand. However, stopping Plavix can increase your risk of a heart attack or stroke. Be sure to follow your doctor’s recommendation about Plavix if you’re having surgery.
Kidney problems. Let your doctor know if you have any problems with your kidneys. Plavix may not work as well for you if your kidneys aren’t functioning effectively.
Allergic reaction. If you’ve had an allergic reaction to Plavix or any of its ingredients, your doctor will likely not prescribe Plavix. Ask your doctor what other medications may be better options for you.
Alcohol with Plavix
There are no known interactions between Plavix and alcohol. However, drinking alcohol can irritate your stomach and intestines. Over time, this irritation may lead to ulcers (sores) and bleeding. Taking Plavix may make these conditions worse.
If you’d like to drink alcohol while you’re taking Plavix, talk with your doctor. They can advise you on how much alcohol, if any, may be safe for you.
Pregnancy and breastfeeding while taking Plavix
Plavix has not been clinically trialed in pregnant humans. However, reports of people taking Plavix during pregnancy have not shown harm to the fetus.
Plavix has not caused fetal harm in animal studies. However, it’s important to note that animal studies don’t always predict what will happen in humans.
If you’re pregnant and taking Plavix, your doctor will likely recommend that you stop the drug 5 to 7 days before you give birth. This is because Plavix increases the risk of serious bleeding during labor.
If you’re pregnant or planning to become pregnant, talk with your doctor. They can discuss the risks and benefits of taking Plavix during pregnancy.
It’s not known whether Plavix may pass into breast milk or what effects it may have on a child who is breastfed. However, animal studies have shown that the drug passes into breast milk.
If you’re breastfeeding or considering it, talk with your doctor. They may recommend that you stop breastfeeding or that you try another treatment than Plavix.
Similar to other drugs, Plavix can cause side effects. Some of them are mild, and others, such as bleeding, are serious. If you’d like to learn more about Plavix, talk with your doctor or pharmacist. They can help answer any questions you have about side effects from taking the drug.
Besides talking with your doctor, you can do some research on your own. These articles might help:
- More information about Plavix. For details about other aspects of Plavix, refer to this article.
- Drug comparison. To learn how Plavix compares with Eliquis, read this article.
- Dosage. For information about the dosage of Plavix, view this article.
- Interactions. To find out about Plavix’s interactions, see this article.
- A look at helping to prevent certain cardiovascular events. For details about certain cardiovascular events such as heart attack or stroke, see our cardiovascular health hub.
Disclaimer: Medical News Today has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or another healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.
FDA Drug Safety Communication: FDA review finds long-term treatment with blood-thinning medicine Plavix (clopidogrel) does not change risk of death
The Dual Antiplatelet Therapy (DAPT)1 trial was a randomized, double-blind, placebo-controlled trial that compared antiplatelet treatment for 30 months vs. 12 months following percutaneous coronary intervention and placement of a drug-eluting stent. After stent placement, patients received 12 months of dual antiplatelet therapy consisting of aspirin plus either clopidogrel (Plavix) or prasugrel (Effient) and then were randomized to continued treatment for 18 additional months of dual antiplatelet therapy (aspirin plus clopidogrel or prasugrel) or to aspirin plus placebo. The investigators selected the antiplatelet agents patients received, with about two-thirds receiving clopidogrel and one-third receiving prasugrel. Acute coronary syndrome was the indication for the stent in about 46% of patients.
The DAPT trial showed that the 30-month extended antiplatelet therapy with clopidogrel or prasugrel decreased the risk of stent thrombosis and heart attacks, but increased the risk of bleeding and overall risk of death compared to the 12-month group. The higher rate of death was primarily due to a larger number of deaths from non-cardiovascular causes, principally cancer and trauma. The increased rate of death was evident in patients receiving clopidogrel but not prasugrel.
In order to investigate the signals of increased risk of death and cancer-related death from the DAPT trial, FDA evaluated the DAPT trial and performed trial-level meta-analyses of other large, long-term trials that had available data on rates of death, rates of death from cancer, or rates of cancer adverse events. Trials included in the meta-analyses had a clopidogrel plus aspirin arm (long term was 12 months or longer), a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less), and had a planned follow-up of at least one year. We focused our investigation on clopidogrel because findings from the DAPT trial suggested an increase in the risk of death and cancer death in that group; data on prasugrel are also presented as context for the clopidogrel findings.
Investigation of the signal of increased all-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2. 2% for 30 months vs. 1.5% for 12 months), whereas no increased risk was observed for prasugrel plus aspirin (1.6% for 30 months vs. 1.6% for 12 months).
The FDA trial-level meta-analysis included 12 trials2-13 (56,799 patients) to explore the effect of clopidogrel on all-cause mortality. The incidence of all-cause mortality was 6.7% for the long-term clopidogrel plus aspirin arm and 6.6% for the comparator resulting in Mantel Haenszel Risk Difference (MH RD) = 0.04%, 95% confidence interval (CI) of (-0.35%, 0.44%).
A similar meta-analysis that focused on the subset of 9 of these trials (45,374 patients) that enrolled patients with coronary artery disease or patients at risk of coronary artery disease also suggested no difference in the risk of all-cause mortality: [MH RD of -0.07%, 95% CI (-0.43%, 0.29%)].
Investigation of the signal of increased risk of cancer death
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2. 4% ) and 12-month (2.3%) groups receiving clopidogrel when considering cancers reported after enrollment (from month 0 to 33 of the study). We performed several analyses of the cancer adverse event data, including “new” cancers in patients with no history of cancer or a history of cancer in a location different than the reported adverse event, and by cancer site. The relative risk of cancer for the 30-month vs. 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis. Analyses of time to first reported cancer adverse event demonstrated a hazard ratio of 1.06, 95% CI (0.80, 1.41) for all cancer and 0.95, 95% CI (0.70, 1.28) for new cancer. Similar analyses for the prasugrel group resulted in relative risks of cancer-related adverse events ranging from 1.4 to 1.6, and hazard ratios of 1.51, 95% CI (0.97, 2.36) for all cancer and 1.51, 95% CI (0.96, 2.40) for new cancer. The patterns of the reported cancer sites did not suggest site-specific effects.
Despite no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm of the DAPT trial, the risk of cancer-related death was increased compared to the 12-month arm (0. 7% for 30 months vs. 0.2% for 12 months). In contrast, for prasugrel there was a trend towards a higher risk of cancer adverse events in the 30-month arm compared to the 12-month arm (see above), but the risk of cancer death was identical in both study arms (0.4% vs. 0.4%). These findings are difficult to reconcile.
To explore the cancer signal for clopidogrel in clinical trials other than the DAPT study, FDA performed two trial-level meta-analyses. The first was an analysis of cancer-related adverse events from four trials with information on cancer adverse events2-5 (37,835 patients) that compared long-term use of clopidogrel and aspirin to use of either aspirin alone or short-term clopidogrel plus aspirin. The incidence of cancer adverse events was 4.2% for the long-term clopidogrel plus aspirin vs. 4.0% for the comparator. There was no apparent difference in the incidence of cancer adverse events between patients who received long-term clopidogrel plus aspirin and control patients across the four trials [MH RD = 0. 19%, 95% CI (-0.2%, 0.59%)].
The second trial-level meta-analysis was performed to assess cancer-related death and included five trials with information on cancer deaths2-6 (40,855 patients). The incidence of cancer death was 0.9% for the long-term clopidogrel plus aspirin group vs. 1.1% for the comparator. There was no apparent difference in the incidence of cancer deaths between the long-term clopidogrel plus aspirin and control groups across the five trials [MH RD = -0.14%, 95% CI (-0.33%, 0.06%)].
The findings from the DAPT trial with regard to cancer-related adverse events (increased for prasugrel, but not for clopidogrel) and cancer-related death (increased for clopidogrel, but not for prasugrel) have not been observed in our analyses of other randomized-controlled clinical trials. FDA’s trial-level meta-analyses of other trials performed to evaluate the potential signal from DAPT do not suggest an increased risk of cancer adverse events or cancer-related death associated with long-term clopidogrel therapy.
Our reviews found no evidence of either a harmful or beneficial effect of clopidogrel on overall mortality in a population with, or at risk for, coronary artery disease, and no effect on cancer.
What helps, side effects, active ingredient, composition
THERE ARE CONTRAINDICATIONS. POSSIBLE SIDE EFFECTS. A SPECIALIST’S CONSULTATION IS REQUIRED. Arrhythmia For the heart and blood vessels Stroke Pills
Author of the article
Ripatti Yuliya Igorevna,
Diploma of pharmaceutical education: 105924 3510926, reg. number 32018
Contents of the article
- Plavix: composition
- Plavix tablets: from what
- Plavix: side effects
- Plavix and alcohol: compatibility
- Plavix or Clopidogrel: which is better
- Plavix or Cardiomagnyl: which is better
- Plavix or ThromboASS: which is better
- Ask an expert on the topic of article
Stroke is the predominant cause population disability. It is traditionally believed that the disease affects people of the older age group, but the frequency of its detection in young people has been increasing since the 80s. At the same time, 16% of all cases of stroke are of the atherothrombotic type, when the vessels are blocked by a “cholesterol” build-up – an atherosclerotic plaque or a thrombus detached from it. One of the groups used to treat a pathological condition are antiplatelet agents.
The pharmacist will tell you about Plavix: introduce you to its composition, indications for use, side effects and compatibility with alcohol, and compare it with analogues.
International Nonproprietary Name (INN) Plavix, as well as its active ingredient – clopidogrel. The drug is available in the form of tablets with two different concentrations of the active ingredient:
- Plavix 75 mg;
- Plavix 300 mg.
Plavix tablets also contain auxiliary components that are used to impart the necessary physical and chemical properties. One of them requires attention, namely lactose – milk sugar. For patients with lactose intolerance, as well as some rare hereditary diseases, taking the drug is contraindicated.
All products Plavix
Plavix tablets: what
Plavix is a medicine from the group of antithrombotic agents. When ingested, the active substance Plavix acts on blood cells – platelets, preventing them from sticking together.
Gluing (aggregation) of platelets is a normal physiological reaction of the body to vascular damage and one of the key stages in stopping bleeding. However, under the influence of adverse factors, platelet aggregation activity increases, leading to the formation of blood clots. In such a situation, Plavix comes to the rescue. According to the Medicines Registry (RLS), Plavix is prescribed for:
- Prevention of thromboembolic complications (blockage of blood vessels by a thrombus detached from the place of formation) in patients with atrial fibrillation;
- Prevention of atherothrombotic complications (formation of a thrombus due to rupture of an atherosclerotic plaque – a “cholesterol” build-up on the inner walls of blood vessels) in patients with coronary syndrome, as well as those who have had myocardial infarction and ischemic stroke;
- Treatment of transient ischemic attack – a condition associated with impaired blood flow in the vessels of the brain.
The dosage of Plavix and the duration of treatment are determined by the physician. The drug has contraindications and side effects. You can not independently start taking or cancel the medicine.
Plavix side effects
- Decreased number of platelets, leukocytes and other blood cells;
- Intracranial hemorrhage;
- Headache and dizziness;
- Eye hemorrhages;
- Bleeding from the gastrointestinal tract;
- Abdominal pain;
- Skin rash and itching;
- Nausea and vomiting;
Plavix and alcohol: compatibility
Plavix and alcohol are incompatible. At the time of treatment, it is recommended to refrain from drinking alcohol. Otherwise, the risk of bleeding, cardiovascular pathologies and other life-threatening conditions increases significantly.
Plavix or Clopidogrel: which is better? Plavix and Clopidogrel are complete analogues and interchangeable drugs.
The main difference lies in drug companies:
- Plavix: Sanofi, France;
- Clopidogrel is produced by different companies, mostly Russian.
All products Clopidogrel
Plavix or Cardiomagnyl: which is better
Cardiomagnyl is a drug based on acetylsalicylic acid and magnesium oxide. The drug also prevents platelets from sticking together, but does so by a different mechanism. Acetylsalicylic acid and clopidogrel (active ingredient Plavix) are included in the standards for the treatment of ischemic stroke and transient ischemic attack.
Plavix and Cardiomagnyl are prescribed for the prevention of thrombotic and cardiovascular complications. At the same time, Plavix is a drug with proven clinical effectiveness, and in general a stronger medicine. Cardiomagnyl still causes a lot of controversy in the medical and pharmaceutical fields. Both drugs significantly increase the risk of internal bleeding.
Which is better: Plavix or Cardiomagnyl. The decision to prescribe the drug is made by the doctor, taking into account the patient’s condition and the risk of thrombosis. Sometimes drugs are combined.
All products Cardiomagnyl
Plavix or ThromboASS: which is better
ThromboASS is an antiplatelet agent with acetylsalicylic acid. As in the situation with Cardiomagnyl, the decision to prescribe the drug remains with the doctor. Only a specialist who knows the patient’s medical history can correctly assess the risks and benefits of therapy. In some cases, a combination of acetylsalicylic acid and Plavix is indicated.
All products Trombo ASS
- International nonproprietary name (INN) Plavix, as well as its active ingredient – clopidogrel.
- Plavix is a medicine from the group of antithrombotic agents.
- Plavix has contraindications and side effects.
- Plavix and alcohol are incompatible.
- Clopidogrel is not only the active ingredient of Plavix, but also an independent drug reproduced in its likeness.
- Cardiomagnyl prevents platelets from sticking together, but does so by a different mechanism.
- ThromboASS is an antiplatelet agent with acetylsalicylic acid.
Ask an expert about the topic of the article
Still have questions? Ask them in the comments below and our experts will answer you. There you can also share your experience with other Megatips readers.
Zotina Natalya Igorevna,
Like the article? Tell mom, dad, grandmother and aunt Galya from the third entrance
PHARMATECA » Despite Current Treatments, Patients Who Have Acute Coronary Syndromes (acs) Without St-segment Elevation (unstable Angina Pectoris) Have High Rates Of Major Vascular Events.
Many Patients With Acs Are Managed Conservatively. The Clopidogrel In Unstable A
Despite current treatments, patients who have acute coronary syndromes (ACS) without ST-segment elevation (unstable angina pectoris) have high rates of major vascular events. Many patients with ACS are managed conservatively. The Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) has examined whether the addition of clopidogrel to aspirin improves outcomes in this setting. More than 12,500 patients presenting with non-ST-elevation ACS were recruited for this randomized, placebo-controlled study. Clopidogrel significantly reduces the risk of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, on stroke, as well as a range of related ischemic events. Clopidogrel was well tolerated and was not associated with any adverse effects beyond a modest increase in bleeding complications. There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group, but there were not significantly more patients with episodes of life-threatening bleeding or hemorrhagic strokes.
It is now generally accepted that various types of acute coronary syndrome (ACS), in particular, unstable angina (non-ST elevation ACS), are usually based on arterial thrombosis caused by the destruction of atherosclerotic plaque . Appointment of aspirin and heparin in ACS reduces the risk of cardiovascular death and myocardial infarction, but both in the short and long term does not solve the problem of preventing severe atherothrombotic outcomes [2,3]. The blockers of IIbeta-IIIlfa-glycoprotein receptors (fibans) did not quite justify the hopes placed on them. As it turned out, they reduce the incidence of coronary disorders only when administered intravenously, mainly during percutaneous coronary interventions (PCI) [4,5]. On the contrary, long-term use of oral fibans, according to a meta-analysis of randomized clinical trials, even increases cardiovascular mortality . So far, there is no evidence of the effectiveness of long-term use of low molecular weight heparins and oral anticoagulants in ACS [7,8].
Thus, the currently available arsenal of drugs used in ACS does not allow to effectively solve the problem of prevention of atherothrombotic outcomes. In this regard, the results of the recently completed large-scale study CURE (the Clopidogrel in Unstable angina to prevent Recurrent Events trial) are of great interest, in which thienopyridine clopidogrel was used to reduce the risk of various adverse vascular outcomes in ACS without ST segment elevation (unstable angina) ( Plavix, Sanofi-Synthelabo) in combination with aspirin .
Clopidogrel as a means of preventing atherothrombotic outcomes
It is well known that platelet activation/aggregation under the influence of adenosine diphosphate (ADP) plays a key role in the development of atherothrombotic ischemic disorders . Today, drugs that inhibit ADP-induced platelet aggregation and belong to the class of antiplatelet drugs, such as aspirin and thienopyridines, are increasingly used in clinical practice and, in principle, should be recommended to all patients with established atherosclerosis.
A number of studies have shown that, in terms of the effectiveness of preventing severe atherothrombotic outcomes, the thienopyridines clopidogrel and ticlopidine are significantly superior to aspirin. Thus, according to the large-scale CAPRIE study, the number of severe ischemic outcomes prevented by clopidogrel is 26% higher than with aspirin . To the greatest extent, clopidogrel was superior to aspirin in terms of secondary prevention of acute myocardial infarction, and especially in patients with a longer and more severe atherosclerotic history .
There is strong evidence that the combination of thienopyridine drugs with aspirin is more effective than either alone. In particular, such combinations are considered as the most effective measure for the prevention of occlusive thrombotic complications in the first weeks after PCI with the installation of intra-arterial stents . In such patients, short-term use of thienopyridines in combination with aspirin has been shown to reduce the risk of myocardial infarction more effectively than aspirin or warfarin alone . According to the CLASSICS study, in patients with coronary stents, clopidogrel and ticlopidine in combination with aspirin equally prevent stent thrombosis and severe cardiac complications, including coronary death and acute myocardial infarction . At the same time, when using clopidogrel, non-cardiac vascular disorders, primarily stroke, develop less frequently . An important advantage of clopidogrel in comparison with ticlopidine is the greater safety of use. In particular, its use is much less frequently associated with such serious hematological side effects as neutropenia, thrombocytopenia, aplastic anemia and thrombotic thrombocytopenic purpura [13,16].
It should be recognized, however, that clinical experience with long-term use of clopidogrel in combination with aspirin in patients with a high risk of severe cardiovascular disorders of an ischemic nature is practically absent. This emphasizes the results of the CURE study, which included patients with unstable angina, a common and high incidence of major vascular outcomes manifestation of coronary heart disease, who had been taking clopidogrel and aspirin for up to 1 year.
CURE study design and design
The multicentre, randomized, double-blind, placebo-controlled CURE study included 12,562 patients with unstable angina, the vast majority of whom had no ST elevation on ECG. The study was conducted in 482 centers from 28 countries from December 1998 to September 2000. Initially, based on the expected rate of adverse vascular outcomes in the placebo group (12-14%), enrollment in the study was 9000 sick. However, due to the lower actual frequency of these outcomes, the number of patients included in the study was increased.
CURE included patients of both sexes over 60 years of age who were hospitalized within 24 hours of the onset of clinical symptoms of angina in the absence of ST interval elevation. Initially, the inclusion criterion was the absence of any recent electrocardiographic changes with the obligatory presence of manifestations of coronary heart disease in history. However, following the discovery of a low rate of vascular outcomes among the first 3,000 patients, the criteria were revised to include ECG changes (excluding ST elevation) or elevated serum cardiac enzymes/markers at the time of hospital admission.
Exclusion criteria were contraindications to antithrombotic or antiplatelet therapy, including high risk of bleeding, severe heart failure, oral anticoagulants, coronary revascularization within the previous 3 months, and intravenous use of IIβ-III alpha-glycoprotein receptor inhibitors in the last 3 days.
Among the patients included in the CURE study (61.5% men, 38.5% women), 32.2% had a history of myocardial infarction, 4% had a stroke, 58.8% had arterial hypertension, 22.6% had diabetes diabetes. About 18% of them underwent PCI or coronary artery bypass grafting (CABG). At the time of randomization, 66.1% of patients were already receiving aspirin, almost 3/4 of them were administered unfractionated and low molecular weight heparin, more than half were taking beta-blockers, over 45% were receiving intravenous nitrate. In addition, many patients used angiotensin-converting enzyme (ACE) inhibitors (37.1%), calcium channel blockers (28.3%) and lipid-lowering drugs (25. 4%).
After receiving informed consent from patients, they were randomized and immediately began to receive clopidogrel or placebo while taking aspirin (75-325 mg/day). The first loading dose of clopidogrel was 300 mg (placebo in the comparison group), and then patients took daily clopidogrel (75 mg) or placebo for 3 to 12 months (mean duration of treatment – 9 months).
The first composite primary endpoint used in the CURE study to evaluate outcomes was CV death, non-fatal myocardial infarction, or stroke. The second complex primary end point, in addition to the listed outcomes, also included refractory (non-stopping) myocardial ischemia. In addition, the study considered secondary outcomes such as severe myocardial ischemia, heart failure, and the need for revascularization. Refractory ischemia was characterized by the development of recurrent pain syndrome lasting more than 5 minutes with negative electrocardiographic dynamics, which was not cured by massive antianginal therapy (including intravenous administration of nitrates), in which additional invasive measures were performed, such as thrombolytic therapy, cardiac catheterization, coronary revascularization, etc. .d. In the context of the CURE study, severe ischemia differed from refractory only in that no invasive procedures were performed when it occurred.
When assessing the safety of therapy, hemorrhagic complications were also taken into account, which were divided into life-threatening, serious and non-severe (minor). Serious hemorrhagic episodes were those requiring a transfusion of at least 2 vials of blood or intraocular bleeding leading to loss of vision. Serious hemorrhagic complications were assessed as life-threatening if they were fatal, led to a marked decrease in hemoglobin levels (by 5 g/dl or more), or caused severe arterial hypotension requiring intravenous administration of inotropic drugs, as well as if surgery or transfusion was necessary at least 4 vials of blood and finally in case of symptomatic intracranial bleeding. All other hemorrhagic complications leading to the abolition of clopidogrel and aspirin were considered non-severe.
Results of the CURE study
Efficacy of clopidogrel
Table 1 shows that the main vascular outcomes included in the first primary endpoint – cardiovascular death, non-fatal myocardial infarction or stroke – were observed in 582 of 6259 patients (9. 3 %) in the clopidogrel group and 719 out of 6303 (11.4%) in the placebo group. The difference between groups in favor of clopidogrel was statistically significant (P
The pooled frequency of outcomes of the second primary endpoint in the clopidogrel group was also significantly lower than in the placebo group (16.5% and 18.8%, respectively; relative risk 0.86; P
With regard to secondary outcomes, in the clopidogrel group, there were significantly fewer cases of severe myocardial ischemia – 2.8% vs. 3.8% in the placebo group (relative risk 0.74; P = 0.003) and recurrent angina pectoris – 20.9% versus 22.9% in the placebo group (relative risk 0.91; P = 0.01). The number of patients who underwent coronary revascularization during the study in the clopidogrel and placebo groups was almost the same (36% and 36.9%, respectively), however, during the first hospitalization, the frequency of revascularization procedures in the clopidogrel group was significantly lower (20.8% vs 22. 7% placebo, relative risk 0.92; P = 0.03). In addition, heart failure was less common in the clopidogrel group (3.7% vs. 4.4% in the placebo group; relative risk 0.82; P = 0.03).
A thorough analysis of the results of the CURE study confirms the constancy of the therapeutic effect of clopidogrel in all subgroups of patients identified depending on gender, age, electrocardiographic characteristics, serum levels of markers of myocardial ischemia, the presence of diabetes mellitus, history of coronary heart disease episodes, characteristics of therapy (dose aspirin, use of lipid-lowering agents, beta-blockers, heparin, or ACE inhibitors at the time of randomization), etc. At the same time, it can be noted that the positive effect of clopidogrel was more pronounced in men, persons of both sexes, whose age did not exceed 65 years, and, especially, patients with a history of revascularization. In the latter category of patients, the relative risk of developing outcomes that form the first primary endpoint was 0. 56, while in the absence of revascularization interventions in history, this indicator was significantly higher (0.88; P = 0.002). On the other hand, the efficacy of clopidogrel in relation to the frequency of these outcomes was almost the same among patients who underwent revascularization after randomization and those who did not require this intervention.
The use of clopidogrel had a significant impact on the nature of concomitant therapy. Thus, patients in the clopidogrel group were significantly less likely to need thrombolytic agents (1.1% vs. 2.0% in the placebo group; relative risk 0.57; P
Safety of clopidogrel
Given the synergistic antiplatelet effects of clopidogrel and aspirin, the focus of the CURE study on the safety of the combined use of these drugs was on taking into account the hemorrhagic complications associated with the therapy. Data on their frequency are presented in Table 2.
It was found that in the clopidogrel group, serious hemorrhagic complications were observed in 3. 7% of patients or almost 36% more often than in the placebo group, significantly more with the combined use of clopidogrel and aspirin, there were also non-severe bleeding. In addition, the use of clopidogrel was associated with an increase in the number of bleeding events requiring significant blood transfusions.
A slightly different picture was noted for the most severe, life-threatening bleeding. Although they were slightly more common in the clopidogrel group (by 20%), the difference with the placebo group was not statistically significant. At the same time, clopidogrel did not affect the incidence of fatal hemorrhagic complications accompanied by severe anemia, manifested as a hemorrhagic stroke or requiring surgical intervention. With regard to the localization of hemorrhages, in the clopidogrel group, gastrointestinal bleeding and bleeding at the site of arterial puncture were more often observed.
In patients in the clopidogrel group undergoing CABG, there was a non-significant increase in the number of serious hemorrhagic complications (1. 3% vs. 1.1% in the placebo group), but it was found that the frequency of these episodes (especially in the first week after surgery) directly depends on the duration of the period of withdrawal of antithrombotic therapy before shunting, decreasing with its prolongation for more than 5 days.
There was no difference between the clopidogrel and placebo groups in the incidence of thrombocytopenia (26 and 28) and neutropenia (8 and 5, respectively.
In general, clopidogrel was well tolerated by patients, and premature discontinuation of the test drug (clopidogrel or placebo) occurred in both groups with almost the same frequency (21.1% and 18.8%, respectively). Temporary discontinuation of the test drug, mainly due to the need for PCI, CABG and other surgical interventions, occurred in the clopidogrel and placebo groups with a frequency of 46.2% and 45.4%, respectively.
Results from the CURE study suggest that clopidogrel provides additional clinical benefit in patients with unstable angina who are receiving standard medical therapy, including aspirin and other drugs routinely used for this condition. It can be assumed that the additive effect of clopidogrel is associated with a selective and irreversible blockade of ADP binding to specific platelet receptors, resulting in inhibition of their aggregation [17,18].
Treatment with clopidogrel led to a significant reduction in the risk of major ischemic outcomes of atherothrombotic disease in general, mainly due to a decrease in the incidence of myocardial infarction and its recurrent (refractory and severe) ischemia. In addition, with the use of clopidogrel, there was a trend towards a decrease in the incidence of ischemic stroke (without an increase in the number of cases of intracranial hemorrhage) and cardiovascular death. Finally, in the clopidogrel group, there was a significant reduction in the prevalence of heart failure, similar in magnitude to the reduction in the incidence of ischemic outcomes. This suggests that attenuation of myocardial ischemia may prevent the development of heart failure.
The additive therapeutic effect of clopidogrel was observed in all categories of patients included in the study. It was especially pronounced in patients who had previously undergone coronary revascularization. The usefulness of adding clopidogrel to the conventional therapy of unstable angina did not depend on the risk of adverse cardiovascular outcomes and was manifested against the background of the use of other drugs, the effectiveness of which in preventing these disorders is considered proven (aspirin, statins, ACE inhibitors) [19-22]. It was noted that when taking clopidogrel, much less often than in the control group, there was a need for the use of thrombolytic therapy and intravenous blockers of IIbeta-III alpha-glycoprotein receptors. It is possible that from this point of view, the use of clopidogrel in unstable angina has pharmacoeconomic advantages, but this issue requires special study.
The effect of clopidogrel appeared already in the first 24 hours after randomization, which indicates the effectiveness of its loading dose. The drug reduced the risk of atherothrombotic outcomes both in the first 30 days and later. Thus, differences between groups of patients in favor of clopidogrel persisted throughout the follow-up.
It is important to emphasize that the CARE study was conducted in a day-to-day environment of health centers that did not adhere to a policy of early routine invasive procedures, which could lead to a very frequent withdrawal of trial therapy at the initial stage with the transfer of patients to open-label use of thienopyridine drugs. On the other hand, the study did not include any restrictions on any therapeutic or surgical interventions. If, in the opinion of the clinician, the patient needed angiography, revascularization, or the use of thienopyridines, the treatment being tested was discontinued or patients were switched to open-label clopidogrel or ticlopidine. During the study period, angiography was performed in 5491 patient (43.7%), 2072 patients (16.5%) underwent CABG and 2658 (21.2%) – PCI. In CABG and PCI, test treatment was discontinued, in most cases for more than 5 days, with patients undergoing PCI usually switched to open-label clopidogrel or ticlopidine for 2-4 weeks. After CABG, test therapy was restarted after a median of 11 days. It cannot be ruled out that all these breaks “smooth out” the differences between the clopidogrel and placebo groups, however, on the other hand, they allow a better assessment of the usefulness and safety of clopidogrel during long-term use in conditions close to real practice. Note that a special study (PCI-CURE)  was devoted to the combined use of clopidogrel and aspirin during PCI, which deserves separate discussion.
In the CURE study, the addition of clopidogrel to therapy led to an increased risk of serious and non-severe hemorrhagic episodes. As a result, the need for blood transfusions slightly increased (in 0.6% of patients compared with the placebo group). However, clopidogrel did not increase the frequency of life-threatening bleeding, incl. with a lethal outcome. The use of clopidogrel was not associated with an increased risk of hemorrhagic stroke, bleeding requiring surgical intervention, the use of inotropic drugs, or massive blood transfusions.