Perioperative Anticoagulant Use for Surgery Evaluation -2 (PAUSE-2) Study Patients Receiving a Direct Oral Anticoagulant (DOACs-Dabigatran, Rivaroxaban, Apixaban or Edoxaban) and Needing Elective High-Bleed-Risk Surgery or an Invasive Procedure
- Conditions
- Atrial Fibrillation (AF)VTE
- Registration Number
- NCT06957366
- Lead Sponsor
- McMaster University
- Brief Summary
PAUSE 2 study is a prospective, open-label, blinded-endpoint non-inferiority RCT of PAUSE vs. ASRA management in DOAC treated high risk patients with AF/VTE who need elective high bleed risk surgery/procedure and/or any procedure involving neuraxial anesthesia. The purpose of the PAUSE 2 study is to show that PAUSE management will be as safe (i.e., non-inferior) as ASRA management, with 95% of patients having low/undetectable pre-operative DOAC levels \<30 ng/mL in each group., at the time of surgery/neuraxial.
- Detailed Description
As use of direct oral anticoagulants (DOACs) continues to increase so too will the need to manage such patients who require a surgery/procedure. Perioperative DOAC management is established and guideline supported in patients who need a low/moderate-bleed-risk surgery/procedure (e.g., hernia repair, colonoscopy), but there is uncertainty about managing high-risk patients who need a high-bleed-risk surgery (e.g., orthopedic, cardiac) or any neuraxial (i.e., spinal, epidural) anesthesia/procedure. The management of patients who are taking a DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) and need a surgery/procedure is common, and will increase due to an ageing population and an associated increase in DOAC use. PAUSE-2 is applicable to approximately 96K patients/year in Canada, based on 1.6M prevalent patients with AF or VTE, of whom approximately 90% are taking a DOAC. Of these about 20% (approximately 288K) need perioperative management each year and approximately 1 in 3 (approximately 96K) are considered high-risk patients who need a high-bleed-risk surgery or neuraxial procedure. Perioperative DOAC management is of interest to a wide array of clinicians, including medical, surgical and anesthesia specialties, nurse practitioners, and pharmacists. In support of this statement, the Up-to-Date chapter on Perioperative Anticoagulation is in the top 0.6% (126th of 20,425) of all viewed chapters. However, guidelines provide weak recommendations on perioperative DOAC management in high-bleed-risk patients due to a lack of high-quality data.
There are two competing strategies for DOAC-treated patients who need a high-bleed-risk surgery/neuraxial:
1. PAUSE management is simple and easy to apply as patients having a high-bleed-risk surgery/neuraxial procedure interrupt DOACs for 2 days before and 2 days after surgery without heparin bridging or DOAC level testing. This approach is based on the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study of 3,007-patients with atrial fibrillation (AF) who had elective surgery/procedure.
2. ASRA management is more complex, requiring 72-120 hours DOAC interruption and, in selected patients, pre-operative heparin bridging and DOAC level testing. This management is based on recommendations from the American Society of Regional Anesthesia (ASRA) Guidelines, developed in 2015 and updated in 2018. ASRA's approach is very cautious so as to ensure no residual DOAC level at the time of a high-bleed-risk surgery/neuraxial procedure, using longer pre-operative DOAC interruption intervals.
Clinicians are divided on whether to use PAUSE or ASRA management for perioperative DOAC management in high-bleed-risk patients: Anesthetists strongly favor ASRA, as they consider it safer, in accordance with anesthesia society guidelines, and more prudent medico-legally than PAUSE. On the other hand, internists strongly favor PAUSE, which they consider more evidence-based than ASRA.
As shown in the table below, ASRA management is more complex (variable DOAC interruption) and harder to implement (DOAC testing, heparin bridging) than PAUSE (standard DOAC interruption, no DOAC testing/bridging). Though well-intentioned, ASRA management may not optimize patient safety and, indeed, may hinder adoption of standardized perioperative DOAC management.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 920
- Adults, age 18 years of age or greater, with AF/flutter (permanent, persistent or paroxysmal) or VTE (leg deep vein thrombosis or pulmonary embolism) that require a full (therapeutic)-dose DOAC regimen, appropriate for age and renal function, comprising one of (a) apixaban 2.5 mg or 5 mg bid; (b) dabigatran 110 mg or 150 mg bid; (c) edoxaban 30 mg or 60 mg daily; or (d) rivaroxaban 15 mg or 20 mg daily
- High-risk patient having an elective high-bleed-risk surgery or any elective surgery with neuraxial anesthesia (epidural, spinal, regional) or any deep nerve root block.
- Indication for anticoagulation is unusual site thrombosis (e.g. splanchnic, cerebral, sinus, arm)
- Receiving a low-dose DOAC regimen used for secondary VTE prevention (e.g. rivaroxaban 10 mg daily, apixaban 2.5 mg bid) or another low-dose DOAC regimen (e.g. rivaroxaban 2.5 mg bid)
- CrCL<25mL/min (if on apixaban, edoxaban, rivaroxaban) or <30 mL/min (if on dabigatran)
- cognitive impairment or psychiatric illness that precludes reliable contact during follow up.
- Unable or unwilling to provide consent
- Previous participation in PAUSE 2
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Proportion of patients randomized to each study arm with a residual pre-operative DOAC level < 30 ng/mL Day 1 The primary outcome in PAUSE-2 will be the proportion of patients with a residual pre-operative DOAC level \< 30 ng/mL. Pre-operative DOAC levels will be measured using calibrated anti-Xa assays for direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) and will be measured using a dilute thrombin time assay for dabigatran-treated patients.
- Secondary Outcome Measures
Name Time Method Proportion of patients with a residual pre-operative DOAC level < 50 ng/mL. Day 1 Pre-operative DOAC levels will be measured using calibrated anti-Xa assays for direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) and will be measured using a dilute thrombin time assay for dabigatran-treated patients.
Clinically relevant nonmajor bleeding Day 28 Any overt bleeding not satisfying the criteria for major bleeding but considered clinically important with one or more of the following criteria met: - Requires minimal medical intervention (blood in urine or stool that is ongoing and requires a sigmoidoscopy, cystoscopy, CBI etc.) by a healthcare professional - Lead to hospitalization or increased level of care - Prompted a face-to-face (ie. not telephone, electronic) evaluation by a physician (this does not include visits prompted by pain, infection, other symptoms etc.)
Arterial thromboembolic Events (ATE) Day 28 Any of the following: stroke, systemic embolism, and/or transient ischemic attack. - Ischemic stroke: any new focal neurologic deficit that persists for \>24 hours or any new focal neurologic deficit of any duration, that occurs with evidence of acute infarction on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. - Systemic embolism: symptomatic embolism to upper or lower extremity or abdominal organ, confirmed intra-operatively or by objective imaging (e.g., CT angiography). - Transient ischemic attack: symptomatic focal neurologic deficit (lasting typically \<1 hour), that occurs with no evidence of acute infarction on CT/MRI of brain.
Major bleeding Day 28 ≥1 of the criteria below: - bleeding that is fatal or is symptomatic and retroperitoneal, intracranial, intraspinal, intraocular, pericardial, intramuscular with compartment syndrome, or intra-articular - non-surgical bleeding causing a drop in hemoglobin ≥20 g/L (1.24 mmol/L) or leading to transfusion ≥2 units whole blood or red cells within 48 hours of the bleed - surgical bleed that leads to intervention (e.g., re-operation) or has one of: (i) interferes with mobilization; (ii) leads to delayed wound healing; or (iii) leads to deep wound infection - surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause hemodynamic instability associated with: (i) drop in hemoglobin ≥20 g/L (1.24 mmol/L); or (ii) transfusion of ≥2 units whole blood or red cells within 48 hours of the bleed.
Minor bleeding Day 28 Any overt bleeding not satisfying the criteria for major and clinically relevant non-major bleeding.
Venous thromboembolic Events (VTE) Day 28 Any of the following: symptomatic deep vein thrombosis and/or pulmonary embolism, confirmed by objective imaging studies (e.g., ultrasound, CT pulmonary angiogram).
Myocardial infarction Day 28 All-cause death Day 28 Death due to any cause.
Trial Locations
- Locations (14)
Hartford Health Care
🇺🇸Hartford, Connecticut, United States
North Shore University Health
🇺🇸Evanston, Illinois, United States
Brigham and Woman's Hospital
🇺🇸Boston, Massachusetts, United States
Henry Ford Health Care
🇺🇸Detroit, Michigan, United States
Northwell Health System
🇺🇸New York, New York, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
University of Leuven
🇧🇪Leuven, Belgium
Winnipeg Health Sciences Center
🇨🇦Winnipeg, Manitoba, Canada
St. Joesph's Healthcare
🇨🇦Hamilton, Ontario, Canada
Juravinski
🇨🇦Hamilton, Ontario, Canada
The Ottawa Hospital
🇨🇦Ottawa, Ontario, Canada
L'Hospital Montfort
🇨🇦Ottawa, Ontario, Canada
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
University of Thessaly
🇬🇷Larissa, Greece