Signals of Venous Thromboembolism Risk from Drug-Drug Interactions Involving Benzodiazepines and Other Sedative...

Benzodiazepines and sedative hypnotics such as zolpidem ("z-drugs") are commonly prescribed for anxiety and sleep disorders. Epidemiologic evidence links their use to increased risk of venous thromboembolism. We investigated venous thromboembolism risk among concomitant users of individual benzodiazepines/z-drugs (examined separately) with other prescription medications to generate data-driven hypotheses about drug interactions resulting in clinically meaningful harm to inform future etiologic studies of specific drug combinations.

We conducted a series of self-controlled case series studies within a 50% random sample of US Medicaid and Medicare data. Each cohort comprised person-time exposed to a benzodiazepine/z-drug, dichotomized into focal versus referent periods based on concomitant drug use versus non-use. We used conditional Poisson regression to estimate incidence rate ratios for hospital or emergency department presentation for venous thromboembolism. We generated ratios of incidence rate ratios, leveraging negative control analyses of eye drop-concomitant drug pairs, to minimize confounding by indication for the concomitant drug. We used semi-Bayes shrinkage to minimize false positives.

Among 1590 self-controlled case series studies involving 8853 individuals with venous thromboembolism, 38 (2.4%) potential drug interaction signals were identified before calibration. After adjustment for multiple testing and negative control findings, five (0.3%) signals remained, involving gabapentin combined with eszopiclone, lorazepam, clonazepam, or alprazolam, and apixaban combined with diazepam (ratio of incidence rate ratio range: 1.92-3.57). Four (80%) involved concurrent use of gabapentin, a medication largely used to treat neuropathic pain.

Most benzodiazepine/z-drug combinations conferred no increased venous thromboembolism risk. However, concurrent use of a benzodiazepine/z-drug with gabapentin may increase the relative rate of venous thromboembolism up to 3.5-fold. As this work was hypothesis generating, a future etiologic study should confirm this potential drug interaction.