PERIOPERATIVE BRIDGING ANTICOAGULATION IN PATIENTS WITH ATRIAL FIBRILLATION

BRIDGE STUDYPUBLISHED IN NEJM ON JUNE22, 2015

NEERAJ VARYANI

BACKGROUND

For AF patients, need for perioperative bridging anticoagulation has long been uncertain and unanswered.

Scenario affecting 1 in 6 warfarin treated patients with AF.

Warfarin is typically stopped 5 days before an elective procedure and resumed when hemostasis secured postprocedure , requiring 5 to 10 days treatment to attain therapeutic anticoagulation.

Contd…

Rationale of bridging with LMWH: to minimize the time patient do not have adequate anticoagulation so as to minimize the risk of perioperative arterial thromboembolism.

Observational studies have assessed the timing and dosing of perioperative bridging with LMWH.

Because of lack of evidence, practice guidelines have provided weak recommendations for bridging anticoagulation.

Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery(BRIDGE):Hypothesis

Forgoing bridging would be noninferior to bridging with LMWH for prevention of perioperative arterial thromboembolism and superior to bridging with regard to major bleeding.

METHODS

STUDY DESIGN AND OVERSIGHT

Randomized Double-blind Placebo-controlled Protocol designed by steering committee and

approved by institutional review board at each center.

Duke Clinical Research Institute managed the study.

Contd..

Clinical coordination center: coordination, randomization and distribution of study drug.

Data coordinating center: database,validation and analyses.

Eisai donated dalteparin and University of Iowa Pharmaceuticals prepared matching placebo.

Eisai had no role in the study

PATIENTS

INCLUSION CRITERIA: ≥ 18 yearsChronic (permanent or paroxysmal) AF or

flutter confirmed by ECG or pacemaker interrogation (patients with valvular AF eligible)

Warfarin therapy for ≥ 3 months (INR 2.0 to 3.0).

Elective operation or procedure requiring interruption of warfarin therapy.

At least one of CHADS2 stroke risk factors

EXCLUSION CRITERIAMechanical heart valveStroke,TIA or systemic embolism within

previous 12 weeksMajor bleeding within previous 6weeksCreatinine clearance of less than 30

ml/min.Platelet count < 100,000/mm3.Planned cardiac,intracranial or

intraspinal surgery.

PROCEDURES

Randomization stratified either with interactive voice response system or through internet.

Study drugs were provided in identical vials. Postprocedure study drug was continued

until the INR was ≥ 2 on one occasion. Final determination of low or high bleeding

risk and perioperative management of antiplatelet therapy was left to investigator’s discretion.

STUDY OUTCOMES

Assessed by 37 days after procedure and independently and blindly adjudicated

PRIMARY EFFICACY OUTCOME: arterial thromboembolism at 30 days including stroke( ischemic or hemorrhagic), TIA, and systemic embolism.

PRIMARY SAFETY OUTCOME: major bleeding at 30 days.

SECONDARY EFFICACY OUTCOME : MI,DVT,PE and death.

SECONDARY SAFETY OUTCOME: minor bleeding.

STATISTICAL ANALYSIS

Primary analysis of efficacy was a noninferiority analysis. Bernard’s test was used for calculating 95% confidence interval for difference in event rates. Confidence interval values calculated by StatXact software,version 9( Cytel).

Null hypothesis of no difference in incidence of primary safety outcome tested with two-sided test. P value calculated by fisher’s mid-P test and 95% confidence interval were calculated in SAS software,version 9.3 .

Sample size of 1882 was estimated to provide 90% power for the two primary end points.

RESULTS

Baseline characteristics

Most common procedures were gastrointestinal(44%), cardiothoracic(17.2%), and orthopedic(9.2%).

89.4% patients underwent procedure with low bleeding risk ; however 69.1% were treated as low bleeding risk by site investigator.

PERIOPERATIVE ANTICOAGULANT MANAGEMENT

STUDY OUTCOMES

DISCUSSION

Discontinuing warfarin treatment without bridging anticoagulation was noninferior to bridging anticoagulation for prevention of arterial thromboembolism.

Bridging conferred a risk of major bleeding that was triple the risk associated with no bridging also less minor bleeding without bridging .

No significant difference between the groups with regard to myocardial infarction,venous thromboembolism, or death.

Findings consistent with other nonrandomized similar trials.

Meta-analysis of observational studies with AF or mechanical heart valves showed no significant difference in arterial thromboembolism but higher rate of major bleeding in association with bridging.

In substudy of RE-LY trial bridging was associated with higher rate of major bleeding than no bridging with no significant effect on arterial thromboembolism.

ORBIT-AF study also showed higher rates of bleeding if bridging was used during perioperative interruption of warfarin treatment.

BRIDGE trial and other nonrandomized trial suggest perioperative arterial thromboembolism in AF is overstated and may not be mitigated by bridging and may be related to type of procedure and intraoperative alterations in blood pressure.

Concept of rebound hypercoagulability on warfarin interruption and prothrombotic milieu leading to arterial thromboembolism is not supported by this trial

LIMITATIONS

Certain groups were underrepresented in the the study population( surgeries with high rates of thromboembolism and mechanical valves)

Rate of arterial thromboembolism was lower affecting power of trial to detect benefit with bridging.

Rate of major bleeding in bridging group may be considered to be modest

Contdd….

Reduction in study sample size may raise concerns.

Diminished relevance in the treatment of AF given availability of newer anticoagulants.