Major Bleeding in Patients With Atrial Fibrillation Receiving Apixaban or Warfarin

The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes

Elaine M. Hylek, MD, MPH; Claes Held, MD, PHD; John H. Alexander, MD, MHS; Renato D. Lopes, MD, PHD; Raffaele De Caterina, MD, PHD; Daniel M. Wojdyla, MS; Kurt Huber, MD; Petr Jansky, MD; Philippe Gabriel Steg, MD; Michael Hanna, MD; Laine Thomas, PHD; Lars Wallentin, MD, PHD; Christopher B. Granger, MD

Disclosures

J Am Coll Cardiol. 2014;63(20):2141-2147. 

In This Article

Abstract and Introduction

Abstract

Objectives. This study sought to characterize major bleeding on the basis of the components of the major bleeding definition, to explore major bleeding by location, to define 30-day mortality after a major bleeding event, and to identify factors associated with major bleeding.

Background. Apixaban was shown to reduce the risk of major hemorrhage among patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.

Methods. All patients who received at least 1 dose of a study drug were included. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. Factors associated with major hemorrhage were identified using a multivariable Cox model.

Results. The on-treatment safety population included 18,140 patients. The rate of major hemorrhage among patients in the apixaban group was 2.13% per year compared with 3.09% per year in the warfarin group (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.60 to 0.80; p <0.001). Compared with warfarin, major extracranial hemorrhage associated with apixaban led to reduced hospitalization, medical or surgical intervention, transfusion, or change in antithrombotic therapy. Major hemorrhage followed by mortality within 30 days occurred half as often in apixaban-treated patients than in those receiving warfarin (HR 0.50, 95% CI: 0.33 to 0.74; p <0.001). Older age, prior hemorrhage, prior stroke or transient ischemic attack, diabetes, lower creatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal anti-inflammatory drugs were independently associated with an increased risk.

Conclusions. Apixaban, compared with warfarin, was associated with fewer intracranial hemorrhages, less adverse consequences following extracranial hemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of major hemorrhage.

Introduction

Atrial fibrillation (AF) is a potent risk factor for stroke. Warfarin is highly efficacious in reducing this risk, but its effectiveness in clinical practice is challenged by its variable dose response, need for frequent monitoring, and associated risk of hemorrhage. Among patients age 65 years or older, warfarin was noted to be the drug most often implicated in medication-related adverse events leading to emergency hospital stay.[1] Apixaban, a factor Xa inhibitor, was shown to reduce the risk of major hemorrhage by 31% compared with warfarin among patients with AF in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.[2] In this report, we sought to: 1) define 30-day mortality after a major bleeding event and determine whether this factor differed between warfarin- and apixaban-treated patients; 2) identify predictors of major bleeding and determine whether predictors of major bleeding varied between warfarin- and apixaban-treated patients; 3) further characterize the reduction in major bleeding based on the components of the major bleeding definition and determine whether these components varied between warfarin- and apixaban-treated patients; and 4) explore major bleeding by location and determine whether bleeding locations varied between warfarin- and apixaban-treated patients.

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