Abstract
Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit warfarin deactivation via the hepatic cytochrome P450 system. Therefore, antihyperlipidemic discontinuation has been hypothesized to result in underanticoagulation, as warfarin metabolism is no longer inhibited. We quantified the risk of venous thromboembolism (VTE) and ischemic stroke (IS) due to statin and fibrate discontinuation in warfarin users, in which warfarin was initially dose-titrated during ongoing antihyperlipidemic therapy. Using 1999–2011 United States Medicaid claims among 69 million beneficiaries, we conducted a set of bidirectional self-controlled case series studies—one for each antihyperlipidemic. Outcomes were hospital admissions for VTE/IS. The risk segment was a maximum of 90 days immediately following antihyperlipidemic discontinuation, the exposure of interest. Time-varying confounders were included in conditional Poisson models. We identified 629 study eligible-persons with at least one outcome. Adjusted incidence rate ratios (IRRs) for all antihyperlipidemics studied were consistent with the null, and ranged from 0.21 (0.02, 2.82) for rosuvastatin to 2.16 (0.06, 75.0) for gemfibrozil. Despite using an underlying dataset of millions of persons, we had little precision in estimating IRRs for VTE/IS among warfarin-treated persons discontinuing individual antihyperlipidemics. Further research should investigate whether discontinuation of gemfibrozil in warfarin users results in serious underanticoagulation.
Highlights
Drug-drug interactions are a serious public health problem
In our dataset of over 69 million beneficiaries, we identified 629 subjects who: a) concomitantly used warfarin and an antihyperlipidemic of interest; b) experienced at least one venous thromboembolism / ischemic stroke outcome during observation time; and c) met all other inclusion criteria
We examined rates of venous thromboembolism/ischemic stroke among users of warfarin upon discontinuation of concomitantly-prescribed antihyperlipidemic drugs
Summary
Drug-drug interactions are a serious public health problem. This problem is magnified in older adults, of whom >76% take two or more drugs[1] and >50% take five or more drugs per month[2]. The United States Department of Health and Human Services National Action Plan for Adverse Drug Event Prevention called for real world data on anticoagulant drug interactions[7]. Such interactions are of major concern since warfarin continues to be very commonly used (despite the rapid market uptake of direct oral anticoagulants)[8,9], has a narrow therapeutic index[6], may interact with almost every therapeutic class[10], and is the leading cause of adverse drug event-related hospitalizations in older adults (the most common users of the drug9)[11]. We conducted a set of self-controlled case series studies to quantify and compare the rates of venous thromboembolism / ischemic stroke among concomitant users of warfarin upon discontinuation of individual antihyperlipidemic drugs
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