Incremental Effect of Clopidogrel on Important Outcomes in Patients with Cardiovascular Disease
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To quantify the impact of clopidogrel plus aspirin on the individual outcomes of death, myocardial infarction, or stroke in patients with established cardiovascular disease, or in patients with multiple risk factors for vascular disease.
Randomized trials have demonstrated a reduction in composite outcomes when clopidogrel is added to aspirin therapy in patients with coronary artery disease; however, the magnitude of benefit on individual outcomes is unknown.
We conducted a meta-analysis on randomized, controlled trials that compared aspirin plus clopidogrel with aspirin plus placebo for the treatment of coronary artery disease.
This analysis included five randomized trials (CURE, CREDO, CLARITY, COMMIT, and CHARISMA) in 79 624 patients. The incidence of all-cause mortality was 6.3% in the aspirin plus clopidogrel group versus 6.7% in the aspirin group (odds ratio [OR] 0.94; 95% CI 0.89, 0.99; p = 0.026). The incidence of myocardial infarction was 2.7% and 3.3% (OR 0.82; 95% CI 0.75, 0.89; p < 0.0001), and stroke was 1.2% and 1.4% (OR 0.82; 95% CI 0.73, 0.93; p = 0.002). Similarly, the incidence of major bleeding was 1.6% and 1.3% (OR 1.26; 95% CI 1.11, 1.41; p < 0.0001), and fatal bleeding was 0.28% and 0.27% (OR 1.04; 95% CI 0.76, 1.43; p = 0.79).
The addition of clopidogrel to aspirin results in a small reduction in all-cause mortality in patients with ST-elevation myocardial infarction and a modest reduction in myocardial infarction and stroke in patients with cardiovascular disease. The overall incidence of major bleeding however is increased, although there is no excess of fatal bleeds or hemorrhagic strokes.
KeywordsAspirin Clopidogrel Major Bleeding Cardiovascular Mortality Ticlopidine
Dr Bhatt was the primary investigator for the CHARISMA study and received research grants from both Bristol Myers Squib (New York, USA) and Sanofi Aventis (Paris, France). He was also the co-primary investigator on the LANCELOT and CHAMPION studies and received research grants from Eisai (Woodcliff Lake, NJ, USA) and The Medicines Company (Parsippany, NJ, USA), respectively. All research grant funds were given directly to the institution (Cleveland Clinic) and not to Dr Bhatt personally, for the above studies.
In addition, Dr Bhatt has received within the past 5 years honoraria for consulting on scientific advisory boards and lecture fees from both Sanofi Aventis (Paris, France) and Bristol Myers Squibb (New York, USA), the makers of clopidogrel and honoraria for consulting on scientific advisory boards from Astra Zeneca (Wilmington, DE, USA) and Eli Lilly (Indianapolis, IN, USA), who are aiming to develop compounds similar to clopidogrel. In addition, in the past 5 years Dr Bhatt has received honoraria for consulting on scientific advisory boards and lecture fees from The Medicines Company, and honoraria for consulting on scientific advisory boards from Millennium (Cambridge, MA, USA) and Schering Plough (Kenilworth, NJ, USA), all of whom are involved in developing antiplatelet compounds. He has also received honoraria for consulting on scientific advisory boards from Centocor (Horsham, PA, USA), Daiichi-Sankyo (Parsippany, NJ, USA), Eisai (Woodcliff Lake, NJ, USA), Glaxo Smith Kline (Philadelphia, PA, USA), Otsuka (Rockville, MD, USA), Paringenix (Tucson, AZ, USA), and PDL (Fremont, CA, USA). Finally, Dr Bhatt has provided expert testimony regarding clopidogrel (the compensation was donated to a non-profit organization).
Dr Bavry has received honoraria from consulting with Genesis Associates, HRA, The Frankel Group (New York, USA), Propagate Pharma (Surrey, Enland) and Hagen/Sinclair Research Recruiting (Santa Rosa, CA, USA) for an amount of <$US10 000.
Drs Helton, Roukoz, and Duggal have no potential conflicts of interest to disclose.
No sources of funding were used in the preparation of the current meta-analysis. This manuscript represents original work of the authors and is not under consideration elsewhere. None of the paper’s contents have been previously published but results were presented as an oral abstract at the American Heart Association Scientific Sessions on 14 November 2006 in Chicago (IL).
The authors do meet criteria for authorship and accept responsibility for scientific content of the manuscript. Dr Helton designed the study, abstracted and analyzed the data, and drafted the manuscript. Drs Bavry, Kumbhani, and Bhatt were involved in the design of the study, analyzed the data and revised the manuscript. Drs Duggal and Roukoz abstracted and analyzed the data and revised the manuscript. All authors have read and approved the final version of the manuscript.
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