1) The CAPRIE trial compared the efficacy and safety of clopidogrel versus aspirin in reducing adverse cardiovascular events in 19,185 patients with clinical manifestations of atherosclerosis. 2) Clopidogrel therapy resulted in a relative risk reduction of 8.7% compared to aspirin therapy in reducing the primary outcome of myocardial infarction, ischemic stroke, or vascular death. 3) Clopidogrel was found to be safer than aspirin, with significantly fewer gastrointestinal hemorrhages, and no significant differences in intracerebral hemorrhages or hemorrhagic deaths.

1. Vascular Medicine http://vmj.sagepub.com/
Results of the CAPRIE trial: efficacy and safety of clopidogrel
Mark A Creager
Vasc Med 1998 3: 257
DOI: 10.1177/1358836X9800300314
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2. Vascular Medicine 1998; 3: 257–260
Results of the CAPRIE trial: efficacy and safety of
clopidogrel
Mark 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; stroke
Introduction CAPRIE (clopidogrel versus aspirin in patients at risk of
ischaemic events), compared the effects of clopidogrel with
The Antiplatelet Trialists’ Collaboration,1 a meta-analysis those of aspirin in patients thought to be at high risk for
of 145 clinical trials involving antiplatelet prophylaxis in vascular events.
over 70 000 patients at high risk for vascular events, found
an approximate 25% overall risk reduction with the use of
antiplatelet therapy, consisting primarily of aspirin. Among CAPRIE
all 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 summarize
Although trials using a variety of aspirin doses were those results. The two major objectives of the CAPRIE trial
included in the meta-analysis, there was no evidence that were1 to assess the relative efficacy of clopidogrel and
higher 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 who
patients, was at least 1 year. After 1, 2 and 3 years of fol- had survived a recent ischemic stroke, recent myocardial
low-up, there was a reduction in the risk of an adverse car- infarction, or had symptomatic atherosclerotic peripheral
diovascular event of 28%, 24% and 12% respectively, in arterial disease; and (2) to assess the relative safety and
patients treated with antiplatelet therapy compared with tolerability of clopidogrel and aspirin. CAPRIE enrolled
controls.1 Although the Collaboration’s meta-analysis did over 19 000 patients with clinical disorders indicative of
not 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 vascular
bronchoconstriction.2–6 death.
Clopidogrel is a thienopyridine derivative that inhibits Inclusion criteria for patients with ischemic stroke were
platelet aggregates by antagonizing the platelet adenosine a focal neurologic deficit likely to be of atherothrombotic
diphosphate 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 tomography
Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, or magnetic resonance imaging evidence that the cause of
Brigham and Women’s Hospital, Boston, MA, USA stroke was not hemorrhagic or of non-vascular origin.
Patients with myocardial infarction were eligible if its onset
Address for correspondence: Mark A Creager, Vascular Medicine and was 35 or fewer days before enrollment, as indicated by
Atherosclerosis Unit, Cardiovascular Division, Brigham and Women’s
Hospital, 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
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3. 258 MA Creager
ated to twice the laboratory normal without explanation; group at an average rate of 5.32% per year. In the 17 519
the development of new у40 msec Q waves in at least two patient years at risk among aspirin-treated patients, 1021
adjacent 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 achieved
Organization criterion – leg pain while walking that disap- by clopidogrel compared with aspirin was 8.7% (95% CI
pears after less than 10 min of standing still. The pain must 0.3–16.5; p = 0.043). An on-treatment analysis of the data
have been of presumed atherosclerotic origin. Further, the (including patients receiving only the study drug or data
patients were required to have an ankle–arm systolic blood taken from patients within 28 days of discontinuation of
pressure 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 experiencing
tent 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 data
complications from the intervention, were eligible for for the secondary outcomes provided similar relative risk
enrollment. Thus, patients who enrolled with peripheral reductions of 7–8% in favor of clopidogrel for the cluster
arterial disease were distinguished from the other two of ischemic stroke, myocardial infarction, amputation, or
groups, 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 death
allowed 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 common
lant or antithrombotic medications were discontinued outcome event among those admitted because of stroke, and
before randomization. myocardial infarctions were most common among those
admitted because of myocardial infarction. Among patients
Patient follow-up enrolled because of peripheral arterial disease, outcome
The 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 were
with an increased risk of neutropenia and thrombocytop- performed with CAPRIE data, the study was not originally
enia. Thus, during the first 3 months of the study, weekly powered to perform such calculations and caution should
blood counts and bimonthly biochemical assessments were be used in their interpretation. By clinical subgroup, the
obtained from the first 500 patients in an intensive safety relative risk reduction achieved by clopidogrel therapy for
examination. Review of those data alleviated concern about myocardial infarction, stroke and peripheral arterial disease
clopidogrel’s safety, and the intense scrutiny was relaxed patients were −3.7%, 7.3% and 23.8%, respectively.
to 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 prior
occurrence of ischemic stroke, myocardial infarction, or myocardial infarction, an additional analysis was performed
death from vascular causes (vascular death). Secondary out- that included 2144 patients in the stroke and peripheral
come clusters consisted of the above outcome events plus arterial disease groups who had, in addition, a history of
amputation; 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, there
of patients: 6431 patients were enrolled because of stroke, were 455 events in clopidogrel-treated patients and 479
6302 because of myocardial infarction and 6452 because events in aspirin-treated patients; this is a relative risk
of 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.7
tors. Risk factors for atherosclerosis, including diabetes A subsequent analysis of all 19 185 patients in CAPRIE8
mellitus, 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 equivalent
were evenly balanced between treatment groups. Treatment to a relative risk reduction by clopidogrel of 19.2% for fatal
was 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 in
including adverse side-effects, withdrawn consent, and this study are probably in addition to the benefit already
non-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 vascular
An 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
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4. Results of the CAPRIE trial 259
Figure 1 Cumulative risk of experiencing an event in the primary outcome cluster (ischemic stroke, myocardial infarction, or
vascular 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 with
The 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. Rashes
lar 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); severe
cannot 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 patients
with symptomatic atherosclerosis.
Conclusions
Safety
The assessment of clopidogrel’s safety was an important
objective 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 than
apy. Intracranial hemorrhages and hemorrhagic deaths long-term aspirin therapy in reducing the combined risk of
occurred 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 seen
intestinal hemorrhages occurred in 1.99% of patients in the CAPRIE trial, is added to the benefit provided by
treated with clopidogrel and 2.66% of those treated with aspirin when compared with placebo. Clopidogrel is an
aspirin (p Ͻ 0.05). There were 30% more hospitalizations effective antiplatelet agent that reduces cardiovascular
for 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 References
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