Randomised comparative effectiveness trial of Pulmonary Embolism Prevention after hiP and kneE Replacement (PEPPER): the PEPPER trial protocol

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.

Keywords: adult orthopaedics; anaesthesia in orthopaedics; anticoagulation; hip; knee; thromboembolism.

Conflict of interest statement

Competing interests: VDP, JWE, CME, PDF, KLG, SZG, RI, CAL, JM and LM receive funding from PCORI in support of their work pursuant to this trial. JWE reports honoraria and grant support from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb/Pfizer, Daiichi Sankyo, Glaxo Smith Kline, Janssen, Sanofi Aventis and Eli Lilly as well as a personal award from the Heart and Stroke Foundation. PDF reports grant support from PCORI, NIAMS, AHRQ and DePuy outside the submitted work. SZG reports grant support from Bayer, Boehringer-Ingelheim, BMS, Boston Scientific's BTG EKOS, Daiichi, Janssen, and NHLBI, and other from Bayer and Boehringer-Ingelheim outside the submitted work. JM reports grant support from the Patient Centered Outcomes Research Institute during the conduct of the study; personal fees from Novartis, Viking, Pluristem and UCB outside of the submitted work.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Pulmonary Embolism Prevention after HiP and KneE Replacement trial enrolment progression. Establishment of central IRB finalised 3 months after study contract signed with Patient Centered Outcomes Research Institute in March 2016. Study enrolment commenced in December 2016. Progressively more sites were added during first 12 months of trial; average time for contracting and infrastructure startup to enrolment ranged from 6 to 9 months. Study PI and prime contract transferred home institutions in June 2019. COVID-19 impact suspended elective surgery and research activity in nearly all sites commencing on or following March 2020 with sporadic resumption of research activities by 1 year later. Extension of the trial may be necessary as a result of the negative impact of COVID-19 on elective surgery and clinical research activities in the USA and Canada. IRB, institutional review board.

Figure 2

Pulmonary Embolism Prevention after HiP and KneE Replacement (PEPPER) trial Consolidated Standards of Reporting Trials (CONSORT) diagram. As of the end of November 2021, 13 663 patients were randomised into PEPPER. More than 33% of all eligible patients undergoing total hip or knee replacement at participating centres agreed to participate in the trial. Approximately 80% of patients provided follow-up at 6 months through a centralised mechanism, as depicted in the CONSORT diagram. Local site efforts contribute to aggregate 6-month follow-up of greater than 95%.