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

Sponsor

Dartmouth-Hitchcock Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT02810704

Collaborator

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

20,000

Enrollment

Locations

Arms

Anticipated Duration (Months)

666.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

Anticipated Enrollment :

20000 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 :

Dec 1, 2016

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

Feb 1, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Aggregate primary clinical endpoints of all-cause mortality plus PE and DVT [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.
The frequency and nature of bleeding complications [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.
Specific Joint Function [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.
Patient Well- Being [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

"Standard of care" methods of anesthesia on clinical effectiveness of three different prophylaxis regimens based on adverse events [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.
Comparative frequency of thromboembolic events and bleeding complications occurring after hip and knee replacement [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Scottsdale	Arizona	United States	85259
2	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
3	UCLA	Los Angeles	California	United States	90404
4	Stanford University Hospital	Stanford	California	United States	94305
5	Arthritis Surgery Research Foundation	South Miami	Florida	United States	33143
6	Rush University Medical Center	Chicago	Illinois	United States	60612
7	Indiana University	Indianapolis	Indiana	United States	46037
8	Sinai Hospital	Baltimore	Maryland	United States	21215
9	Johns Hopkins University	Baltimore	Maryland	United States	21218
10	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
11	Boston University Medical Center	Boston	Massachusetts	United States	02118
12	Lahey Clinic	Burlington	Massachusetts	United States	01805
13	Mayo Clinic	Rochester	Minnesota	United States	55905
14	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
15	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
16	New York University	New York	New York	United States	10016
17	Northwell Health	New York	New York	United States	10075
18	Duke University Medical Center	Durham	North Carolina	United States	27710
19	Cleveland Clinic	Cleveland	Ohio	United States	44195
20	Penn State Hershey Med Center	Hershey	Pennsylvania	United States	17033
21	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
22	Lifespan Health	East Providence	Rhode Island	United States	02914
23	Medical University of South Carolina	Charleston	South Carolina	United States	29425
24	Anderson Orthopaedic Institute (VA)	Alexandria	Virginia	United States	22306
25	University of Virginia	Charlottesville	Virginia	United States	22908
26	Virginia Commonwealth University Medical Center	Richmond	Virginia	United States	23284
27	University of Washington	Seattle	Washington	United States	98133
28	West Virginia University	Morgantown	West Virginia	United States	26506
29	London Health Sciences Centre	London	Ontario	Canada	N6A 4V2
30	University of Ottawa	Ottawa	Ontario	Canada	K1H 8L6

Sponsors and Collaborators

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

Investigators

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