LETTER TO THE EDITOR
Statistical versus clinical significance of the cure study in acute coronary syndromes
Campbell D. Joyner, MD, FRCPCa
a Division of Cardiology, Sunnybrook and Women’s College, Health Sciences Centre, 2075 Bayview Avenue, Suite E250, Toronto, Ontario M4N 3M5, Canada
Marcus Flather, MB, BS
cam.joyner{at}swchsc.on.ca
In a recent issue of JACC, Drs. Khot and Nissen focused on the statistical versus clinical significance of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study in acute coronary syndromes (1). Several of their comments and concerns are appropriate, but we would like to point out a number of inaccuracies in their report.
They suggest that the CURE study (2) used a definition of myocardial infarction (MI) that included patients with only elevated serum troponin levels. In fact, the CURE definition of MI required at least two of the following: ischemic symptoms; elevation of markers (creatine kinase-MB fraction or troponin) to at least twice the upper limit of normal; electrocardiographic changes. This definition is more strict than the recent European Society of Cardiology/American College of Cardiology (ESC/ACC) consensus document (3). Further evidence of a reduction in significant MIs was a 1.2% absolute decline in the rate of subsequent Q-wave infarctions. All MI events were adjudicated.
With respect to bleeding, it was suggested that the definition of minor bleeding was revised between the time of ACC presentation and its publication. In fact, no such change occurred in the definition. The 15.3% rate of minor bleeding reported by the ACC was an error that was corrected in the final report.
Regarding the applicability of the CURE trial to practice in the U.S., the proportion of patients in CURE undergoing cardiac procedures (catheterization [Cath] 44%; percutaneous coronary intervention [PCI] 21%; coronary artery bypass graft surgery [CABG] 16%) is very similar to other recent ACS trials (e.g., PURSUIT [4] [Cath 59%; PCI 24%; CABG 14%]). We agree that clopidogrel should be stopped five days before CABG if at all possible. With respect to the timing of surgery in U.S. practice, more recent data from the TACTICS/TIMI-18 study (5) demonstrate that the average time to cardiac surgery in the invasive arm in the U.S. was 5.5 days. In routine clinical practice outside of a clinical trial, it is likely that the waiting period is longer. Most patients in the U.S. who require surgery can therefore potentially benefit from this medication. In the small percentage of patients who require early surgery for clinical indications, the increased risk from bleeding on clopidogrel is only one of the issues that has to be considered in this high-risk patient group.
With respect to cost-effectiveness of clopidogrel in acute coronary syndromes, data from the CURE study (6) show that the cost per event avoided with clopidogrel in the study is comparable to other cost-effective therapies in cardiovascular disease.
Strategies to prevent major cardiovascular events such as MI, cardiovascular death, and stroke are clinically important. Preventing two events per 100 people for nine months of therapy is comparable to most other treatments in the prevention of cardiovascular events, including aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and statins in patients following MI (7). Moreover, the cumulative impact of these various strategies add up to a large benefit. Therefore, we believe that CURE is not only statistically significant, but also that the results are clinically relevant and important.
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References
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- Khot UN, Nissen SE. Is CURE a cure for acute coronary syndromes? Statistical versus clinical significance. J Am Coll Cardiol. 2002;40:218–219[Abstract/Free Full Text]
- The CURE trial 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[Abstract/Free Full Text]
- The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined—A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol. 2000;36:959–969[Free Full Text]
- The PURSUIT trial investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med. 1998;339:436–443[Abstract/Free Full Text]
- 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;344:1879–1887[Abstract/Free Full Text]
- Lamy A, Chrolavicius S, Gafni A, et al. The cost-effectiveness of the use of clopridogrel in acute coronary syndromes based upon the CURE study. (abstr)Circulation. 2002;106:II758
- Yusuf S. Two decades of progress in preventing vascular disease. Lancet. 2002;360:2–3[CrossRef][Medline]
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A risk score to estimate the likelihood of coronary artery bypass surgery during the index hospitalization among patients with unstable angina and non-ST-segment elevation myocardial infarction
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799 - 803.
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