Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement

NCT ID: NCT02810704

Last Updated: 2025-11-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 18883 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-31
• Study Completion Date: 2025-09-30

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.

Detailed Description

PEPPER is a large pragmatic clinical trial to inform patient choice and balance risk tolerances of individuals who face decisions about different drugs and strategies for deep vein thrombosis (DVT) and pulmonary embolism (PE) prevention after total hip (THA) and knee (TKA) replacement. Indeed, clinical equipoise exists to ethically support such a randomized trial that has great potential to change current practice. We have selected the three prophylaxis methods that represent current orthopaedic practice in North America and collectively account for more than 80% of all hip and knee replacements; a) enteric coated aspirin (regimen with lowest bleeding risk; clinical PE and all-cause mortality rates comparable to more intensive anticoagulants), b) low intensity (INR Target 2.0) warfarin (time honored and one of the most common North American regimens; low bleeding risk [1-2%]), and c) rivaroxaban, a new oral direct Factor Xa inhibitor (regimen with lowest PE and DVT rate but higher bleeding risk [3-5%]). Prophylaxis will continue for 30 days, in accordance with clinical guidelines, and pneumatic compression will be utilized in hospital in conjunction with each treatment group. Each regimen is commonly used in contemporary practice, supported by observational and clinical trial data, and endorsed by the American College of Chest Physicians (ACCP) and American Academy of Orthopaedic Surgeons (AAOS) guidelines

Conditions

Pulmonary Embolism; Venous Thrombosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Arm 1: Enteric Coated Aspirin

Enteric 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.

Group Type: EXPERIMENTAL

Enteric Coated Aspirin

Intervention Type: DRUG

Arm 2: Warfarin Other Names: Coumadin

Warfarin 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).

Group Type: EXPERIMENTAL

Warfarin

Intervention Type: DRUG

Arm 3: Rivaroxaban Other Names: Xarelto

Rivaroxaban 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.

Group Type: EXPERIMENTAL

Rivaroxaban

Intervention Type: DRUG

Interventions

Enteric Coated Aspirin

Intervention Type: DRUG

Warfarin

Intervention Type: DRUG

Rivaroxaban

Intervention Type: DRUG

Other Intervention Names

Aspirin; Coumadin; Xarelto

Eligibility Criteria

Inclusion Criteria

1. 21 years of age or older;

2. Undergoing elective primary, revision or second stage re-implantation total hip/knee replacement or uni-compartmental knee replacement or hip resurfacing arthroplasty;

3. Has necessary mental capacity to participate and is able to comply with study protocol requirements;

4. Eligible for randomization to at least two of the three study regimens;

5. Is not pregnant on the day of surgery;

6. Has signed the consent form; and

7. Is willing to be randomized and participate in the study.

Exclusion Criteria

1. Undergoing bilateral hip or knee replacement;

2. Has been previously enrolled;

3. Is pregnant or breastfeeding;

4. Is on chronic anticoagulation other than antiplatelet medications;

5. Concurrently enrolled in another active interventional clinical trial testing a drug or intervention known or believed to interact with aspirin, warfarin, or rivaroxaban;

6. Has documented gastrointestinal, cerebral, or other hemorrhage within 3 months;

7. Has a known diagnosis of defective hemostasis and past history of clinical bleeding requiring transfusion and treatment;

8. Has had an operative procedure involving the eye, ear, or central nervous system within one month;

9. Has uncontrolled hypertension with systolic BP > 220mmHg or diastolic BP > 120mmHg;

10. Body weight of less than 41 kilograms at baseline visit;

11. Member of a vulnerable patient population.

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role: collaborator

University of Maryland, Baltimore

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: collaborator

Medical University of South Carolina

OTHER

Sponsor Role: collaborator

Dartmouth-Hitchcock Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Vincent D. Pellegrini

Professor of Orthopaedics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Vincent D Pellegrini, MD

Role: PRINCIPAL_INVESTIGATOR

Dartmouth-Hitchcock Medical Center

Carol A Lambourne, PhD

Role: STUDY_DIRECTOR

Dartmouth-Hitchcock Medical Center

Locations

Mayo Clinic

Scottsdale, Arizona, United States

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

UCLA

Los Angeles, California, United States

Stanford University Hospital

Stanford, California, United States

Arthritis Surgery Research Foundation

South Miami, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

Sinai Hospital

Baltimore, Maryland, United States

Johns Hopkins University

Baltimore, Maryland, United States

Brigham & Women's Hospital

Boston, Massachusetts, United States

Boston University Medical Center

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Lahey Clinic

Burlington, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

New York University

New York, New York, United States

Northwell Health

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

Penn State Hershey Med Center

Hershey, Pennsylvania, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Lifespan Health

East Providence, Rhode Island, United States

Medical University of South Carolina

Charleston, South Carolina, United States

University of Utah

Salt Lake City, Utah, United States

Anderson Orthopaedic Institute (VA)

Alexandria, Virginia, United States

University of Virginia

Charlottesville, Virginia, United States

Virginia Commonwealth University Medical Center

Richmond, Virginia, United States

University of Washington

Seattle, Washington, United States

West Virginia University

Morgantown, West Virginia, United States

London Health Sciences Centre

London, Ontario, Canada

University of Ottawa

Ottawa, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: BACKGROUND

PMID: 31895235 (View on PubMed)

Pellegrini 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.

Reference Type: BACKGROUND

PMID: 35260464 (View on PubMed)

Hanson 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.

Reference Type: DERIVED

PMID: 37977307 (View on PubMed)

Ko 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.

Reference Type: DERIVED

PMID: 36303136 (View on PubMed)

Finch 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.

Reference Type: DERIVED

PMID: 31926776 (View on PubMed)

Other Identifiers

FED19132

Identifier Type: -

Identifier Source: org_study_id