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

October 30, 2023 updated by: Vincent D. Pellegrini, Dartmouth-Hitchcock Medical Center

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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

Study Type

Interventional

Enrollment (Estimated)

20000

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Monica Baczko, MPA
  • Phone Number: 843-792-8169
  • Email: baczko@musc.edu

Study Locations

  • Canada
    • Ontario
      • London, Ontario, Canada, N6A 4V2
        • Recruiting
        • London Health Sciences Centre
        • Contact:
        • Principal Investigator:
          • Brent Lanting, MD
      • Ottawa, Ontario, Canada, K1H 8L6
        • Recruiting
        • University of Ottawa
        • Contact:
        • Principal Investigator:
          • Paul Beaule, MD
  • United States
    • Arizona
      • Scottsdale, Arizona, United States, 85259
        • Recruiting
        • Mayo Clinic
        • Contact:
        • Principal Investigator:
          • Mark Spangehl, MD
    • Arkansas
      • Little Rock, Arkansas, United States, 72205
        • Terminated
        • University of Arkansas for Medical Sciences
    • California
      • Los Angeles, California, United States, 90404
        • Terminated
        • UCLA
      • Stanford, California, United States, 94305
        • Recruiting
        • Stanford University Hospital
        • Contact:
        • Principal Investigator:
          • William Maloney, MD
    • Florida
      • South Miami, Florida, United States, 33143
        • Terminated
        • Arthritis Surgery Research Foundation
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Terminated
        • Rush University Medical Center
    • Indiana
      • Indianapolis, Indiana, United States, 46037
        • Terminated
        • Indiana University
    • Maryland
      • Baltimore, Maryland, United States, 21215
      • Baltimore, Maryland, United States, 21218
        • Recruiting
        • Johns Hopkins University
        • Contact:
        • Principal Investigator:
          • Robert Sterling, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Recruiting
        • Beth Israel Deaconess Medical Center
        • Contact:
        • Principal Investigator:
          • Jacob Drew, MD
      • Boston, Massachusetts, United States, 02118
        • Recruiting
        • Boston University Medical Center
        • Contact:
        • Principal Investigator:
          • Michael Kain, MD
      • Boston, Massachusetts, United States, 02115
        • Recruiting
        • Brigham & Women's Hospital
        • Contact:
        • Principal Investigator:
          • Richard Iorio, MD
      • Burlington, Massachusetts, United States, 01805
        • Terminated
        • Lahey Clinic
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Terminated
        • Mayo Clinic
    • Nebraska
      • Omaha, Nebraska, United States, 68198
        • Recruiting
        • University of Nebraska Medical Center
        • Contact:
        • Principal Investigator:
          • Kevin Garvin, MD
    • New Hampshire
      • Lebanon, New Hampshire, United States, 03756
        • Recruiting
        • Dartmouth-Hitchcock Medical Center
        • Contact:
        • Principal Investigator:
          • Wayne Moschetti, MD
    • New York
      • New York, New York, United States, 10075
        • Recruiting
        • Northwell Health
        • Contact:
        • Principal Investigator:
          • Jason Oh, MD
      • New York, New York, United States, 10016
        • Terminated
        • New York University
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Terminated
        • Duke University Medical Center
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic
        • Contact:
        • Principal Investigator:
          • Robert Malloy, MD
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033
        • Terminated
        • Penn State Hershey Med Center
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • University of Pennsylvania
        • Contact:
        • Principal Investigator:
          • Charles L Nelson, MD
    • Rhode Island
      • East Providence, Rhode Island, United States, 02914
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Recruiting
        • Medical University of South Carolina
        • Contact:
        • Principal Investigator:
          • Zeke Walton, MD
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • Not yet recruiting
        • University of Utah
        • Contact:
          • Christopher Pelt, MD
    • Virginia
      • Alexandria, Virginia, United States, 22306
        • Terminated
        • Anderson Orthopaedic Institute (VA)
      • Charlottesville, Virginia, United States, 22908
        • Recruiting
        • University of Virginia
        • Contact:
        • Principal Investigator:
          • James Browne, MD
      • Richmond, Virginia, United States, 23284
        • Recruiting
        • Virginia Commonwealth University Medical Center
        • Contact:
        • Principal Investigator:
          • Stephen Kates, MD
    • Washington
      • Seattle, Washington, United States, 98133
        • Recruiting
        • University of Washington
        • Contact:
        • Principal Investigator:
          • Navin D Fernando, MD
    • West Virginia
      • Morgantown, West Virginia, United States, 26506
        • Recruiting
        • West Virginia University
        • Contact:
        • Principal Investigator:
          • Brock Lindsey, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: Enteric Coated Aspirin
Other Names:
  • Aspirin
Experimental: 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).
Drug: Warfarin
Other Names:
  • Coumadin
Experimental: 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.
Drug: Rivaroxaban
Other Names:
  • Xarelto

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Aggregate primary clinical endpoints of all-cause mortality plus PE and DVT
Time Frame: Within 6 months of operation
To compare the frequency of the aggregate primary clinical endpoints of important venous thromboembolism (clinical PE and DVT leading to hospital readmission) 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
Time Frame: Within 6 months of operation
To compare the frequency and nature of bleeding complications (major, clinically important, and wound-related) leading to wound drainage, reoperation, or deep infection, or myocardial infarction among three different VTE prophylaxis regimens.
Within 6 months of operation
Specific Joint Function
Time Frame: Within 6 months of operation
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
Time Frame: Within 6 months of operation
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
"Standard of care" methods of anesthesia on clinical effectiveness of three different prophylaxis regimens based on adverse events
Time Frame: Within 6 months of operation
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.
Within 6 months of operation
Comparative frequency of thromboembolic events and bleeding complications occurring after hip and knee replacement
Time Frame: Within 6 months of operation
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.
Within 6 months of operation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Dartmouth-Hitchcock Medical Center

Collaborators

Patient-Centered Outcomes Research Institute
Medical University of South Carolina
University of Maryland, Baltimore
Northwestern University
Brigham and Women's Hospital

Investigators

  • Principal Investigator: Vincent D Pellegrini, MD, Dartmouth-Hitchcock Medical Center
  • Study Director: Carol A Lambourne, PhD, Dartmouth-Hitchcock Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2016

Primary Completion (Estimated)

July 1, 2025

Study Completion (Estimated)

July 1, 2025

Study Registration Dates

First Submitted

May 11, 2016

First Submitted That Met QC Criteria

June 20, 2016

First Posted (Estimated)

June 23, 2016

Study Record Updates

Last Update Posted (Actual)

November 1, 2023

Last Update Submitted That Met QC Criteria

October 30, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FED19132

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing Time Frame

Spring 2024

IPD Sharing Access Criteria

to be determined

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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