Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement
PEPPER
1 other identifier
interventional
18,883
2 countries
32
Brief Summary
PEPPER is a randomized study comparing the three most commonly used anticoagulants in North America in patients who have elected to undergo primary or revision hip or knee joint replacement surgery. The anticoagulants being compared are enteric coated aspirin, low intensity warfarin, and rivaroxaban.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_4
Started Dec 2016
Longer than P75 for phase_4
32 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 11, 2016
CompletedFirst Posted
Study publicly available on registry
June 23, 2016
CompletedStudy Start
First participant enrolled
December 1, 2016
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 1, 2025
CompletedStudy Completion
Last participant's last visit for all outcomes
September 1, 2025
CompletedApril 9, 2026
November 1, 2025
8.8 years
May 11, 2016
April 5, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (4)
Aggregate primary clinical endpoints of all-cause mortality plus PE and DVT
To compare the frequency of the aggregate primary clinical endpoints of important venous thromboembolism (clinical PE and DVT confirmed by imaging and leading to hospital readmission and/or therapeutic anticoagulation) and all-cause mortality (aggregate indicator of fatal events, including both PE and major hemorrhage related to anticoagulant use) among three different venous thromboembolism (VTE) prophylaxis regimens. An audit of all hospital readmissions within 6 months of operation will be accomplished by routine postoperative follow-up through a mechanism of central telephone surveillance of patient-reported outcome events that is augmented by on-site research coordinator follow-up and validation of suspected endpoint events and adverse outcomes.
Within 6 months of operation
The frequency and nature of bleeding complications
To compare the frequency and nature of bleeding complications (major, clinically important, and wound-related) leading to wound drainage, reoperation, deep infection, or myocardial infarction among three different VTE prophylaxis regimens.
Within 6 months of operation
Specific Joint Function
To compare the groups with respect to patient-reported outcomes in order to assess their impact on specific function of the replaced joint. Validated functional outcome tools will be compared among patients with and without primary endpoint events, as well as with historical baseline data warehoused in the FORCE registry, a national Agency for Healthcare Research and Quality (AHRQ) funded joint replacement outcomes database. Study site overlap with the FORCE registry is planned.
Within 6 months of operation
Patient Well- Being
To compare the groups with respect to patient-reported outcomes in order to assess their impact on general patient well-being. Validated functional outcome tools will be compared among patients with and without primary endpoint events, as well as with historical baseline data warehoused in the FORCE registry, a national AHRQ funded joint replacement outcomes database. Study site overlap with the FORCE registry is planned.
Within 6 months of operation
Secondary Outcomes (2)
"Standard of care" methods of anesthesia on clinical effectiveness of three different prophylaxis regimens based on adverse events
Within 6 months of operation
Comparative frequency of thromboembolic events and bleeding complications occurring after hip and knee replacement
Within 6 months of operation
Study Arms (3)
Arm 1: Enteric Coated Aspirin
EXPERIMENTALEnteric coated aspirin (162 mg po) will be administered on the day of operation, prior to surgery, with a sip of water. Thereafter, starting on postoperative day #1, all patients in the aspirin group will receive 81 mg po bid to complete the treatment period of 30 days. Patients on preoperative cardiac dose aspirin may continue their usual dosing regimen prior to the morning of surgery, and then commence the PEPPER trial aspirin dose of 81 mg po bid on the day after operation.
Arm 2: Warfarin Other Names: Coumadin
EXPERIMENTALWarfarin will be administered starting on the day of operation, prior to surgery, with a sip of water. The initial dose will be empirically determined by body weight: less than 125 lbs (56.7 kg) - 2.5 mg; 125-250 lbs (56.7-113.4 kg) - 5 mg; greater than 250 lbs (113.4 kg) - 7.5mg. The initial dose will be repeated on the evening of surgery if the preoperative dose was administered prior to noon on the day of operation; no warfarin will be given on the evening of surgery if the preoperative dose was received after noon on the day of operation. Thereafter, starting on postoperative day #1, warfarin will be given each evening based on INR values to achieve a target of 2.0 (range 1.7-2.2).
Arm 3: Rivaroxaban Other Names: Xarelto
EXPERIMENTALRivaroxaban 10 mg will be first administered approximately 24 hours after completion of the index operation. Medication will then be administered in the evening on postoperative day #2 and thereafter each evening until completion.
Interventions
Eligibility Criteria
You may qualify if:
- years of age or older;
- Undergoing elective primary, revision or second stage re-implantation total hip/knee replacement or uni-compartmental knee replacement or hip resurfacing arthroplasty;
- Has necessary mental capacity to participate and is able to comply with study protocol requirements;
- Eligible for randomization to at least two of the three study regimens;
- Is not pregnant on the day of surgery;
- Has signed the consent form; and
- Is willing to be randomized and participate in the study.
You may not qualify if:
- Undergoing bilateral hip or knee replacement;
- Has been previously enrolled;
- Is pregnant or breastfeeding;
- Is on chronic anticoagulation other than antiplatelet medications;
- Concurrently enrolled in another active interventional clinical trial testing a drug or intervention known or believed to interact with aspirin, warfarin, or rivaroxaban;
- Has documented gastrointestinal, cerebral, or other hemorrhage within 3 months;
- Has a known diagnosis of defective hemostasis and past history of clinical bleeding requiring transfusion and treatment;
- Has had an operative procedure involving the eye, ear, or central nervous system within one month;
- Has uncontrolled hypertension with systolic BP \> 220mmHg or diastolic BP \> 120mmHg;
- Body weight of less than 41 kilograms at baseline visit;
- Member of a vulnerable patient population.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Dartmouth-Hitchcock Medical Centerlead
- Patient-Centered Outcomes Research Institutecollaborator
- University of Maryland, Baltimorecollaborator
- Brigham and Women's Hospitalcollaborator
- Northwestern Universitycollaborator
- Medical University of South Carolinacollaborator
Study Sites (32)
Mayo Clinic
Scottsdale, Arizona, 85259, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205, United States
UCLA
Los Angeles, California, 90404, United States
Stanford University Hospital
Stanford, California, 94305, United States
Arthritis Surgery Research Foundation
South Miami, Florida, 33143, United States
Rush University Medical Center
Chicago, Illinois, 60612, United States
Indiana University
Indianapolis, Indiana, 46037, United States
Sinai Hospital
Baltimore, Maryland, 21215, United States
Johns Hopkins University
Baltimore, Maryland, 21218, United States
Brigham & Women's Hospital
Boston, Massachusetts, 02115, United States
Boston University Medical Center
Boston, Massachusetts, 02118, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215, United States
Lahey Clinic
Burlington, Massachusetts, 01805, United States
Mayo Clinic
Rochester, Minnesota, 55905, United States
University of Nebraska Medical Center
Omaha, Nebraska, 68198, United States
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, 03756, United States
New York University
New York, New York, 10016, United States
Northwell Health
New York, New York, 10075, United States
Duke University Medical Center
Durham, North Carolina, 27710, United States
Cleveland Clinic
Cleveland, Ohio, 44195, United States
Penn State Hershey Med Center
Hershey, Pennsylvania, 17033, United States
University of Pennsylvania
Philadelphia, Pennsylvania, 19104, United States
Lifespan Health
East Providence, Rhode Island, 02914, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
University of Utah
Salt Lake City, Utah, 84132, United States
Anderson Orthopaedic Institute (VA)
Alexandria, Virginia, 22306, United States
University of Virginia
Charlottesville, Virginia, 22908, United States
Virginia Commonwealth University Medical Center
Richmond, Virginia, 23284, United States
University of Washington
Seattle, Washington, 98133, United States
West Virginia University
Morgantown, West Virginia, 26506, United States
London Health Sciences Centre
London, Ontario, N6A 4V2, Canada
University of Ottawa
Ottawa, Ontario, K1H 8L6, Canada
Related Publications (5)
Pellegrini VD Jr, Eikelboom J, McCollister Evarts C, Franklin PD, Goldhaber SZ, Iorio R, Lambourne CA, Magaziner JS, Magder LS; Steering Committee of The PEPPER Trial. Selection Bias, Orthopaedic Style: Knowing What We Don't Know About Aspirin. J Bone Joint Surg Am. 2020 Apr 1;102(7):631-633. doi: 10.2106/JBJS.19.01135. No abstract available.
PMID: 31895235BACKGROUNDPellegrini VD Jr, Eikelboom JW, Evarts CM, Franklin PD, Garvin KL, Goldhaber SZ, Iorio R, Lambourne CA, Magaziner J, Magder L; Steering Committee of the PEPPER Trial and the PEPPER Trial Investigators, funded by PCORI. Randomised comparative effectiveness trial of Pulmonary Embolism Prevention after hiP and kneE Replacement (PEPPER): the PEPPER trial protocol. BMJ Open. 2022 Mar 8;12(3):e060000. doi: 10.1136/bmjopen-2021-060000.
PMID: 35260464BACKGROUNDHanson TM, Magder LS, Pellegrini VD Jr; PEPPER Trial Investigators. Substantial Improvement in Self-Reported Mental Health Following Total Hip Arthroplasty Occurs Independent of Anesthetic Technique. J Arthroplasty. 2024 May;39(5):1220-1225.e1. doi: 10.1016/j.arth.2023.11.011. Epub 2023 Nov 17.
PMID: 37977307DERIVEDKo H, Pelt CE, Martin BI; PEPPER Investigators; Pellegrini VD Jr. Patient-reported outcomes following cemented versus cementless primary total knee arthroplasty: a comparative analysis based on propensity score matching. BMC Musculoskelet Disord. 2022 Oct 27;23(1):934. doi: 10.1186/s12891-022-05899-1.
PMID: 36303136DERIVEDFinch DJ, Martin BI, Franklin PD, Magder LS, Pellegrini VD Jr; PEPPER Investigators. Patient-Reported Outcomes Following Total Hip Arthroplasty: A Multicenter Comparison Based on Surgical Approaches. J Arthroplasty. 2020 Apr;35(4):1029-1035.e3. doi: 10.1016/j.arth.2019.10.017. Epub 2019 Oct 17.
PMID: 31926776DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Vincent D Pellegrini, MD
Dartmouth-Hitchcock Medical Center
- STUDY DIRECTOR
Carol A Lambourne, PhD
Dartmouth-Hitchcock Medical Center
Study Design
- Study Type
- interventional
- Phase
- phase 4
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- SUPPORTIVE CARE
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Professor of Orthopaedics
Study Record Dates
First Submitted
May 11, 2016
First Posted
June 23, 2016
Study Start
December 1, 2016
Primary Completion
September 1, 2025
Study Completion
September 1, 2025
Last Updated
April 9, 2026
Record last verified: 2025-11
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
- Time Frame
- Spring 2024
- Access Criteria
- to be determined
The participating institutions will follow NIH guidelines concerning the sharing of research data. As outlined by the NIH and Patient-Centered Outcomes Research Institute (PCORI), the participating institutions will make available to the public the results of this collaboration and any accompanying data that were supported by PCORI. There are no specimens or biological resources for sharing as a result of this planned project. In the course of this research project, we anticipate generating ranges of estimated complications and adverse events as they relate to the use of VTE prophylaxis in the context of hip and knee replacement. Access to these data and associated recommendations generated under the project will be available for educational, research and non-profit purposes. Such access will be provided using web-based applications, as appropriate and consistent with the data distribution policies of the Medical University of South Carolina and the University of Maryland.