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

Objectives 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. Background There is evidence that both traditional NSAIDs and selective inhibitors of COX-2 may increase the risk of MI. Methods 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. Results 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 (>= 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). Conclusions 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. (J Am Coll Cardiol 2008; 52: 1628-36) (c) 2008 by the American College of Cardiology Foundation