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Stroke and the statistics of the aspirin/clopidogrel secondary prevention trials
George Howard1, Leslie A McClure, John W Krakauer
1Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA. ghoward@uab.edu
Insights
Four trials on clopidogrel plus aspirin for vascular prevention yielded complex results. Optimal secondary prevention strategies remain unclear due to study variations and subgroup analyses.
Area of Science:
- Cardiovascular Medicine
- Clinical Trials
- Pharmacology
Background:
- Secondary prevention of vascular events is crucial.
- Combination therapy with clopidogrel and aspirin has been investigated.
- Translating trial results into clinical practice presents challenges.
Purpose of the Study:
- To review four major randomized trials on clopidogrel plus aspirin for secondary vascular prevention.
- To identify statistical and methodological reasons for difficulties in clinical application.
- To discuss the implications for future research.
Main Methods:
- Analysis of four large randomized controlled trials (CAPRIE, CURE, MATCH, CHARISMA).
- Review of study populations, designs, and reported outcomes.
- Examination of statistical considerations and subgroup analyses.
Main Results:
- Trials showed varied results: clopidogrel alone vs. aspirin alone (CAPRIE), combination vs. aspirin alone (CURE), combination vs. clopidogrel alone (MATCH).
- The CHARISMA trial comparing aspirin alone to aspirin plus clopidogrel was negative.
- Inconsistent findings across trials complicate treatment recommendations.
Conclusions:
- Optimal secondary prevention of stroke using clopidogrel and aspirin remains uncertain.
- Differences in study populations, designs, and outcome measures hinder direct comparisons.
- Future trials should focus on specific vascular diseases and mechanisms.
Purpose Of Review:
Four randomized trials have investigated the combination of clopidogrel plus aspirin for secondary prevention of vascular outcomes in 54,949 patients. Here we argue that attempts to translate the results of these trials into clinical practice have proven frustrating because of the following statistical considerations: differences in study populations and study design make comparisons difficult (comparisons of 'apples and oranges'), incomplete factorial designs prevent proper contrasts (examining 'bits and pieces' of a larger picture), results concern widely different vascular diseases ('puzzling subgroups'), and negative results are easily misinterpreted.
Recent Findings:
Between 1996 and 2004 three major randomized trials assessed combinations of aspirin and clopidogrel, finding: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) in favor of clopidogrel alone versus aspirin alone, Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) in favor of clopidogrel plus aspirin versus aspirin alone, and Management of Atherothombosis with Clopidogrel in High-risk Patients (MATCH) in favor of clopidogrel plus aspirin versus clopidogrel alone. A recently completed fourth trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance; CHARISMA) was a 'negative study' comparing aspirin alone to aspirin plus clopidogrel.
Summary:
Even after four large randomized trials we still do not know the optimal treatment for secondary prevention of stroke. We suggest that subsequent trials should focus on a particular vascular disease and test hypotheses that relate to a specific mechanism.
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