Bridging Therapy for A-fib Patients Fails to Prevent Thromboembolism, Increases Bleeding
Among A-fib patients who need to interrupt warfarin treatment for an elective procedure, bridging anticoagulation does nothing to curb the likelihood of arterial thromboembolism, according to a study published online June 22, 2015, ahead of print in the New England Journal of Medicine. Moreover, bridging increases the risk of major bleeding compared with placebo.
In the BRIDGE Study, researchers led by Thomas L. Ortel, MD, PhD, of Duke University Medical Center (Durham, NC), enrolled 1,884 patients (mean age 71.7 years; 73.4% men) with chronic A-fib at 108 US and Canadian centers who were slated to undergo an elective operation or other elective invasive procedure that required interruption of warfarin therapy.
Patients were randomized to receive low-molecular-weight heparin (100 IU of dalteparin [Fragmin; Eisai; Woodcliff Lake, NJ] per kg subcutaneously twice daily; n = 934) or matching placebo (n = 950) from 3 days to 24 hours before the procedure and then for 5 to 10 days after. Warfarin was stopped 5 days prior to the procedure and resumed within 24 hours postprocedure.
Mean CHADS2 score was 2.3, and 38.3% of patients had a score of 3 or higher. Roughly one-third of patients were taking aspirin, and 7.2% were taking another antiplatelet drug.
Only 1,722 patients actually underwent their planned procedure. The procedures were GI in 44.0%, cardiothoracic in 17.2%, and orthopedic in 9.2%; most (89.4%) were classified as minor. Adherence to the study-drug protocol was reported in 86.5% of patients before the procedure and 96.5% after.
No Harm in Forgoing Bridging
At 30 days, the incidence of arterial thromboembolism (stroke, TIA, and systemic embolism; primary efficacy outcome) was noninferior in the no-bridging vs bridging group. Also, major bleeding (primary safety outcome) occurred less often among patients in the placebo arm, indicating superiority compared with bridging therapy. Most secondary outcomes occurred at similar rates in both groups, although minor bleeding was more common with bridging (table 1).
An as-treated analysis for arterial thromboembolism provided outcomes consistent with the main findings.
None of the major bleeds were fatal, and the median time to a major bleeding event after the procedure was 7 days (range 4-18 days).
‘Net Clinical Benefit’ for Not Bridging
“Taken together, these findings show that there is a net clinical benefit in favor of a strategy of forgoing bridging, as compared with perioperative bridging with low-molecular-weight heparin,” Dr. Ortel and colleagues write, adding that the findings are consistent with what has been shown in substudies of the RE-LY trial and ORBIT-AF.
The thought process behind bridging treatment, they write, “has been anchored on the premise that the associated higher bleeding risk was clinically acceptable because it would be offset by a lower risk of perioperative arterial thromboembolism.” However, the authors say this and other studies show that “the perioperative risk of arterial thromboembolism in patients with atrial fibrillation during interruption of warfarin treatment may have been overstated and may not be mitigated by bridging anticoagulation.”
Mechanisms of arterial thromboembolism could potentially be more closely associated with the type of procedure and interoperative blood pressure changes, the authors suggest. “The premise that warfarin interruption leads to rebound hypercoagulability and that the milieu of the procedure confers a prothrombotic state, which in turn leads to arterial thromboembolism, is not supported by the results of this trial,” they add.
Limitations of the study, the investigators point out, include its underrepresentation of patient groups: those with a CHADS2 score of 5 or 6, patients undergoing major surgical procedures, and those with mechanical heart valves. Additionally, “the overall rate of arterial thromboembolism was lower than expected, which potentially affected the power of the trial to detect a benefit associated with bridging,” they write.
Also, the observed rate of major bleeding was “modest,” the authors say. “However, our bridging protocol was designed to minimize bleeding, and the higher rates of bleeding reported in other studies of bridging anticoagulation probably reflect resumption of bridging therapy too soon after operations with a high bleeding risk or a lack of standardized bridging protocols.”
Dr. Ortel and colleagues also acknowledge the concerning reduction in sample size due to a lower than expected rate of arterial thromboembolism. They considered extending the trial, they report, but did not “because the added statistical power would have been negligible and because recruitment had been challenging throughout the course of the trial.”
Lastly, the investigators suggest that with the advent of new oral anticoagulants, some might find the results irrelevant. But “warfarin remains widely used among patients with atrial fibrillation,” they contend. “Furthermore, the trial findings may also apply to the newer agents.”
Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;Epub ahead of print.
- BRIDGE was supported by grants from the National Heart, Lung, and Blood Institute.
- Eisai provided dalteparin for the study.
- Dr. Ortel reports receiving research grants from Instrumentation Laboratory and the National Heart, Lung, and Blood Institute and consulting for CSL Behring, Daiichi Sankyo, and Instrumentation Laboratory.