BRIDGE - Peri-procedure bridging of anticoagulation of AF patients on warfarin

Douketis JD, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. NEJM 2015;373:823-33.

Bottom line: In patients with AF & CHADS2 score <4 requiring interruption of warfarin, bridging with parenteral anticoagulation increases major bleeding (NNH 53 from bridging) without reducing thromboembolic events.

Patients (n=1884)

• Randomized 1884, analyzed 1813

• Included

  • Atrial fibrillation or flutter (paroxysmal or permanent) confirmed by EKG or pacemaker interrogation

  • Non-valvular or valvular AF both eligible

  • CHADS2 score 1 or higher

  • Receiving warfarin for 3+ months with INR 2.0-3.0

  • Undergoing elective invasive procedure felt to require interruption of warfarin

• Excluded

  • Mechanical heart valve

  • Recent stroke, systemic embolism or TIA (in past 12 weeks) or major bleeding (in past 6 weeks)

  • CrCl <30 mL/min

  • Platelets <100

  • Planned cardiac, brain or spine surgery

• Baseline characteristics

  • Age 72 y, male (73%), white (91%)

  • CHADS2 score

    • Mean score 2.3

    • 1 (23%), 2 (40%), 3 (24%), 4 (10%), 5 (3%), 6 (<1%)

    • HF/LV dysfunction ~33%

    • HTN 87%

    • Diabetes 41%

    • Prior stroke 8%

    • Prior TIA 8%

    • MI 15%

  • Undergoing procedure classified as having low bleeding risk 89%

  • Labs: INR 2.4, CrCl 88 mL/min

  • Concomitant ASA ~35%

Intervention & comparator

• I: No bridging

  • Warfarin stopped 5 days before the procedure & restarted evening of surgery or POD 1, without bridging

• C: Anticoagulant bridging

  • Warfarin stopped 5 days before the procedure & restarted POD0 evening or POD 1

  • Pre-op bridging: Dalteparin 100 units/kg subcut BID started 3 days before the procedure, last dose AM day before procedure (~24h before)

  • Post-op bridging: Dalteparin restarted 12-24h after low-bleeding-risk procedure & 48-72h after high-bleeding-risk procedure; continued x5-10 days until INR 2 or higher once

• Adherence in both groups was ~86% pre-op & 96% post-op

Results @ day 30-37

• Not bridging was non-inferior to bridging for the primary efficacy outcome (arterial thromboembolism; a composite of ischemic/hemorrhagic stroke, TIA, systemic embolism)

  • Intention-to-treat (ITT) population: No bridging 04.%, bridging 0.3% (difference 0.1%, 95% confidence interval [95%CI] -0.6% to +0.8%)

    • Stroke: 0.2% vs 0.3%

  • Per-protocol population: 0.3% vs 0.4% (difference 0.0%; 95% CI -0.7% to +0.7%)

• Not bridging reduced the risk of major bleeding (ITT population): 1.3% vs 3.2% (NNT 53)

  • Minor bleeding: 12.0% vs 20.9% (NNT 12)

• No difference in all-cause mortality: 0.5% vs 0.4%

Internal validity

• Low risk of allocation, performance & detection bias

  • Interactive voice-response system

  • Dalteparin & matching placebo in identical vials

  • Blinded adjudication of all outcomes

• Possible attrition bias due to moderate loss-to-follow-up (3.8%), which is higher than the rate of primary outcome events

• Non-inferiority trial

  • Non-inferiority margin set as an absolute difference of 1.0% for arterial thromboembolism (wide);

  • Assumed ~1.0% absolute risk of arterial thromboembolism in both groups (actual event rate <1/2 expected);

  • Analysis of both ITT & per-protocol populations, which were nearly identical.

Heparin, enoxaparin & fondaparinux in ACS

NSTE-ACS

Heparin: Systematic review of 6 RCTs (3 were double-blind) published 1988-1995

• P: NSTE-ACS patients treated with ASA (n=1353)
• I: Heparin bolus + infusion x2-7 days
• C: Placebo/no treatment
• O:
  • Death/MI: Heparin 7.9%, control 10.4% (NNT 40), OR 0.67 (0.45-0.99)
  • Recurrent angina: OR 0.94 (0.58-1.54)
  • Revascularization: OR 1.25 (0.76-2.06)
  • Major bleed: OR 1.88 (0.60-5.87)

Enoxaparin (A to Z, ESSENCE, SYNERGY, TIMI 11B)

View fullsize

Fondaparinux: OASIS 5 - Double-blind non-inferiority RCT

• P: NSTE-ACS (n=20,078)
  • Clopidogrel given to 2/3
• I: Fondaparinux 2.5 mg  once daily up to 8 days or until discharge
• C: Enoxaparin 1 mg/kg q12h (if CrCl <30: 1 mg/kg q24h) x2-8 days or until "clinically stable"
• O @ day 9:
  • Primary outcome (death/MI/refractory ischemia): Fondaparinux 5.8%, enoxaparin 5.7%, HR 1.01 (0.90-1.13)
    • Death: 1.8% vs 1.9%
    • MI: 2.6% vs 2.7%
    • Refractory ischemia: 1.9% for both
  • Major bleed: 2.2% vs 4.1% (NNT 53), HR 0.52 (0.44-0.61)
• O @ 180 days:
  • Primary outcome: 12.3% vs 13.2% (NNT 112), HR 0.93 (0.86-1.00)
    • Death: 5.8% vs 6.5%
  • Major bleed: 4.3% vs 5.8%, HR 0.72 (0.64-0.82)
• Benefit & safety preserved in 1/3 of patients who underwent PCI during initial ACS hospitalization (in fondaparinux group, heparin given during PCI)

 

STEMI

Enoxaparin: (ASSENT 3, EXTRACT TIMI 25)

• ASSENT 3
  • P: STEMI undergoing fibrinolysis with TNK (n6095)
  • I: Enoxaparin 30 mg IV bolus, then 1 mg/kg subcutaneously q12h continued for max 7 days
  • C: Heparin bolus, then infusion for at least 48h (also 3rd group given abciximab & no anticoagulant)
  • O @ 30 days:
    • Primary outcome (death, in-hospital re-infarction or refractory ischemia): Enoxaparin 11.4%, heparin 15.4% (NNT 25)
      • Death: 5.4% vs 6.0% (p=0.25)
      • Re-infarction: 2.7% vs 4.2%
      • Refractory ischemia: 4.6% vs 6.5%
    • ICH: 0.9% in both groups
    • Major bleed, non-ICH: 3.0% vs 2.2% (NNH 125)
• EXTRACT TIMI 25
  • P: STEMI undergoing fibrinolysis (n=20,506)
  • I: Enoxaparin 30 mg IV bolus, then 1 mg/kg subcutaneously q12h continued for max 8 days or until discharge
    • If >75 y/o: No bolus, 0.75 mg/kg q12h
    • If CrCl <30 mL/min: 1 mg/kg q24h
  • C: Heparin infusion to aPTT 1.5-2.0x above normal, given for at least 48h
  • O @ 30 days:
    • Primary outcome (death/MI): Enoxaparin 9.9%, heparin 12.0% (NNT 48), RR 0.83 (0.77-0.90)
      • Death: 6.9% vs 7.5%
      • MI: 3.0% vs 4.5%
    • Urgent revascularization: 2.1% vs 2.8%
    • Major bleed: 2.1% vs 1.4% (NNH 143), RR 1.53 (1.23-1.89)

Fondaparinux: OASIS 6 - Double-blind RCT

• P: STEMI (n=12,092)
• I: Fondaparinux 2.5 mg daily (first dose IV if lytic/PCI) for up to 8 days or until discharge
• C: Stratified by indication for placebo
  • No indication for heparin: Placebo
  • Indication for heparin (fibrin-specific thrombolytic or scheduled for 1o PCI): Heparin x1-2 days
• O @ 30 days (only presenting data for those with indication for heparin)
  • Primary outcome (death/MI): Fondaparinux 8.3%, heparin 8.7%, HR 0.96 (0.81-1.13)
  • Major bleed: Fondaparinux 2.1%, heparin 2.3%, HR 0.93 (0.67-1.30)