Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events

Background:  Studies have not been conducted using the dual antiplatelet therapy, clopidogrel and low-dose aspirin, in a broad patient population at high risk for atherothrombotic events.

 

Objective:  The objective was to determine if long-term treatment with a combination of clopidogrel plus aspirin provides greater protection against cardiovascular events than aspirin alone in patients at high risk. 

 

Methods:  This was a double-blind, randomized, multicenter, placebo controlled, parallel study.  A total of 15,603 patients were enrolled in the study.  The inclusion criteria were ≥ 45 years of age plus one of the following conditions: documented coronary disease, cerebrovascular disease, or symptomatic PAD, or the presence of multiple atherothrombotic risk factors.  Patients were excluded if taking oral antithrombotic medications or NSAIDs on a long-term basis, if they had an established indication for clopidogrel therapy, or if scheduled to undergo a revascularization.  The study group (7,802 patients) received clopidogrel 75 mg/day plus aspirin 75-162 mg/day and the control group (7,801 patients) received placebo plus aspirin 75-162 mg/day.  Standard therapy was continued by patients at the discretion of investigators.  Follow-up was provided at 1, 3, and 6 months and then every 6 months.  The primary efficacy endpoint was the first occurrence of MI, stroke, or death from CV causes.  The secondary efficacy endpoint added hospitalization for unstable angina, a revascularization procedure, or TIA.  The primary safety end point was severe bleeding or bleeding that required blood or fluid replacement, inotropic support, or surgical intervention.  Moderate bleeding was also examined.  Analyses of the primary end point were also performed in symptomatic and asymptomatic subgroups.  Data were analyzed using intent-to-treat.  The statistical power was 90%. 

 

Results: The study ended after 1,040 events.  20.4 % of the clopidogrel group and 18.2 % of the placebo group discontinued treatment; 4.8 % of the clopidogrel group and 4.9 % of the placebo group discontinued treatment because of an adverse event.  The rate of the primary event was 6.8 % in the clopidogrel group and 7.3 % in the placebo group (P= 0.22).  The rate of the secondary efficacy end point was 16.7 % in the clopidogrel group and 17.9 % in the placebo group (RR =0.92, CI= 0.86 to 0.995, P= 0.04).  The rate of the primary safety end point was 1.7 percent in the clopidogrel group and 1.3 percent in the placebo group (P=0.09).  The rate of moderate bleeding was 2.1 percent in the clopidogrel group and 1.3 percent in the placebo group (RR=1.62, 95% CI= 1.27 - 2.08, P <0.001).  In the 3,284 asymptomatic patients, there was a 20% relative increase in the rate of primary events with clopidogrel compared to placebo (6.6 % vs. 5.5 %; P=0.20). Also, there was a significant increase in the rate of death from all causes in the experimental group vs. the control group (5.4 % vs. 3.8 %; P=0.04) as well as an increase in the rate of death from cardiovascular causes (3.9 % vs. 2.2 %; P=0.01).  Severe and moderate bleeding in the asymptomatic subgroup were increased by clopidogrel but not significantly.  Analysis of the 12,153 symptomatic patients showed a marginally significant reduction in the primary end point with clopidogrel (6.9 % vs. 7.9 %; RR=0.88; 95% CI= 0.77 - 0.998; P=0.046).   Clopidogrel had no significant effect on death from cardiovascular causes in the symptomatic subgroup.   Moderate bleeding in symptomatic patients was 2.1 % in the clopidogrel group vs. 1.3 % in the placebo group (P<0.001).

 

Strengths: This was a well-designed study.  The large sample size allowed for the assessment of both efficacy and safety of dual antiplatelet therapy in a broad patient population.  The regimens used were appropriate, evidence based therapies and were tested for a sufficient duration with compliance and adverse events evaluated.

 

Weaknesses:  The authors did not provide information regarding how the dose of aspirin used was determined (71-162 mg range), how compliance was addressed, or the adverse events experienced.  Patients were allowed to use their standard therapy, which included statins, antihypertensive drugs, and antidiabetic agents.   The extent of control of their underlying conditions might have affected the endpoints achieved.  Open-label clopidogrel was used in 10.2% of the patients.  Although this could not have affected the results of the trial (1,040 blinded events had to be reached), it contradicts the study design.  The results for the other subgroups mentioned in the study were not provided in this article.

 

Conclusion:

Clopidogrel plus aspirin is not significantly more effective than aspirin alone for reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes among patients with stable cardiovascular disease or multiple cardiovascular risk factors.  The combination also increased the death rate in asymptomatic patients and the risk of moderate-to-severe bleeding.  Although there was a potential benefit in symptomatic patients, its use in this population requires further study.  Patients without a history of established vascular disease should not use the combination.

 

Bhatt DL, Fox KA, Hacke W, et al.  Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events. N Engl J Med 2006; 354:1706-1717.

Laura K. Rhoades, Pharm D Candidate.