BRIDGE (2015) – Peri-Procedural Bridging Anticoagulation

Clinical question: in patients with atrial fibrillation, is peri-operative heparin bridging required during interruption of warfarin therapy?

Study design: randomized, double-blind placebo-controlled trial

Inclusion criteria:

• Age ≥ 18
• Permanent or paroxysmal atrial fibrillation / atrial flutter (confirmed by ECG / pacemaker interrogation), including valvular AF
• On warfarin for ≥ 3 months with a target INR of 2 – 3
• CHADS₂ score ≥ 1 (congestive heart failure, hypertension, age > 75, diabetes, previous stroke)
• Undergoing invasive procedure / surgery requiring interruption of warfarin therapy

Exclusion criteria:

• Mechanical heart valve
• Stroke, TIA or systemic embolism within the last 12 weeks
• Major bleeding within the last 6 weeks
• Creatinine clearance < 30ml/min
• Platelet count < 100 x 10⁹/L
• Planned for cardiac, intracranial or intraspinal surgery
• Heparin-induced thrombocytopaenia or heparin allergy
• Multiple planned procedures

Intervention:

• Patients randomized to bridging group or control group
• Bridging group: delteparin 100 IU/kg BD three days pre and 5-10 days post-procedure
• Control: subcutaneous placebo BD three days pre and 5-10 days post-procedure

Patient characteristics:

• 1884 patients, 934 in bridging group and 950 in placebo group
• Mean age 71.7 years
• Mean CHADS₂ score of 2.3
• Approximately 40% on an antiplatelet, no difference in proportion of patients on antiplatelets

Outcomes and results:

• All outcomes assessed at 37 days post-procedure
• Primary outcomes at 30 days post-procedure:
  • Arterial thromboembolism – 0.4% in bridging, 0.3% in placebo (p = 0.01 for non-inferiority, p = 0.73 for superiority)
  • Major bleeding – 3.2% in bridging, 1.3% in placebo (p = 0.005 for superiority)
• Secondary outcomes
  • Acute myocardial infarction – no difference
  • Deep vein thrombosis – no difference
  • Pulmonary embolism – no difference
  • Minor bleeding – 20.9% in bridging, 12.0% in placebo (p < 0.001 for superiority)

Limitations:

• Use of CHADS₂ vs CHADS₂VASC₂ score
• Male preponderance (73.4%)
• Mean CHADS₂ score of 2.3, only 3% of patients with CHADS₂ ≥ 5 (limited conclusions in high-risk patients)
• Numbers of actual thromboembolism were lower than expected – target power of the study had to be lowered, hence reducing chance that superiority of bridging over placebo could be detected
• Primary outcome of arterial thromboembolism assessed and defined by presence of clinical symptoms – smaller, sub-clinical events may have been missed

Conclusions:

• In patients on warfarin for atrial fibrillation, placebo was non-inferior to delteparin for the prevention of arterial thromboembolism
• Patients who are bridged peri-operatively with delteparin are at high risk of major bleeding

Reference: Douketis JD, Spyropoulos AC, Kaatz S, Becker RC, Caprini JA, Dunn AS, Garcia DA, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015;373(9):823-33