Dabigatran noninferior to warfarin for VTE

Feb 21st – Dabigatran also has a significantly lower incidence of major bleeding events vs. warfarin.

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1. Long term treatment with dabigatran is noninferior to warfarin and superior to placebo at preventing recurrent or fatal venous thromboemobolism (VTE) after 3 months of initial treatment.

2. Dabigatran has significantly lower incidence of major and clinically significant bleeding events than warfarin; however, it significantly increases risk of bleeding compared to placebo.

Published today in the New England Journal of Medicine, this study demonstrates that dabigatran is noninferior to warfarin and superior to placebo in the prevention of recurrent VTE. Importantly, while dabigatran demonstrated a better safety profile in regard to major and minor but clinically significant bleeding, being noninferior to warfarin does not imply equivalent efficacy in prevention of VTE recurrence. The authors’ criteria for noninferiority allows for up to a 2.85 fold increase in recurrence risk before dabigatran is considered to be inferior. In the current study, dabigatran showed a hazard ratio of 1.44 (95%CI, 0.80 to 2.64).  Warfarin is numerically superior in preventing the primary endpoint of recurrent VTE and related death. Additionally, this study and others have demonstrated an increase in acute coronary syndrome events with dabigatran use. While there are clear advantages to dabigatran use, continued evaluation of its efficacy, safety and cost profile in comparison to standard and other novel therapeutics is warranted.

Click to read the study in NEJM

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1. Long term treatment with dabigatran is noninferior to warfarin and superior to placebo at preventing recurrent or fatal venous thromboemobolism.

2. Dabigatran has significantly lower incidence of major and clinically significant bleeding events than warfarin; however, it significantly increases risk of bleeding compared to placebo.

This [double-blind, randomized] two-part trial sought to determine if dabigatran was noninferior to warfarin and superior to placebo for prevention of recurrent or fatal venous thromboembolism (VTE). Enrolled patients were >18 years old and had been on approved anticoagulant treatment for objectively confirmed proximal deep-vein thrombosis or pulmonary embolism. 2866 patients were randomized to receive either Dabigatran or warfarin for 6 to 36 months; 1353 patients received dabigatran or dabigatran-like placebo for up to 12 months. The primary efficacy endpoint was prevention of recurrent, symptomatic VTE or death related to VTE. Safety analysis looked at major, minor but clinically significant minor bleeding and acute coronary syndrome events.

Compared to warfarin, the hazard ratio for the primary end point of recurrent or fatal VTE was 1.44 (95% CI 0.78-2.64, p=0.01).While dabigatran demonstrated significantly fewer major and clinically relevant bleeding events than warfarin (HR 0.54 (95% CI 0.41-0.71, p<0.001), it was associated with a significantly increased risk of major and minor bleeding events compared to placebo 2.92 (95% CI 1.52-5.60, p=0.001). Acute coronary syndrome was also higher in the dabigatran group when compared to warfarin (rates of 0.9% vs. 0.2%, respectively; p=0.02)

In sum: Long-term anticoagulation with vitamin K antagonists is recommended for patients with venous thromboembolism (VTE) and risk factors for recurrence. However, treatment with warfarin requires extensive monitoring and dose adjustment. Moreover, anticoagulation comes with the inherent risk of bleeding. Unlike warfarin, dabigatran, a direct thrombin inhibitor, is given at a standard dose of 150 mg twice a day and does not require intensive monitoring.  This article comes after a series of trials, RE-COVER and RE-COVER II, which investigated the use of dabigatran for the treatment of VTE. This study investigates the use of dabigatran in the long-term prevention of VTE recurrence.

Published today, this study demonstrates that dabigatran is noninferior to warfarin and superior to placebo in the prevention of recurrent VTE. Importantly, while dabigatran demonstrated a better safety profile in regard to major and minor but clinically significant bleeding, being noninferior to warfarin does not imply equivalent efficacy in prevention of VTE recurrence. The authors’ criteria for noninferiority allows for up to a 2.85 fold increase in recurrence risk before dabigatran is considered to be inferior. In the current study, dabigatran showed a hazard ratio of 1.44 (95%CI, 0.80 to 2.64).  Warfarin is numerically superior in preventing the primary endpoint of recurrent VTE and related death. Additionally, this study and others have demonstrated an increase in acute coronary syndrome events with dabigatran use. While there are clear advantages to dabigatran use, continued evaluation of its efficacy, safety and cost profile in comparison to standard and other novel therapeutics is warranted.

Click to read the study in NEJM

By Jessica Mitchell and Mitalee Patil

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