Role of Dose Potency in the Prediction of Risk of Myocardial Infarction Associated With Nonsteroidal Anti-Inflammatory Drugs in the General Population

Abstract

We studied the association between the frequency, dose, and duration of different nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of myocardial infarction (MI) in the general population. We verified whether the degree of inhibition of whole blood cyclooxygenase (COX)-2 by average circulating drug levels can be a surrogate biochemical predictor of the risk of MI by NSAIDs. There is evidence that both traditional NSAIDs and selective inhibitors of COX-2 may increase the risk of MI. From the THIN (The Health Improvement Network) database, we identified 8,852 cases of nonfatal MI in patients 50 to 84 years old between 2000 and 2005 and conducted a nested case-control analysis. We correlated the risk of MI with the degree of inhibition of platelet COX-1 and monocyte COX-2 in vitro by average therapeutic concentrations of individual NSAIDs. The risk of MI was increased with current use of NSAIDs (relative risk [RR]: 1.35; 95% confidence interval [CI]: 1.23 to 1.48). The risk increased with treatment duration and daily dose. We found a significant correlation between the degree of inhibition in vitro of whole blood COX-2 (r(2) = 0.7458, p = 0.0027), but not whole blood COX-1 (r(2) = 0.0007, p = 0.947), and the risk of MI associated with individual NSAIDs that lacked complete suppression (> or =95%) of platelet COX-1 activity. Individual NSAIDs with a degree of COX-2 inhibition <90% at therapeutic concentrations presented an RR of 1.18 (95% CI: 1.02 to 1.38), whereas those with a greater COX-2 inhibition had an RR of 1.60 (95% CI: 1.41 to 1.81). Our findings suggest that the variable risk of MI among NSAIDs that do not inhibit platelet COX-1 completely and persistently is largely related to their extent of COX-2 inhibition.