Effect of polypharmacy on bleeding with rivaroxaban versus vitamin K antagonist for treatment of venous thromboembolism

BackgroundPolypharmacy, including use of inhibitors of CYP3A4 and P‐glycoprotein (P‐gp), is common in patients with venous thromboembolism (VTE) and is associated with increased bleeding.MethodsIn 8246 patients included in the EINSTEIN‐VTE studies for acute VTE, we evaluated the effect of polypharmacy on bleeding and on the relative differences between rivaroxaban and enoxaparin/vitamin K antagonist (VKA). We assessed the incidence of clinically relevant bleeding (major and clinically relevant nonmajor bleeding) by number of comedications (none, 1–3, ≥4) at baseline, and by use of CYP3A4 and/or P‐gp inhibitors. Interaction between rivaroxaban versus enoxaparin/VKA and comedication was assessed by Cox regression analysis with pinteraction estimates.ResultsWith increasing number of comedications, the incidence of clinically relevant bleeding rose from 5.7% to 13.3% in rivaroxaban recipients and from 9.1% to 11.1% in enoxaparin/VKA recipients. Whereas rivaroxaban was associated with a reduced bleeding risk compared with enoxaparin/VKA in patients without comedication (hazard ratio [HR] 0.6, 95% confidence interval [CI] 0.4–0.9), the risk was similar in patients with ≥4 comedications (HR 1.2, 95% CI 0.97–1.5, pinteraction .002). Use of CYP3A4 and/or P‐gp inhibitors was associated with a doubled bleeding risk compared with no use, without a difference between rivaroxaban and enoxaparin/VKA.ConclusionWe conclude that fixed‐dose rivaroxaban as compared with enoxaparin followed by dose‐adjusted VKA is not associated with an increased bleeding risk in patients with VTE administered polypharmacy in general and CYP3A4 and/or P‐gp inhibitors specifically. This implies that the observed increased bleeding risks with polypharmacy and use of CYP3A4 and/or P‐gp inhibitors are likely explained by comorbidities and frailty, and not by pharmacokinetic interactions.