Effectiveness and Safety of Rivaroxaban Versus Warfarin in Patients with Pulmonary Embolism and Right Ventricular Dysfunction

Background: Rivaroxaban has been shown to be noninferior compared with warfarin in reducing the risk of venous thromboembolism (VTE) recurrence. However, limited data exist about comparative effectiveness and safety of rivaroxaban versus warfarin in patients with right ventricular dysfunction (RVD), a commonly encountered complication in acute pulmonary embolism (PE). This study assesses the effectiveness and safety of rivaroxaban versus warfarin among patients with PE and RVD.

Methods: Data from Mass General Brigham's Research Patient Data Registry (MGB RPDR) database (01/2013 - 05/2023) were used to identify adult patients newly prescribed rivaroxaban 15 mg or 20 mg or warfarin (initiation) during a PE-related hospitalization with evidence of RVD (index PE hospitalization). Evidence of RVD was assessed via natural language processing of clinical notes. Patients had at least 6 months of clinical activity prior to the index PE hospitalization (pre-index period), were alive at discharge, and had rivaroxaban or warfarin as their first oral anticoagulant (OAC) prescribed after discharge. Patients were excluded if they had VTE in the 3 months prior, prescription of an OAC within ≤6 months before, or prescription of rivaroxaban 2.5 mg during the index PE hospitalization; hip or knee replacement surgery within ≤35 days before initiation; severe renal dysfunction (estimated glomerular filtration rate [eGFR] <30) or pregnancy within ≤6 months before initiation; or antiphospholipid syndrome, active cancer, or mechanical heart valve procedure within ≤6 months before or during the index PE hospitalization. Effectiveness and safety outcomes were evaluated during the on-treatment period, which spanned from the discharge from the index PE hospitalization to the earliest between treatment discontinuation, switch to another OAC, end of clinical activity or data, or active cancer. The proportion of international normalized ratio (INR) measurements within therapeutic range (INR within 2-3) for warfarin users on-treatment was described. Effectiveness was assessed using time-to-first VTE recurrence, defined as a hospitalization with a primary diagnosis of VTE, and safety was assessed using time-to-first major bleeding event, defined using the Cunningham algorithm which identifies non-traumatic bleeding-related hospitalizations. To account for truncation at the end of follow-up (i.e., due to treatment discontinuation or switch, end of clinical activity or data, or death), effectiveness and safety were described using Kaplan-Meier analysis, and event rates were compared at 6-month intervals up to 36 months on-treatment using hazard ratios (HR), 95% confidence intervals (CI), and p-values from Cox proportional hazards models. Propensity score overlap weighting (PS-OW) was used to adjust for confounding between cohorts, with balance in baseline characteristics evaluated using standardized differences (std. diff.).

Results: From 39,068 patients with PE observed in the data, a total of 246 rivaroxaban and 315 warfarin users were included. After PS-OW, mean age was 63 years; 53% of patients were female; the mean Quan-Charlson comorbidity index and modified RIETE bleeding scores were 1.8 and 2.7, respectively (all std. diff.=0%). The median on-treatment period was 270 and 235 days for rivaroxaban and warfarin users, respectively, and 50.9% of INR measurements per patient were within therapeutic range among warfarin users. Compared with warfarin, rivaroxaban was associated with a significantly reduced risk of recurrent VTE at 12 months (10.8% vs. 18.0%; HR [95% CI]: 0.55 [0.32, 0.92]), 24 months (16.4% vs. 22.0%; HR [95% CI]: 0.61 [0.38, 0.99]), and 36 months (20.4% vs. 30.3%; HR [95% CI]: 0.59 [0.38, 0.92]) (all P<0.05). No statistically significant differences were observed in the risk of major bleeding between rivaroxaban and warfarin users; Kaplan-Meier rates were 8.0% and 6.7% at 12 months, 8.2% and 10.4% at 24 months, and 8.2% and 13.6% at 36 months for rivaroxaban and warfarin users, respectively (all P>0.05).

Conclusion: These findings suggest that among patients with PE and RVD, rivaroxaban was associated with a reduced risk of recurrent VTE compared with those treated with warfarin and similar risk of major bleeding.

Laliberté:Analysis Group, Inc.: Current Employment, Other: François Laliberté is an employee of Analysis Group, Inc., which received funding from Janssen Scientific Affairs, LLC, to conduct this study.. Ashton:Janssen Scientific Affairs, LLC: Current Employment. Germain:Analysis Group, Inc.: Other: Guillaume Germain is an employee of Analysis Group, Inc., which received funding from Janssen Scientific Affairs, LLC, to conduct this study.. Boudreau:Analysis Group, Inc.: Current Employment, Other: Julien Boudreau is an employee of Analysis Group, Inc., which received funding from Janssen Scientific Affairs, LLC, to conduct this study.. Sundar:Analysis Group, Inc.: Current Employment, Other: I am an employee of Analysis Group, which received funding from Bristol Myers Squibb and Janssen.for conducting research studies. MacKnight:Analysis Group, Inc.: Current Employment, Other: Sean D MacKnight is an employee of Analysis Group, Inc., which received funding from Janssen Scientific Affairs, LLC, to conduct this study.. Bookhart:Janssen Scientific Affairs, LLC: Current Employment. Wentworth:Janssen Scientific Affairs, LLC: Current Employment. Murphy:Mass General Brigham: Current Employment, Other: Shawn Murphy is an employee of Mass General Brigham which received funding from Janssen Scientific Affairs, LLC, to conduct this study. Piazza:BSC: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy; BCRI: Consultancy; PERC: Consultancy; NAMSA: Consultancy; BMS: Consultancy; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Regeneron: Consultancy; BMS/Pfizer: Research Funding; Alexion: Research Funding; Bayer: Research Funding; Esperion: Research Funding.