Clopidogrel Versus Aspirin In Patients At Risk Of Ischemic Events Research Articles

Clopidogrel and Ticlopidine: P2Y12Adenosine Diphosphate-Receptor Antagonists for the Prevention of Atherothrombosis

Ticlopidine and clopidogrel belong to the same chemical family of thienopyridine adenosine diphosphate (ADP)-receptor antagonists. They have shown their efficacy as platelet antiaggregant and antithrombotic agents in many animal models, both ex vivo and in vivo. Although ticlopidine was discovered more than 30 years ago, it was only recently that the mechanism of action of ADP-receptor antagonists was characterized in detail. Ticlopidine and clopidogrel both behave in vivo as specific antagonists of P2Y (12), one of the ADP receptors on platelets. Metabolic steps that involve cytochrome P450-dependent pathways are required to generate the active metabolite responsible for this in vivo activity. The active moiety is a reactive thiol derivative that targets P2Y (12) on platelets. The interaction is irreversible, accounting for the observation that platelets are definitely antiaggregated, even if no active metabolite is detectable in plasma. The interaction is specific for P2Y (12); other purinoceptors such as P2Y (1) and P2Y (13) are spared. This results in inhibition of the binding of the P2Y (12) agonist 2-methylthio-ADP and the ADP-induced downregulation of adenylyl cyclase. Platelet aggregation is affected not only when triggered by ADP but also by aggregation inducers when used at concentrations requiring released ADP as an amplifier. The efficacy and safety of clopidogrel has been established in several large, randomized, controlled trials. The clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) trial demonstrated the superiority of clopidogrel over acetylsalicylic acid (ASA) in patients at risk of ischemic events, including ischemic stroke, myocardial infarction (MI), and peripheral arterial disease. The clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial showed a sustained, incremental benefit when clopidogrel was added to standard therapy (including ASA) in patients with unstable angina and non-Q-wave MI. The clopidogrel for the reduction of events during observation (CREDO) trial demonstrated the benefit of continuing clopidogrel (plus ASA) for 12 months, as opposed to 1 month, after percutaneous coronary intervention. The proven efficacy of clopidogrel, coupled with its favorable safety and tolerability profile, has prompted its evaluation in an extensive, ongoing clinical trial program that will help to further characterize the benefit of clopidogrel in patients with a range of atherothrombotic profiles.

Response

Response

Does the Modern Concept of ‘Best Medical Therapy’ Render Carotid Surgery Obsolete?

Few operations have aroused such intense scientific scrutiny as carotid endarterectomy (CEA). Despite the provision of level I (Grade A) evidence supporting the role of CEA in symptomatic and asymptomatic patients, its role still generates widely conflicting opinions around the globe. The latest controversies relate to; (i) recent improvements in the concept of ‘best medical therapy’, (ii) continued scepticism about the overall generalisability of the operative risks reported in the international trials and (iii) the emergence of angioplasty as an alternative to surgery. This article will focus on an increasingly popular viewpoint (especially among stroke physicians) that improvements in best medical therapy (BMT) now render carotid surgery (and thus by implication, angioplasty) obsolete. While the European Carotid Surgery Trial (ECST), the North American Symptomatic Carotid Endarterectomy trial (NASCET), the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST) were recruiting, the concept of BMT was relatively primitive. To many clinicians it simply meant stopping smoking, starting aspirin and treating hypertension/angina ‘as best possible’. Few were prescribed lipid-lowering drugs and many hypertensive patients simply did not achieve satisfactory control of blood pressure. Moreover, the responsibility for ensuring implementation of BMT was often delegated to a junior member of the team. So what has changed? Improvements in what currently constitutes ‘modern’ BMT can be summarised as; (i) alternative (dual) antiplatelet therapy, (ii)

Clopidogrel versus aspirin for secondary prophylaxis of vascular events: a cost-effectiveness analysis

Purpose Clopidogrel is more effective than aspirin in preventing recurrent vascular events, but concerns about its cost-effectiveness have limited its use. We evaluated the cost-effectiveness of clopidogrel and aspirin as secondary prevention in patients with a prior myocardial infarction, a prior stroke, or peripheral arterial disease. Methods We constructed Markov models assuming a societal perspective, and based analyses on the lifetime treatment of a 63-year-old patient facing event probabilities derived from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial as the base case. Outcome measures included costs, life expectancy in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and events averted. Results In patients with peripheral arterial disease, clopidogrel increased life expectancy by 0.55 QALYs at an incremental cost-effectiveness ratio of $25,100 per QALY, as compared with aspirin. In poststroke patients, clopidogrel increased life expectancy by 0.17 QALYs at a cost of $31,200 per QALY. Aspirin was both less expensive and more effective than clopidogrel in post–myocardial infarction patients. In probabilistic sensitivity analyses, our evaluation for patients with peripheral vascular disease was robust. Evaluations of stroke and myocardial infarction patients were sensitive predominantly to the cost and efficacy of clopidogrel, with aspirin therapy more effective and less expensive in 153 of 1000 simulations (15.3%) in poststroke patients and clopidogrel more effective in 119 of 1000 simulations (11.9%) in the myocardial infarction sample. CONCLUSION Clopidogrel provides a substantial increase in quality-adjusted life expectancy at a cost that is within traditional societal limits for patients with either peripheral arterial disease or a recent stroke. Current evidence does not support increased efficacy with clopidogrel relative to aspirin in patients following myocardial infarction.

Vascular viewpoint

Question: Is a history of pre-existing atherothrombotic disease associated with an increased risk of subsequent ischemic events, and is it associated with a reduction in efficacy of clopidogrel? Population: Patients with recent ischemic stroke (IS), myocardial infarction (MI), or established peripheral arterial disease, and a history of pre-existing symptomatic atherothrombotic disease (IS and=or MI) were enrolled in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. CAPRIE was a randomized, blinded, clinical trial comparing the efficacy of clopidogrel with aspirin in patients at risk of ischemic events. Design and methods: Retrospective, subgroup analysis of 4496 patients with a prior history of symptomatic atherothrombotic disease from the CAPRIE study. Results: Compared with the overall population of CAPRIE, patients with pre-existing symptomatic atherothrombotic disease have elevated rates of IS, MI, or vascular death. The 3-year rates of IS, MI, or vascular death were 20.4% with clopidogrel and 23.8% with aspirin (absolute risk reduction: 3.4%; 95% CI: -0.2 to 7.0; number needed to treat: 29; relative risk reduction: 14.9% (95% CI: 0.3 to 27.3; p = 0.045)). Conclusion: Patients with a history of previous symptomatic atherothrombotic disease suffer a high rate of subsequent ischemic events. Among these patients, the absolute risk reduction of clopidogrel over aspirin is greater compared with patients without pre-existing atherothrombotic disease.

The Value of Clopidogrel versus Aspirin in Reducing Atherothrombotic Events

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.

Are Antiplatelet Effects of Clopidogrel Inhibited by Atorvastatin?

With respect to antiplatelet therapy, randomized trials and their meta-analyses 1 indicate benefits of clopidogrel either as an alternative 2 or an adjunct 3 to aspirin in some high-risk patients. Regarding the metabolic pathways of clopidogrel, the active thiol metabolite binds rapidly and irreversibly to platelet adenosine diphosphate (ADP) receptors, thus inhibiting platelet aggregation. 4 Clopidogrel, a thienopyridine, is a platelet ADP-receptor blocker that is known to be beneficial during and after coronary stenting.2–5 Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which has no effect on platelet aggregation. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. Results of in vitro studies in human liver microsomes and recombinant cytochromes P450 have shown that several cytochromes are involved in the oxidative metabolism of clopidogrel.6 In randomized trials of secondary and primary prevention of cardiovascular disease and their meta-analyses, 7 statins reduce risks of myocardial infarction, stroke, and cardiovascular death. Recently, in a randomized trial in patients undergoing percutaneous coronary intervention, 8 statins have been shown to reduce the incidence of major adverse coronary events, especially among the subgroups of diabetics and those with multivessel disease. In these high-risk patients, the National Cholesterol Education Program III guidelines recommend statin therapy to achieve low-density lipoprotein (LDL) goals of less than 100 mg/dL. 9 Of the 5 marketed statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin), four (atorvastatin, fluvastatin, lovastatin, and simvastatin) are also metabolized by the cytochrome P450 pathway. 10 Thus, in patients receiving coronary stents, both clopidogrel and statin therapy are likely to contribute to beneficial effects on subsequent cardiovascular disease. A recent report has raised the possibility that the ability of clopidogrel to affect platelets is inhibited by atorvastatin. 11 We have a number of concerns about the validity of these findings and therefore believe the totality of evidence to be far from complete and not consistent. In that study, the sample size was small (n44), patient selection was poorly defined, no control for the presence of medications affecting CYP 450 3A4 pathway was performed before initiation, and the data were retrospective and non-randomized. Using a single method to assess platelet function was also unconventional. Furthermore, data from the larger retrospective Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial compared platelet inhibition with clopidogrel in 100 patients undergoing coronary intervention who also received statins. 12 In PRONTO, there was no evidence of any specific deleterious interaction between clopidogrel and atorvastatin in terms of platelet activity. The analysis showed that only 4 of 25 patients in the atorvastatin treated group did not exhibit sustained platelet inhibition on days 2 and 5 after treatment with clopidogrel and aspirin. A similar pattern was observed in 2 of 9 patients treated with fluvastatin and 1 of 6 patients treated with pravastatin, neither of which is metabolized by the cytochrome P450 3A4 pathway. Finally, of perhaps even greater relevance to this hypothesis, a similar pattern was observed in 12 of 75 patients who did not receive any statin. In total, about 20% of patients did not achieve profound platelet inhibition with clopidogrel, but this seemed unrelated to treatment with any statins. It is tempting to speculate that in certain patients, the burden of platelet activation is so excessive that usual treatment regimens are not sufficient to achieve even moderate platelet inhibition. Retrospective data from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) and Clopidogrel Unstable angina to prevent Recurrent Events (CURE) trials among subgroups of patients concurrently administered clopidogrel and statins indicated no clinically significant adverse interactions. Further data, especially from prospective studies, are necessary to test the hypothesis of potential interactions between clopidogrel and statins. One such study, INTERACTIONs of atorvastatin and clopidogrel therapy (INTERACT), has been designed to address this issue by serial measurements of various platelet characteristics by conventional as well as whole blood aggregometry, by point of care tests with 2 rapid analyzers, and by assessment of 14 receptors on the platelet surface by whole blood flow cytometry.

Effectiveness of clopidogrel versus aspirin in preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE trial)

Article Outline• ReferencesBased on recent results with glycoprotein IIb/IIIa inhibitors and low molecular weight heparin having a greater relative benefit in higher risk groups,[1 and 2] we hypothesized that acute myocardial infarction (AMI) could be predicted with baseline characteristics and that patients at a higher risk of developing AMI would have a greater relative benefit from clopidogrel than from aspirin in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.The design and results of the CAPRIE trial have been previously reported.[3] In brief, 3 groups of patients were eligible: patients with an ischemic stroke at least 1 week but less than 6 months before randomization, with a persistent neurologic deficit and no evidence of cerebral hemorrhage; patients with AMI within the prior 35 days; and patients with documented peripheral arterial disease, defined as patients with intermittent claudication and an ankle/brachial systolic blood pressure index of ≤0.85 in either leg on 2 separate occasions, or prior leg amputation or angioplasty. Exclusion criteria included uncontrolled hypertension, severe renal or hepatic insufficiency, a history of a bleeding disorder, or abnormal white or red blood cell counts. Informed consent was obtained from all but 10 patients before randomization. Patients were treated and followed for ≤3 years, with an average follow-up of 1.9 years.Patients were divided into 2 groups: those who did versus those who did not develop AMI during follow-up. AMI was defined as the presence of ≥2 of the following 3 criteria: (1) characteristic ischemic pain lasting ≥20 minutes; (2) elevation of creatine kinase or creatine kinase-MB, lactate dehydrogenase, or aspartate aminotransferase ≥2 times the upper limit of normal with no other explanation; (3) development of new Q waves of at least 0.4 mV in 2 adjacent electrocardiographic leads or a new dominant R wave in lead V1 (with the R wave ≥1 mm greater than the S wave in V1). A central validation committee that was blinded to treatment assignment adjudicated all outcomes.Baseline clinical factors were compared between patients who developed a documented AMI during the subsequent follow-up (1 to 3 years) and those who did not. The factors that were found to be significantly different were entered into a multivariate analysis to identify independent predictors of AMI. The odds ratio and 95% confidence intervals were calculated from multivariate analysis. From this list, the significant factors were selected as a risk score and the number of risk factors was assigned to each individual patient in the trial. Then, the rate of AMI during follow-up was assessed according to the number of risk factors. This latter analysis was then stratified by study drug assignment.Of the total 19,185 patients, a new AMI developed in 617 patients. Kaplan-Meier event rates showed that in patients treated with aspirin, 5.04% developed AMI during follow-up (1 to 3 years) compared with 4.2% of patients treated with clopidogrel, a 19.2% relative risk reduction (p = 0.008) (Figure 1). The relative benefit was constant over time.

Preventing atherothrombotic events in peripheral arterial disease: the use of antiplatelet therapy.

Patients with peripheral arterial disease (PAD) are at increased risk of generalized atherothrombotic events. Epidemiologic data shows a high rate of co-prevalence of PAD and atherosclerosis in other vascular beds. Aggressive risk-factor modification and antiplatelet therapy has become the cornerstone of treatment to prevent ischaemic events associated with PAD. Recent clinical trials have confirmed the clinical benefit of clopidogrel and ticlopidine in patients with PAD, agents that irreversibly inhibit the binding of adenosine diphosphate to its platelet receptor. In the clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) trial, clopidogrel was associated with an overall risk reduction of 8.7% (compared with aspirin, P=0.043) in myocardial infarction (MI), ischaemic stroke and vascular death. These results demonstrated that long-term administration of clopidogrel was effective in preventing ischaemic events in patients with atherosclerotic vascular disease including PAD. Aspirin and/or clopidogrel are the antiplatelet agents of choice for the reduction of atherothrombotic events in patients with PAD.

Clopidogrel Versus Aspirin After Cardiac Surgery

To the Editor: The subgroup analysis from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial by Bhatt et al1 suggests a superiority of clopidogrel versus aspirin in patients who have had cardiac surgery. However, this post-hoc analysis of a non-prespecified subgroup does not properly address the qualifying event by which patients were randomized into the larger CAPRIE trial,2 except for the last sentence of Study Limitations. Only patients who had had previous cardiac surgery and a qualifying event (such as a recent [within <30 days] myocardial infarction or ischemic stroke, or objective evidence of lower-extremity ischemia) were eligible for the trial and thus for the analysis by Bhatt.1 Almost all patients with previous cardiac surgery will have been on aspirin therapy. When such a group of patients develops a new ischemic event like those …

Rationale for the use of platelet aggregation inhibitors in PAD patients

Peripheral arterial disease (PAD) is a major risk marker for systemic ischaemic events. The understanding of PAD has moved from PAD as an organ-specific disease to PAD as the lower-limb localization of a multifocal disease, i.e. atherothrombosis. Blood platelet activation and aggregation is a common denominator in atherothrombotic events, and use of antiplatelet agents in patients with PAD can inhibit thrombus formation and reduce the occurrence of myocardial infarction (MI), ischaemic stroke (IS) and vascular death. Many studies have investigated various antiplatelet regimens for preventing acute cardiovascular events in patients with a prior ischaemic event, although many of these studies had a number of limitations. The Antiplatelet Trialists' Collaboration performed a meta-analysis of 23 stroke trials and found an average odds risk reduction of 25% for a combined endpoint of stroke, MI or vascular death. The concept of atherothrombosis as a multifocal disease was challenged by the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial. This study showed an 8.7% decrease in the relative risk reduction for further atherothrombotic events with clopidogrel over aspirin (p = 0.043) for the overall population, in terms of the combined endpoint of IS, Ml or vascular death.

Benefit of ADP Receptor Antagonists in Atherothrombotic Patients: New Evidence

In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, clopidogrel showed a statistically significant superiority over aspirin in the prevention of ischaemic stroke, myocardial infarction and vascular death in patients with symptomatic atherosclerosis. More recently, post-hoc analysis of the data also showed that repeat hospitalization for ischaemic or bleeding events was decreased with clopidogrel compared with aspirin. Complementary analyses show that the benefit of clopidogrel over aspirin is amplified in a large population at very high risk of further atherothrombotic events (diabetics, patients with high cholesterol, and patients with previous manifestations of atherothrombosis). A potential clinically useful advantage of clopidogrel is its low propensity for adverse interaction with angiotensin-converting enzyme (ACE) inhibitors, contrary to what may be seen with aspirin, as observed in a post-hoc CAPRIE analysis. The putative aspirin-ACE inhibitor interaction is being tested prospectively in the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial – a randomized comparison of warfarin, clopidogrel and aspirin in patients with chronic heart failure. The good gastrointestinal tolerance of clopidogrel seen in CAPRIE has been further demonstrated in a study in healthy volunteers where there was a markedly lower gastroduodenal erosion score after 8 days’ administration of clopidogrel 75 mg/day compared with aspirin 325 mg/day (p < 0.001). Following the positive findings obtained with clopidogrel plus aspirin in the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) trial, other studies of clopidogrel plus aspirin have been initiated or are planned. These include Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH), a randomized comparison of clopidogrel plus aspirin versus clopidogrel in high-risk patients with recent stroke or transient ischaemic attack.

Active-control trials: How would a new agent compare with placebo? A method illustrated with clopidogrel, aspirin, and placebo

Background In an active-control trial with a new treatment and a comparator that has placebo-controlled trials, how might the effect of the new therapy versus placebo be estimated? For many diseases it is not ethically justified to use a placebo-control trial, yet in the United States regulatory efficacy is conceptually defined in comparison with placebo. Methods By use of the logarithm of the odds ratio for the active-control trial and for the placebo-controlled trials of the active-control, we estimated the effect of the new agent versus placebo. This “putative placebo” estimate assumes that the odds ratio in the active-control versus placebo trials is the same as would have been obtained had a placebo arm been possible in the trial with the new agent. A formula is given for sample size calculation in such a setting. Results Clopidogrel, an adenosine diphosphate (ADP) receptor antagonist, and aspirin were compared in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Study of patients with recent myocardial infarction, recent ischemic stroke, or symptomatic peripheral arterial disease. The 40 trials comparing aspirin with placebo are summarized by the Antiplatelet Trialists’ Collaboration. For the outcome cluster of stroke, myocardial infarction, or vascular mortality, the estimated odds ratio for clopidogrel versus placebo is 0.70 (95% confidence interval 0.64–0.78, P <.000001). The relative risk reduction of approximately 30% represents a clinically meaningful benefit. Conclusions For active-control trials use of prior trials of the active-control versus placebo may be usefully used to estimate the effect of the new therapy versus a putative placebo. (Am Heart J 2001;141:26-32.)

Abstracts of literature

Abstracts of literature

Value of antiplatelet therapy in preventing thrombotic events in generalized vascular disease.

Atherothrombosis is the major underlying cause of acute coronary syndromes, ischemic stroke, and peripheral artery disease, and thus is the leading cause of death and disability in Western countries. Platelet inhibitors play a major role in preventing these ischemic complications. There is strong evidence from the Antiplatelet Trialists' Collaboration meta-analysis that aspirin reduces the combined risk of stroke, myocardial infarction (MI), or vascular death in atherosclerotic patients. The Ticlopidine Aspirin Stroke Study (TASS) compared aspirin and ticlopidine in the secondary prevention of high-risk patients after ischemic stroke and demonstrated a significant advantage for ticlopidine over aspirin. In peripheral arterial disease, the Swedish Ticlopidine Multicentre Study (STIMS) showed that ticlopidine was very effective against placebo. Intravenous antiplatelet agents, such as abciximab, tirofiban, and eptifibitide were also proven effective in acute coronary syndromes and unstable angina. In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, clopidogrel was compared with aspirin in patients with symptomatic atherothrombosis regardless of the initial localization of the ischemic event (coronary, cerebral, or peripheral). The efficacy of clopidogrel based on the first occurrence of ischemic stroke, MI, or vascular death showed a relative risk reduction of 8.7% over and above the 25% reduction currently accepted with aspirin (p < 0.05). The greatest benefit of clopidogrel was in the reduction of fatal and nonfatal MI in the most severe groups of patients, providing a 19% relative risk reduction (p = 0.008). The recent disappointing results obtained with oral glycoprotein IIb/IIIa receptor blocking agents may emphasize the need for other antiplatelet combination therapy, such as aspirin-clopidogrel, in coronary disease, stents, stroke, and possibly atherothrombosis in high-risk patients.

Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin

Background Repeat hospitalizations of patients with atherosclerosis represent a considerable burden on the health care system. We sought to determine whether clopidogrel compared with aspirin decreases the need for rehospitalization for ischemia and bleeding. Methods and Results The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was a randomized, blinded, multicenter, trial of 19,185 patients with atherosclerotic disease manifested as recent ischemic stroke or myocardial infarction or symptomatic peripheral arterial disease. Without any double-counting of events, the number of rehospitalizations for ischemic events (defined as angina, transient ischemic attack, or limb ischemia) or bleeding events was determined for the entire cohort. There was a significant reduction in the total number of rehospitalizations for ischemic events or bleeding with clopidogrel use compared with aspirin (1502 vs 1673; P =.010) over an average of 1.6 years of treatment. This reduction in rehospitalization was consistent across individual outcomes of angina, transient ischemic attack, limb ischemia, and bleeding. Compared with aspirin, clopidogrel also resulted in a 7.9% relative risk reduction in a combined end point of vascular death, stroke, myocardial infarction, or rehospitalization for ischemic events or bleeding (15.1% to 13.7% at 1 year; P =.011). Adjusting for baseline prognostic variables, clopidogrel therapy was an independent predictor for reduction of vascular death, stroke, myocardial infarction, or rehospitalization for ischemic events or bleeding (P =.009). Conclusions Treatment with clopidogrel results in a significant decrease in the need for rehospitalization for ischemic events or bleeding compared with aspirin. This meaningful end point tracks well with other, more traditional measures of outcome and has incremental value beyond such end points. (Am Heart J 2000;140:67-73.)

Generalizing the results of clinical trials to actual practice: the example of clopidogrel therapy for the prevention of vascular events

PURPOSE: An important element in translating the results obtained in clinical trials of a new treatment to clinical practice is the estimated event rate in patients who would be eligible to receive that treatment. We estimated the effect of clopidogrel, compared with aspirin, in actual practice using the relative risk reduction observed in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial. SUBJECTS AND METHODS: Ischemic event rates were estimated for 12,931 aspirin users drawn from the Saskatchewan Health population between 1990 and 1995 who had an index diagnosis of myocardial infarction, ischemic stroke, or peripheral arterial disease. To estimate the absolute risk reduction, the 8.7% relative risk reduction from clopidogrel compared with aspirin that was observed in CAPRIE was applied to these rates. RESULTS: The rates of ischemic events were greater in actual practice than among the control patients in the CAPRIE trial. In the Saskatchewan population, patients experienced an outcome event (myocardial infarction, stroke including intracranial hemorrhage, or death) at a rate of 15.9 per 100 patient-years, compared with only 6.9 per 100 patient-years in CAPRIE. If the same 8.7% relative risk reduction seen in the CAPRIE trial is also true for patients seen in routine clinical practice, the greater absolute risk in actual practice would reduce the number needed to treat to prevent one event from 200 patients to 70 patients. CONCLUSION: Absolute risk rates may be substantially greater in clinical practice than in the selected patients enrolled in randomized trials. As a result, similar reductions in relative risk, if true for clinical practice, may yield substantially more benefit in clinical practice than in randomized trials.

Clopidogrel for Cerebrovascular Prevention

Ischemic stroke, myocardial infarction and peripheral arterial disease are different clinical manifestations commonly due to the same underlying disease, i.e. atherosclerosis with subsequent thrombosis/embolism (atherothrombosis). Many clinical trials of secondary prevention after stroke or TIA have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of subsequent vascular events. Aspirin and triclopidine have been shown to be effective in placebo-controlled studies for the composite outcome of stroke, myocardial infarction, or vascular death. Contrasting with these benefits, there were potentially serious, though rare, adverse effects. These considerations certainly justify the development of new antiplatelet agents. Clopidogrel is a new ADP-receptor antagonist, with a greater activity in animal models of thrombosis. CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) was a randomized, blinded, international trial designed to assess the relative efficacy of clopidogrel and aspirin in reducing the risk of the outcome cluster of ischemic stroke, myocardial infarction, or vascular death, as well as to assess their relative safety. 19,185 patients were recruited. The intention-to-treat analysis showed that the relative risk reduction was 8.7% (95% CI 0.3–16.5, p = 0.043) in favor of clopidogrel from an overall annual event rate of ischemic stroke, myocardial infarction, or vascular death, ranging from 5.83% in the aspirin group to 5.33% in the clopidogrel group. The percentage of adverse events reported was higher in the aspirin group for all categories except rash, diarrhea, and abnormal liver function. It seems likely that clopidogrel will replace ticlopidine for stroke prevention, because of its better safety profile, and comparable efficacy. Clopidogrel probably will not replace aspirin as the first line therapy for many clinicians because of its higher cost and lack of widespread experience. However, other clinicians have already decided that they will use clopidogrel as first choice, because of the significant advantage over aspirin demonstrated in the CAPRIE study.

Antiplatelet agents in the prevention of cardiovascular morbidity and mortality in older patients with vascular disease.

Antiplatelet drugs have been demonstrated to reduce the incidence of myocardial infarction (MI), stroke or vascular death in patients with vascular disease. There are no data suggesting that antiplatelet therapy acts differently in older people than in younger people and recommendations based on randomised clinical trials are probably generalisable to older people. Aspirin (acetylsalicylic acid) has been shown to reduce the incidence of non-fatal MI, nonfatal stroke and vascular death in patients with acute MI, a previous MI, angina pectoris or peripheral occlusive arterial disease (POAD), and to reduce cardiovascular morbidity and mortality in patients with a prior ischaemic stroke or transient ischaemic attack (TIA). It has also been shown to reduce the incidence of thrombus formation after coronary artery bypass graft surgery and percutaneous transluminal angioplasty, and in patients with atrial fibrillation and heart valve replacements. Deep vein thrombosis and pulmonary embolism after surgery are also prevented by aspirin. The available data allows the following recommendations to be made. Aspirin 160 to 325 mg daily should be administered to older men and women without contraindications to aspirin who have acute MI, prior MI, unstable or stable angina pectoris, ischaemic stroke, TIA or POAD, and continued indefinitely to reduce the risk of MI, stroke or vascular death. Aspirin should be started in patients before or immediately after revascularisation, and after heart valve replacement. Older men and women with nonvalvular atrial fibrillation who have contraindications to oral anticoagulant therapy but no contraindications to aspirin should be treated with aspirin 325 mg daily. It is reasonable to treat older men and women without contraindications to aspirin with aspirin 160 to 325 mg daily if they are at high risk for developing new coronary events. The incidence of stroke, MI or vascular death in patients after a stroke or TIA is reduced by ticlopidine. Therefore, ticlopidine 250 mg twice daily may be used in older men and women with a history of stroke or TIA who do not respond to or who cannot tolerate aspirin. Patients at high risk for coronary artery stent thrombosis benefit from combined therapy with aspirin plus ticlopidine. The annual incidence of ischaemic stroke, MI or vascular death was significantly reduced by clopidogrel in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. Therefore, clopidogrel 75 mg daily may be used in older men and women with symptomatic atherosclerosis who do not respond to or who cannot tolerate aspirin to reduce the incidence of ischaemic stroke, MI or vascular death. It should be noted that the acquisition cost for either ticlopidine or clopidogrel is considerably greater than that for aspirin. Most data indicate that the combination of aspirin and dipyridamole is not more effective than aspirin alone in preventing vascular events, and available data do not support the use of sulfinpyrazone in patients with vascular disease.

Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects

Since our last report on antithrombotic therapy in 1995, 1 Hirsh J Dalen JE Fuster V et al. Aspirin and other platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 1995; 108: 247S-257S Abstract Full Text Full Text PDF PubMed Google Scholar new information has been published on the role of aspirin and other platelet-active drugs in the treatment and prevention of atherothrombosis. These new data can be summarized as follows: (1) two large randomized studies have tested the efficacy and safety of aspirin in patients with acute ischemic stroke; 2 International Stroke Trial Collaborative GroupThe International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. Lancet. 1997; 349: 1569-1581 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ,3 CAST (Chinese Acute Stroke Trial) Collaborative GroupCAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke. Lancet. 1997; 349: 1641-1649 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (2) two recent studies have shown that low-dose aspirin therapy is effective and safe in the primary prevention of ischemic heart disease in men at high risk 4 The Medical Research Council's General Practice Research FrameworkThrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. Lancet. 1998; 351: 233-241 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar as well as in men and women with hypertension; 4a Hansson L Zanchetti A Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998; 351: 1755-1762 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (3) the clinical efficacy of dipyridamole has to be reassessed in the light of the European Stroke Prevention Study-2 (ESPS-2); 5 Diener HC Cunha L Forbes C et al. European Stroke Prevention Study: II. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143: 1-13 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (4) a novel thienopyridine derivative, clopidogrel, has been shown to be at least as effective as aspirin in one very large phase III trial 6 CAPRIE Steering CommitteeA randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet. 1996; 348: 1329-1339 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and may be a safer alternative to aspirin than ticlopidine; (5) besides abciximab, now on the market in many countries, several platelet glycoprotein (GP) IIb/IIIa (integrin αIlbβ3) antagonists are in various stages of clinical development and have shown improved efficacy over conventional antithrombotic treatment in high-risk acute coronary settings; 7 Anderson KM Weisman HF Coller BS. Platelet glycoprotein IIb/IIIa receptor inhibitors. in: Hennekens CH Buring JE Manson JE Clinical trials in cardiovascular disease. WB Saunders, Philadelphia1999 Google Scholar and (6) the additive effect of ticlopidine and aspirin in the prevention of coronary stent thrombosis has been demonstrated, 8 STARSN Engl J Med. 1998; (in press) Google Scholar while controversial results have been reported for the combination of low-dose aspirin with low-intensity oral anticoagulation with warfarin. 4 The Medical Research Council's General Practice Research FrameworkThrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. Lancet. 1998; 351: 233-241 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ,9 Coumadin Aspirin Reinfarction Study (CARS) InvestigatorsRandomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet. 1997; 350: 389-396 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar