Brief Overview of the Outcomes from Pivotal Clinical Trials Comparing the Efficacy and Safety of NOACs with Warfarin for Stroke Prevention in Patients with Atrial Fibrillation

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Dabigatran¹

• Efficacy and safety was investigated in the RE-LY trial, a randomised, non-inferiority trial, designed to compare two fixed doses of dabigatran (150mg and 110mg), each administered in a blinded manner, with open-label use of warfarin [target INR, 2.0 to 3.0] in patients with AF and at increased risk for stroke (n=18,113 patients).

• Primary outcome was stroke or systemic embolism.

• Both dabigatran doses were found to be non-inferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism.

• Dabigatran 150mg was superior to warfarin with respect to stroke or systemic embolism.

• Dabigatran 150mg demonstrated superior efficacy to warfarin in preventing ischaemic stroke with a significant reduction in intracranial haemorrhage.

• Dabigatran 110mg twice showed similar efficacy to warfarin in preventing ischaemic stroke with a significant reduction in intracranial haemorrhage.

• Although the overall rates of bleeding was lower at other anatomical sites, there was an increase in the rate of GI bleeding with the dabigatran 150mg dose.

Rivaroxaban²

• Efficacy and safety was investigated in the ROCKET AF trial, a randomised, double-blind, double-dummy, event-driven trial.

• Patients with a moderate-to-high risk for stroke (n=14,264) were randomised to receive either rivaroxaban (20mg daily, or 15mg daily in patients with a cc of 30 to 49ml/min) or warfarin (target INR 2.0 to 3.0).

• Elevated risk was indicated by a history of stroke, transient ischemic attack, or systemic embolism, or 2 or more of the following risk factors: Heart failure, or a LVEF of 35% or less, hypertension, 75 years of age or more, or diabetes mellitus.

• Primary efficacy end point was the composite of stroke (ischaemic or haemorrhagic) and systemic embolism.

• Principal safety end point was a composite of major and non-major clinically relevant bleeding events.

• Rivaroxaban was found to be non-inferior to warfarin for the prevention of stroke or systemic embolism.

• There were significant reductions in intracranial haemorrhage and fatal bleeding in the rivaroxaban group.

• However, bleeding from GI sites occurred more frequently with rivaroxaban than with warfarin.

Apixaban³

• Efficacy and safety was investigated in the ARISTOTLE trial, a double-blind, double-dummy study randomising patients (n=18,201) to treatment with apixaban or warfarin (target INR 2.0 to 3.0).

• Apixiban 5mg was administered twice daily; 2.5mg doses were used in a subgroup of patients with 2 or more of the following: 80 years of age or more, BW 60kg or less, or serum Cr 1.5mg/dL or more.

• Primary objective was to test whether apixaban was non-inferior to warfarin in reducing the rate of stroke (ischaemic or haemorrhagic) or systemic embolism among patients with AF and at least one other risk factor for stroke. Primary safety outcome was major bleeding.

• Key secondary outcomes were superiority of apixaban compared to warfarin with respect to the primary outcome and to the rates of major bleeding and death from any cause.

• Showed similar efficacy to warfarin in preventing ischaemic stroke with a significant reduction in intracranial haemorrhage. Compared with warfarin, apixaban significantly reduced the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death by 11%.

• Reduction in the rate of GI bleeding and consistently lower bleeding rates across age groups was associated with apixaban use.

Edoxaban⁴

• Efficacy and safety was investigated in the ENGAGE AF-TIMI 48 trial, a three-group, randomised, double-blind, double-dummy trial comparing two dose regimens of edoxaban with warfarin (n=21,105 patients).

• Patients received once-daily doses of 60mg (high-dose edoxaban group), or 30mg (low-dose group). Dosage was halved if any of the following were present at the time of randomisation or during the study: Estimated cc of 30 to 50ml/min, BW 60kg or less, or concomitant use of verapamil, quinidine or dronedarone.

• Primary efficacy end point was the time to first stroke (ischaemic or haemorrhagic) or systemic embolic event. Principal safety end point was major bleeding.

• Both edoxaban regimens were non-inferior to well-managed warfarin (median time in therapeutic range, 68.4%) for the prevention of stroke or systemic embolism.

• Rate of ischaemic stroke was similar with high-dose edoxaban and warfarin but was higher with low-dose edoxaban.

• Incidence of haemorrhagic stroke and the rate of death from cardiovascular causes were significantly lower with both edoxaban doses than with warfarin.

• Edoxaban was associated with consistently lower, dose-related rates of all types of bleeding (including major bleeding, intracranial bleeding, and life threatening bleeding) compared with warfarin; except for GI bleeding, which occurred more frequently with high-dose edoxaban but less frequently with low-dose edoxaban than occurred with warfarin.

References: 1. Connolly SJ et al. N Engl J Med 2009;361:1139-1151. 2. Patel MR et al. N Engl J Med 2011;365:883-891. 3. Granger CB et al. N Engl J Med 2011;365:981-99. 4. Giugliano RP et al. N Engl J Med 2013;369:2093-104. 5. Hanley CM and Kowey PR. J Thorac Dis 2015;7(2):165-171.

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Caroline McDermott