Reply: Long-term clopidogrel following PCI: marginal antithrombotic effects are offset by increased bleeding risks

Peter Eriksson*

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 PCI–CURE 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 101–199 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 PCI–CURE 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 PCI–CURE 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, PCI–CURE 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.

References

  1. Steinhubl SR, Berger PB, Mann 3rd JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial JAMA 2002;288:2411-2420[Erratum JAMA 2003; 289: 987].[Abstract/Free Full Text]
  2. Eriksson P. Long-term clopidogrel therapy after percutaneous coronary intervention in PCI–CURE and CREDO: the "Emperor's New Clothes" revisited Eur Heart J 2004;25:720-722.[Free Full Text]
  3. The clopidogrel in unstable angina to present recurrent events trial with acute coronary syndromes without ST-segment elevation. New Engl J Med 2001; 345: 494–502[Abstract/Free Full Text] [Erratum New Engl J Med 2001; 345: 1716].[Free Full Text]
  4. Yusuf S, Mehta SR, Zhao F, et al. Clopidogrel in unstable angina to prevent recurrent events trial investigators. Early and late effects of clopidogrel in patients with acute coronary syndromes Circulation 2003;107:966-972.[Abstract/Free Full Text]
  5. Peters RJ, Mehta SR, Fox KA, et al. Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial investigators. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study Circulation 2003;108:1682-1687.[Abstract/Free Full Text]
  6. Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI–CURE study Lancet 2001;358:527-533.[CrossRef][ISI][Medline]
  7. Diener H-C, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial Lancet 2004;364:331-337.[CrossRef][Medline]




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