News About Clopidogrel
Abstracts & Commentary
By Michael H. Crawford, MD, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Synopsis: Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular disease.
Sources: Bhatt DL, et al. Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events. N Engl J Med. 2006;354:1706-1717; Wolfram RM, et al. Clopidogrel Loading Dose (300 versus 600 mg) Strategies for Patients with Stable Angina Pectoris Subjected to Percutaneous Coronary Intervention. Am J Cardiol. 2006;97:984-989.
Clopidogrel plus aspirin have been shown to reduce subsequent events in patients with unstable angina, myocardial infarction (MI), and post percutaneous interventions. Its role in long-term prophylaxis in high-risk patients without these acute events is unclear. Thus, the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial was conducted in 15,603 patients with either clinically evident cardiovascular disease or multiple atherothrombotic risk factors. They were randomized in a double-blind fashion to clopidogrel (75mg/d) plus aspirin or aspirin (75-160 mg/d) alone (plus placebo). The primary efficacy end point was death, stoke, or MI. The primary safety end point was severe bleeding. There were a variety of secondary end points and prespecified subgroup analyses. After a median follow-up of 28 months, the primary end point occurred in 6.8% of the clopidogrel group and 7.3% of the placebo group (P = .22). The primary safety end point occurred in 1.7% of the clopidogrel patients and 1.3% of the placebo group (P = .09). Bhatt and colleagues concluded that overall clopidogrel plus aspirin was no more effective than aspirin alone at preventing subsequent events in patient with known cardiovascular disease or multiple risk factors for it.
Although clopidogrel is an important adjunct to aspirin therapy in patients undergoing percutaneous coronary interventions (PCI), there has been controversy over the appropriate loading dose. Thus, Wolfram and colleagues compared a 300 mg to a 600 mg loading dose immediately prior to PCI in 445 patients with stable angina. The primary end points were post procedure biomarkers of myocardial necrosis, bleeding, and vascular complications at 30 days. There was no difference in the primary end points between the 2 groups. Wolfram et al concluded that a 600 mg loading dose of clopidogrel pre-PCI is safe, but does not improve 30-day outcomes following PCI as compared to 300 mg.
Clopidogrel has become a staple of modern cardiovascular care, but higher doses and more wide-spread use do not seem to be indicated. With regard to pre-PCI use, a 300 mg load seems adequate. The lingering question is when clopidogrel is given many hours before PCI, what is the appropriate dose? Other trials have shown improved outcomes with a 600 mg load, but only when given hours before, which is not the usual practice in the United States. Also, higher doses may be warranted in patients with unstable syndromes. The patients described above had stable angina. One drawback to this study is that it is retrospective and the dose of clopidogrel was not randomized. Thus, there may have been individual selection biases that influenced the results. In fact, about two-thirds of the patients received 600 mg, suggesting that is/was the conventional wisdom at the Washington Hospital Center.
The idea that if clopidogrel plus aspirin is good for acute cardiovascular event patients that it must be good for all cardiovascular disease patients seems logical, but could not be proven in the CHARISMA trial. In some ways this is not surprising because cardiovascular events and procedures are associated with coronary endothelial damage and a greater risk for thrombotic complications, but stable patients probably have largely intact endothelium, and the risks of clopidogrel outweigh its benefit. There may be subgroups of stable patients who may have damaged endothelium and would benefit, but they may be difficult to identify. This study suggested that symptomatic patients may fall in this category, but such subgroup analyses are often inaccurate, and a prospective trial would be required to confirm this. For now it appears that aspirin alone is sufficient unless an acute coronary syndrome develops or PCI is required in stable cardiovascular disease patients or those with high likelihood of this disease.