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Atrial Fibrillation (AF)PAUSE 2 RCTNCT06957366

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 study testing PAUSE Perioperative DOAC Management and ASRA Perioperative DOAC Management in people with Atrial Fibrillation (AF) and VTE, run by McMaster University at 14 sites in 4 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Atrial Fibrillation (AF), VTE
What is being tested?
PAUSE Perioperative DOAC Management and ASRA Perioperative DOAC Management
Could I receive a placebo?
No, everyone receives an active treatment
How many people
920 participants
Where
14 sitesin 4 countries
Study dates
1 Apr 2025to 31 Dec 2027
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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

Trial locations and contacts

14 sites in 4 countries. Contact the study team or a site near you to ask about taking part.

James Douketis, MD contact

905-522-1155 ext. 36178

jdouket@mcmaster.ca

Melanie St John contact

stjohm1@mcmaster.ca

14 sites in 4 countries

United States6 sites, 6 recruiting

  • Brigham and Woman's Hospital

    Boston, Massachusetts, 02115

    Jean Connors, MD

    Not yet recruiting

  • Henry Ford Health Care

    Detroit, Michigan, 48202

    Scott Kaatz, MD

    Not yet recruiting

  • North Shore University Health

    Evanston, Illinois, 60201

    Alfonso Tafur, MD

    Not yet recruiting

  • Hartford Health Care

    Hartford, Connecticut, 06106

    Mandeep Kumar, MD

    Not yet recruiting

  • Northwell Health System

    New York, New York, 10305

    Alex Spyropoulos, MD

    Not yet recruiting

  • Thomas Jefferson University Hospital

    Philadelphia, Pennsylvania, 19107

    Geno Merli, MD

    Not yet recruiting

Other trials in United States

Canada6 sites, 6 recruiting

  • St. Joesph's Healthcare

    Hamilton, Ontario, L8N 4A6

    Ralph Laurence Gaa, 9055221155, gaar@mcmaster.ca

    James Douketis, MD

    Recruiting

  • Juravinski

    Hamilton, Ontario

    Davide Matino, MD

    Not yet recruiting

  • The Ottawa Hospital

    Ottawa, Ontario, K1H 8L6

    Joseph Shaw, MD

    Not yet recruiting

  • L'Hospital Montfort

    Ottawa, Ontario

    Gregorie Le Gal, MD

    Not yet recruiting

  • Toronto General Hospital

    Toronto, Ontario

    Peter Gross, MD

    Not yet recruiting

  • Winnipeg Health Sciences Center

    Winnipeg, Manitoba

    Ryan Zarychanski, MD

    Not yet recruiting

Other trials in Canada

Belgium1 site, 1 recruiting

  • University of Leuven

    Leuven, Belgium

    Thomas Vanassche, MD

    Not yet recruiting

Other trials in Belgium

Greece1 site, 1 recruiting

  • University of Thessaly

    Larissa, Greece

    Eleni Arnaoutoglou, MD

    Not yet recruiting

Other trials in Greece

About this study

Official title: 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.

Read the 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.

Being tested
PAUSE Perioperative DOAC Management, ASRA Perioperative DOAC Management
Keywords
anticoagulation, atrial Fibrillation, Surgery, Oral Anticoagulant, Blood thinner, DOAC, VTE, Interruption, PAUSE
Medical subject headings
Atrial Fibrillation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PAUSE Perioperative DOAC ManagementOther

    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.

  • ASRA Perioperative DOAC ManagementOther

    ASRA management is more complex, requiring 72-120 hours DOAC interruption and, in selected patients, pre-operative heparin bridging and DOAC level testing.

Study groups in NCT06957366
Study groupRoleWhat they receive
ApixabanActive comparatorPatients currently taking Apixaban that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Receives: Other: PAUSE Perioperative DOAC Management; Other: ASRA Perioperative DOAC Management
DabigatranActive comparatorPatients currently taking Dabigatran that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Receives: Other: PAUSE Perioperative DOAC Management; Other: ASRA Perioperative DOAC Management
RivaroxabanActive comparatorPatients currently taking Rivaroxaban that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Receives: Other: PAUSE Perioperative DOAC Management; Other: ASRA Perioperative DOAC Management
EdoxabanActive comparatorPatients currently taking Edoxaban that have atrial fibrillation or Venous Thromboembolism and require an elective high bleed risk surgery or neuraxial anesthesia.
Receives: Other: PAUSE Perioperative DOAC Management; Other: ASRA Perioperative DOAC Management

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Proportion of patients randomized to each study arm with a residual pre-operative DOAC level < 30 ng/mL

    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.

    Measured: Day 1

Secondary outcomes (8)

  1. Proportion of patients with a residual pre-operative DOAC level < 50 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.

    Measured: Day 1

  2. Clinically relevant nonmajor bleeding

    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.)

    Measured: Day 28

  3. Arterial thromboembolic Events (ATE)

    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.

    Measured: Day 28

  4. Major bleeding

    ≥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.

    Measured: Day 28

  5. Minor bleeding

    Any overt bleeding not satisfying the criteria for major and clinically relevant non-major bleeding.

    Measured: Day 28

  6. Venous thromboembolic Events (VTE)

    Any of the following: symptomatic deep vein thrombosis and/or pulmonary embolism, confirmed by objective imaging studies (e.g., ultrasound, CT pulmonary angiogram).

    Measured: Day 28

  7. Myocardial infarction

    Measured: Day 28

  8. All-cause death

    Death due to any cause.

    Measured: Day 28

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 May 2025
  2. Study start1 Apr 2025
  3. Primary completion31 Dec 2027 (estimated)
  4. Study completion31 Dec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Patients taking Apixaban, Dabigatran, Rivaroxaban or Edoxaban will be randomly assigned to follow 1) PAUSE or 2) ASRA perioperative DOAC management.
Masking
None (open label)
Enrolment
920 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06957366
Sponsor's protocol ID
PAUSE 2 RCT (CTO 4938)
Acronym
PAUSE 2 RCT
Status last verified
May 2025
First submitted
25 Apr 2025
Last updated
9 May 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: No IPD data will be shared. All data reported as part of the study is aggregate data.

Publications

  • Shaw JR, Unachukwu U, Cyr J, Siegal DM, Castellucci LA, Dreden PV, Dowlatshahi D, Buyukdere H, Ramsay T, Carrier M. Effect of PCC on Thrombin Generation among Patients on Factor Xa Inhibitors with Major Bleeding or Needing Urgent Surgery (GAUGE): Design and Rationale. TH Open. 2023 Jul 25;7(3):e229-e240. doi: 10.1055/s-0043-1771300. eCollection 2023 Jul.

    PubMed 37497426

  • Shaw JR, Castellucci LA, Siegal D, Carrier M. DOAC-associated bleeding, hemostatic strategies, and thrombin generation assays - a review of the literature. J Thromb Haemost. 2023 Mar;21(3):433-452. doi: 10.1016/j.jtha.2022.11.029. Epub 2022 Dec 22.

    PubMed 36696204

  • Harenberg J, Beyer-Westendorf J, Crowther M, Douxfils J, Elalamy I, Verhamme P, Bauersachs R, Hetjens S, Weiss C; Working Group Members. Accuracy of a Rapid Diagnostic Test for the Presence of Direct Oral Factor Xa or Thrombin Inhibitors in Urine-A Multicenter Trial. Thromb Haemost. 2020 Jan;120(1):132-140. doi: 10.1055/s-0039-1700545. Epub 2019 Nov 8.

    PubMed 31705521

  • Kim PY, Di Giuseppantonio LR, Wu C, Douketis JD, Gross PL. An assay to measure levels of factor Xa inhibitors in blood and plasma. J Thromb Haemost. 2019 Jul;17(7):1153-1159. doi: 10.1111/jth.14451. Epub 2019 May 10.

    PubMed 30985986

  • Mitrovic D, van Elp M, Veeger N, Lameijer H, Meijer K, van Roon E. Protocols for perioperative management of direct oral anticoagulants in hospitals: opportunities for improvement. Curr Med Res Opin. 2023 Jan;39(1):13-18. doi: 10.1080/03007995.2022.2141962. Epub 2022 Nov 12.

    PubMed 36305802

  • Flaker GC, Theriot P, Binder LG, Dobesh PP, Cuker A, Doherty JU. Management of Periprocedural Anticoagulation: A Survey of Contemporary Practice. J Am Coll Cardiol. 2016 Jul 12;68(2):217-26. doi: 10.1016/j.jacc.2016.04.042.

    PubMed 27386777

  • Kurlander JE, Barnes GD, Anderson MA, Haymart B, Kline-Rogers E, Kaatz S, Saini SD, Krein SL, Richardson CR, Froehlich JB. Mind the gap: results of a multispecialty survey on coordination of care for peri-procedural anticoagulation. J Thromb Thrombolysis. 2018 Apr;45(3):403-409. doi: 10.1007/s11239-018-1625-2.

    PubMed 29423559

  • Wamala H, Scott IA, Caney X. Perioperative management of new oral anticoagulants in patients undergoing elective surgery at a tertiary hospital. Intern Med J. 2017 Dec;47(12):1412-1421. doi: 10.1111/imj.13513.

    PubMed 28589690

  • Korenke M, Samba S, Stam B, Leis A, Kheterpal S, Colquhoun DA. The perioperative management of direct oral anticoagulants, a single center observational study. J Clin Anesth. 2020 Mar;60:92-93. doi: 10.1016/j.jclinane.2019.08.035. Epub 2019 Sep 11. No abstract available.

    PubMed 31520860

  • Nascimento T, Birnie DH, Healey JS, Verma A, Joza J, Bernier ML, Essebag V. Managing novel oral anticoagulants in patients with atrial fibrillation undergoing device surgery: Canadian survey. Can J Cardiol. 2014 Feb;30(2):231-6. doi: 10.1016/j.cjca.2013.11.027. Epub 2013 Dec 4.

    PubMed 24461924

  • Skeith L, Lazo-Langner A, Kovacs MJ. The equipoise of perioperative anticoagulation management: a Canadian cross-sectional survey. J Thromb Thrombolysis. 2014 May;37(4):411-3. doi: 10.1007/s11239-013-0960-6. No abstract available.

    PubMed 23868474

  • Faraoni D, Samama CM, Ranucci M, Dietrich W, Levy JH. Perioperative management of patients receiving new oral anticoagulants: an international survey. Clin Lab Med. 2014 Sep;34(3):637-54. doi: 10.1016/j.cll.2014.06.006. Epub 2014 Jul 23.

    PubMed 25168948

  • Chiang YZ, Al-Niaimi F, Craythorne E, Mallipeddi R. Perioperative management of novel oral anticoagulants in skin surgery: a national survey. Br J Dermatol. 2016 Sep;175(3):615-8. doi: 10.1111/bjd.14462. Epub 2016 Jun 2. No abstract available.

    PubMed 26854272

  • Douketis JD, Spyropoulos AC, Anderson JM, Arnold DM, Bates SM, Blostein M, Carrier M, Caprini JA, Clark NP, Coppens M, Dentali F, Duncan J, Gross PL, Kassis J, Kowalski S, Lee AY, Le Gal G, Le Templier G, Li N, MacKay E, Shah V, Shivakumar S, Solymoss S, Spencer FA, Syed S, Tafur AJ, Vanassche T, Thiele T, Wu C, Yeo E, Schulman S. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant Who Need an Elective Surgery or Procedure: Design and Rationale. Thromb Haemost. 2017 Dec;117(12):2415-2424. doi: 10.1160/TH17-08-0553. Epub 2017 Dec 6.

    PubMed 29212129

  • Merrelaar AE, Bogl MS, Buchtele N, Merrelaar M, Herkner H, Schoergenhofer C, Harenberg J, Douxfils J, Siriez R, Jilma B, Spiel AO, Schwameis M. Performance of a Qualitative Point-of-Care Strip Test to Detect DOAC Exposure at the Emergency Department: A Cohort-Type Cross-Sectional Diagnostic Accuracy Study. Thromb Haemost. 2022 Oct;122(10):1723-1731. doi: 10.1055/s-0042-1750327. Epub 2022 Jul 4.

    PubMed 35785816

Questions about this trial

What is this clinical trial studying?

A study testing PAUSE Perioperative DOAC Management and ASRA Perioperative DOAC Management in people with Atrial Fibrillation (AF) and VTE, run by McMaster University at 14 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 9 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States, Canada, Belgium, Greece. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact James Douketis, MD (905-522-1155 ext. 36178, jdouket@mcmaster.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of patients randomized to each study arm with a residual pre-operative DOAC level < 30 ng/mL (time frame: Day 1). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06957366, which also lists 46 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2025.

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