Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement

Conditions

Pulmonary Embolism, Venous Thrombosis

Keywords

Anticoagulant, Venous Thromboembolism, Pulmonary Embolism, Total Knee Arthroplasty, Total Hip Arthroplasty

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.

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

Drees P, Schmidtmann I, Herbst M, Becker D, Barco S, Klok FA, Keller K, Hobohm L, Christodoulou KC, Abele C, Bauersachs R, Ageno W, Grove EL, Kehlet H, Hufen F, Klonschinski T, Afghanyar Y, Eckhard L, Martin N, Fischer S, Gorbulev S, Rath D, Mavromanoli AC, Jabbour C, Lang I, Couturaud F, Heiss C, Binder H, Konstantinides S.

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Interventions

DRUGEnteric Coated Aspirin

DRUGWarfarin

DRUGRivaroxaban

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

SUPPORTIVE_CARE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

21 Years to No maximum

Healthy volunteers

No

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.

Design outcomes

Primary

Measure	Time frame	Description
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 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.
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, 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

Measure	Time frame	Description
"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.

Countries

Canada, United States

Contacts

PRINCIPAL_INVESTIGATORVincent D Pellegrini, MD

Dartmouth-Hitchcock Medical Center

STUDY_DIRECTORCarol A Lambourne, PhD