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 (PAUSE 2 RCT)

May 6, 2025 updated by: James Douketis, McMaster University

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: A Randomized Control Trial

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

920

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Belgium
      • Leuven, Belgium
        • Not yet recruiting
        • University of Leuven
        • Principal Investigator:
          • Thomas Vanassche, MD
  • Canada
    • Manitoba
      • Winnipeg, Manitoba, Canada
        • Not yet recruiting
        • Winnipeg Health Sciences Center
        • Principal Investigator:
          • Ryan Zarychanski, MD
    • Ontario
      • Hamilton, Ontario, Canada, L8N 4A6
        • Recruiting
        • St. Joesph's Healthcare
        • Principal Investigator:
          • James Douketis, MD
        • Contact:
      • Hamilton, Ontario, Canada
        • Not yet recruiting
        • Juravinski
        • Principal Investigator:
          • Davide Matino, MD
      • Ottawa, Ontario, Canada, K1H 8L6
        • Not yet recruiting
        • The Ottawa Hospital
        • Principal Investigator:
          • Joseph Shaw, MD
      • Ottawa, Ontario, Canada
        • Not yet recruiting
        • L'Hospital Montfort
        • Principal Investigator:
          • Gregorie Le Gal, MD
      • Toronto, Ontario, Canada
        • Not yet recruiting
        • Toronto General Hospital
        • Principal Investigator:
          • Peter Gross, MD
  • Greece
      • Larissa, Greece
        • Not yet recruiting
        • University of Thessaly
        • Principal Investigator:
          • Eleni Arnaoutoglou, MD
  • United States
    • Connecticut
      • Hartford, Connecticut, United States, 06106
        • Not yet recruiting
        • Hartford Health Care
        • Principal Investigator:
          • Mandeep Kumar, MD
    • Illinois
      • Evanston, Illinois, United States, 60201
        • Not yet recruiting
        • North Shore University Health
        • Principal Investigator:
          • Alfonso Tafur, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Not yet recruiting
        • Brigham and Woman's Hospital
        • Principal Investigator:
          • Jean Connors, MD
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Not yet recruiting
        • Henry Ford Health Care
        • Principal Investigator:
          • Scott Kaatz, MD
    • New York
      • New York, New York, United States, 10305
        • Not yet recruiting
        • Northwell Health System
        • Principal Investigator:
          • Alex Spyropoulos, MD
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Not yet recruiting
        • Thomas Jefferson University Hospital
        • Principal Investigator:
          • Geno Merli, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Apixaban
Patients currently taking Apixaban that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Other: PAUSE Perioperative DOAC Management
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.
Other: ASRA Perioperative DOAC Management
ASRA management is more complex, requiring 72-120 hours DOAC interruption and, in selected patients, pre-operative heparin bridging and DOAC level testing.
Active Comparator: Dabigatran
Patients currently taking Dabigatran that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Other: PAUSE Perioperative DOAC Management
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.
Other: ASRA Perioperative DOAC Management
ASRA management is more complex, requiring 72-120 hours DOAC interruption and, in selected patients, pre-operative heparin bridging and DOAC level testing.
Active Comparator: Rivaroxaban
Patients currently taking Rivaroxaban that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Other: PAUSE Perioperative DOAC Management
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.
Other: ASRA Perioperative DOAC Management
ASRA management is more complex, requiring 72-120 hours DOAC interruption and, in selected patients, pre-operative heparin bridging and DOAC level testing.
Active Comparator: Edoxaban
Patients currently taking Edoxaban that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Other: PAUSE Perioperative DOAC Management
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.
Other: ASRA Perioperative DOAC Management
ASRA management is more complex, requiring 72-120 hours DOAC interruption and, in selected patients, pre-operative heparin bridging and DOAC level testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients randomized to each study arm with a residual pre-operative DOAC level < 30 ng/mL
Time Frame: 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.
Day 1

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients with a residual pre-operative DOAC level < 50 ng/mL.
Time Frame: 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.
Day 1
Clinically relevant nonmajor bleeding
Time Frame: 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.)
Day 28
Arterial thromboembolic Events (ATE)
Time Frame: 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.
Day 28
Major bleeding
Time Frame: 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.
Day 28
Minor bleeding
Time Frame: Day 28
Any overt bleeding not satisfying the criteria for major and clinically relevant non-major bleeding.
Day 28
Venous thromboembolic Events (VTE)
Time Frame: 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).
Day 28
Myocardial infarction
Time Frame: Day 28
Day 28
All-cause death
Time Frame: Day 28
Death due to any cause.
Day 28

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McMaster University

Investigators

  • Principal Investigator: James Douketis, MD, McMaster University/St. Joseph's Healthcare
  • Principal Investigator: Joseph Shaw, MD, The Ottawa Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2025

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

April 25, 2025

First Submitted That Met QC Criteria

April 25, 2025

First Posted (Actual)

May 4, 2025

Study Record Updates

Last Update Posted (Actual)

May 9, 2025

Last Update Submitted That Met QC Criteria

May 6, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PAUSE 2 RCT (CTO 4938)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No IPD data will be shared. All data reported as part of the study is aggregate data.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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