Implications of the BRIDGE Trial: Should We Forgo Perioperative Anticoagulation?

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Pharmacy Times, January 2016 The Aging Population, Volume 82, Issue 1

Atrial fibrillation is characterized by abnormal impulse formations that cause the heart to beat irregularly.

Atrial fibrillation (AF) is characterized by abnormal impulse formations that cause the heart to beat irregularly. AF accounts for onethird of cardiac rhythm hospitalizations and affects more than 5 million Americans.1 All types of AF increase the risk of thromboembolism (TE), which can lead to stroke, myocardial infarction, transient ischemic attack, and other complications.

Periprocedural management of anticoagulation is based on a risk:benefit assessment comparing an individual’s risk of TE with the risk of bleeding. The American College of Cardiology and the American Heart Association’s 2014 guidelines recommend bridging therapy with unfractionated heparin or low molecular weight—heparin (LMWH) in patients with AF who have a mechanical heart valve, history of stroke, or CHA2DS2-VASc score of at least 2. However, there is sparse evidence regarding the use of bridging in nonvalvular AF. Warfarin is typically stopped up to 1 week prior to the procedure, but the interruption duration and time to resume the oral anticoagulant remains unclear.2

The results of a trial—Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE)—were recently published in the New England Journal of Medicine and addressed the uncertainty of bridging in the perioperative setting. The BRIDGE investigators hypothesized that forgoing bridging altogether would be noninferior to bridging with LMWH for the prevention of perioperative arterial TE and would be superior to bridging in regard to the outcome of major bleeding.

This randomized, double-blind, placebo-controlled trial enrolled patients 18 years or older with chronic (permanent or paroxysmal) AF or flutter who had received warfarin therapy with a goal international normalized ratio of 2.0 to 3.0 for the previous 3 months and who were undergoing an elective procedure that required an interruption of warfarin (see the trial for detailed inclusion/ exclusion criteria).

A total of 1884 patients were randomly assigned placebo (n = 950) or dalteparin 100 IU/kg subcutaneously twice daily (n = 934). Bridging therapy began 3 days before the procedure and continued until 24 hours before the procedure; it was then restarted postoperatively at the investigator’s discretion, depending on the procedure’s bleeding risk, and continued for 5 to 10 days. Warfarin therapy was stopped 5 days before the procedure and then restarted on the evening of or the day after the procedure at the patient’s usual dose. The management of perioperative antiplatelet therapy was left to the site investigator’s discretion.

The mean age of the patient population was 71.7 years, the mean CHADS2 score was 2.3, and 34.7% of patients were taking aspirin. A total of 1722 of the 1884 patients underwent the planned procedure (89.4% classified as minor/low bleeding risk). In the final analysis at 30 days after the procedure, the incidence of arterial TE was 0.4% in the no-bridging group and 0.3% in the bridging group (95% CI, —0.6 to 8.0; P = .01 for noninferiority). The no-bridging group showed superiority to bridging in the major bleeding rate analysis: 1.3% versus 3.2%, respectively (relative risk, 0.41; 95% CI, 0.20-0.78; P = .005). The median time to major bleeding was 7 days after the procedure (interquartile range, 4-18 days).

The BRIDGE investigators concluded from their analysis that patients with chronic AF who require temporary discontinuation of warfarin therapy for an elective operation or other elective invasive procedure do not require bridging therapy. This reinforces the hypothesis that the interruption in warfarin therapy does not lead to rebound hypercoagulability. They also concluded that bridging with an LMWH increases these patients’ risk of major bleeding without the benefit of decreasing risk of arterial TE.

It is important to note that because the average CHADS2 score of this trial was 2.3% and 89.4% of procedures were classified as minor, the overall rate of thrombosis was low. Although the high percentage of minor procedures resulted in a population with a relatively low bleeding risk and a population with mostly low-bleed risk was studied, both major and minor bleeding end points were found to be significantly higher in the bridging group.

It is possible that the LMWH bridging agent selection may reduce the external validity of the findings because not only is dalteparin uncommonly used in practice, but its only off-label use is limited to patients with mechanical heart valves—a population excluded from stratification. Despite these shortcomings, the BRIDGE trial confirms what most observational studies have already suggested when comparing TE and bleeding risks in bridging groups versus no-bridging groups3-5: for patients stable on warfarin for AF with low TE risk, it is reasonable to forgo bridging with LMWH prior to a minor elective procedure. This strategy would especially benefit patients with a significant bleeding risk.

Dr. Adams is a clinical assistant professor at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, and a clinical pharmacist in critical care at Robert Wood Johnson University Hospital in Somerset, New Jersey. Dr. Resseguie is an advanced practice anticoagulation pharmacist for the Brigham & Women’s Hospital Anticoagulation Management Service in Boston, Massachusetts.

References

  • Douketis JD, Spyropoulos AC, Kaatz S, et al; BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-833. doi: 10.1056/NEJMoa1501035.
  • January CT, Wann LS, Alpert JS, et al; ACC/AHA Task Force Member. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):2246-2280. doi: 10.1161/CIR.0000000000000040.
  • Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure: substudy of the RE-LY Trial. Thromb Haemost. 2015;113(3):625-632. doi: 10.1160/TH14-04-0305.
  • Steinberg BA, Peterson ED, Kim S, et al; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators and Patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation. 2015;131(5):488-494. doi: 10.1161/CIRCULATIONAHA.114.011777.
  • Kim TH, Kim JY, Mun HS, et al. Heparin bridging in warfarin anticoagulation therapy initiation could increase bleeding in non-valvular atrial fibrillation patients: a multicenter propensity-matched analysis. J Thromb Haemost. 2015;13(2):182-190. doi: 10.1111/jth.12810.