Dabigatran May Increase Risk of Major Bleeding Compared to Warfarin in Older Patients with Atrial Fibrillation

EBM Focus - Volume 10, Issue 5

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Reference: JAMA Intern Med 2015 Jan 1;175(1):18 (level 2 [mid-level] evidence)

Patients with atrial fibrillation are at increased risk of thromboembolism and oral antithrombotic therapy is therefore recommended for most patients with atrial fibrillation or atrial flutter (Chest 2012 Feb;141(2 Suppl):53S, J Am Coll Cardiol 2014 Dec 2;64(21):e1, Eur Heart J 2012 Nov;33(21):2719). While antithrombotic therapy may decrease the risk of stroke, it also carries an increased risk of bleeding, and physicians and patients must weigh the benefits and risks when selecting an antithrombotic agent. In 2009, the RE-LY trial suggested dabigatran 150 mg could reduce the risk of stroke without increasing the risk of major bleeding compared to warfarin in patients with atrial fibrillation and additional stroke risk factors (N Engl J Med 2009 Sep 17;361(12):1139). Further analysis found a reduction in major bleeding in patients aged < 75 years old that did not extend to patients aged 75 years or older and additional studies found an increased risk of gastrointestinal bleeding with dabigatran (Circulation 2011 May 31;123(21):2363, J Am Geriatr Soc 2014 May;62(5):857, Gastroenterology 2013 Jul;145(1):105, Am J Cardiol 2014 Mar 15;113(6):1066). A recent retrospective cohort study investigated the risk of bleeding in Medicare patients (mean age 76 years) with newly diagnosed atrial fibrillation initiating dabigatran or warfarin oral anticoagulation within 60 days of diagnosis. Dabigatran was prescribed to 1,302 patients with a mean follow-up of 177 days, while 8,102 patients received warfarin with a mean follow-up of 228 days.

Patients were selected from a random cohort of 5% of Medicare beneficiary recipients in 2010 and 2011. Bleeding was categorized as major or minor by 9 anatomical positions with major bleeding including intracranial hemorrhage and hemoperitoneum as well as inpatient or emergency department stays for gastrointestinal, hematuria, or other hemorrhage. A propensity score weighted analysis was performed to balance baseline demographic and clinical characteristics between the dabigatran and warfarin treatment groups. Compared to warfarin, dabigatran was associated with increased risk of overall bleeding (hazard ratio [HR] 1.3, 95% CI 1.2-1.41), major bleeding (HR 1.58, 95% CI 1.36-1.83), and gastrointestinal bleeding (HR 1.85, 95% CI 1.64-2.07). In subgroup analyses, the risk of major bleeding with dabigatran was increased in African American patients compared to white patients, in patients aged 75 years or older compared to patients aged less than 65 years, and in patients with chronic kidney disease. Not all bleeding risk was increased with dabigatran, however, as dabigatran was also associated with a decreased risk of intracranial hemorrhage (HR 0.32, 95% CI 0.2-0.5).

Although previous randomized trials have suggested that dabigatran and warfarin have similar risk of bleeding, this real-world cohort study indicates that dabigatran may be associated with increased risk of overall bleeding and major bleeding compared to warfarin, especially in higher risk populations. The risk of stroke could not be determined in this study due to the short duration of follow-up data available, however the increased risk of bleeding observed suggests that dabigatran should be prescribed with caution in patients with higher risk of bleeding as well as African American patients, patients aged 75 years or older, and patients with chronic kidney disease. Dabigatran may be appropriate for low risk patients and those with an increased risk of intracranial hemorrhage.

For more information, see the topic Thromboembolic prophylaxis in atrial fibrillation topic in DynaMed.

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