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Pulmonary EmbolismPhase 4PEPPERNCT02810704

Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement

A Phase 4 study testing Enteric Coated Aspirin, Warfarin and Rivaroxaban in people with Pulmonary Embolism and Venous Thrombosis, run by Dartmouth-Hitchcock Medical Center at 32 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 21 years and older
Conditions the study is for
Pulmonary Embolism, Venous Thrombosis
What is being tested?
Enteric Coated Aspirin, Warfarin and Rivaroxaban
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18,883 participants
Where
32 sitesin 2 countries
Study dates
Dec 2016to Sep 2025
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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;
Show all 11Show fewer
  • 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.

Trial locations and contacts

32 sites in 2 countries.

32 sites in 2 countries

United States30 sites

  • Anderson Orthopaedic Institute (VA)

    Alexandria, Virginia, 22306

  • Sinai Hospital

    Baltimore, Maryland, 21215

  • Johns Hopkins University

    Baltimore, Maryland, 21218

  • Brigham & Women's Hospital

    Boston, Massachusetts, 02115

  • Boston University Medical Center

    Boston, Massachusetts, 02118

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Lahey Clinic

    Burlington, Massachusetts, 01805

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • University of Virginia

    Charlottesville, Virginia, 22908

  • Rush University Medical Center

    Chicago, Illinois, 60612

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Lifespan Health

    East Providence, Rhode Island, 02914

  • Penn State Hershey Med Center

    Hershey, Pennsylvania, 17033

  • Indiana University

    Indianapolis, Indiana, 46037

  • Dartmouth-Hitchcock Medical Center

    Lebanon, New Hampshire, 03756

  • University of Arkansas for Medical Sciences

    Little Rock, Arkansas, 72205

  • UCLA

    Los Angeles, California, 90404

  • West Virginia University

    Morgantown, West Virginia, 26506

  • New York University

    New York, New York, 10016

  • Northwell Health

    New York, New York, 10075

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

  • University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Virginia Commonwealth University Medical Center

    Richmond, Virginia, 23284

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • University of Utah

    Salt Lake City, Utah, 84132

  • Mayo Clinic

    Scottsdale, Arizona, 85259

  • University of Washington

    Seattle, Washington, 98133

  • Arthritis Surgery Research Foundation

    South Miami, Florida, 33143

  • Stanford University Hospital

    Stanford, California, 94305

Other trials in United States

Canada2 sites

  • London Health Sciences Centre

    London, Ontario, N6A 4V2

  • University of Ottawa

    Ottawa, Ontario, K1H 8L6

Other trials in Canada

About this study

Official title: Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement: Balancing Safety and Effectiveness

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.

Read the 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

Being tested
Enteric Coated Aspirin, Warfarin, Rivaroxaban
Keywords
Anticoagulant, Venous Thromboembolism, Pulmonary Embolism, Total Knee Arthroplasty, Total Hip Arthroplasty
Medical subject headings
Pulmonary Embolism, Venous Thrombosis, Venous Thromboembolism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Enteric Coated AspirinDrug

    Also called Aspirin

  • WarfarinDrug

    Also called Coumadin

  • RivaroxabanDrug

    Also called Xarelto

Study groups in NCT02810704
Study groupRoleWhat they receive
Arm 1: Enteric Coated AspirinExperimentalEnteric 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.
Receives: Drug: Enteric Coated Aspirin
Arm 2: Warfarin Other Names: CoumadinExperimentalWarfarin 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).
Receives: Drug: Warfarin
Arm 3: Rivaroxaban Other Names: XareltoExperimentalRivaroxaban 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.
Receives: Drug: Rivaroxaban

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Within 6 months of operation

  2. 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.

    Measured: Within 6 months of operation

  3. 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.

    Measured: Within 6 months of operation

  4. 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.

    Measured: Within 6 months of operation

Secondary outcomes (2)

  1. "Standard of care" methods of anesthesia on clinical effectiveness of three different prophylaxis regimens based on adverse events

    Analysis of the contribution of "standard of care" methods of anesthesia on clinical effectiveness of three different prophylaxis regimens. Stratification and subgroup analysis between patients with general compared with regional neuraxial (spinal/epidural) anesthesia will assess contribution of anesthesia to efficacy of VTE prophylaxis.

    Measured: Within 6 months of operation

  2. Comparative frequency of thromboembolic events and bleeding complications occurring after hip and knee replacement

    Analysis of the the relative frequency of thromboembolic events and bleeding complications in total hip compared with knee replacement patients. Evidence suggests etiology of venous thromboembolic disease (VTED) differs between THA and TKA and each may warrant a distinctive prophylaxis regimen based on likely outcomes.

    Measured: Within 6 months of operation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jun 2016 (estimated)
  2. Study startDec 2016
  3. Primary completionSep 2025
  4. Study completionSep 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Supportive care
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
18,883 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02810704
Sponsor's protocol ID
FED19132
Acronym
PEPPER
Status last verified
Nov 2025
First submitted
11 May 2016
Last updated
5 Oct 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • 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.

    PubMed 31895235

  • 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.

    PubMed 35260464

  • 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.

    PubMed 37977307

  • 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.

    PubMed 36303136

  • 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.

    PubMed 31926776

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Enteric Coated Aspirin, Warfarin and Rivaroxaban in people with Pulmonary Embolism and Venous Thrombosis, run by Dartmouth-Hitchcock Medical Center at 32 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 32 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Aggregate primary clinical endpoints of all-cause mortality plus PE and DVT (time frame: Within 6 months of operation). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02810704, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2026.

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