Muhammad Rizwan Husain, MD
Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, Vanassche T, Verhamme P, Shivakumar S, Gross PL, et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med. 2019;179:1469-1478.
In this entry, I discuss a publication by Douketis and colleagues regarding the perioperative management of patients who have atrial fibrillation (AF) and are on a Direct oral anticoagulants (DOAC) and do not undergo a perioperative heparin bridge, who are then evaluated for rates of major bleeding and arterial thromboembolism.
DOACs have been in common use for AF since 2010, and there has been an increased use over the years due to its easy-to-administer dosing, no need for regular INR checks, nor any requirements for dietary adjustments. The concerns of intraoperative and post-operative bleeding with recent DOAC use, followed by the risk of an arterial embolic event like stroke while briefly off DOACs, has raised many concerns amongst physicians about when to stop and resume DOACs in patients scheduled for surgery. Furthermore, is there any benefit to bridge these patients with heparin during the perioperative period? The authors conduced the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study to help answer these questions, which involved a simple strategy to hold DOACs briefly depending on the bleeding risk of the elective procedure and to not bridge with heparin so as to keep a simple and standard interruption and resumption protocol for all physicians to follow. The primary outcome was to evaluate major bleeding and arterial thromboembolism (ischemic strokes or TIA and systemic embolism) from the time DOACs were stopped until 30 days post-operatively. Secondary outcomes included non-major bleeding, minor bleeding, death, MI, DVT or PE.
This was a prospective management study. All eligible patients were 18 years or older, with known AF and on a DOAC, who were planned to have elective surgery. The patients were divided according to type of DOAC they were on; apixaban (5mg daily or 2.5mg twice a day), dabigatran (150 mg or 110 mg twice a day), or rivaroxaban 20mg or 15mg daily). Patients were excluded if they were on apixaban and had a creatinine clearance of less than 25ml/min or if they were on dabigatran or rivaroxaban and had a creatinine clearance of less than 30ml/min, or had more than 1 surgical procedure planned within the 30 days. Timing of when to stop and resume DOAC was based on the bleeding risk of the procedure (divided between high bleeding versus low bleeding risk surgery). No perioperative bridging therapy (heparin) was done.
For low bleeding risk surgeries, DOACs were stopped 1 day prior and resumed 1 day after surgery. For high bleeding risk surgeries, DOACs were stopped 2 days prior and resumed 2 to 3 days (48-72 hours) postoperatively. The only exception was for patients on dabigatran for whom timing of interruption was longer if patients had a creatinine clearance of less than 50mL/min (2 days prior for low bleeding vs 4 days prior for high bleeding risk surgeries).
Between August 2014 and July 2018, a total of 3007 patients were included in the primary analysis — apixaban (41.8%), dabigatran (22.2%), and rivaroxaban (36.0%) — and due to protocol deviation, a total of 2624 patients were included in the per protocol analysis.
The primary analysis demonstrated a 30-day postoperative rate of major bleeding of 1.35% for apixaban (95% CI,0-2.00%), 0.9% for dabigatran (95%CI,0-1.73%) and 1.85% for rivaroxaban (95%CI,0-2.65%). The rate of bleeding for high risk procedures was 2.96% for apixaban (95% CI, 0-4.68%), 0.88 % for dabigatran (95% CI, 0-2.62%) and 2.95% for rivaroxaban (95% CI, 0-4.76%). Arterial thromboembolism (ischemic strokes or TIA and systemic embolism) was 0.16% for apixaban (95% CI, 0-0.48%), 0.60% for dabigatran (95%CI, 0-1.33%) and 0.37% for rivaroxaban (95% CI, 0-0.82%). In the secondary analysis, non-major bleeding occurred in 2% and death occurred in 0.3% of patients.
Anticoagulant levels checked prior to surgery (though did not guide clinical judgement) to see the number of patients who had a level less than 50ng/ml was found to be 90.5% for the apixaban group, 95.1% for Dabigatran and 96.8% for rivaroxaban.
The study indeed demonstrated that a simple interruption of DOAC prior to surgery and resumption post-operatively without any heparin bridge resulted in low rates of major bleeding, as well as systemic embolism.
The study also has a few limitations. This was a cohort study, so risk of selection bias is present, especially considering that around 10-15% of patients included in the different cohorts (apixaban, dabigatran, rivaroxaban) dropped out in the per-protocol analysis. Since patient follow-up was mostly by telephone and clinic visits as required, it is hard to ascertain if any post-operative symptoms like TIA were not accurately recorded. Edoxaban, another DOAC in use today, was not part of the study, due to its non-availability during trial initiation. The study also did not include patients who had VTE.
Overall, the study provides guidance for physicians to help with decision-making regarding timing of DOAC interruption prior to surgical procedures in patients with atrial fibrillation.