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LBA-5 Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
Adult, Diseases, Bleeding and clotting, Study Population, Clinically relevant, Thromboembolism, Thrombotic Disorders, VTE
Tuesday, December 4, 2018, 7:30 AM-9:15 AM
Hall AB (San Diego Convention Center)

James Douketis, MD1, Alex C. Spyropoulos, MD2*, Joanne M Duncan, MSc1*, Marc Carrier, MD3, Gregoire Le Gal, MD, PhD4, Alfonso J Tafur, MD, MS, RPVI, FSVM5*, Thomas Vanassche, MD6*, Peter Verhamme, MD, PhD6*, Sudeep P Shivakumar, MD, BSc7*, Peter L. Gross, MD1*, Agnes Yuet Ying Lee, MD, MSc, FRCPC8, Erik Yeo, MD, FACP, FRCPC9, Susan Solymoss, MD10, Jeannine Kassis, MD11, Genevieve Le Templier12*, Stephen Kowalski, MD13*, Mark Blostein, MD FRCPC14*, Vinay Shah, MD15*, Elizabeth MacKay, MD, FRCPC16*, Cynthia M. Wu, MD, FRCPC17*, Nathan Clark, PharmD18*, Shannon M. Bates, MD, FRCPC, MSc1, Fred Spencer, MD, FRCP1*, Eleni Arnaoutoglou, MD19*, Michiel Coppens, MD20*, Donald M. Arnold, MD, MSc, FRCPC1, Joseph A Caprini, MD, MS, FACS, RVT5*, Na Li, PhD1*, Karen Moffat, MT21*, Syed Summer, MD22* and Sam Schulman, MD, PhD, FRCPC1,23

1Department of Medicine, McMaster University, Hamilton, ON, Canada
2The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Medicine, Northwell Health at Lenox Hill Hospital, New York, NY
3Department of Medicine, Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
4L’Institut du Savoir Montfort, L’Hopital Montfort,, Ottawa, ON, Canada
5NorthShore University HealthSystem, Evanston, IL
6Department of Cardiovascular Sciences, Universitaire Ziekenhuizen, Leuven, Belgium
7Department of Medicine, Dalhousie University, Halifax, NS, Canada
8Department of Medicine, University of British Columbia, Vancovuer, BC, Canada
9Department of Medicine, University of Toronto, Toronto, ON, Canada
10Department of Medicine, Montreal General Hospital, McGill University, Montreal, QC, CAN
11Department of Medicine, Université de Montréal, Montreal, ON, Canada
12Department of Internal Medicine, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada
13Department of Anesthesiology, University of Manitoba, Winnipeg, MB, Canada
14Department of Medicine, Jewish General Hospital, McGill University, Montreal, QC, Canada
15Department of Medicine, Henry Ford Hospital, Detroit, MI
16Department of Medicine, University of Calgary, Calgary, AB, Canada
17Department of Medicine, University of Alberta, Edmonton, AB, Canada
18Department of Pharmacy, Kaiser Permanente, Denver, CO
19Department of Anesthesiology, University of Thessaly, Larissa, Larissa, Greece
20Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
21Hamilton Regional Laboratory Medicine Program, McMaster University, Hamilton, ON, Canada
22Department of Anesthesiology, Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada
23Department of Medicine, Division of Hematology and Thromboembolism, Department of Obstetrics and Gynecology, The First I.M. Sechenov Moscow State Medical University, Russia, Hamilton, Canada

Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure.

Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl<50 mL/min (Figure 1). A blood sample was obtained just before the procedure to measure residual DOAC levels (Appendix 2). Heparin bridging and preoperative coagulation testing were not used to manage patients. Patient follow-up occurred weekly for 30 days post-procedure for the primary clinical outcomes of major bleeding and arterial thromboembolism (Appendix 3). The incidence (95% confidence interval [CI]) of clinical outcomes was determined for each DOAC cohort using an intention-to-treat (ITT) analysis (interrupted at least 1 DOAC dose) and per-protocol analysis (adhering to DOAC interruption and resumption protocol).

Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level <50 ng/ml occurred in 90.5% of patients in the apixaban cohort, in 95.1% of the dabigatran cohort and in 96.8% of the rivaroxaban cohort. Of 1007 patients having a high bleeding risk procedure, 832 (82.6%) had DOAC levels measured: 98.8% had a level <50 ng/mL (Table 4). Rates of major bleeding and arterial thromboembolism in the per protocol analysis were comparable to those of the ITT analysis (Table 5).

Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (<2%) and ATE (<1%). Further, a high proportion of patients (>90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care.

Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays).

Acknowledgements: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap.

Disclosures: Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos: Janssen Scientific Affairs, LLC: Consultancy. Carrier: Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche: Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme: Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar: Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross: Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee: Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier: BMS-pfizer: Honoraria. Wu: Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Bates: Bayer, Inc.: Other: site investigator for sponsored study, “Phase III, Multicentre, randomized trial to compare rivaroxaban with placebo for the treatment of symptomatic leg superficial vein thrombosis” (study funding to institution, no direct payments received); Eli Lilly Canada/May Cohen Chair in Women's Health: Other: unencumbered salary support (Eli Lilly Canada does not manufacture anticoagulants or antithrombotic agents). Coppens: Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold: Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; UCB: Consultancy. Caprini: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer: Octapharma: Honoraria. Schulman: Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.