Evaluation of serious bleeding signals during concomitant use of clopidogrel and hypnotic drugs

Background: In a previous drug-drug interaction (DDI) screening study intended to generate hypotheses, clopidogrel + either eszopiclone or zolpidem (vs. clopidogrel alone) were associated with serious bleeding. Objectives: To confirm or refute these DDI signals and examine associations with other hypnotics in an independent population of United States Medicaid beneficiaries Methods: We employed a bi-directional self-controlled case series design in eligible individuals concomitantly exposed to one of 12 hypnotics (precipitants, exposures of interest) plus either clopidogrel (the object drug) or pravastatin (the negative control object drug). The outcome was hospital presentation with serious bleeding. Using conditional Poisson regression, we calculated confounder-adjusted rate ratios (RRs) and 95% confidence intervals for serious bleeding during clopidogrel + precipitant use (vs. clopidogrel alone). To distinguish a DDI from a precipitant’s inherent effect on bleeding, we divided effect measures by the adjusted RR for the corresponding pravastatin + precipitant pair to obtain ratios of RR (RRRs). Results: Among 23,194 users of clopidogrel and 3824 of pravastatin who experienced serious bleeding during an active prescription for one of these agents, confounder-adjusted RRRs for serious bleeding were 6.63 (0.39–113.01) and 0.77 (0.53–1.11) with eszopiclone and zolpidem, respectively, whereas confounder-adjusted RRRs for other hypnotics ranged from 0.18 (0.04–0.85) for triazolam to 1.79 (0.16–20.44) for zaleplon. Statistical imprecision therefore precluded us from confirming or refuting these prior signals with eszopiclone and zolpidem. Conclusions: While we could not confirm or refute previously identified DDI signals, numerically elevated RRRs for serious bleeding with several clopidogrel + hypnotic pairs warrant further examination.