Clinical trial NCT06611319: ENhanced Recovery and ABbreviated LEngth of Anticoagulation for Thromboprophylaxis After Primary Hip Arthroplasty
Official title: ENhanced Recovery and ABbreviated LEngth of Anticoagulation for Thromboprophylaxis After Primary Hip Arthroplasty
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hip Arthroplasty, Total
Prevention of Venous Thromboembolism
Keywords: Thromboprophylaxis after hip surgery
Rivaroxaban
Abbreviated length of Anticoagulation
Enhanced recovery after surgery
Fast-track surgery
Early mobilization
Pulmonary embolism
Deep vein thrombosis
Lead sponsor: Johannes Gutenberg University Mainz
Sponsor class: OTHER
First posted: 2024-09-24
Enrollment: 2932
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Investigator-initiated and academically sponsored multicenter randomized double blind active-control non-inferiority trial
Primary purpose: PREVENTION

Brief summary: Surgical hip replacement (total hip arthroplasty, THA) is associated with a high risk of venous thromboembolism, but the appropriate duration of postoperative medical thromboprophylaxis ("anticoagulation") remains highly controversial. The international randomized controlled trial (RCT) "ENhanced recovery and ABbreviated LEngth of Anticoagulation for Thromboprophylaxis after primary Hip Arthroplasty" (ENABLE-Hip) will enroll patients undergoing elective THA that are eligible for early mobilization after surgery. The trial will compare a regimen of short-duration (10-day) postoperative anticoagulation (experimental group) to standard-duration (35-day) postoperative anticoagulation (control group) using the direct oral anticoagulant Rivaroxaban (brand name: Xarelto) at the recommended dose. Thus, ENABLE-Hip will be the first major RCT to directly test an overall reduction in the duration of post-THA thromboprophylaxis instead of replacing one antithrombotic drug or regimen by another. Follow-up visits after hospital discharge will be on day 35 and on day 90 after surgery. The primary outcome is acute symptomatic proximal deep vein thrombosis, or symptomatic or fatal pulmonary embolism, within 90 days after surgery. If ENABLE-Hip will demonstrate 'non-inferiority' of the experimental intervention, its benefits will be obvious, as patients are spared many days of unnecessary (and potentially harmful in terms of bleeding risk) anticoagulation.

Detailed description: An increasing proportion of the ageing population in Europe and other parts of the world suffers from hip osteoarthritis and will need surgical joint arthroplasty at some time in their lives. Surgical total hip arthroplasty (THA) is associated with a high risk of venous thromboembolism (VTE), but the appropriate duration of postoperative anticoagulation remains highly controversial. Although current German guidelines continue to advocate anticoagulation for 28-35 days after THA, clinical practice recommendations in other countries are shifting towards much earlier discontinuation of anticoagulants - despite the absence of solid evidence backed by controlled data. The "Enhanced recovery and Abbreviated duration of Anticoagulation for thromboprophylaxis after primary hip Arthroplasty" (ENABLE-Hip) study is a multicentre investigator-initiated and academically sponsored prospective randomised active-control non-inferiority trial. A regimen of short-duration (10-day) prophylactic anticoagulation (experimental arm) will be compared to standard-duration (35-day) anticoagulation as per current guidelines (control arm). Patients will be mobilised early after surgery, following a standardised enhanced recovery protocol. Following randomisation and an initial two-day open-label period of prophylactic anticoagulation as per local protocol, treatment with the study drug (rivaroxaban at the standard, approved prophylactic dose of 10 mg daily) will be started and continued until 10 days after surgery. After this time, patients will be switched (in a double-blinded manner) to placebo in the experimental arm, or continue on active drug in the control arm, until a total of 35 days have elapsed since surgery. The primary outcome is acute symptomatic proximal deep vein thrombosis (DVT), or symptomatic or fatal pulmonary embolism (PE), within the first 3 months after surgery. Participating investigators will be advised to adhere to guideline recommendations regarding clinical suspicion of and diagnostic work-up for VTE. The planned study population of 2,932 patients will provide ≥ 80% power to reject the null hypothesis that δ ≥ 0.01 (where δ = difference between the two arms in symptomatic VTE probability within 3 months) and accept the alternative hypothesis that δ \< 0.01, at an overall significance level α = 0.05. A formal interim analysis will be performed after 3-month follow-up of the first 1,760 randomised patients at a significance level α = 0.50, leading to stopping for futility if significance is not obtained, or if recalculation yields an overall sample size of \> 3,200 patients. The trial has the potential to inform future national and European guidelines for this large and continuously growing patient population.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent
2. Age between 18 and 85 years
3. Scheduled to undergo elective unilateral primary THA and eligible for perioperative management based on the ERAS protocol
4. Baseline Timed Up and Go (TUG) test scoring \&amp;lt; 20 seconds, corresponding to a good mobility status before surgery
5. Capability to understand and comply with the protocol requirements (e.g., sufficient knowledge of German language to answer the questionnaires, ability to swallow intact capsules).
6. Pregnancy and contraception:

   1. Pregnancy test: Negative serum pregnancy test at screening for women of childbearing potential (WOCBP).
   2. Contraception: WOCBP and men who are able to father a child, willing to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at informed consent, for the duration of drug treatment and allowing for a safe wash out period of at least 5 days for female or for male subjects after the last dose of trial medication. This is a very conservative estimate, considering the 'worst case scenario' of a substantially prolonged half-life up to 13 hours (e.g., in older patients and/or those with renal dysfunction) (28), and calculating for at least 8 half-lives to ensure practically non-detectable levels and effects of rivaroxaban.

Exclusion Criteria:

1. Previous DVT or PE
2. Hip or lower limb fracture in the previous three months
3. Major surgical procedure within the previous three months
4. Active cancer defined as metastatic cancer, or cancer requiring chemotherapy or radiation therapy
5. Active peptic ulcer disease, gastritis, or prior gastrointestinal bleeding
6. Obesity with body mass index (BMI) \&amp;gt; 40 kg/m2 body surface area
7. Severe renal impairment defined as estimated glomerular filtration rate \&amp;lt; 30ml/min
8. Severe hepatic impairment defined as Child Pugh Class B or C
9. Uncontrolled intercurrent illness (i.e., active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, interstitial lung disease, serious gastrointestinal conditions \[e.g., diarrhea, malabsorption\], psychiatric illness)
10. Active or recent major bleeding at any site, or presence of any major risk factor for bleeding, which, in the judgment of the investigator, may significantly increase the bleeding risk during postoperative anticoagulation treatment
11. Any other medical condition representing a contraindication to discharge within 6 days after surgery
12. Expected requirement for major surgery within a 90-day period post THA
13. Need for long-term anticoagulation (e.g., atrial fibrillation, previous VTE)
14. Need for chronic antiplatelet therapy except for acetylsalicylic acid (ASA) at a dose ≤ 100 mg daily or clopidogrel 75 mg daily
15. Previous participation in this trial
16. Life expectancy \&amp;lt; 6 months
17. Participation in another interventional clinical trial within the last 30 days prior to inclusion, unless during the observational follow-up period
18. History of hypersensitivity to the investigational medicinal product (IMP) or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the IMP

Primary outcomes:
measure: The primary efficacy endpoint is the rate of acute symptomatic or fatal VTE
timeFrame: within 90 days after surgery
Secondary outcomes:
measure: Length of hospital stay
timeFrame: within 90 days after surgery
measure: Changes in patient-reported hip joint-specific disability
timeFrame: within 90 days after surgery
measure: Rate of clinically relevant non-major bleedings
timeFrame: within 90 days after surgery
measure: Rate of death from any cause
timeFrame: within 90 days after surgery
measure: Rate of isolated symptomatic distal DVT
timeFrame: within 90 days after surgery
measure: Rate of myocardial infarction (MI) or stroke
timeFrame: within 90 days after surgery
measure: Rate of readmission to the hospital
timeFrame: within 90 days after surgery
measure: Number and terms of serious adverse events (SAEs)
timeFrame: within 90 days after surgery
measure: Change in patient mobility
timeFrame: within 90 days after surgery
measure: Amount of postoperative healthcare resource utilization
timeFrame: within 35 days after surgery
measure: Rate of major bleedings
timeFrame: within 90 days after surgery
measure: Generic quality of life measured by EQ-5D-5L
timeFrame: within 90 days after surgery
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Kepler University Medical Center, Orthopedics and Traumatology
state: Upper Austria
city: Kremmen
country: Germany
facility: Sana Clinics Sommerfeld, Dpt. for Surgical Orthopaedics
state: Brandenburg
city: Rüsselsheim
country: Germany
facility: GPR Rüsselsheim Health and Care Center
state: Hesse
city: Mainz
country: Germany
facility: University Medical Center Mainz, Center for Orthopedics and Trauma Surgery
state: Rhineland-Palatine
city: Dresden
country: Germany
facility: University Medical Center Dresden, University Center for Orthopaedics, Trauma & Plastic Surgery
state: Saxony
city: Berlin
country: Germany
facility: Evangelical Forest Hospital Berlin - Orthopaedics and Trauma Surgery
Study officials:
affiliation: University Medical Center Mainz, Center for Thrombosis and Hemostasis
name: Stavros V. Konstantinides, MD, Univ.-Prof.
role: STUDY_CHAIR
affiliation: University Medical Center Mainz, Center for Orthopedics and Trauma Surgery
name: Philipp Drees, MD, Univ.-Prof.
role: STUDY_CHAIR
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