BRIDGE Study

Screen Shot 2016-03-09 at 22.14.34

BRIDGE Study: Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

Douketis and the BRIDGE Investigators. NEJM 2015. Published on line first 22nd June 2015. doi:10.1056/NEJMoa1501035

Clinical Question

  • In elective surgical patients with atrial fibrillation who are suspending their normal warfarin peri-operatively, does no bridging anticoagulation compared to bridging anticoagulation with dalteparin increase the incidence of thromboembolism or reduce the incidence of major bleeding?

Design

  • Randomised, double-blind, placebo-controlled trial
  • Randomisation was stratified according to the study centre
  • A revised calculation based on 1882 patients provided 90% power for each primary end point based on an arterial thromboembolism rate of 0.46% and bleeding rate of 2.3% in all patients
  • Eisau donated the study drug (dalteparin) and the University of Iowa Pharmaceuticals prepared the matching placebo

Setting

  • 108 hospitals in US and Canada
  • July 2009 – December 2014

Population

  • Inclusion: patients with chronic (permanent or paroxysmal) atrial fibrillation or flutter; 18 years or older; received warfarin therapy for 3 months or longer with an INR therapeutic range of 2-3; undergoing an elective operation or procedure that required interruption of warfarin therapy; at least one CHADS2 stroke risk factor
    • congestive heart failure or left ventricular dysfunction, hypertension, age of 75 years or older, diabetes mellitus, or previous ischaemic stroke, systemic embolism, or transient ischaemic attack (TIA)
  • Exclusion: presence of a mechanical heart valve; stroke, systemic embolism, or TIA within the previous 12 weeks; major bleeding within the previous 6 weeks; creatinine clearance of < 30mls/min; platelets < 100; planned cardiac, intracranial or intraspinal surgery.
  • 1813 patients
    • baseline characteristics of patients were matched between groups
      • mean age 71.7
      • 2/3 male
      • mean CHADS2 score 2.35
      • 1/3 patients on aspirin
      • most common procedures were gastrointestinal (44%), cardiothoracic (17.2%) and orthopaedic (9.2%)

Intervention

  • Placebo (no bridging therapy)
    • placebo administered subcutaneously twice daily

 Control

  • Bridging anticoagulation therapy with low-molecular-weight heparin
      • 100 IU of dalteparin / kg of body weight administered subcutaneously twice daily

Management common to both groups

  • Warfarin was stopped 5 days before the procedure
  • Study drug (dalteparin) or placebo was commenced 3 days before the procedure until 24 hours before the procedure
    • It was then continued for 5 to 10 days after the procedure
    • It was restarted 12-24 hours after a low-bleeding risk procedure and 48-72 hours after a major-bleeding risk procedure
      • risk of bleeding was guided by means of a classification system but final determination of risk was left at the investigator’s discretion
  • Warfarin was restarted on the evening of or the day after the procedure at the patients usual dose
  • Study drug or placebo was continued until the INR was 2 or higher on one occasion
  • Any anti-platelet therapy was left to the site investigator’s discretion

Outcome

  • Primary outcome: incidence of arterial thromboembolism (stroke, TIA and systemic embolism) and major bleeding at 30 days
    • arterial thromboembolism: 3 patients (0.3%) in the bridging group vs. 4 patients (0.4%) in the no-bridging group. 95% CI -0.6 to 0.8, P=0.73
    • major bleeding: 29 patients (3.2%) in the bridging group vs. 12 patients (1.3%) in the no-bridging group. RR 0.41; 95% CI 0.20 to 0.78, P=0.05
      • no fatal events
  • Secondary outcome:
    • minor bleeding at 30 days
      • 187 patients (20.9%) in the bridging group vs. 110 patients (12%) in the no-bridging group. P=<0.001
    • no statistical difference in the following at 30 days:
      • acute myocardial infarction
      • deep-vein thrombosis
      • pulmonary embolism
      • death

Minor and major bleeding = one or more of the events defined by the International Society on Thrombosis and Haemostasis (see page 5 supplementary appendix)

Authors’ Conclusions

  • In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding

Strengths

  • Randomised and multi-centre
  • Allocation concealment
  • An important study which addresses useful outcome measures
  • Both the study drug and placebo were provided in identical vials

Weaknesses

  • The CHADS2 score was low (mean 2.3) and only 3% of patients had scores of 5 or 6
  • Patients undergoing major surgical procedures associated with high rates of arterial thromboembolism and bleeding (e.g carotid endarterectomy, major cancer surgery, cardiac surgery or neurosurgery) were not included in this study
  • The power study was recalculated during the study as the rate of arterial thromboembolism was lower than expected. The planned recruitment numbers at the start of the study was 3282
  • As a non-inferiority trial, it is important to avoid biases that may favour a smaller observed difference between the groups. The statistical approaches used in this trial (e.g. intention-to-treat analysis, absolute non-inferiority margin) may have led to a false positive conclusion (i.e. rejecting the null hypothesis of inferiority when the intervention is actually inferior)
  • The majority of patients underwent procedures that were considered to be low bleeding-risk (89.4% based on pre-specified classification; 69.1% based on site investigator decision)
  • No data is available regarding the number of patients with paroxysmal vs. permanent atrial fibrillation
  • No data is available regarding the investigators decision to continue or stop anti-platelet therapy. A 1/3 of the patients were taking aspirin

The Bottom Line

  • In patients with chronic (permanent or paroxysmal) atrial fibrillation or atrial flutter, stopping warfarin peri-operatively for a short duration does not result in an increased risk of thromboembolism and reduces the incidence of minor bleeding. Patients with mechanical heart valves were excluded from this study

One comment

Leave a Reply