Potential limitations of electronic database studies of prescription non-aspirin non-steroidal anti-inflammatory drugs (NANSAIDs) and risk of myocardial infarction (MI)

Purpose: To determine whether specific limitations in electronic database studies may lead to biased estimates of the association between prescription, non-selective non-aspirin non-steroidal anti-inflammatory drugs (NANSAIDs) and myocardial infarction (MI). Methods: Using our case-control study of NANSAIDs and first, non-fatal MI, we determined the odds ratio (OR) for prescription NANSAIDs and MI. In the 'Replicating Electronic Database Analysis,' we considered non-prescription NANSAID users to be 'non-users,' did not stratify by aspirin use, and did not adjust for confounders typically unavailable or incomplete in existing databases. In the 'Misclassification Assessment Analysis,' we removed non-prescription NANSAIDs from the 'non-user' category. In the 'Confounding Assessment Analysis #1,' we additionally adjusted for smoking, family history, and years of education. In the 'Confounding Assessment Analysis #2,' we also adjusted for body mass index (BMI) and physical activity. In the 'Interaction Assessment Analysis,' we stratified on aspirin use and repeated the latter analysis. Results: The prevalence of current NANSAID and aspirin use was higher in our controls than in electronic database studies, consistent with the fact that non-prescription NANSAIDs accounted for 81% of all NANSAID use. Education, physical activity, and BMI also were associated with prescription NANSAID use. When each potential source of bias was removed, the OR for NANSAIDs moved further from 1.0 (i.e.,toward a protective association with MI): 'Replicating Electronic Database' analysis (OR 1.00, 95% confidence interval [CI]: 0.78-1.28); 'Misclassification Assessment Analysis' (OR 0.89, 95%CI: 0.70-1.14); 'Confounding Assessment Analysis #1' (OR 0.85, 95%CI: 0.66-1.10); 'Confounding Assessment Analysis #2' (OR 0.78, 95%CI: 0.60-1.01); 'Interaction Assessment Analysis' (OR 0.69, 95%CI: 0.51-0.95). Conclusions: Limitations in electronic databases may be responsible for the lack of association of NANSAIDs on lower MI risk noted in these studies. Further studies - preferably randomized trials - are needed to address the risk-benefit ratio of NANSAID use. Copyright © 2005 John Wiley & Sons, Ltd.