Interventional Cardiology Laboratory, Heart Centre, University Hospital, S-901 85 Umeå, Sweden
* Tel.: +46 (0)90 785 69 25; fax: +46 (0)90 13 76 33 (E-mail: peter.eriksson{at}medicin.umu.se).
Dear Sir,
Dr. Steinhubl and Dr. Topol, authors of CREDO,1 disagree with my analysis of long-term clopidogrel therapy after percutaneous coronary intervention (PCI) in the PCICURE and CREDO trials.2 However, their arguments seem biased and misleading.
The CURE trial3 showed a minor absolute reduction of 1.1% (p=0.009) in the composite of death, myocardial infarction or stroke from one month to the end of follow-up (mean nine months) in patients receiving clopidogrel in addition to aspirin, compared with aspirin alone. However, the number of ischaemic events was nearly identical in the clopidogrel and placebo groups after the first three months.4 In fact, among patients given 101199 mg aspirin per day in CURE, clopidogrel did not contribute to any further reduction in ischaemic events.5 If 1000 patients in CURE received clopidogrel instead of placebo for nine months, 15 myocardial infarctions would be avoided (12 of which during the first three months) at the price of an extra 10 major and 27 minor bleedings. No life would be saved, no stroke prevented, and the costs of clopidogrel to accomplish this would be around 500000 EUR. This is clearly an injudicious way to utilize healthcare resources.
In the PCICURE substudy of CURE,6 clopidogrel between 30 days following PCI and the end of follow-up did not result in a significant reduction of cardiovascular death or myocardial infarction. Thus, neither CURE, nor PCICURE support clopidogrel long-term.
The CREDO trial1 showed a small absolute reduction in the composite of death, myocardial infarction or stroke (1.9 %, p=0.04) between day 29 and 1 year following PCI in patients on long-term clopidogrel. However, there was no difference in the composite of death, myocardial infarction, stroke or major bleeding between day 29 and 1 year post-PCI in CREDO: clopidogrel, 88/1053 (8.4%) versus placebo, 95/1063 (8.9%). Besides, PCICURE and CREDO demonstrated conflicting results regarding the incidence of myocardial infarction and the need for repeat revascularization from one month to end of follow-up.2
Steinhubl and Topol1 ignore the other side of the picture. In CREDO there was a 2.1% (p=0.07) absolute increase in severe bleedings, in CURE3 1.0% (p=0.001), and in MATCH7 2.6% (p<0.001) in patients given both clopidogrel and aspirin. In particular, the MATCH trial highlights the hazards of prescribing clopidogrel with aspirin for longer periods of time. The combination actually carries a risk that is larger than the potential benefit, at least in subsets of patients with atherothrombotic disease. The increased risk of severe bleedings also overthrows Steinhubl's and Topol's comparison of long-term clopidogrel with some other long-term preventative therapies with a far less risk of severe adverse events.
In summary, clopidogrel long-term (in addition to aspirin) following PCI does not reduce mortality and has a marginal influence on ischaemic events. An increase in severe bleedings may further offset any possible benefit. Consequently, there is no evidence at present to support the routine continuation of clopidogrel for more than a few months after PCI. Let us await the results of the CHARISMA trial with open minds.
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