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Re: Clopidogrel and CURE

Dear Editor

Harding, Boon and Flapan review the role of antiplatelet agents in patients with non-ST elevation acute coronary syndrome.[1] Whilst their strategy for using glycoprotein (GP) IIb/IIIa antagonists is supported by abundant clinical trial data, their recommendations regarding clopidogrel are based on the results of a single randomised study [2] and therefore lack authority. We would suggest, on the basis of our own interpretation of the CURE data, that the role of clopidogrel in treating patients with acute coronary syndrome remains unclear, and question the validity of making firm recommendations on the basis of limited trial evidence.

Although the CURE study reported a highly significant reduction in the composite primary end-point after nine months follow-up (relative risk (RR) 0.80; p<0.001), this was largely due to a 23 % relative reduction in myocardial infarction with no significant reduction in death or stroke. From the clinicians perspective the absolute reduction in myocardial infarction appears less impressive. Thus, treating 100 patients with clopidogrel for 9 months would prevent approximately 1.5 non-fatal myocardial infarctions (MI) at a cost of 2.5 minor and 1 major bleeding complications; 5 patients would sustain an MI despite treatment. Whilst recognising the limitations of subgroup analysis, a number of observations are worthy of comment. First, patients categorised as high risk appear to benefit less than those at low or intermediate risk. Second, the relative risk reduction associated with clopidogrel was most striking in patients with a history of previous revascularisation. For the majority of patients in whom there was no history of revascularisation (82% of the study population), the treatment benefit in terms of reduction in primary end-point was relatively modest (RR <0.9).

In PCI Cure [3] the event rate (cardiovascular death, MI, or repeat revascularisation) 30 days after percutaneous coronary intervention (PCI) was reduced from 6.4 % in the placebo group to 4.5 % in the treatment group but confidence intervals for relative risk were wide (RR 0.7, 95 % CI 0.50 -0.97; p= 0.03). Furthermore the restricted use of GP IIb/IIIa antagonists, in a study where 80% of patients received an intracoronary stent, limits the applicability of these results to current clinical practice where these agents are used routinely as adjunct therapy during urgent coronary intervention.

Although the early event rate during the time preceding PCI was lower in the clopidogrel arm of the study, this was largely due to a reduction in refractory ischaemia and the absolute reduction in MI was just 1.5 % (RR 0.68, 95 % CI: 0.47-0.99; p0.04). This early treatment benefit should be interpreted in the context of a relatively long delay from initial presentation to PCI (median 10 days in PCI CURE) and timely intervention may be the most effective strategy for reducing early ischaemic events.

In summary, it may be premature to recommend the routine use of clopidogrel in addition to aspirin for the treatment of patients with acute coronary syndrome. Cost effectiveness [4] and the potential for bleeding complications may weigh against its modest efficacy in an area where aspirin and GP IIb/IIIa antagonists are already firmly established therapies.

efernecs

(1) Harding SA, Boon NA, Flapan AD. Antiplatelet treatment in unstable angina: aspirin, clopidogrel, glycoprotein IIb/IIIa antagonist, or all three? Heart 2002;88: 11-14.

(2) The CURE investigators. 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.

(3) Metha SR, Yusuf S, Peters RJG et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention. Lancet 2001; 358: 527-33

(4) Gaspoz J-M, Coxson PG, Goldman PA et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med 2002; 346: 1800-6.