Author + information
- Umesh N Khot, MDa ()
- Steven E Nissen, MD
We appreciate the interest by Drs. Joyner and Flather in our Viewpoint.
We did not intend to imply that troponin elevations alone were sufficient to meet the end point of myocardial infarction (MI), but rather that the addition of troponin to creatine kinase-MB fraction (CK-MB) measurements would increase the number of events counted as MI within the appropriate clinical context (chest pain/electrocardiographic changes). Nevertheless, as noted in our Viewpoint, we acknowledge that clopidogrel reduces nonfatal MI.
The definition of minor bleeding—“other hemorrhages that led to interruption of the study medication” (1)—is considerably more selective than that used in other similar clinical trials (2). Requiring interruption of the study medication to achieve this end point will dramatically reduce reported minor bleeding (3). Thus, it is important to know the incidence of minor bleeding with clopidogrel using conventional definitions.
The rate of procedures in Clopidogrel in Unstable angina to prevent Recurrent Events (CURE), although similar to PURSUIT as a whole, is markedly less than that for U.S. patients in PURSUIT (catheterization 83%; percutaneous coronary intervention 35%; coronary artery bypass graft surgery [CABG] 20%) (4). Furthermore, the rate of revascularization during initial hospitalization is 55% in the U.S. compared with only 22% in CURE. Thus, CURE reflects a conservative management strategy not widely used in the U.S.
Citing an average time to surgery of 5.5 days in the U.S. from TACTICS/TIMI-18, the CURE investigators contend that stopping clopidogrel for five days prior to surgery would not delay the performance of CABG. This, however, is misleading. For one, they have chosen to cite the meantime to surgery from randomization rather than the mediantime. The meantime will, by its nature, be skewed higher by outliers yielding a larger value for the time to surgery. In contrast, the mediantime to surgery for allpatients in TACTICS/TIMI-18 was only 3.7 days from randomization; it is almost certainly less in the U.S. (5). Furthermore, the most relevant time frame is the time from catheterizationrather than randomization, as the decision to withhold clopidogrel will not occur until surgical anatomy is determined by cardiac catheterization. With catheterization being performed a median of one day after randomization, the CURE investigators are asking cardiologists and surgeons to routinely delay CABG for an average of six days after initial presentation. We find it very difficult to rationalize a routine six-day waiting period in this high-risk subgroup, who typically have severe left main and/or critical multivessel coronary artery disease.
Although clopidogrel may be “cost-effective,” this does not mean that it is without cost. Our simple calculations vividly illustrate the billions of dollars that would be spent to achieve the purported benefits of clopidogrel.
Finally, suggesting that clopidogrel is similar to aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and statins greatly overstates its benefit. These four therapies all clearly reduce mortality; clopidogrel does not. Clopidogrel’s benefit is limited to nonfatalMI, making it crucially important to account for clinically significant end points such as major bleeding and strategic concerns regarding early CABG. Accounting for these real risks leads to the conclusion that routine administration of clopidogrel remains unwarranted, particularly in centers practicing an early revascularization strategy.
- American College of Cardiology Foundation
- The Second Symphony investigators
- Lincoff A.M.,
- Harrington R.A.,
- Califf R.M.,
- et al.