By Megan Brooks
NEW YORK (Reuters Health) - 7/8/2019
Researchers have developed and validated a simple, standardized way to manage patients treated with a direct oral anticoagulant (DOAC) who need an elective surgery or procedure.
The "PAUSE" protocol can be summarized as "2 days off before/after high-bleed-risk surgery, and 1 day off before/after low-bleed-risk procedure," Dr. James Douketis from McMaster University, in Hamilton, Canada, told Reuters Health by email.
"Prior to PAUSE, there was really no evidence-based standard-of-care to manage these patients and practice guidelines . . . were based on low-quality studies or expert opinion; it was our impression that practice varied widely," said Dr. Douketis.
The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study was conducted at 23 clinical centers in Canada, the United States and Europe. It had 3,007 adult participants with atrial fibrillation who were long-term users of apixaban, dabigatran etexilate, or rivaroxaban, and who were scheduled for an elective surgery or procedure and could adhere to the DOAC-interruption protocol.
The DOAC regimens were omitted (without heparin bridging or preop coagulation function testing) for one day before a low-bleeding-risk procedure and two days before a high-bleeding-risk procedure. They were resumed one day after a low-bleeding-risk procedure and two to three days after a high-bleeding-risk procedure. Patients were followed for 30 days after the operation.
"The aim of PAUSE was to provide a standardized perioperative management approach for DOAC-treated patients that was deemed safe, easy to apply by clinicians, and easy to follow by patients," Dr. Douketis told Reuters Health.
According to the results, online August 5 in JAMA Internal Medicine, the 30-day postoperative rates of major bleeding were less than 2% and the rates of stroke were less than 1%.
"Furthermore, a high proportion of patients (>90% overall; 98.8% of those at high bleeding risk) had a minimal or no residual anticoagulant level at the time of the procedure," the researchers report.
Based on the primary analysis cohort, the team's hypothesis that the PAUSE protocol would exclude a 2% rate of major bleeding was supported in the dabigatran cohort (0.90%) but not in the apixaban cohort (1.35%) or rivaroxaban cohort (1.85%), they say. The hypothesis that the PAUSE strategy would exclude a 1.5% rate of arterial thromboembolism was supported in all three cohorts.
In the per-protocol analysis, excluding a 2% rate of major bleeding was supported in the dabigatran cohort (1.0%) and the apixaban cohort (1.2%), but not in the rivaroxaban cohort (1.69%), whereas excluding a rate of arterial thromboembolism of 1.5% was supported in all three cohorts, they report.
The researchers note that most other studies that have assessed perioperative DOAC management are not comparable to the PAUSE study because the management was not standardized, perioperative heparin bridging was allowed, and fewer patients with high bleeding risk were included.
Dr. Douketis and colleagues say a strength of their study is the "generalizability of the results to patients assessed in clinical practice, as a high proportion of screened patients were enrolled (83%) and few were lost to follow-up (<1%). Another strength is the clinical applicability of the DOAC regimen management we assessed, as most patients adhered to the perioperative DOAC therapy interruption (95%) and resumption (93%) management protocol."
"The simple strategy of omitting DOAC regimens for 1 day before and after a low-bleeding-risk procedure and 2 days before and after a high-bleeding-risk procedure (except for patients using dabigatran with a CrCl <50 mL/min) is, therefore, likely to be easily adoptable in clinical practice," the research team concludes.
"Despite each manufacturer's recommendations, many physicians remain uneasy regarding when and for how long to stop oral anticoagulants prior to surgery or other interventions," Dr. Stephen L. Winters, director, Cardiac Rhythm Management Program, Atlantic Health System's Morristown Medical Center in New Jersey, commented in email to Reuters Health.
"In many situations, these stroke-sparing drugs are stopped for periods of time far in excess to even individual manufacturer's recommendations, placing patients at greater risk," said Dr. Winters, who wasn't involved in the study.
"The results from this study should give physicians a greater degree of confidence regarding the timing and needed duration for discontinuation of anticoagulants prior to operations and other invasive procedures. Applying the recommendations from this study will help physicians keep patients on oral anticoagulants remain as well protected as possible around the time of surgery and other interventions," said Dr. Winters.
The PAUSE study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada and the CanVECTOR research network. Dr. Douketis reported personal fees from Pfizer, Sanofi, Leo Pharma, Bristol-Myers Squibb, Janssen, The Merck Manual, and UpToDate.
JAMA Intern Med 2019.