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
- Stroke or systemic embolism
- 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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