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

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ClinicalTrials.gov Identifier: NCT02810704
Recruitment Status : Recruiting
First Posted : June 23, 2016
Last Update Posted : January 30, 2018
Sponsor:
Collaborators:
Patient-Centered Outcomes Research Institute
University of Maryland
University of Massachusetts, Worcester
Brigham and Women's Hospital
Information provided by (Responsible Party):
Medical University of South Carolina

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.

Condition or disease Intervention/treatment Phase
Pulmonary Embolism Venous Thrombosis Drug: Enteric Coated Aspirin Drug: Warfarin Drug: Rivaroxaban Phase 4

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  (Clinical Trial)
Estimated Enrollment : 25000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement: Balancing Safety and Effectiveness
Actual Study Start Date : December 2016
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : February 2021

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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 Name: 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 Name: 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 Name: Xarelto



Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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 AHRQ funded joint replacement outcomes database. Study site overlap with the FORCE registry is planned.

  4. 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.


Secondary Outcome Measures :
  1. "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.

  2. 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.



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Ages Eligible for Study:   21 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females 21 years of age or older;
  2. Undergoing elective primary, resurfacing arthroplasty, revision, or second stage re-implantation total hip replacement;
  3. Undergoing elective primary, revision, or second stage re-implantation total or uni compartmental knee replacement;
  4. Patient has necessary mental capacity to participate and is able to comply with study protocol requirements;
  5. Patient is willing and able to give informed consent; and
  6. Patient is willing to be randomized and participate.

Exclusion Criteria:

  1. Patients undergoing bilateral hip or knee replacement;
  2. Patients undergoing total hip or knee replacement who have been enrolled in this study for a prior hip or knee replacement;
  3. Patients who are concurrently enrolled in another active interventional clinical trial testing a drug or intervention known or believed to interact with aspirin, warfarin, or rivaroxaban;
  4. Patients who have a contraindication to two or more of the three study prophylaxis regimens;
  5. Women who are pregnant or breastfeeding, as well as those of reproductive potential unless there is a negative urine pregnancy test on the day of surgery;
  6. Patients on chronic (longer than the prior 6 months) anticoagulation other than with antiplatelet medications;
  7. Patients with documented gastrointestinal, cerebral, or other hemorrhage within 3 months of the operation;
  8. Patients with a known diagnosis of defective hemostasis and past history of clinical bleeding requiring transfusion and treatment;
  9. Patients who have had an operative procedure involving the eye, ear, or central nervous system within one month;
  10. Patients with severe uncontrolled hypertension with systolic BP > 220mmHg or diastolic BP > 120mmHg;
  11. Patients with an absolute body weight of less than 41 kilograms (90.4 lbs) at baseline visit;
  12. Vulnerable patient populations including prisoners and institutionalized individuals.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02810704


Contacts
Contact: Monica E Baczko, MPA 843-792-8169 baczko@musc.edu

  Show 25 Study Locations
Sponsors and Collaborators
Medical University of South Carolina
Patient-Centered Outcomes Research Institute
University of Maryland
University of Massachusetts, Worcester
Brigham and Women's Hospital
Investigators
Principal Investigator: Vincent D Pellegrini, MD Medical University of South Carolina
Study Director: Carol A Lambourne, PhD Medical University of South Carolina

Responsible Party: Medical University of South Carolina
ClinicalTrials.gov Identifier: NCT02810704     History of Changes
Other Study ID Numbers: 1402
First Posted: June 23, 2016    Key Record Dates
Last Update Posted: January 30, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Data Sharing Plan: The participating institutions will follow NIH guidelines concerning the sharing of research data. As outlined by the NIH and 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.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

Keywords provided by Medical University of South Carolina:
Anticoagulant
Venous Thromboembolism
Pulmonary Embolism
Total Knee Arthroplasty
Total Hip Arthroplasty

Additional relevant MeSH terms:
Thrombosis
Embolism
Pulmonary Embolism
Venous Thrombosis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Aspirin
Rivaroxaban
Warfarin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Anticoagulants
Factor Xa Inhibitors
Antithrombins