Dataset Information

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

ABSTRACT:

Background

Polypharmacy, 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.

Methods

In 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 p_interaction estimates.

Results

With 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, p_interaction .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.

Conclusion

We 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.

SUBMITTER: Bistervels IM

PROVIDER: S-EPMC9313834 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveSeveral trials had compared the efficacy and safety between non-vitamin K antagonist oral anticoagulants and warfarin for acute venous thromboembolism, but the results were incomplete. This updated review comprehensively assessed the efficacy and safety of non-vitamin K antagonist oral anticoagulants for venous thromboembolism.DesignMeta-analysis of randomised control trials. Six databases were searched from January 2000 to December 2018.SettingAdult patients had got non-vitamin K antagonist oral anticoagulants or warfarin for venous thromboembolism.ParticipantsRandomised control trials that compared the efficacy and safety between non-vitamin K antagonist oral anticoagulants and warfarin.Main outcome measuresThe efficacy and safety of non-vitamin K antagonist oral anticoagulants .ResultsSeven studies involving 29,879 cases were included, among which 14,943 cases were assigned to non-vitamin K antagonist oral anticoagulants group and 14,936 cases to warfarin group. Meta-analysis showed that compared with warfarin, recurrent venous thromboembolism (odds ratio 0.94 [95% confidence interval 0.81 to 1.11]), death related to venous thromboembolism or fatal pulmonary embolism (odds ratio 1.00 [95% confidence interval 0.63 to 1.60]), symptomatic deep-vein thrombosis (odds ratio 0.88 [95% confidence interval 0.72 to 1.09]), symptomatic nonfatal pulmonary embolism (odds ratio 1.03 [(95% confidence interval 0.82 to 1.30]) and all deaths (odds ratio 0.92 [95% confidence interval 0.76 to 1.12]) are similar in non-vitamin K antagonist oral anticoagulants group, but major bleeding event (odds ratio 0.61 [95% confidence interval 0.50 to 0.75]) and clinically relevant non-major bleeding event (odds ratio [95% confidence interval 0.53 to 0.85]) are less in non-vitamin K antagonist oral anticoagulants group. .ConclusionsFor the treatment of venous thromboembolism, non-vitamin K antagonist oral anticoagulants is as effective as warfarin, and has a better safety profile than warfarin.