What does this research mean for the field?

For venous thromboembolism prophylaxis after hip arthroplasty, aspirin is associated with higher VTE rates compared to anticoagulants, while rivaroxaban is associated with higher mortality and bleeding. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The trial aims to compare the effectiveness and safety of different VTE prophylactic strategies in patients undergoing hip and knee arthroplasty.

May 16, 2026

Pulmonary Embolism Prevention After Hip and Knee Arthroplasty: The Pepper Trial

Key Points

The trial aims to compare the effectiveness and safety of different VTE prophylactic strategies in patients undergoing hip and knee arthroplasty.
Prospective randomized noninferiority trial involving 18,883 patients across 32 North American sites.
Patients were randomized to receive aspirin, warfarin, or rivaroxaban for one month post-surgery.
Primary outcomes included symptomatic VTED, all-cause mortality, bleeding complications, and patient-reported outcomes at 1, 3, and 6 months postoperatively.
Aspirin use led to a higher VTE rate (1.27% vs 0.83%, p=0.035) compared to rivaroxaban.
Rivaroxaban was linked to increased mortality (0.38% vs 0.15%, p=0.04) and bleeding events (3.49% vs 1.92%, p=0.002).
Overall bleeding was significantly higher with warfarin compared to aspirin (3.54% vs 2.03%, p=0.008) with major bleeding also higher (1.34% vs 0.65%, p=0.045).

Abstract

Introduction The Pulmonary Embolism Prevention after HIP and KNEE Replacement (PEPPER) Trial is a prospective randomized noninferiority study of venous thromboembolic disease (VTED) prophylaxis funded by PCORI. It is powered to both thromboembolic events (effectiveness) and bleeding complications (safety) as well as related patient-reported outcomes (PROs). Methods Eligible patients undergoing elective primary or revision hip (THA) or knee (TKA) replacement were consented and randomized to either Aspirin 81mg po bid (162mg day of surgery), Warfarin (target INR 1.5) starting day of surgery, or Rivaroxaban 10mg po qd (starting 24 hrs after surgery) for one month. Enrollment began December 2016 at 25 North American sites. Warfarin was dropped from the protocol in May 2023 and enrollment ended December 2024. No protocol changes were mandated by the DSMB. Primary outcomes are symptomatic VTED (DVT, PE) plus all-cause mortality (ACM), systemic (major) and wound (non-major) bleeding manifestations, and PROs at 1, 3, and 6 months postoperatively. Primary analysis is specified as per-protocol with concurrent intention-to-treat and as-treated analyses. Results 18,883 patients were enrolled at 32 sites in North America with target enrollment of 18,829. In 8,357 THA, all-cause mortality was 0.31% and VTE 0.84% with 2.9% bleeding events (1.1% major). In direct comparison, aspirin resulted in excess VTE (1.27% vs 0.83%, p=0.035) and Rivaroxaban in excess mortality (0.38% vs 0.15%, p=0.04) and excess bleeding (3.49% vs 1.92%, p=0.002) in both major (1.37%) and non-major (2.21%) categories. Differences in VTE and death were not significant between aspirin and warfarin, but warfarin had excess overall (3.54% vs 2.03%, p=0.008) and major (1.34% vs 0.65%, p=0.045) bleeding. Aspirin was associated with greater VTE compared with either anticoagulant (1.26% vs 0.89%, p=0.04). Conclusion Aspirin was associated with greater VTE and Rivaroxaban with greater mortality and bleeding after THA. Shared decision-making is warranted for VTE prophylaxis after THA.

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Pulmonary Embolism Prevention After Hip and Knee Arthroplasty: The Pepper Trial

Key Points

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