Response to Letter Regarding Article, “Nonsteroidal Antiinflammatory Drugs, Acetaminophen, and the Risk of Cardiovascular Events”
We thank Dr Kurth for his interest in our work.1 We agree that the results of the Physicians’ Health Study (PHS) support the conclusion that frequent use of nonsteroidal antiinflammatory drugs (NSAIDs) may inhibit the benefit of aspirin on myocardial infarction.2 Dr Kurth cites evidence that NSAIDs compete with aspirin for cyclooxygenase (COX)-1 enzyme binding as the basis for their findings.3 Although this mechanism may be relevant, more recent experimental data and evidence from randomized trials of COX-2 selective inhibitors also highlight the important role of NSAID-related COX-2 inhibition, which disturbs vascular homeostasis and leads to thrombosis and vasoconstriction.4 We would suggest that the PHS data support the growing body of evidence that this prothrombotic state is not abrogated by concomitant aspirin use: Among men randomly assigned to aspirin, those who frequently used NSAIDs (≥60 days per year) compared with men who did not use NSAIDs had a relative risk (RR) for myocardial infarction of 2.86 (95% confidence interval, 1.25 to 6.56). This is consistent with findings from a recent placebo-controlled trial in which participants randomly assigned to the COX-2 selective NSAID celecoxib had a 2- to 3-fold higher risk of serious cardiovascular events that was not modified by use of aspirin.5
Dr Kurth suggests that the RR of 2.86 does not support an association between frequent NSAID use and cardiovascular events because it is based on a comparison with men who were at a particularly low risk for myocardial infarction as the result of random assignment to aspirin. However, according to their data, the RR was elevated at 1.57 for frequent NSAID users assigned aspirin when compared with men who were nonusers of NSAIDs and were assigned placebo. Although not statistically significant, this finding, based on a lower dose of NSAIDs in their highest use category (on average >6 days per month) and a smaller sample size (22 071) with shorter follow-up (5 years), appears consistent with the multivariate-adjusted RR of 1.58 (95% confidence interval, 1.32 to 1.89) for coronary heart disease that we observed among frequent NSAID users (≥22 days per month) in our study, which had a larger sample size (70 971) with longer follow-up (14 years).1
Overall, when viewed in the context of our current understanding of the influence of COX-2 inhibition on thrombosis, evidence from randomized trials of COX-2 selective agents, and emerging data from other epidemiological studies, we would suggest that data from the PHS support our results of a modestly increased risk of cardiovascular events associated with frequent use of NSAIDs.
Chan AT, Manson JE, Albert CM, Chae CU, Rexrode KM, Curhan GC, Rimm EB, Willett WC, Fuchs CS. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation. 2006; 113: 1578–1587.
Kurth T, Glynn RJ, Walker AM, Chan KA, Buring JE, Hennekens CH, Gaziano JM. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation. 2003; 108: 1191–1195.