Vascular Medicine of the CAPRIE trial: efficacy and safety of clopidogrel                ...
Vascular Medicine 1998; 3: 257–260Results of the CAPRIE trial: efficacy and safety ofclopidogrelMark A Creager             ...
258   MA Creagerated to twice the laboratory normal without explanation;                      group at an average rate of ...
Results of the CAPRIE trial        259Figure 1 Cumulative risk of experiencing an event in the primary outcome cluster (is...
260   MA Creager  K. Adverse effects of low-dose aspirin in a healthy elderly population.                8 Gent M. Benefit ...
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  1. 1. Vascular Medicine of the CAPRIE trial: efficacy and safety of clopidogrel Mark A Creager Vasc Med 1998 3: 257 DOI: 10.1177/1358836X9800300314 The online version of this article can be found at: Published by: On behalf of: Society for Vascular Medicine Additional services and information for Vascular Medicine can be found at: Email Alerts: Subscriptions: Reprints: Permissions: Citations: >> Version of Record - Aug 1, 1998 What is This? Downloaded from by guest on March 19, 2013
  2. 2. Vascular Medicine 1998; 3: 257–260Results of the CAPRIE trial: efficacy and safety ofclopidogrelMark A Creager Abstract: The recent CAPRIE trial (clopidogrel versus aspirin in patients at risk of ischaemic events) compared clopidogrel with aspirin in reducing the risk of vascular events in 19 185 patients with clinical manifestations of atherosclerosis. Participants were randomized to receive daily oral clopidogrel (75 mg) or aspirin (325 mg). Treatment periods ranged from 1 to 3 years. The primary outcome measurement was an aggregate of myocardial infarction, ischemic stroke and vascular death. Event rates of 5.32% and 5.83% were associated with clopidogrel and aspirin therapy, respectively. Clopidogrel therapy resulted in a relative risk reduction of 8.7% (CI 0.3–16.5%) compared with aspirin therapy (p = 0.043). Gastrointestinal hemorrhages occurred in 1.99% of patients treated with clopidogrel and 2.66% of patients treated with aspirin (p Ͻ 0.002). There were no significant treatment-based differences in the rates of intracerebral hemorrhages and hemorrhagic deaths or thrombocytopenia. These results indicate that clopidogrel is more effective and safer than aspirin in reducing adverse cardiovascular events in patients with atherosclerosis. Key words: aspirin; atherosclerosis; clopidogrel; myocardial infarction; strokeIntroduction CAPRIE (clopidogrel versus aspirin in patients at risk of ischaemic events), compared the effects of clopidogrel withThe Antiplatelet Trialists’ Collaboration,1 a meta-analysis those of aspirin in patients thought to be at high risk forof 145 clinical trials involving antiplatelet prophylaxis in vascular events.over 70 000 patients at high risk for vascular events, foundan approximate 25% overall risk reduction with the use ofantiplatelet therapy, consisting primarily of aspirin. Among CAPRIEall high-risk patients, non-fatal myocardial infarction (MI)and non-fatal strokes were reduced by about one-third, The results of the CAPRIE study have been published pre-while vascular deaths were reduced by about one-sixth. viously.7 In this article, I wish to review and summarizeAlthough trials using a variety of aspirin doses were those results. The two major objectives of the CAPRIE trialincluded in the meta-analysis, there was no evidence that were1 to assess the relative efficacy of clopidogrel andhigher doses conferred a greater protective effect. The dur- aspirin in reducing the incidence of ischemic stroke, myo-ation of 21 of the trials, comprising approximately 56 000 cardial infarction, or vascular death among patients whopatients, was at least 1 year. After 1, 2 and 3 years of fol- had survived a recent ischemic stroke, recent myocardiallow-up, there was a reduction in the risk of an adverse car- infarction, or had symptomatic atherosclerotic peripheraldiovascular event of 28%, 24% and 12% respectively, in arterial disease; and (2) to assess the relative safety andpatients treated with antiplatelet therapy compared with tolerability of clopidogrel and aspirin. CAPRIE enrolledcontrols.1 Although the Collaboration’s meta-analysis did over 19 000 patients with clinical disorders indicative ofnot examine safety data for aspirin therapy, long-term ther- atherothrombotic vascular disease, including stroke, myo-apy is associated with a variety of side-effects. The most cardial infarction, and peripheral arterial disease. The pri-common adverse effects include bleeding, gastrointestinal mary endpoint of the study was a composite outcome clus-discomfort, ulcer and, in certain hypersensitive patients, ter of myocardial infarction, ischemic stroke, or vascularbronchoconstriction.2–6 death. Clopidogrel is a thienopyridine derivative that inhibits Inclusion criteria for patients with ischemic stroke wereplatelet aggregates by antagonizing the platelet adenosine a focal neurologic deficit likely to be of atherothromboticdiphosphate receptor. A recent, large, multicenter trial, origin with an onset greater than 1 week, but less than 6 months, before enrollment; neurologic signs persisting for longer than 1 week from onset; and computed tomographyVascular Medicine and Atherosclerosis Unit, Cardiovascular Division, or magnetic resonance imaging evidence that the cause ofBrigham and Women’s Hospital, Boston, MA, USA stroke was not hemorrhagic or of non-vascular origin. Patients with myocardial infarction were eligible if its onsetAddress for correspondence: Mark A Creager, Vascular Medicine and was 35 or fewer days before enrollment, as indicated byAtherosclerosis Unit, Cardiovascular Division, Brigham and Women’sHospital, 75 Francis Street, Boston, MA 02115, USA. the presence of any two of the following criteria: ischemic pain lasting у20 min; creatine kinase, creatine kinase-MB,Adapted with permission of the CAPRIE Steering Committee lactic dehydrogenase, or aspartate transaminase levels elev-© Arnold 1998 1358-863X(98)VM247MP Downloaded from by guest on March 19, 2013
  3. 3. 258 MA Creagerated to twice the laboratory normal without explanation; group at an average rate of 5.32% per year. In the 17 519the development of new у40 msec Q waves in at least two patient years at risk among aspirin-treated patients, 1021adjacent ECG leads or a new dominant R wave in V1 events occurred at an average of 5.83% per year. Therefore,(R у 1 mm Ͼ S in V1). Patients enrolled because of per- the absolute risk reduction achieved with clopidogrel com-ipheral arterial disease were required to have a history of pared with aspirin was 0.51% per year. Using a Cox pro-intermittent claudication as indicated by the World Health portional-hazard model, the relative risk reduction achievedOrganization criterion – leg pain while walking that disap- by clopidogrel compared with aspirin was 8.7% (95% CIpears after less than 10 min of standing still. The pain must 0.3–16.5; p = 0.043). An on-treatment analysis of the datahave been of presumed atherosclerotic origin. Further, the (including patients receiving only the study drug or datapatients were required to have an ankle–arm systolic blood taken from patients within 28 days of discontinuation ofpressure ratio р0.85 in either leg at rest on two separate the study drug) revealed a relative risk reduction of 9.4%occasions. In addition, patients with a history of intermit- in favor of clopidogrel. The cumulative risk of experiencingtent claudication who had undergone reconstructive sur- an outcome event within the primary outcome cluster dur-gery, angioplasty, or leg amputation with no persisting ing the study is shown in Figure 1. Analysis of the datacomplications from the intervention, were eligible for for the secondary outcomes provided similar relative riskenrollment. Thus, patients who enrolled with peripheral reductions of 7–8% in favor of clopidogrel for the clusterarterial disease were distinguished from the other two of ischemic stroke, myocardial infarction, amputation, orgroups, in part, by the chronicity of symptoms. vascular death (p = 0.076), for vascular death (p = 0.29); Patients were randomly assigned to receive either aspirin and for any stroke, myocardial infarction, or death from(325 mg/day) or clopidogrel (75 mg/day). The protocol any cause (p = 0.81) The relative risk reduction for deathallowed the use of standard therapies appropriate to the from any cause was 2.2% (p = 0.71).patient’s symptoms during the study; however, anticoagu- As would be expected, strokes were the most commonlant or antithrombotic medications were discontinued outcome event among those admitted because of stroke, andbefore randomization. myocardial infarctions were most common among those admitted because of myocardial infarction. Among patientsPatient follow-up enrolled because of peripheral arterial disease, outcomeThe 19 185 patients enrolled in CAPRIE were followed for events were evenly divided among myocardial infarction,up to 3 years, with a mean follow-up period of 1.91 years. stroke and other vascular deaths.The thienopyridine derivative, ticlopidine, is associated Although analyses based on the clinical subgroups werewith an increased risk of neutropenia and thrombocytop- performed with CAPRIE data, the study was not originallyenia. Thus, during the first 3 months of the study, weekly powered to perform such calculations and caution shouldblood counts and bimonthly biochemical assessments were be used in their interpretation. By clinical subgroup, theobtained from the first 500 patients in an intensive safety relative risk reduction achieved by clopidogrel therapy forexamination. Review of those data alleviated concern about myocardial infarction, stroke and peripheral arterial diseaseclopidogrel’s safety, and the intense scrutiny was relaxed patients were −3.7%, 7.3% and 23.8%, monthly follow-up for the first 4 months and once every Because of these findings, concern has been raised regard-4 months for the remainder of the study. ing the acute myocardial infarction subgroup. To assess the The primary outcome event cluster consisted of the first effect of clopidogrel therapy further in patients with prioroccurrence of ischemic stroke, myocardial infarction, or myocardial infarction, an additional analysis was performeddeath from vascular causes (vascular death). Secondary out- that included 2144 patients in the stroke and peripheralcome clusters consisted of the above outcome events plus arterial disease groups who had, in addition, a history ofamputation; vascular death; any stroke, myocardial infarc- myocardial infarction. In this group, clopidogrel was asso-tion, or death from any cause; and death from any cause. ciated with a 22.7% relative risk reduction over aspirin in The clinical subgroups defined by the three sets of preventing vascular events.7 When this group was com-inclusion criteria comprised approximately equal numbers bined with the acute myocardial infarction subgroup, thereof patients: 6431 patients were enrolled because of stroke, were 455 events in clopidogrel-treated patients and 4796302 because of myocardial infarction and 6452 because events in aspirin-treated patients; this is a relative riskof peripheral arterial disease. The two treatment groups reduction of 7.4%, which is consistent with the overall fin-were well matched in terms of age, sex, race and risk fac- dings of the study.7tors. Risk factors for atherosclerosis, including diabetes A subsequent analysis of all 19 185 patients in CAPRIE8mellitus, high blood pressure, hypercholesterolemia and examined the relative risk reductions for the individual out-current cigarette smoking, were roughly comparable come events of myocardial infarction (fatal and non-fatal).between the two groups. In the clopidogrel group there were 276 events, whereas in Only 42 patients (0.22%) were lost to follow-up; they the aspirin group there were 341 events. This is equivalentwere evenly balanced between treatment groups. Treatment to a relative risk reduction by clopidogrel of 19.2% for fatalwas discontinued early during the study in approximately and non-fatal myocardial infarction (p Ͻ 0.008).21% of patients in each group for a variety of reasons, The relative risk reductions achieved with clopidogrel inincluding adverse side-effects, withdrawn consent, and this study are probably in addition to the benefit alreadynon-compliance. afforded by aspirin therapy, since the latter has been com- pared to placebo in the Antiplatelet Trialists’ Collaboration,Efficacy which suggested that aspirin reduces the risk of vascularAn intention-to-treat analysis found that during 17 636 events by about 25% compared with placebo. This 25%patient years at risk, 939 events occurred in the clopidogrel reduction is equivalent to the prevention of 19 serious vas-Vascular Medicine 1998; 3: 257–260 Downloaded from by guest on March 19, 2013
  4. 4. Results of the CAPRIE trial 259Figure 1 Cumulative risk of experiencing an event in the primary outcome cluster (ischemic stroke, myocardial infarction, orvascular death). (Reproduced from ref. 7 with permission.)cular events per 1000 high-risk patients treated for 1 year. The incidence of diarrhea was significantly greater withThe additional 8.7% risk reduction provided by clopidogrel clopidogrel (4.5%) than with aspirin (3.4%; p Ͻ 0.05),in CAPRIE translates to the prevention of 24 serious vascu- although it occurred infrequently with either drug. Rasheslar events per 1000 high-risk patients treated for 1 year. also occurred significantly more frequently in the clopidog-The absolute efficacy of clopidogrel compared with placebo rel group (6% versus 5% with aspirin; p Ͻ 0.05); severecannot be determined from the CAPRIE study since there rashes occurred in only 0.26% of patients treated with clop-was no placebo arm, and it would have been unethical to idogrel and 0.10% of patients receiving aspirin.omit antiplatelet therapy from the management of patientswith symptomatic atherosclerosis. ConclusionsSafetyThe assessment of clopidogrel’s safety was an importantobjective of the CAPRIE study. Clopidogrel has a favorable To summarize the findings of CAPRIE, long-term adminis-safety profile compared to that of aspirin. Hemorrhagic tration of clopidogrel to patients primarily with atheroscler-events are a concern in patients receiving antiplatelet ther- osis as a cause of vascular disease is more effective thanapy. Intracranial hemorrhages and hemorrhagic deaths long-term aspirin therapy in reducing the combined risk ofoccurred in 0.39% of the clopidogrel patients and 0.53% ischemic stroke, myocardial infarction, or vascular death.of patients receiving aspirin (p = NS). However, gastro- The relative risk reduction provided by clopidogrel, as seenintestinal hemorrhages occurred in 1.99% of patients in the CAPRIE trial, is added to the benefit provided bytreated with clopidogrel and 2.66% of those treated with aspirin when compared with placebo. Clopidogrel is anaspirin (p Ͻ 0.05). There were 30% more hospitalizations effective antiplatelet agent that reduces cardiovascularfor gastrointestinal bleeding in the aspirin-treated group events and it does so with a favorable safety profile.than in the clopidogrel-treated group. In terms of gastro-intestinal disorders, including indigestion, nausea, or vomit-ing, 15.01% of clopidogrel-treated patients experienced Referencesevents versus 17.59% of the aspirin group (p Ͻ 0.05). Itis important to note that patients with a history of aspirin 1 Antiplatelet Trialists’ Collaboration. Collaborative overview of ran-intolerance were excluded from the CAPRIE trial. Thus, domised trials of antiplatelet therapy. I. Prevention of death, myocar-rates of adverse gastrointestinal events reported with aspirin dial infarction, and stroke by prolonged antiplatelet therapy in variousin this study may differ from that which occurs in the gen- categories of patients. BMJ 1994; 308: 81–106.eral population. 2 Wilcox CM, Shalek KA, Cotsonis G. Striking prevalence of over-the- Neutropenia is an adverse effect of ticlopidine, an ana- counter nonsteroidal anti-inflammatory drug use in patients with upperlogue of clopidogrel, occurring in about 1% of treated gastrointestinal hemorrhage. Arch Intern Med 1994; 154: 42–46. 3 Faulkner G, Prichard P, Somerville K, Langman MJS. Aspirin andpatients. In CAPRIE, the rate of neutropenia was similar bleeding peptic ulcers in the elderly. BMJ 1988; 297: 1311– the aspirin and clopidogrel groups. Neutropenia occurred 4 Samter M, Beers RF. Intolerance to aspirin: clinical studies and con-in about 0.1% of patients treated with clopidogrel and sideration of its pathogenesis. Ann Intern Med 1968; 68: 975–83.0.17% of those receiving aspirin (p = NS). Severe neutro- 5 Steering Committee of the Physicians’ Health Study Research Group.penia occurred in 0.05% (five patients) of those treated with Final report on the aspirin component of the ongoing Physicians’clopidogrel versus 0.04% (four patients) of those treated Health Study. N Engl J Med 1989; 321: 129–35.with aspirin (p = NS). 6 Silagy CA, McNeil JJ, Donnan GA, Tonkin AM, Worsam B, CampionVascular Medicine 1998; 3: 257–260 Downloaded from by guest on March 19, 2013
  5. 5. 260 MA Creager K. Adverse effects of low-dose aspirin in a healthy elderly population. 8 Gent M. Benefit of clopidogrel in patients with coronary disease Clin Pharmacol Ther 1993; 54: 84–89. (abstr). Circulation 1997; 96: I-467.7 CAPRIE Steering Committee. A randomised, blinded, trial of clopido- grel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–39.Vascular Medicine 1998; 3: 257–260 Downloaded from by guest on March 19, 2013