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PAUSE Study Establishes Simple Approach to Perioperative Management of Direct Oral Anticoagulants


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The largest study to date addressing the common problem of perioperative direct oral anticoagulant (DOAC) management has shown that patients with atrial fibrillation can safely stop taking their anticoagulant for 1 day before and after procedures with a low risk of bleeding and for 2 days before and after procedures with a higher bleeding risk, according to data presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1

In patients with atrial fibrillation who were receiving a DOAC and required anticoagulant interruption for an elective surgery or procedure, the PAUSE (Perioperative Anticoagulant Use for Surgery Evaluation) protocol—a simple, standardized perioperative management strategy that forgoes heparin bridging and preoperative coagulation testing—was associated with low rates of major bleeding (< 2%) and arterial thromboembolism (< 1%). The management strategy was also associated with a high proportion of patients (> 90% overall and 98.8% at high bleeding risk) having a minimal-to-no residual preoperative anticoagulant level at the time of the surgery or procedure.2 At a press briefing held during the ASH meeting, experts emphasized that this study could establish an important standard for patient care.

James Douketis, MD, FRCP

James Douketis, MD, FRCP

“This is the first study to demonstrate the safety of a standardized perioperative management approach in patients with atrial fibrillation who are taking a direct oral anticoagulant,” said lead author of the study, James Douketis, MD, FRCP, Staff Physician in Vascular Medicine and General Internal Medicine at St. Joseph’s Healthcare Hamilton, and Professor of Medicine at McMaster University in Ontario, Canada. “We hope this study will provide the foundation for a simple and safe standard of care and offer clear, evidence-based guidance that can be used consistently across different medical specialties.”

Study Background

As Dr. Douketis explained, the perioperative management of patients taking a DOAC for atrial fibrillation around the time of an elective surgery or procedure is a common clinical problem. Moreover, atrial fibrillation is increasing in prevalence as the population ages. Nevertheless, said Dr. Douketis, since the introduction of DOACs almost 10 years ago, few studies have looked at how to manage patients who require an array of operative treatments, from dental procedures to major surgery.

“It’s not surprising that there’s a lot of variability in clinical practice and inconsistency around guideline recommendations,” said Dr. Douketis. Clinicians are uncertain as to the timing of DOAC interruption and resumption, the use perioperative bridging anticoagulation, and the need for blood tests to measure coagulation function prior to surgery, he noted.

We hope this study will provide the foundation for a simple and safe standard of care and offer clear, evidence-based guidance that can be used consistently across different medical specialties.
— James Douketis, MD, FRCP

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For this study, Dr. Douketis and colleagues aimed to establish a safe but standardized and easy-to-use perioperative DOAC management approach. The study was anchored on having a DOAC-specific interruption, resumption intervals, no perioperative heparin bridging, and no preoperative coagulation function testing. The study was also designed to show that over 90% of patients had a minimal-to-undetectable residual anticoagulant level at the time of surgery.

Investigators recruited patients with atrial fibrillation taking one of three DOACs (apixaban, dabigatran, rivaroxaban) who required anticoagulant interruption for an elective surgery or procedure. Those with severely impaired renal function were excluded from the study.

As Dr. Douketis reported, patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance. DOAC therapy was interrupted for 1 day before and after surgery for a low–bleeding risk surgery and 2 days before and after a high–bleeding risk surgery. A blood sample was obtained just before the procedure to measure residual DOAC levels; however, the levels were not used to guide clinical care and were, in fact, batch analyzed well after the patient’s procedure had been completed. Patients received weekly follow-up for 4 weeks and did not receive heparin bridging or preoperative coagulation testing.

Major Bleeding and Arterial Thromboembolism

As Dr. Douketis reported, 3,640 patients were screened for the study, with 17% of subjects excluded. Ultimately, investigators enrolled 1,257 patients in the apixaban cohort, 668 patients in the dabigatran cohort, and 1,082 patients in the rivaroxaban cohort. The study was conducted in 23 centers over a 4-year period.

Investigators had anticipated that rates of arterial thromboembolism, including stroke and transient ischemic attack, would be approximately 0.5% and wanted to have enough power statistically to exclude a rate of 1.5%, which was achieved in all three cohorts. The rate of arterial thromboembolism was 0.16% (95% confidence interval [CI] = 0%–0.48%) in the apixaban cohort, 0.6% (95% CI = 0%–1.33%) in the dabigatran cohort, and 0.37% (95% CI = 0%–0.82%) in the rivaroxaban cohort.

PAUSE STUDY

  • A simple, perioperative direct oral anticoagulant (DOAC) management strategy was associated with low rates of major bleeding (< 2%) and arterial thromboembolism (< 1%) in patients with atrial fibrillation undergoing elective surgery or procedure.
  • A high proportion of patients also had a minimal-or-no residual DOAC level at the time of the surgery or procedure.

The study was also designed to have a rate of major bleeding of approximately 1% but to have enough power to exclude a rate of 2%. Although this was achieved in the dabigatran cohort, both the apixaban and rivaroxaban cohorts fell just short. The 30-day postoperative rate of major bleeding was 1.35% (95% CI = 0%–2%) in the apixaban cohort, 0.90% (95% CI = 0%–1.73%) in the dabigatran cohort, and 1.85% (0%–2.65%) in the rivaroxaban cohort.

Blood analysis showed that a high proportion of patients had minimal to no residual preoperative anticoagulant levels at the time of surgery or procedure. A DOAC level of less than 50 ng/mL occurred in 90.5% of patients in the apixaban cohort, 95.1% of the dabigatran cohort, and 96.8% of the rivaroxaban cohort. In patients undergoing a high–bleeding risk procedure, 98.8% had minimal to undetectable levels of DOAC at the time of surgery or procedure.

When asked about the implications of this study regarding the need for a reversal agent with DOAC therapy, Dr. Douketis responded: “For patients having an elective procedure or surgery, I think it means that a reversal agent is probably not needed in the vast majority of cases. This study shows that very few people undergoing high–bleeding risk surgeries have any residual anticoagulant level that would warrant a reversal agent. I think the reversal agent should be directed toward patients requiring an emergency surgery, which is a very different clinical scenario.” 

DISCLOSURE: The study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, and Aniara/Hyphen BioMed. Dr. Douketis has reported financial relationships with Bayer, Janssen, BMS, Biotie, Daiichi Sankyo, Boehringer Ingelheim, The Medicines Company, Sanofi, AstraZeneca, Portola, and Pfizer.

REFERENCES

1. Douketis J, Spyropoulos AC, Duncan JM, et al: Perioperative anticoagulant use for surgery evaluation (PAUSE) study. 2018 ASH Annual Meeting & Exposition. Abstract LBA-5. Presented December 4, 2018.

2. Schulman S, Carrier M, Lee AY, et al: Perioperative management of dabigatran: A prospective cohort study. Circulation 132:167-173, 2015.


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