EBQ:RE-LY

Under Review Journal Club Article

Connolly SJ, et al. "Dabigatran versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 2009. 361(12):1139-51.
PubMed Full text PDF

Clinical Question

Is dabigatran (brand name Pradaxa) safe for use in patients with atrial fibrillation when compared to warfarin in terms of stroke and bleeding risks.

Conclusion

In comparison to warfarin in patients with atrial fibrillation, dabigatran given at a dose of 110 mg demonstrated similar stroke and lower bleeding rates. At 150 mg, dabigatran use was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.

Major Points

• RE-LY was the first large RCT to demonstrate a novel oral anticoagulant (dabigatran) as an alternative to warfarin for stroke prevention in atrial fibrillation
• Dabigatran 150mg BID was superior to warfarin for stroke prevention with similar major bleeding rates
• Dabigatran 110mg BID was non-inferior to warfarin for stroke prevention with lower major bleeding rates
• Both dabigatran doses had lower rates of intracranial hemorrhage compared to warfarin
• Dabigatran 150mg BID was associated with higher rates of GI bleeding compared to warfarin

Design

• Randomized, prospective, blinded, multinational study
• Patients recruited from 951 clinical sites in 44 countries
• 3 treatment groups: Warfarin, Dabigatrin 110 mg BID, Dabigatrin 150 mg BID
• Dabigatrin groups were blinded, Warfarin was not
• Followed for 2 years

Inclusion Criteria

• A-Fib on screening ECG or within the past 6 months AND one of the following:
  • Previous stroke or TIA
  • LVEF<40%
  • NYHA class II or higher w/ in past 6 months
  • age at least 75 yrs or 64-74 plus DM, HTN, or CAD

Exclusion Criteria

• Severe heart-valve disorder
• Stroke within 14 days or severe stroke within 6 months
• Condition increasing risk of hemorrhage
• CRCL <30mL/min
• Active liver disease
• Pregnancy
• Recent surgery

Interventions

Three groups, of which Dabigatran participants were blinded and Warfarin participants were not

• Warfarin, adjusted dose, goal INR 2.0-3.0
• Dabigatran 110 mg BID
• Dabigatran 150 mg BID

Outcome

Primary Outcomes

• Stroke or Systemic Embolism
  • stroke: sudden onset of focal neuro deficit, location consistent with major vessel
  • systemic embolism: acute vascular occlusion of extremity or organ, by imaging, surgical confirmation, or autopsy
  • Warfarin: 1.69%/year
  • Dabigatran 110mg: 1.53%/yr RR of 0.91 (CI 0.74-1.11)
  • Dabigatran 150mg: 1.11%/yr RR of 0.66 (CI 0.53-0.82)
  • Both Dabigatran doses non-inferior to Warfarin with 150 mg dose being superior to Warfarin

• Primary safety outcome: Major Bleeding (all other bleeding considered minor)
  • Defined as: Hg drop of 20 g/L, transfusion of 2 units PRBC, or symptomatic bleed in critical area or organ
  • Life-threatening bleed (subcategory)
    • fatal bleed, symptomatic ICH, decrease in Hgb of at least 50 g/L, transfusion of 4 units PRBC, inotropic agents or surgery required
  • Warfarin: 3.36%/yr
  • Dabigatran 110mg: 2.71%/yr RR of 0.80 (CI 0.69–0.93)
  • Dabigatran 150mg: 3.11%/yr RR of 0.93 (CI 0.81–1.07)
  • Intracranial bleeding higher in Warfarin group than either Dabigatran group (stat significant)
  • Dabigatran 150 mg higher rate of GI bleed than Warfarin

Secondary Outcomes

• Hemorrhagic stroke
• Death
• MI
• PE
• TIA
• Hospitalization

Group	Hem Stroke	MI	PE	Hospitalization	Death
Warfarin	0.38%/yr	0.53%/yr	0.09%/yr	20.8%/yr	4.13%/yr
Dabigatran 110	0.12%/yr	0.72%/yr	0.12%/yr	19.4%/yr	3.75%/yr
Dabigatran 150	0.10%/yr	0.74%/yr	0.15%/yr	20.2%/yr	3.64%/yr
Dabigatran 110 RR	0.31 (CI 0.17-0.56)	1.35 (0.98–1.87)	1.26 (0.57–2.78)	0.92 (0.87–0.97)	0.91 (0.80–1.03)
Dabigatran 150 RR	0.26 (CI 0.14-0.49)	1.38 (1.00–1.91)	1.61 (0.76–3.42)	0.97 (0.92–1.03)	0.88 (0.77–1.00)

Criticisms

• Open-label design with respect to warfarin (blinded for dabigatran doses but not vs warfarin)
• Industry-sponsored trial (Boehringer Ingelheim) raises potential for bias
• Patients in the warfarin arm had time in therapeutic range (TTR) of only 64%, which is suboptimal
• The study excluded patients with severe renal impairment (CrCl <30 mL/min), limiting applicability
• No reversal agent was available at the time of the study (idarucizumab was later developed)

Funding

Funded by Boehringer Ingelheim and coordinated by the Population Health Research Institute (Hamilton, ON, Canada)

See Also

• Atrial fibrillation
• Dabigatran