Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Pulmonary Embolism, Venous Thrombosis

Intervention / Treatment
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* Drug: Enteric Coated Aspirin
* Drug: Warfarin
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Enteric Coated Aspirin<br>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<br> <br> * Other names: Aspirin;|
| Experimental: Arm 2: Warfarin Other Names: Coumadin<br>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<br> <br> * Other names: Coumadin;|
| Experimental: Arm 3: Rivaroxaban Other Names: Xarelto<br>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<br> <br> * Other names: Xarelto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anticoagulant, Venous Thromboembolism, Pulmonary Embolism, Total Knee Arthroplasty, Total Hip Arthroplasty