March 1, 2022BMJ Open40 citationsOpen Access
Randomised comparative effectiveness trial of Pulmonary Embolism Prevention after hiP and kneE Replacement (PEPPER): the PEPPER trial protocol
Key Result
The PEPPER trial is an ongoing randomized non-inferiority trial aiming to enroll 20,000 patients to compare aspirin, warfarin, and rivaroxaban for preventing VTE and mortality after joint replacement.
Study Design
Type
RCT (n=20,000)
Randomization
Block randomized by site and procedure
Multicenter
Yes
Structured PICO
Do aspirin, low-intensity warfarin, or rivaroxaban differ in preventing VTE and all-cause mortality in patients undergoing hip or knee replacement?
P
Population
Patients aged 21 or older undergoing primary or revision hip or knee replacement, excluding those on chronic anticoagulation. Target n=20,000.
I
Intervention
Aspirin (81 mg twice daily), low-intensity warfarin (INR target 1.7-2.2), or rivaroxaban (10 mg/day)
C
Comparator
Comparative effectiveness trial comparing the three agents against each other
O
Outcome
Aggregate of clinical venous thromboembolism (VTE) and all-cause mortality (ACM)composite
The PEPPER trial is a large pragmatic randomized trial designed to compare the effectiveness and safety of aspirin, warfarin, and rivaroxaban for VTE prophylaxis after hip or knee replacement.
Limitations
- COVID-19 may force an extension
Abstract
Introduction More than 1 million elective total hip and knee replacements are performed annually in the USA with 2% risk of clinical pulmonary embolism (PE), 0.1%–0.5% fatal PE, and over 1000 deaths. Antithrombotic prophylaxis is standard of care but evidence is limited and conflicting. We will compare effectiveness of three commonly used chemoprophylaxis agents to prevent all-cause mortality (ACM) and clinical venous thromboembolism (VTE) while avoiding bleeding complications. Methods and analysis Pulmonary Embolism Prevention after HiP and KneE Replacement is a large randomised pragmatic comparative effectiveness trial with non-inferiority design and target enrolment of 20 000 patients comparing aspirin (81 mg two times a day), low-intensity warfarin (INR (International Normalized Ratio) target 1.7–2.2) and rivaroxaban (10 mg/day). The primary effectiveness outcome is aggregate of VTE and ACM, primary safety outcome is clinical bleeding complications, and patient-reported outcomes are determined at 1, 3 and 6 months. Primary data analysis is per protocol , as preferred for non-inferiority trials, with secondary analyses adherent to intention-to-treat principles. All non-fatal outcomes are captured from patient and clinical reports with independent blinded adjudication. Study design and oversight are by a multidisciplinary stakeholder team including a 10-patient advisory board. Ethics and dissemination The Institutional Review Board of the Medical University of South Carolina provides central regulatory oversight. Patients aged 21 or older undergoing primary or revision hip or knee replacement are block randomised by site and procedure; those on chronic anticoagulation are excluded. Recruitment commenced at 30 North American centres in December 2016. Enrolment currently exceeds 13 500 patients, representing 33% of those eligible at participating sites, and is projected to conclude in July 2024; COVID-19 may force an extension. Results will inform antithrombotic choice by patients and other stakeholders for various risk cohorts, and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants. Trial registration NCT02810704 .