Editor's Note: Commentary based on Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015 Jun 22. [Epub ahead of print].

Study Question

In patients with atrial fibrillation (AF) on chronic warfarin therapy, does heparin bridging during interruption of warfarin therapy before and after an invasive procedure improve clinical outcomes?

Methods

This randomized, double-blind, placebo-controlled trial included patients with chronic AF or flutter who had received warfarin therapy for three months or longer, had an international normalized ratio (INR) in the therapeutic range, and were undergoing an elective invasive procedure requiring interruption of warfarin therapy. Patients with a mechanical heart valve; recent stroke, transient ischemic attack (TIA), or major bleeding event; and significant renal impairment were excluded. Participants were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (LMWH) or a matching subcutaneous placebo, from three days before the procedure until 24 hours before the procedure and then for five to ten after the procedure. Warfarin was stopped five days before the procedure and restarted within 24 hours after the procedure. The primary efficacy outcome was arterial thromboembolism at 30 days (stroke/TIA and systemic embolism), and the primary safety outcome was major bleeding at 30 days. Secondary outcomes included acute myocardial infarction, deep vein thrombosis, pulmonary embolism, death, and minor bleeding. Non-inferiority analysis with a non-inferiority margin of 1%, and a one-sided alpha level of 0.025 was used for the primary efficacy outcome.

Results

This study enrolled 1,884 patients (950 in the LMWH bridging arm and 934 in the placebo arm). The study participants were old (mean age of 71 years) with a mean CHADS₂ score of 2.3 (CHADS₂ score ≥3 in 38%). The incidence of arterial thromboembolism was 0.4% in the placebo arm and 0.3% in the LMWH bridging arm, with a mean between-group difference of 0.1% (95% confidence interval [CI] -0.6 to 0.8; P = 0.01 for non-inferiority). The incidence of major bleeding events was 1.3% in the placebo arm and 3.2% in the LMWH bridging arm. The relative risk for major bleeding associated with placebo as compared with LMWH bridging was 0.41 (95% CI 0.005). There were no significant differences between the two study arms for secondary efficacy outcomes.

Conclusion

Among patients with AF on chronic warfarin therapy who undergo invasive procedures requiring temporary interruption of warfarin, a periprocedural strategy of no bridging anticoagulation was non-inferior to periprocedural bridging with LMWH for prevention of arterial thromboembolic events. Furthermore, no bridging anticoagulation was also associated with a lower risk of major bleeding events.

Commentary/Perspective

Effectiveness of Bringing Anticoagulation for Surgery (The BRIDGE Study)¹ addresses a frequently encountered clinical question of whether AF patients on chronic anticoagulation who undergo invasive procedures requiring warfarin interruption need periprocedural anticoagulation bridging. Current guidelines recommend periprocedural discontinuation of oral anticoagulants and bridging with LMWH or unfractionated heparin in AF patients at high risk for thromboembolic complications (American Heart Association grade 1C).² In contemporary clinical practice, one in four AF patients who have interruption in oral anticoagulation therapy undergo periprocedural bridging.³ The present study provides conclusive evidence in favor of forgoing bridging anticoagulation among these patients, with a non-inferior risk of arterial thromboembolic events and significantly lower risk for major bleeding as compared with heparin bridging. Although thromboembolic events are generally more serious than major bleeding events, it is notable that bridging therapy led to an excess of 19 bleeding events for each thrombotic event prevented.

These findings are consistent with previously reported observational findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)³ and Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) sub-study⁴ that have demonstrated an increased risk of bleeding and no difference in thromboembolic complication risk among AF patients with versus without anticoagulation bridging in the periprocedural period. These findings also call into question the clinical practice pattern of prioritizing periprocedural thromboembolic risk prevention over the increased bleeding risk from bridging anticoagulation among AF patients.

However, as highlighted by the authors, the results of the BRIDGE study should be interpreted in multiple clinical contexts. First, a majority of the study participants had low-to-moderate risk of stroke, and the study findings may not be applicable to higher risk patients. Second, patients undergoing procedures such as cardiac/neurological surgery, cancer surgeries, and vascular surgeries who are at a much higher risk for stroke were excluded from the study; thus, the study results may not apply to this patient population. Finally, the lower than expected rate of thromboembolic events among the study participants led to an overestimation of the non-inferiority margin and may have affected the power of the study to detect a significant benefit associated with bridging. Future studies are needed to address these unanswered questions about the effectiveness of periprocedural bridging strategy among AF patients who are at a high risk for systemic thromboembolic events and/or are undergoing high-risk procedures.

References

1. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015 Jun 22. [Epub ahead of print]
2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: 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:e1-76.
3. Steinberg BA, Peterson ED, Kim S, et al. 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;131:488-94.
4. Douketis JD, Healey JS, Brueckmann M, Eikelboom JW, Ezekowitz MD, Fraessdorf M, Noack H, Oldgren J, Reilly P, Spyropoulos AC, Wallentin L and Connolly SJ. 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;113:625-32.

Keywords: Anticoagulants, Atrial Fibrillation, Double-Blind Method, Embolism, Heart Valves, Heparin, Heparin, Low-Molecular-Weight, Incidence, International Normalized Ratio, Ischemic Attack, Transient, Myocardial Infarction, Neoplasms, Pulmonary Embolism, Registries, Risk, Stroke, Thromboembolism, Venous Thrombosis, Warfarin

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