Christopher Adams, PharmD, RPh, BCPS

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.

 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 CHA

-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.

The results of a trial—Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE)&mdash;were recently published in the 

 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 CHADS

 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 groups

: 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.

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Articles

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

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

Target-specific oral anticoagulants (TSOACs) dabigatran, rivaroxaban, apixaban, and edoxaban are now being used in a larger and more diverse patient population. Despite the fact that bleeding with TSOACs is not expected to be higher compared with the use of other anticoagulant agents, life-threatening bleeding is still a concern. For most situations, a specific antidote may not be needed due to the short half-life of TSOACs. However, the availability of an antidote is essential for the management of any emergency situation. At this time, there are no clinically available reversal agents and there is a lack of guidance on how to restore hemostasis in the presence of significant bleeding from TSOACs.

Current reversal strategies focus on drug removal and managing bleeding. Immediate discontinuation of all anticoagulant and antiplatelet therapy is standard. Activated charcoal is a possible option if treatment is begun within 2 hours of the drug ingestion. Hemodialysis may facilitate removal of dabigatran if clinically feasible (approximately 60% removed in 2-3 hours). Hemostatic agents used as options for management of bleeding include antifibrinolytics (aminocaproic acid and tranexamic acid) and desmopressin. Other hemostatic agents, including activated prothrombin complex concentrate (aPCC), 3- and 4-factor prothrombin complex concentrate (PCC), and recombinant factor VIIa (rVIIa) have all been investigated, but their roles remain inconclusive.

In various healthy volunteer trials, 3-factor PCC and 4-factor PCC have had variable effects on correcting surrogate lab markers.

 A recent study with 3- and 4-factor PCC showed a decrease in prothrombin time in rivaroxaban-treated patients but no effect on abnormal activated partial thromboplastin time or anti-Xa activity.

 aPCC has shown promise in in vitro analyses and was shown to correct abnormal thrombin generation indices in healthy volunteers treated with dabigatran and rivaroxaban.

 Recombinant factor VIIa has also shown variable results in in vitro and ex vivo studies but comes with an increased risk of arterial thrombosis in patients without hemophilia.

An aPCC, such as Feiba, dosed at 50 units/kg is suggested for patients exposed to dabigatran. For rivaroxaban, apixaban, and edoxaban, a 4-factor PCC, such as KCentra, is suggested at a dose of 50 units/ kg. It is important to remember that factor concentrates are not antidotes; a thrombotic risk is present by creating hypercoagulability, not reversal. One meta-analysis demonstrated a 1.8% risk of thromboembolic events after 4-factor PCC usage,

 and Sarode et al found a 7.8% rate of thromboembolism with use of 4-factor PCC (3.9% deemed related to therapy).

Idarucizumab and andexanet alfa are 2 agents that have been granted breakthrough therapy status by the FDA. Idarucizumab is a fragmented monoclonal antibody with a high affinity for dabigatran. Theoretically, this agent does not elicit procoagulant effects; however, it did successfully reverse bleeding in animal models.

 In a phase 1 study, idarucizumab reversed prolonged clotting times in men and women of various ages and with a range of kidney function.

Andexanet alfa is a recombinant factor Xa derivative that lacks specific binding activity and is currently undergoing development for the reversal of anti-Xa agents.

 In a phase 2 trial, the andexanet dose dependently decreased anti-Xa activity and reduced plasma concentrations of free apixaban compared with placebo.

 Preliminary results of a phase 3 trial displayed reversal of coagulation test abnormalities and restoration of thrombin generation in an older patient population treated with apixaban.

Aripazine is a small synthetic molecule that binds to all TSOACs, as well as heparins, low molecular— weight heparins, fondaparinux, and argatroban. Aripazine has multiple binding sites present on the molecule for each anticoagulant. This reversal agent is currently undergoing phase 2 trials as a nonspecific reversal agent. It has shown promise in animal models

 and has decreased clotting times in edoxaban-treated healthy volunteers.

Many factors affect the multimodal strategy to control or reverse clinical bleeding. Understanding what agents are in our armamentarium to combat bleeding in the setting of a TSOAC is vital, especially in an acute situation. The development of specific antidotes is promising and will increase the safety profile of TSOACs, but does not diminish the caution that needs to be practiced with high-risk patients.

Dr. Adams is a clinical pharmacist for Robert Wood Johnson University Hospital in Somerset, New Jersey, and an adjunct clinical assistant professor at Rutgers University in Piscataway, New Jersey. Dr. Resseguie is an advanced practice anticoagulation pharmacist for the Brigham & Women’s Hospital Anticoagulation Management Service in Boston, Massachusetts.

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		Crowther M, Levy GG, Lu G, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. 

		Crowther M, Levy GG, Lu G, et al. ANNEXA-A: A phase 3 randomized, double-blind, placebo-controlled trial demonstrating reversal of apixaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. 

		Hollenbach S, Lu G, DeGuzman F, et al. Abstract 14657: andexanet-alfa and PER977 (Arapazine) correct blood loss in a rabbit liver laceration model-only andexanet reverses markers of fXa-mediated anticoagulation. 

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Target-specific oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban are now being used in a larger and more diverse patient population.