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.
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
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
18,883
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 confirmed by imaging and leading to hospital readmission and/or therapeutic anticoagulation) 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.
Time frame: 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, deep infection, or myocardial infarction among three different VTE prophylaxis regimens.
Time frame: 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.
Time frame: 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.
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...and 22 more locations
Time frame: Within 6 months of operation
"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.
Time frame: 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.
Time frame: Within 6 months of operation