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acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
Treatment of Acute Coronary Syndromes To the Editor: The results of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study (Aug. 16 issue)1 suggest that the addition of clopidogrel to aspirin is beneficial for patients who have acute coronary syndromes without elevation of the ST segment. The inclusion criteria were changed after the first 3000 patients had been recruited. This change in the entry criteria during the course of recruitment means that the analysis of the results could be interpreted as a meta-analysis of two separate studies, rather than a single study. If one takes this view, the findings necessarily carry less weight. The investigators found the beneficial outcome of clopidogrel by considering two primary outcomes that were a composite of death from cardiovascular causes and various measures of morbidity. No benefit with respect to the risk of death was demonstrated, although the investigators noted that the study was not powered for this purpose. The use of clopidogrel was associated with a significant risk of major bleeding, and it would seem reasonable to include the rate of major bleeding in the measures of morbidity. Thus, if one defines a third primary outcome to be a composite of death from any cause, nonfatal myocardial infarction, stroke, refractory ischemia, and major bleeding, the relative risk of the outcome in the clopidogrel group, as compared with the placebo group, is 0.94 (95 percent confidence interval, 0.88 to 1.00; P>0.05). The use of this measure of efficacy makes the findings somewhat less convincing, especially if one considers the study to be a meta-analysis.
To the Editor: Clopidogrel in combination with aspirin has an established role in reducing the risk of myocardial infarction among patients who are undergoing coronary stenting.1 The CURE study has now demonstrated that clopidogrel also has a beneficial effect when it is added to aspirin for the treatment of acute coronary syndromes in patients without ST-segment elevation. Of particular interest in the CURE study was a comparison of the relative risk reduction in primary-outcome events in subgroups that were categorized as having a low, intermediate, or high risk. Unfortunately, the method used to classify these groups is not defined in the current article, or, indeed, in the article describing the design and rationale of the study.1 Irrespective of the method used, it is surprising that among the patients classified as being at high risk for cardiovascular events (the rate of the primary end point was 18 percent in the placebo group), clopidogrel appeared to have the least significant benefit. This observation is in marked contrast to the findings of other trials of patients with acute coronary syndromes, which have shown that high-risk patients have a substantially greater relative risk reduction than low-risk patients, with the use of either glycoprotein IIb/IIIa inhibitors 2,3 or an early invasive strategy.4 Although further study will be required to clarify the role of clopidogrel therapy in acute coronary syndromes, one implication of this observation is that the addition of clopidogrel to aspirin may be a satisfactory treatment for low-risk patients, but that the combination of glycoprotein IIb/IIIa inhibitors and early revascularization may be more efficacious in high-risk patients. ROGER E. PEVERILL, M.B., B.S., PH.D. STUART MOIR, M.B., B.S. Monash Medical Centre Clayton, VIC 3168, Australia
[email protected]
ANDREW OWEN, PH.D., F.R.C.P. Kent and Canterbury Hospital Canterbury CT1 3NG, United Kingdom 1. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with
1. Mehta SR, Yusuf S. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme: rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J 2000;21:2033-41. 2. Hamm CW, Heeschen C, Goldmann B, et al. Benefit of abciximab in
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patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med 1999;340:1623-9. [Erratum, N Engl J Med 1999; 341:548.] 3. Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 1999;354:1757-62. 4. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879-87.
To the Editor: The CURE trial investigators mention that “slightly fewer patients in the clopidogrel group underwent coronary revascularization during the study (36.0 percent vs. 36.9 percent),” whereas only 5.9 percent of patients in the clopidogrel group and 7.2 percent of those in the placebo group received a glycoprotein IIb/IIIa inhibitor. This feature of the study is problematic in view of the fact that glycoprotein IIb/IIIa inhibitors have now been proved to be consistently effective in patients who are undergoing coronary revascularization.1,2 It is also not clear how many patients in each group had elevated enzyme levels when they entered the trial. Studies have shown that patients with elevated levels of cardiac markers at admission (e.g., creatine kinase MB fraction or a troponin) have a poorer prognosis than those without elevated levels.3,4 Guidelines for treatment of acute coronary syndrome are frequently revised, especially given the expanding armamentarium of drugs available to the clinician. Glycoprotein IIb/IIIa inhibitors have been associated with significant reductions in the combined rate of death and recurrent cardiac events. Glycoprotein IIb/IIIa inhibitors have since been incorporated into the algorithm of the management of acute coronary syndromes.1,5 In the light of the fact that aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors act on different limbs of the platelet aggregation and adhesion pathway, the question of whether all three can safely be used together remains to be addressed. NINA TAHILIANI, M.D. ATUL TRIVEDI, M.D. HANUMANT G. DESHMUKH, M.D. Veterans Affairs Medical Center North Chicago, IL 60064
[email protected] 1. Bhatt DL, Topol EJ. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA 2000;284:1549-58. 2. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879-87. 3. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation: results from an international trial of 9461 patients. Circulation 2000;101:2557-67. 4. Throckmorton DC. Future trials of antiplatelet agents in cardiac ischemia. N Engl J Med 2001;344:1937-9. 5. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970-1062.
To the Editor: I would like to emphasize an important complication described by the CURE trial investigators. Clopidogrel was associated with a trend toward an increased risk of major bleeding episodes after coronary-artery bypass grafting (CABG) among patients who stopped taking the medication within five days before surgery. My colleagues and I have recently reported similar results in patients who were undergoing CABG at our institution.1,2 After CABG, the incidence of reexploration as a result of postoperative bleeding was higher among recipients of clopidogrel (defined as patients who received clopidogrel within five days before CABG) than among those who did not receive clopidogrel (9.8 percent vs. 1.6 percent; P=0.01; odds ratio, 6.9). The risk of reexploration was highest in patients who received clopidogrel as well as aspirin. This increased risk was independent of the presence or absence of preoperative and intraoperative risk factors. Given the increasing use of different antiplatelet agents for the treatment of acute coronary syndromes,3 clinicians should be aware of the increased risk of bleeding in patients taking these agents who undergo emergency and urgent CABG. Withholding clopidogrel for five days before surgery may reduce the incidence of this complication. SACHIN YENDE, M.D. Methodist–Lebonheur Healthcare Memphis, TN 38104
[email protected] 1. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001;29:2271-5. 2. Yende S, Poret A, Schoettle P, Lambert S, Wunderink RG. Effect of clopidogrel (Plavix) on bleeding after coronary artery bypass graft surgery (CABG). Chest 2000;118:Suppl:123S-124S. abstract. 3. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave acute myocardial infarction. N Engl J Med 1998;338:1488-97. [Erratum, N Engl J Med 1998;339:415.]
The authors reply: To the Editor: The CURE trial is not a meta-analysis, since the protocol was prospectively planned and conducted at all stages.1 It is not uncommon to modify some aspects of an ongoing study, and as long as investigators make modifications without knowledge of the treatment effects, the changes are unbiased and do not affect the interpretation of the data. Moreover, the data on the last 9500 patients enrolled in the CURE trial (after the slight modification of the inclusion criteria) produced results that were statistically significant and similar to the overall results. Dr. Owen would like to assess the risk–benefit ratio using a composite end point that includes bleeding. The transfusion of 2 units of blood (which was the main criterion for an episode of major bleeding) is not clinically equivalent to death, myocardial infarction, or stroke. When one combines deaths, myocardial infarctions, and strokes with episodes of life-threatening bleeding, there is a clear benefit in favor of clopidogrel over placebo (relative risk, 0.84; 95 percent confidence interval, 0.76 to 0.93; P=0.001). If one expands this outcome to include refractory ischemia requiring interventions or major bleeding, the relative risk is 0.87 (95
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percent confidence interval, 0.79 to 0.96; P=0.005). Therefore, the demonstrated risk–benefit ratio for clopidogrel is at least as large as the ratios for other accepted therapies for this condition. There is no statistical heterogeneity with respect to the relative benefits of clopidogrel in low-, intermediate-, and high-risk groups, with the use of a score derived from the Organization to Assess Strategies for Ischaemic Syndromes Registry.2 When we reanalyzed the data using the Thrombolysis in Myocardial Infarction grading system, the relative risks were similar in the low-risk group (relative risk, 0.71; P
