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

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

Overview

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.

Interventions

• 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.

Primary outcome measures

• Proportion of patients randomized to each study arm with a residual pre-operative DOAC level < 30 ng/mL [Time frame: Day 1]

Secondary outcome measures (8)

• Proportion of patients with a residual pre-operative DOAC level < 50 ng/mL. [Time frame: Day 1]
• Clinically relevant nonmajor bleeding [Time frame: Day 28]
• Arterial thromboembolic Events (ATE) [Time frame: Day 28]
• Major bleeding [Time frame: Day 28]
• Minor bleeding [Time frame: Day 28]
• Venous thromboembolic Events (VTE) [Time frame: Day 28]
• Myocardial infarction [Time frame: Day 28]
• All-cause death [Time frame: Day 28]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 6 centers

• Hartford Health Care — Hartford
• North Shore University Health — Evanston
• Brigham and Woman's Hospital — Boston
• Henry Ford Health Care — Detroit
• Northwell Health System — New York
• Thomas Jefferson University Hospital — Philadelphia

Canada · 6 centers

• Winnipeg Health Sciences Center — Winnipeg
• St. Joesph's Healthcare — Hamilton
• Juravinski — Hamilton
• The Ottawa Hospital — Ottawa
• L'Hospital Montfort — Ottawa
• Toronto General Hospital — Toronto

Belgium · 1 center

• University of Leuven — Leuven

Greece · 1 center

• University of Thessaly — Larissa

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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 28589690

Identifiers

NCT: NCT06957366 · PAUSE 2 RCT (CTO 4938)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗