CORRESPONDENCE: LETTERS TO THE EDITOR
Economic Effects of Extended Clopidogrel Therapy—A Word of Caution
Peter Eriksson, MD, PhD*
* Interventional Cardiology Laboratory, Heart Center, University Hospital, SE-901 85 Umea, Sweden (Email: peter.eriksson{at}medicin.umu.se).
In the February 1 issue of the Journal, Cowper et al. (1) compared the outcomes and costs of extending clopidogrel therapy (in addition to aspirin) from one month to one year after percutaneous coronary intervention (PCI), with withdrawal of clopidogrel after one month. Unpublished per-protocol data from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial (2) were used to estimate the effects of long-term clopidogrel use on event rates in a sample of patients at the Duke Medical Center undergoing PCI and receiving clopidogrel for only one month after the procedure. The investigators concluded that clopidogrel therapy for one year after PCI is economically attractive in respect to cost per year of life saved, particularly in high-risk patients.
However, the conclusions of Cowper et al. (1) rest solely on the assumption that clopidogrel between one month and one year after PCI significantly reduces the incidence of myocardial infarction (MI). The relative risk (RR) of MI was estimated to be 0.56 with clopidogrel long-term, but the 95% confidence interval (CI) was 0.3 to 1.0, suggesting a possibility of no effect at all. Consequently, the costs per year of life saved may actually be unlimited, as shown in Figure 2 in the study by Cowper et al. (1). Moreover, by using per-protocol rather than intent-to-treat data, an even distribution of confounders produced by randomization was altered, which may have incorrectly favored extended clopidogrel therapy. In fact, the one-year intention-to-treat analysis of the CREDO trial did not show a significant reduction of MI between day 0 and one year or between one month and one year (RR reduction between day 0 to one year, 21.7%; 95% CI –7.1% to 42.7%) (2,3). Similarly, the observational PCI substudy of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial (4) did not show an advantage of long-term clopidogrel use over placebo in terms of death or MI beyond 30 days after PCI (RR reduction 23%; 95% CI, –17% to 50%) (5).
An increase of major bleeding occurs when clopidogrel is added to aspirin long-term (2,6,7), and bleeding (like MIs) may influence prognosis adversely (8). Only the costs of bleeding, but not a potential negative effect on life expectancy, were incorporated into the model used by Cowper et al. (1). In addition, the low compliance with therapy in the CREDO trial ( 60%) may have obscured the true risk of severe bleedings with dual antiplatelet therapy.
Finally, the conclusions of Cowper et al. (1) should be viewed with caution—they seem overenthusiastic and may be incorrect. Health economics cannot help to guide decisions on therapy when there is no firm evidence of clinical efficacy. Combining clopidogrel and aspirin long-term may actually do more harm than good.
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1. Cowper PA, Udayakumar K, Sketch Jr MH, Peterson ED. Economic effects of prolonged clopidogrel therapy following percutaneous coronary intervention J Am Coll Cardiol 2005;45:369-376.[Abstract/Free Full Text]
2. Steinhubl SR, Berger PB, Mann III JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary interventiona randomized controlled trial [erratum in JAMA 2003;289:987]. JAMA 2002;288:2411-2420.[Abstract/Free Full Text]
3. Eriksson P. Long-term clopidogrel therapy after percutaneous coronary intervention in PCI-CURE and CREDOthe "Emperor’s New Clothes" revisited. Eur Heart J 2004;25:720-722.[Free Full Text]
4. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary interventionthe PCI-CURE study. Lancet 2001;358:527-533.[CrossRef][Web of Science][Medline]
5. Stables RH. Clopidogrel in invasive management of non-ST-elevation ACS Lancet 2001;358:520-521.[CrossRef][Web of Science][Medline]
6. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001;345:494-502.[Abstract/Free Full Text]
7. Diener HC, 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][Web of Science][Medline]
8. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions Am J Cardiol 2003;92:930-935.[CrossRef][Web of Science][Medline]
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