BRIDGE

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Douketis JD, et al. "Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation". The New England Journal of Medicine. 2015. 373(9):823-33.
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Clinical Question

In patients with atrial fibrillation undergoing an invasive procedure requiring interruption of warfarin therapy, does bridging anticoagulation reduce rates of arterial thromboembolism compared to no bridging?

Bottom Line

Among patients with low- and intermediate-risk atrial fibrillation receiving anticoagulation and undergoing an invasive procedure, periprocedural bridging anticoagulation with LMWH did not reduce the incidence of arterial thromboembolism when compared to no bridging, but did increase the risk of major bleeding.

Major Points

Randomized trials including SPAF and SPAF-II demonstrated a robust reduction in arterial thromboembolic events with the use of warfarin anticoagulation in patients with AF. The subsequent development of risk prediction models including CHADS2[1] and CHA2DS2-VASc[2] has allowed for the targeted use of therapeutic anticoagulation for those at higher risk for thromboembolic complications. As a result of these studies, therapeutic anticoagulation with warfarin has become standard of care for the vast majority of patients with AF.

Despite its protective effects, warfarin use must frequently be interrupted in anticipation of elective invasive procedures with significant bleeding risk. In these cases, warfarin is often held for 5 days to allow its effects to wane and requires another 5-10 days following the procedure before therapeutic levels are re-attained. Due to fear of increased peri-procedural strokes while warfarin is held, clinicians often use anticoagulation with faster-acting heparin products as a "bridge" for protection while warfarin cannot be given. The BRIDGE study was the first randomized trial investigating whether bridging anticoagulation in this manner results in superior outcomes versus no bridging.

The 2015 Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for Elective Invasive Procedure or Surgery (BRIDGE) trial demonstrated that in AF patients with mean CHADS2 score of 2.3, bridging anticoagulation with the low molecular weight heparin product dalteparin resulted in no difference in arterial thromboembolism at 30 days. Dalteparin use was associated with a 2% absolute increase in major bleeding over this period. These data suggest that the cumulative stroke risk accrued over the days to weeks during which warfarin is interrupted for elective procedures is insufficient to merit bridging anticoagulant therapy. As a result, an argument can be made to withhold bridging for elective procedures in AF patients with intermediate or low stroke risk. Since only 3% of patients in BRIDGE had CHADS2 scores of 5-6, a benefit from bridging anticoagulation in AF patients at highest risk of stroke cannot be excluded.

Of note, the 2013 BRUISE CONTROL[3] trial randomized patients on warfarin at high risk for thrombosis requiring ICD or PPM surgery to LMWH or continuation therapy of warfarin. The warfarin group had lower incidence of device pocket hematomas without an increase in surgical complications or thromboembolism.

Guidelines

As of July 2015, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, double-blind, placebo-controlled controlled trial
  • N=1,884
    • LMWH (n=934)
    • Placebo (n=950)
  • Setting: 108 sites in the US and Canada
  • Enrollment: 2009-2014
  • Follow-up: 30-37 days
  • Analysis: Intention-to-treat
  • Primary efficacy outcome: Arterial thromboembolism
  • Primary safety outcome: Major bleeding

Population

Inclusion Criteria

  • 18 years or older
  • Warfarin therapy targeting INR 2-3 for ≥3 months
  • AF or A-flutter demonstrated on ECG or PPM interrogation
  • CHADS2 Score ≥1

Exclusion Criteria

  • Mechanical heart valve
  • Stroke, systemic embolism, or TIA within 12 weeks
  • Major bleeding within 6 weeks
  • eGFR <30 mL/min
  • Platelet count <100
  • Planned cardiac, intracranial, intraspinal surgery, or other high-risk non-surgical procedures (eg, brain biopsy)
  • Life expectancy <1 month
  • Pregnancy
  • HIT or heparin allergy
  • Multiple planned procedures

Baseline Characteristics

From the placebo group.

  • Demographics: Age 72 years, 73% male sex, 90% White race
  • Health data: Weight 96 kg
  • Thrombosis data:
    • Mean CHADS2 score: 2
      • 0: <1%
      • 1: 23%
      • 2: 40%
      • 3: 24%
      • 4: 10%
      • 5: 2%
      • 6: <1%
  • Cardiac history: HF including LV dysfunction 30%, HTN 89%, DM 41%, stroke 8%, mitral valve disease 17%, MI 14%
  • Other PMH: Kidney disease 11%, solid cancer 7%
  • Labs: Hgb 13.8 g/dL, platelets 209k/mm3, INR 2.4, creatinine 1.1 mg/dL, CrCl 88 mL/min
  • Medications: ASA 34%, clopidogrel 3%, NSAID 4%, COX-2 inhibitor 1%
  • Warfarin: Preprocedure duration off medication 5.2 days, time to first postop dose 1.5 days
  • ASA: Cessation ≥7 days before procedure 28%, interruption <7 days before procedure 13%, no interruption 59%

Interventions

  • Randomized to a group:
    • LMWH - Anticoagulation with dalteparin (100IU/kg BID)
    • Placebo
  • Warfarin stopped 5 days prior to procedure and restarted the evening of the procedure or the following day
  • Treatment administered from 3 days prior to procedure and continued for 5-10 days after procedure
  • Treatment was given 24 hours before the procedure and resumed 12-24 hours after a minor procedure, or 48-72 hours after a major procedure (explicit classifications of procedure risk are outlined on page 9 of the supplemental appendix[4]
  • Treatment continued until INR was 2 or higher on one occasion
  • Patients had follow-up encounters by telephone weekly, with a final encounter 30-37 days after the procedure

Outcomes

Comparisons are placebo vs. LMWH.

Primary Outcomes

Arterial Thromboembolism
0.4% vs. 0.3% (P=0.01 for noninferiority; P=0.73 for superiority)
Stroke: 0.2% vs. 0.3%
TIA: 0.2% vs. 0%
Systemic Embolism: 0% vs. 0%
Major bleeding
1.3% vs. 3.2% (P=0.005 for superiority; NNH=50)

Secondary Outcomes

The remaining p-values are for superiority.

All-cause mortality
0.5% vs. 0.4% (P=0.88)
Myocardial Infarction
0.8% vs. 1.6% (P=0.10)
Deep-vein Thrombosis
0% vs. 0.1% (P=0.25)
Pulmonary Embolism
0% vs. 0.1% (P=0.25)
Minor Bleeding
12.0% vs. 20.9% (P<0.001)

Criticisms

  • Only about 3% of patients included had CHADS2 scores of 5-6, limiting the generalizability of these findings to patients with high risk of thromboembolism.
  • Findings do not extend to patients undergoing anticoagulation with novel oral anticoagulants.
  • Target power was reduced to 90% after the thromboembolism rate was lower than expected, reducing the probability of detecting superiority of bridging over no bridging for this outcome.
  • Patients undergoing major surgical procedures associated with higher rates of arterial thromboembolism such as carotid endarterectomy, major cancer surgery, cardiac surgery, or neurosurgery, were excluded from the study.

Funding

  • NHLBI/NIH grants
  • Eisai donated the dalteparin and University of Iowa Pharmaceuticals prepared the placebo
  • Authors with multiple financial disclosures

Further Reading

  1. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 2004;110(16):2287-92
  2. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrilllation. Chest 2010;137(2):263-72
  3. Birnie DH et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N. Engl. J. Med. 2013. 368:2084-93.
  4. Supplemental appendix