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RE-LY (2009): Dabigatran versus Warfarin in Atrial Fibrillation – Evidence Reviewed

RE-LY (2009): Dabigatran versus Warfarin in Atrial Fibrillation

/, Atrial Fibrillation, Cardiology, Haematology, Haemostasis and Thrombosis, Novel Oral Anticoagulants/RE-LY (2009): Dabigatran versus Warfarin in Atrial Fibrillation

RE-LY (2009): Dabigatran versus Warfarin in Atrial Fibrillation

Clinical question: in patients with atrial fibrillation, is dabigatran non-inferior to warfarin for the prevention of stroke or systemic embolism?

Study design: multinational randomized unblinded controlled trial comparing dabigatran with warfarin. Two doses of dabigatran (150mg BD and 110mg BD) also compared in a blinded fashion.

Inclusion criteria:

  • Documented atrial fibrillation on ECG
  • Age > 18
  • At least one of the following (most are components of the CHADSVASC score):
    • History of stroke, TIA or systemic embolism
    • EF < 40%
    • Symptomatic heart failure (NYHA class II and above)
    • Age ≥ 75
    • Age ≥ 65 and at least one of:
      • Hypertension requiring treatment
      • Diabetes mellitus on treatment
      • Documented coronary artery disease

Exclusion criteria:

  • Valvular heart disease, including infective endocarditis and prosthetic heart valves
  • Severe, disabling stroke in the last 6 months, or any stroke 14 days prior to enrollment date
  • Increased risk of bleeding:
    • Bleeding diathesis
    • Major surgery within the last month, or surgery planned within the coming 3 months
    • Gastrointestinal haemorrhage within the last year
    • Previous intracranial, spinal, retroperitoneal or spontaneous intraarticular bleeding
    • Peptic ulcer disease within the last 30 days
    • Uncontrolled hypertension
    • Malignancy with prognosis ≤ 3 years
  • Contraindication to warfarin
  • Renal impairment (creatinine clearance < 30ml/min)
  • Active liver disease
  • Anaemia (Hb < 10) or thrombocytopaenia (Plt < 100 x 109)

Intervention:

  • Patients randomized to 3 groups, enrolled for 24 months, minimum follow-up 12 months
  • Warfarin, target INR 2-3
  • Low-dose dabigatran 110mg BD (LDD) – dabigatran administered in identical capsules
  • High-dose dabigatran 150mg BD (HDD)

Patient characteristics:

  • 18113 patients enrolled between 2005 and 2007
  • Mean age 71
  • 6% men
  • Mean CHADS2 score 2.1
  • Concurrent antiplatelet use allowed (for aspirin, maximum dose of 100mg/day)
    • Aspirin use evenly distributed throughout 3 groups

Outcomes and results:

  • Primary outcomes:
    • Stroke or systemic embolism
      • Both doses of dabigatran non-inferior to warfarin (p < 0.001)
      • HDD superior to warfarin (RR 0.66, 95% CI 0.53 – 0.82)
      • LDD not superior to warfarin (RR 0.91, 95% CI 0.74 – 1.11)
      • HDD versus LDD reduced risk of stroke or systemic embolism (p = 0.005)
    • Intracranial haemorrhage
      • Higher for warfarin (0.74%/yr) v LDD (0.23%/yr), RR 0.31, 95% CI 0.20 – 0.47
      • Higher for warfarin (0.74%/yr) v HDD (0.30%/yr), RR 0.40, 95% CI 0.27 – 0.60
      • LDD and HDD – no difference
    • Major bleeding
      • Higher for warfarin (3.36%/yr) v LDD (2.71%/yr), RR 0.80, 95% CI 0.69 – 0.93
      • Warfarin vs HDD – no difference
      • HDD vs LDD – no difference, but trend towards increased risk with HDD
    • Gastrointestinal bleeding
      • Warfarin vs LDD – no difference
      • Higher for HDD (1.51%/yr) v warfarin (1.02%/yr), RR 1.50, 95% CI 1.19 – 1.89
      • Higher for HDD v LDD, RR 1.36, 95% CI 1.09 – 1.70
  • Secondary outcomes:
    • Death – no difference
    • Myocardial infarction
      • 53%/year for warfarin, 0.72%/year for LDD (RR 1.35, 95% CI 0.98 – 1.87)
      • 53%/year for warfarin, 0.74%/year for HDD (RR 1.38, 95% CI 1.00 – 1.91)
    • Pulmonary embolism – no difference
    • Hospitalization – LDD lower risk compared to warfarin or HDD
    • Rates of life-threatening bleeding, intracranial bleeding, major or minor bleeding higher with warfarin than either dose of dabigatran (p < 0.05 for all comparisons)

Limitations:

  • Approximately 30% of patients had CHADS2 scores of 0 or 1 – these patients have relatively low risks of stroke
  • 64% of patients in the warfarin group had a therapeutic INR. If a large proportion were sub-therapeutic, it may confound non-inferiority findings. Similarly, if a large proportion were supra-therapeutic, it may confound inferiority findings with regards to bleeding
  • Outcome measures required clinical manifestations; asymptomatic strokes, bleeds or systemic emboli may not have been detected (although patients were regularly administered with symptom questionnaires and available discharge summaries were scrutinized for possibly unreported outcomes)
  • Low mean CHADS2 score, still unsure of utility of dabigatran for patients with higher CHADS2
  • Warfarin use was open-label; possible reporting bias
  • Reported rate of major bleeding with warfarin in this study is higher than that of other studies of warfarin in AF
  • Verapamil and amiodarone are both used in AF and may interact with dabigatran, potentially affecting interpretation of dose requirement for thromboembolic prophylaxis

Conclusions:

  • Dabigatran is non-inferior to warfarin for the prevention of stroke and systemic embolisation in non-valvular atrial fibrillation
  • Dabigatran 150mg BD compared to warfarin is associated with lower risks of stroke and systemic embolisation in non-valvular atrial fibrillation
  • The risk on intracranial haemorrhage, life-threatening haemorrhage are lower with both doses of dabigatran compared to warfarin
  • There is no difference in the risk of gastrointestinal haemorrhage between low-dose dabigatran and warfarin, although high-dose dabigatran is associated with a higher risk of GI bleeding compared with warfarin

Reference: Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51

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