Clopidogrel: a review of its use in the prevention of atherothrombosis

Clopidogrel is an ADP receptor antagonist that is indicated for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease. In the 19 185 patients enrolled in the multicentre, randomised double-blind CAPRIE study, the annual risk of the combined end-point of ischaemic stroke, myocardial infarction and death from vascular disease (vascular death) was significantly lower during treatment with clopidogrel 75 mg/day than aspirin 325 mg/day [5.3 vs 5.8%/year, respectively; relative risk reduction (RRR) 8.7%, p = 0.043] after a mean follow-up of 1.9 years. Clopidogrel provided even greater reductions in the risk of recurrent ischaemic events than aspirin in patients with a history of coronary artery bypass surgery, diabetes mellitus and in those receiving concomitant lipid-lowering therapy. Moreover there was a significant reduction in the incidence of hospitalisation in patients treated with clopidogrel. In a patient population (Saskatchewan, Canada) with a greater risk of ischaemic events than the CAPRIE study population, the number of patients needed to be treated with clopidogrel to prevent 1 ischaemic event was estimated to be 70 (vs 200 in the CAPRIE study). In randomised trials and registry surveys, clopidogrel 75 mg/day plus aspirin had similar efficacy (as measured by adverse cardiac outcomes) to ticlopidine 250mg twice daily plus aspirin during the 30 days after placement of intracoronary stents. Tolerability of clopidogrel was significantly better than ticlopidine in the randomised, double-blind CLASSICS study. Among patients treated with clopidogrel or aspirin in the CAPRIE study, the overall gastrointestinal tolerability of clopidogrel was generally better than that of aspirin; the frequency of gastrointestinal haemorrhage was significantly lower among patients treated with clopidogrel than aspirin. Diarrhoea, rash and pruritis were significantly more common with clopidogrel than aspirin. CONCLUSION: Clopidogrel was significantly more effective than aspirin in the prevention of vascular events (ischaemic stroke, myocardial infarction or vascular death) [corrected] in patients with atherothrombotic disease manifested by recent myocardial infarction, recent ischaemic stroke or symptomatic peripheral arterial occlusive disease [corrected] in the CAPRIE study. The overall tolerability profile of the drug was similar to that of aspirin, although gastrointestinal haemorrhage occurred significantly less often in clopidogrel recipients. The drug is widely used in combination with aspirin for the prevention of atherothrombosis after placement of intravascular stents, and available data suggest that this combination is as effective as ticlopidine plus aspirin for this indication.     

The basis of platelets: platelets and atherothrombosis: an understanding of the lack of efficacy of aspirin in peripheral arterial disease (PAD) and diabetic patients

Platelet activation subsequent to the adhesion of platelets to the vascular wall results in the release of mediators that promote platelet aggregation, which plays a pivotal role in the development of the polyvascular atherosclerotic disease that can be referred to by the acronym 'ATIS' (AtheroThrombosIS). The currently available antiplatelet drugs used to prevent vascular events in patients with cardiovascular disease, including peripheral arterial disease (PAD), include aspirin and thienopyridines such as clopidogrel. These drugs decrease platelet aggregability, each of them by inhibiting a different pathway of platelet activation and recruitment. Aspirin acts by inhibiting thromboxane A2 (TXA2) formation through the inhibition (acetylation) of cyclo-oxygenase. On the other hand, thienopyridines suppress the platelet aggregation adenosine diphosphate (ADP) pathway by inhibiting the platelet P2Y12 subtype of the ADP receptor. The results of the large ATT (Antithrombotic Trialists' Collaboration) meta-analysis of published clinical studies on aspirin, reported in 2002, confirmed the previous meta-analysis and major trials that treatment with aspirin (mixed with other antiplatelet agents in these large meta-analyses) can prevent vascular events in high-risk patients with cardiovascular disease. However, it must be stressed that specifically in PAD patients no significant effect of aspirin was demonstrated in a more recent meta-analysis. This was also the case for primary and secondary prevention in diabetic patients. In keeping with these observations, neither a five-year follow-up study of Japanese diabetic patients in the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) study, a seven-year follow-up study of UK diabetic patients with PAD in the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) study, nor a very recent Scottish study in the same population of diabetics with PAD revealed a significant beneficial effect for aspirin in preventing ischaemic events. This failure may be a consequence of more rapid recovery of platelet aggregability following each dose of aspirin in these PAD or diabetic populations, with the accelerated platelet turnover resulting in a condition of aspirin resistance. Results of the large scale CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial that evaluated clopidogrel in patients with cerebral infarction, myocardial infarction or PAD have found clopidogrel to be significantly more effective than aspirin in preventing ischaemic events in patients with PAD. Furthermore, a subgroup analysis of the study has confirmed the efficacy of clopidogrel in diabetic patients with PAD, showing a significant reduction of events in clopidogrel-treated, compared with aspirin-treated, diabetic patients. These results are also likely to be attributable to the greater frequency of aspirin resistance in aspirin-treated patients in these populations (diabetics and/or PAD). Platelets, through activation and aggregation, have an important role in ATIS. However, although antiplatelet therapy with low-dose aspirin has been reported to prevent vascular events in high-risk patients with cardiovascular disease, recent studies in patients with PAD or diabetes mellitus have failed to support the efficacy of aspirin in preventing vascular events in these patient populations. In contrast, clopidogrel appears to be a useful antiplatelet agent in the prevention of vascular events in patients with PAD or diabetes.     

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.     

Antiplatelet drugs in cardiovascular prevention: coronary events: acute phase and secondary prevention

(1) Aspirin reduces acute-phase mortality after myocardial infarction, and also reduces the risk of myocardial infarction and death in patients with unstable angina. Aspirin reduces the risk of myocardial infarction in patients with stable angina and after unstable angina, and the risk of relapse after myocardial infarction. It reduces the risk of complications during coronary angioplasty, and the risk of venous coronary bypass graft occlusion after coronary surgery. (2) The best risk-benefit ratio with aspirin is achieved at a daily dose of 75-350 mg; 160 mg/day is the best-validated dose in the acute phase of myocardial infarction. (3) Aspirin must be combined with a thrombolytic agent in patients with myocardial infarction, and with heparin in patients with unstable angina. During coronary stenting the aspirin + clopidogrel combination may have a better risk-benefit ratio than the aspirin + ticlopidine combination. (4) Clopidogrel can be used when aspirin is contraindicated or poorly tolerated. (5) Oral anticoagulants seem a better option than aspirin after complicated myocardial infarction.     

Incremental Effect of Clopidogrel on Important Outcomes in Patients with Cardiovascular Disease

OBJECTIVES: To quantify the impact of clopidogrel plus aspirin on the individual outcomes of death, myocardial infarction, or stroke in patients with established cardiovascular disease, or in patients with multiple risk factors for vascular disease. BACKGROUND: Randomized trials have demonstrated a reduction in composite outcomes when clopidogrel is added to aspirin therapy in patients with coronary artery disease; however, the magnitude of benefit on individual outcomes is unknown. METHODS: We conducted a meta-analysis on randomized, controlled trials that compared aspirin plus clopidogrel with aspirin plus placebo for the treatment of coronary artery disease. RESULTS: This analysis included five randomized trials (CURE, CREDO, CLARITY, COMMIT, and CHARISMA) in 79 624 patients. The incidence of all-cause mortality was 6.3% in the aspirin plus clopidogrel group versus 6.7% in the aspirin group (odds ratio [OR] 0.94; 95% CI 0.89, 0.99; p = 0.026). The incidence of myocardial infarction was 2.7% and 3.3% (OR 0.82; 95% CI 0.75, 0.89; p < 0.0001), and stroke was 1.2% and 1.4% (OR 0.82; 95% CI 0.73, 0.93; p = 0.002). Similarly, the incidence of major bleeding was 1.6% and 1.3% (OR 1.26; 95% CI 1.11, 1.41; p < 0.0001), and fatal bleeding was 0.28% and 0.27% (OR 1.04; 95% CI 0.76, 1.43; p = 0.79). CONCLUSION: The addition of clopidogrel to aspirin results in a small reduction in all-cause mortality in patients with ST-elevation myocardial infarction and a modest reduction in myocardial infarction and stroke in patients with cardiovascular disease. The overall incidence of major bleeding however is increased, although there is no excess of fatal bleeds or hemorrhagic strokes.     

Clopidogrel: new preparation. An alternative to aspirin

(1) Clopidogrel, an antiplatelet drug chemically similar to ticlopidine, is marketed in France for secondary prevention of thrombotic complications in patients with a history of myocardial infarction, ischaemic stroke or peripheral arterial disease. (2) Marketing authorisation was based mainly on the CAPRIE trial, a study that involved 19,815 patients. In this trial of secondary cardiovascular prevention, clopidogrel was slightly more effective than aspirin (325 mg/day) according to a statistical analysis of a combined end point (ischaemic stroke, or myocardial infarction, or death of vascular causes). The difference was more marked in the subgroup of patients with obstructive arterial disease of the lower limbs. (3) Clopidogrel was well tolerated in this trial. The only adverse effects more frequent on clopidogrel than on aspirin were rash and diarrhoea. (4) Clopidogrel showed no haematological toxicity, an adverse effect that restricts the use of ticlopidine. (5) The lack of long-term follow-up in real clinical settings prevents any meaningful estimation of the safety profile or of the risk of drug interactions.     

Clopidogrel Bisulfate

Clopidogrel bisulfate (hereafter, clopidogrel), a selective inhibitor of ADP-induced platelet aggregation, is approved for the reduction of atherothrombotic events in patients with ST-segment elevation myocardial infarction (STEMI). In COMMIT/CCS-2, a well designed trial in 45,852 adult patients with STEMI, relative to aspirin alone, clopidogrel 75 mg/day plus aspirin treatment significantly reduced the risk of both coprimary endpoints: the composite endpoint of reinfarction, stroke, or death from any cause and the risk of death from any cause. Based on the findings of this trial, treating 1000 patients for approximately 2 weeks with clopidogrel is associated with nine fewer patient deaths, reinfarctions, or strokes during treatment. In CLARITY-TIMI 28, a well designed supportive study in 3491 adult patients with STEMI, clopidogrel plus aspirin reduced the odds that a composite primary endpoint event of an occluded infarct-related artery, recurrent myocardial infarction, or death from any cause would occur versus aspirin plus placebo. Clopidogrel treatment was generally well tolerated in these clinical trials, with no significant between-group difference in the rate of major bleeding in either trial. Experience in other patient populations (e.g. those with recent myocardial infarction, recent ischemic stroke, or established peripheral arterial disease) has shown that longer-term (< or =3 years) clopidogrel monotherapy is generally well tolerated.     

Clinical perspectives on the role of anti-platelet and statin therapy in patients with vascular diseases

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is associated with a several-fold increased risk of cardiovascular morbidity and mortality. Statins and anti-platelet therapy have been unequivocally shown to be beneficial in patients with coronary artery disease, but minimal data exist on the effectiveness of these agents in patients with PAD and those undergoing peripheral vascular interventions. One recent study has demonstrated that statins are very effective as secondary preventive measures in patients with PAD but continue to be underutilized in this cohort. In our institutional peripheral interventional database, after adjustment for demographics and comorbidities, statin therapy (OR=0.21, 95% CI 0.05-0.86, p=0.03) and clopidogrel therapy (OR=0.17, 95% CI 0.04-0.78, p=0.02) were both associated with a significant reduction of the composite event rate of death, myocardial infarction and stroke at 6 months. In this article, we critically review the existing literature on the role of anti-platelet and statin therapy in reducing cardiovascular events in patients with PAD. Appropriate use of these agents may significantly decrease the cardiovascular morbidity and mortality of patients with PAD.     

Antiplatelet therapy in peripheral artery disease

Peripheral artery disease (PAD) is a term that relates to atherosclerosis and narrowing of the arteries in the lower extremities. The prevalence of PAD is approximately 12% of the adult population. Despite the low rate of peripheral complications and amputation, PAD is complicated by a high rate of cardiovascular events including myocardial infarction, stroke, and vascular death with an annual incidence of about 5%.The detection of PAD is initially based on the appearance of typical symptoms (claudication and critical limb ischemia) related to peripheral arterial insufficiency. However, PAD may also be present in the absence of clinical symptoms (asymptomatic PAD). Accordingly, asymptomatic disease may occur in up to 50% of all patients with PAD. Ankle brachial index (ABI) is a diagnostic test used to evaluate the presence of PAD, defined by an ABI ≤0.90. The ABI is also demonstrated to be useful in the assessment of vascular risk in asymptomatic and symptomatic patients. Antiplatelet therapy remains a key intervention to reduce cardiovascular risk in PAD. Data from Antithrombotic Trialists' Collaboration showed that antiplatelet treatment was associated with a 23% risk reduction of vascular events in overall population with PAD. However, closer scrutiny of these data reveals that nonaspirin antiplatelet drugs, including ticlopidine, clopidogrel, picotamide, and dipyridamole largely drove the benefits in the PAD subgroup. It remains an open issue if PAD represents an atherosclerotic clinical model where aspirin, differently from coronary heart disease, is less effective in reducing atherosclerotic progression. Based on the reported results further trials with aspirin should be done in asymptomatic (ABI ≤0.90) and symptomatic PAD patients. Finally, the role of new antiplatelet drugs such as prasugrel and ticagrelor has not yet been studied in PAD.     

Clopidogrel

? Clopidogrel is a selective inhibitor of ADP-induced platelet aggregation.

? A large, multicenter, randomized study in 12562 patients with acute coronary syndromes without ST-segment elevation demonstrated that treatment with clopidogrel (loading dose of 300mg followed by once daily treatment with 75mg) in addition to standard therapy including aspirin (75 to 325 mg/day) significantly reduced the risk of the combined endpoint of cardiovascular death, myocardial infarction or stroke compared with treatment with standard therapy. Furthermore, the composite risk of these outcomes or refractory ischemia was also significantly reduced in patients treated with clopidogrel plus aspirin. The effects of clopidogrel were independent of background treatment with cardiovascular medications and/or interventions.

? The risk of severe ischemia, recurrent angina or heart failure was also significantly reduced in patients receiving clopidogrel plus aspirin. There was also a significant reduction in the need for coronary revascularization during the initial period of hospitalization.

? In patients undergoing percutaneous coronary intervention (PCI), the relative risk of the combined endpoint of cardiovascular death, myocardial infarction or urgent target-vessel revascularization within 30 days of the intervention was significantly reduced. Moreover, the relative risk of the single endpoint of myocardial infarction within 30 days of PCI was significantly in favor of clopidogrel-treated patients.

? Hemorrhagic events (both major and minor) were significantly more frequent in patients with acute coronary syndromes receiving treatment with clopidogrel plus aspirin than in patients treated with aspirin alone. This was largely attributable to an increased incidence in the rate of gastrointestinal hemorrhage and bleeding at the site of arterial puncture. However, there was no difference between the two groups in the incidence of bleeding episodes that were considered to be life-threatening.

     

Clopidogrel hydrogen sulphate for atrial fibrillation

INTRODUCTION: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin. AREAS COVERED: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included. EXPERT OPINION: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.     

Clopidogrel and [symbol: see text] ticlopidine--improvements on aspirin?

Clopidogrel (Plavix-Sanofi Winthrop/Bristol-Myers Squibb) and [symbol: see text] ticlopidine (Ticlid-Sanofi Winthrop) are inhibitors of platelet function and are promoted as potential alternatives to aspirin. Clopidogrel is licensed for the secondary prevention of vascular events in patients with established atherosclerotic disease. The manufacturer claims that clopidogrel is "significantly more effective at reducing myocardial infarction, stroke and vascular death" compared to aspirin. Ticlopidine is licensed as an alternative to aspirin for secondary prevention of stroke and coronary complications in patients with intermittent claudication. However, in the UK, ticlopidine is more commonly used with aspirin to prevent complications following insertion of coronary stents during angioplasty. We consider whether the claims for clopidogrel and the current use of ticlopidine are justified.     

The value of clopidogrel versus aspirin in reducing atherothrombotic events: the CAPRIE study

Atherothrombotic disease is a growing health problem, and is increasingly more costly to manage. Clopidogrel is an advanced, specific adenosine diphosphate receptor antagonist, which has been shown to be a highly potent antiplatelet agent. Data from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study have demonstrated the significantly superior clinical benefit of clopidogrel over aspirin for secondary prevention of atherothrombotic disease, with a relative risk reduction in myocardial infarction, stroke or vascular death of 8.7% (95% confidence interval 0.3, 16.5; P = 0.043). Moreover, clopidogrel demonstrated an amplified clinical benefit versus aspirin in patients at high risk of atherothrombotic events, such as those with a previous history of symptomatic atherothrombotic disease or with major risk factors such as diabetes mellitus or hypercholesterolaemia. On the basis of commonly accepted threshold criteria (Euros 20000 per life-year gained; LYG), clopidogrel in comparison with aspirin is cost-effective for the secondary prevention of atherothrombotic disease (cost per LYG ranging from Euros 19462 to Euros 3256). Economic analyses have demonstrated consistent cost-effectiveness results with clopidogrel in different countries. Moreover, in high-risk patient subgroups the cost-effectiveness of clopidogrel in comparison with aspirin was evenbetter (cost per LYG ranging from Euros 5900 to Euros 6310). Compared with other treatment strategies used for the prevention of ischaemic or atherothrombotic events, the cost-effectiveness of clopidogrel in comparison with aspirin based on CAPRIE is favourable, with most analyses in the intermediate range of cost-effectiveness. The available data thus support the use of clopidogrel as a clinically efficient and cost-effective option for secondary prevention of atherothrombotic disease, particularly in high-risk patients.     

Clopidogrel: a selective inhibitor of platelet ADP receptors

Platelets play a key role in the development of ischemic complications in the arterial circulation. Antiplatelet therapy has proven effective in the treatment and prevention of ischemic events. Numerous clinical studies have confirmed the therapeutic efficacy of aspirin to such a point that this antiplatelet agent has become the gold standard in clinical practice. Clopidogrel is a thienopyridine compound that inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors. Results of a large, double-blind, randomized study (CAPRIE) confirm that administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction or vascular death. The present article highlights the importance of activation of platelets through ADP receptors and reviews the pharmacology and clinical studies of clopidogrel, a selective inhibitor of these mechanisms.     

Clopidogrel for the secondary prevention of stroke

Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS) have a high risk of recurrence. The inhibition of platelet function is effective in the reduction of secondary vascular events in patients with TIA or stroke. This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the combination of ASA plus slow-release dipyridamole. This overview analyses the results of recent trials and presents ongoing or future trials with clopidogrel as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to ASA in the prevention of vascular events in patients with IS, myocardial infarction (MI) or peripheral arterial disease (PAD). The difference is highest for high-risk patients such as diabetics, patients who underwent coronary bypass surgery and patients with a remote prior history of ischaemic events. A prediction model is presented which allows the identification of patients in whom clopidogrel is superior to ASA for the secondary prevention of stroke. The combination of clopidogrel and ASA is better than ASA alone in patients undergoing coronary stent implantations and patients with unstable angina or non-Q-wave MI. In high-risk patients with TIA or stroke, the addition of ASA to clopidogrel is not superior to ASA monotherapy but results in a higher rate of bleeding complications. The long-term combination therapy is currently investigated in several large trials in > 30,000 patients, with a large number of stroke patients.     

Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events.

OBJECTIVE: The objective of this study was to provide a comprehensive comparison of the long term safety and tolerability of clopidogrel, a new adenosine diphosphate (ADP) receptor antagonist that inhibits platelet activation induced by ADP, and aspirin (acetylsalicylic acid). PATIENTS AND METHODS: The study population comprised 19,185 patients with symptomatic atherosclerosis manifested as recent ischaemic stroke, recent myocardial infarction or symptomatic peripheral arterial disease. Patients were randomised to receive clopidogrel 75 mg/day or aspirin 325 mg/day for a minimum of 1 year and a maximum of 3 years. RESULTS: Compared with aspirin, clopidogrel reduced the combined risk of ischaemic stroke, myocardial infarction or vascular death by 8.7% (p = 0.043). The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups (11.94% for clopidogrel vs 11.92% for aspirin). Reported neutropenia was similar in the clopidogrel and aspirin groups (0.10 vs 0.17%, respectively) with corresponding rates (0.05 vs 0.04%, respectively) for severe neutropenia. Thrombocytopenia was identical in the clopidogrel and aspirin groups (0.26%), with the rates of severe thrombocytopenia being 0.19 vs 0.10%, respectively. None of these observed differences was statistically significant. The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups (9.27% for clopidogrel vs 9.28% for aspirin; p = 0.98). There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group (0.31%) compared with the aspirin group (0.42%). Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) than with aspirin (2.66%) [p < 0.002]. The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71%; p < 0.05. Overall, there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin (27.1 vs 29.8%; p < 0.001), with less abdominal pain, dyspepsia, constipation, or peptic, gastric, or duodenal ulceration with clopidogrel. Diarrhoea was significantly more common in the clopidogrel group (4.46 vs 3.36%; p < 0.001), although the incidence of severe diarrhoea (0.23 vs 0.11%) was low and was not significantly different between groups. There were significantly more patients with rash in the clopidogrel group (6.0%) compared with the aspirin group (4.6%) [p < 0.001]. However, these events were generally mild and transient in nature. CONCLUSION: Given the favourable benefit/risk ratio, clopidogrel represents a clinically important advance in the treatment of patients with manifest atherosclerotic disease.     

Primary and secondary stroke prevention with antiplatelet drugs

Aspirin is not effective in the primary prevention of stroke. Patients with TIA or ischemic stroke carry a risk of recurrent stroke between 5 and 20% per year. In patients with TIA or ischemic stroke of noncardiac origin antiplatelet drugs are able to decrease the risk of stroke by 11-15% and the risk of stroke, MI and vascular death by 15-22%. Aspirin is the most widely used drug. It is affordable and effective. Low doses of 50-325 mg aspirin are as effective as high doses and cause less gastrointestinal side effects. Severe bleeding complications are dose-dependent. The combination of aspirin with slow release dipyridamole is superior to aspirin alone for stroke prevention. Clopidgrel is superior to aspirin in patients at high risk of recurrence. The combination of aspirin plus clopidogrel is not more effective than clopidogrel alone but carries a higher bleeding risk. None of the antiplatelet agents is able to reduce mortality.     

Clopidogrel hydrogen sulphate for atrial fibrillation

Introduction: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin.

Areas covered: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included.

Expert opinion: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.     

Modelling the long term cost effectiveness of clopidogrel for the secondary prevention of occlusive vascular events in the UK

OBJECTIVE: To assess the long term cost effectiveness of clopidogrel monotherapy compared with acetylsalicylic acid (aspirin; ASA) monotherapy in patients at risk of secondary occlusive vascular events (OVEs) in the UK. DESIGN: Cost utility analysis based on clinical data from CAPRIE (a multicentre randomised controlled trial, involving 19185 patients); long-term effects were extrapolated beyond the trial period using a Markov model populated with data from UK observational studies. Health economic evaluation carried out from the perspective of the UK National Health Service. PARTICIPANTS: A representative cohort of 1000 UK patients aged 60 years (approximate mean age of the CAPRIE population), with the qualifying diagnoses of myocardial infarction, ischaemic stroke and peripheral arterial disease, who are at risk of secondary OVEs (non-fatal myocardial infarction, non-fatal stroke or vascular death). INTERVENTIONS: Patients were assumed to receive treatment with either clopidogrel (75 mg/day) for 2 years followed by ASA (325 mg/day, average) for their remaining lifetime, or ASA alone (325 mg/day, average) for life. MAIN OUTCOME MEASURES: Incremental cost per life year gained and incremental cost per quality-adjusted life year (QALY) gained. RESULTS: In the base case, the incremental cost effectiveness of clopidogrel versus ASA in this population is estimated at 18888 pounds per life year gained and 21 489 pounds per QALY gained. Multiple deterministic and probabilistic sensitivity analyses suggest the model is robust to variations in a wide range of input parameters. CONCLUSION: Two years of treatment with clopidogrel can be considered a cost effective intervention in patients at risk of secondary OVEs in the UK.     

Drug evaluation of clopidogrel in patients with ischemic stroke

Clopidogrel is an effective antiplatelet medication used for the secondary prevention of ischemic events in patients with various cardiovascular, cerebrovascular and peripheral vascular disease conditions. The objective of this paper is to discuss the role of clopidogrel in ischemic stroke patients and to review the existing data from randomized trials supplemented by pilot and mechanistic studies that supports these indications for its use. An analysis of the mechanism of action and pharmacology of clopidogrel is provided. After Phase III trials, such as the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients) trials, the role of clopidogrel in secondary prevention is well defined. The role of clopidogrel in acute ischemic stroke and neurointerventional procedures is evolving based on new pilot trials. At present, there is insufficient data to recommend the use of clopidogrel in acute ischemic stroke. Clopidogrel may be a valuable alternative to aspirin. However, more studies are required to assess the role of clopidogrel in selected patient groups with respect to acute ischemic stroke.