Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement

Pulmonary Embolism Clinical Trial

— PEPPER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02810704
• Other study ID #: FED19132
• Status: Recruiting
• Phase: Phase 4
• Start date: December 2016
• Est. completion date: July 2025

Study information

• Verified date: October 2023
• Source: Dartmouth-Hitchcock Medical Center
• Contact: Carol A Lambourne, PhD
• Phone: 603-308-9128
• Email: carol.a.lambourne[@]hitchcock.org
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20000
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• Enteric Coated Aspirin

• Warfarin

• Rivaroxaban

Locations

Country	Name	City	State
Canada	London Health Sciences Centre	London	Ontario
Canada	University of Ottawa	Ottawa	Ontario
United States	Anderson Orthopaedic Institute (VA)	Alexandria	Virginia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Sinai Hospital	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston University Medical Center	Boston	Massachusetts
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Lahey Clinic	Burlington	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Lifespan Health	East Providence	Rhode Island
United States	Penn State Hershey Med Center	Hershey	Pennsylvania
United States	Indiana University	Indianapolis	Indiana
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	UCLA	Los Angeles	California
United States	West Virginia University	Morgantown	West Virginia
United States	New York University	New York	New York
United States	Northwell Health	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Mayo Clinic	Scottsdale	Arizona
United States	University of Washington	Seattle	Washington
United States	Arthritis Surgery Research Foundation	South Miami	Florida
United States	Stanford University Hospital	Stanford	California

Sponsors (6)

Lead Sponsor	Collaborator
Dartmouth-Hitchcock Medical Center	Brigham and Women's Hospital, Medical University of South Carolina, Northwestern University, Patient-Centered Outcomes Research Institute, University of Maryland, Baltimore

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 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
Primary	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, or deep infection, or myocardial infarction among three different VTE prophylaxis regimens.	Within 6 months of operation
Primary	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.	Within 6 months of operation
Primary	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.	Within 6 months of operation
Secondary	"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.	Within 6 months of operation
Secondary	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.	Within 6 months of operation