Risk reduction with long-term clopidogrel following percutaneous coronary intervention

Only recently have we begun to appreciate that the mechanical treatment of a haemodynamically significant coronary lesion does not represent conclusive therapy for atherosclerotic disease, but rather serves as a warning for a heightened risk of future events and the need for aggressive preventative therapies. A recently published analysis attempted to quantify the benefit of long-term clopidogrel therapy in such patients.1 We do not feel the conclusions of the author are supported when the results from the CREDO trial and the subset analysis of PCI patients from the CURE trial are accurately analysed. PCI-CURE was a pre-specified observational subset analysis of the much larger CURE trial.2 When these results are interpreted as they were intended, as part of the overall CURE trial, the key finding was that the long-term benefit of clopidogrel seen in CURE (from day 30 to end of follow-up, 0.82 relative risk in death/ myocardial infarction (MI) or stroke, 95% CI 0.70–0.95, p=0.009) was the same whether the patient underwent a PCI or not.3 This significant risk reduction seen in the entire CURE cohort between 30 days and the end of follow-up is very similar to the 0.79 relative risk of death and MI reported in the PCI-CURE manuscript, and not the 14% "maximal conceivable effect" reported in the Opinion paper.1 CREDO was a blinded, placebo-controlled trial powered to identify the benefit of clopidogrel pretreatment plus long-term therapy in patients undergoing a planned PCI, or at high likelihood to undergo a PCI, on the 1-year combined incidence of death, MI and stroke.4 Although not designed to show a significant benefit between day 29 and 1 year, a statistically significant 37% relative risk reduction, 1.9% absolute risk reduction was observed. (Fig. 1) While it is true that without re-randomization at day 29 it is impossible to separate the benefit of pretreatment and long-term therapy with 100% certainty, it is difficult to hypothesise a mechanism for pretreatment preventing late deaths, as well as MIs and strokes up to a year after a PCI. Contrary to the assertion in the Eriksson paper, data from the placebo-controlled abciximab trials have found an influence on late mortality alone. Finally, the benefits of adding clopidogrel long-term after PCI should be interpreted in the context of other proven therapies. Table 1 summarizes the absolute and relative benefits that have been described for similar populations through placebo-controlled trials of aspirin, statins and ACE-inhibitors. Unfortunately, with no trial data yet available beyond only 1 year of follow-up for clopidogrel and aspirin versus aspirin alone, and with the event curves separating at the end of follow-up in both trials, it is difficult to speculate what the actual benefit of life-long therapy might be, but the available data suggests that it is likely to be even greater than for other accepted therapies. The actual benefit awaits the results of the CHARISMA trial. Kaplan–Meier estimates of death, myocardial infarction or stroke from day 29 to 1 year based on randomized treatment assignment in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Table 1. Reduction in death, myocardial infarction and stroke with long-term preventative therapies Table 1. Reduction in death, myocardial infarction and stroke with long-term preventative therapies