Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement (PEPPER)

  • End date
    Feb 3, 2023
  • participants needed
  • sponsor
    Dartmouth-Hitchcock Medical Center
Updated on 25 February 2022
total knee replacement
pulmonary embolism


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.


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

Condition Pulmonary Embolism, Venous Thrombosis
Treatment Rivaroxaban, Warfarin, Enteric Coated Aspirin
Clinical Study IdentifierNCT02810704
SponsorDartmouth-Hitchcock Medical Center
Last Modified on25 February 2022


Yes No Not Sure

Inclusion Criteria

21 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

Exclusion Criteria

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
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