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


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

In This Article


In the ARISTOTLE trial, there were fewer intracranial hemorrhages on apixaban, fewer adverse consequences of extracranial hemorrhages, and fewer trauma-related hemorrhages. Apixaban, compared with warfarin, was associated with 50% less ISTH major hemorrhage leading to death within 30 days after the event. Warfarin treatment was more often associated with bleeding requiring hospitalization, transfusion, procedures to stop bleeding, and change in antithrombotic therapy, all of which may have contributed to the differences in severity and mortality. Although the mechanisms underlying these differences are unknown, the prolonged half-life of warfarin and warfarin's suppression of factor VIIa may be implicated; an active factor VIIa and tissue factor complex are necessary to initiate hemostasis.[6] Although reversal of warfarin with vitamin K, fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa has been shown to reduce the INR, the effects of these interventions on clinical outcomes are uncertain. Delays in presentation, infusion delays, incomplete INR correction, and prothrombotic risk all undermine the effectiveness of these agents in routine practice.[7–8] In the ARISTOTLE trial, warfarin-associated major hemorrhage also more often triggered a change in antithrombotic therapy. Cessation of warfarin therapy was recently shown to increase the risk of thrombosis and death among individuals who had sustained a gastrointestinal hemorrhage.[10] A better understanding of the sequelae of major hemorrhage in terms of intervention, treatment, and attendant complications would inform its optimal management in clinical practice.

Our findings for independent factors associated with major hemorrhage underscore the challenge of shared risk factors for stroke and hemorrhage among individuals with AF, especially those who are older and have had prior stroke and renal dysfunction.[11–12] Our findings also highlight the challenges of implementing anticoagulant therapy among individuals with a propensity for hemorrhage, as those individuals with a prior episode are at highest risk for recurrence. Because of the substantial overlap in risk factors and the major disability related to ischemic stroke, reliance on currently available hemorrhage risk scores for decisions regarding anticoagulant therapy is problematic. These scores were not derived to predict intracranial hemorrhage but rather a wide spectrum of hemorrhagic complications, most of which do not render permanent sequelae. The inability to account for aspirin and nonprescription nonsteroidal anti-inflammatory drugs is another limitation.[13,17] Use of these tools to identify modifiable risk factors amenable to intervention will translate into fewer hemorrhages and improved long-term persistence with anticoagulant therapy. The potent deleterious effects of antiplatelet drugs and nonsteroidal anti-inflammatory agents urge caution with concomitant use and vigilance regarding indication and duration of therapy.[18,19] Alternative analgesic medications without the attendant effects on platelets and gastric mucosa are needed for this patient population. Ascertainment of any protective effect of gastric acid suppressants in this setting requires randomized assessment. Similar to the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial and the studies by Beyth et al.[12] and Shireman et al.,[20] we also found diabetes mellitus to be an independent risk factor for major hemorrhage.[15] The independent contribution of diabetes mellitus may be obscured by renal dysfunction, given their expected high degree of correlation. Microalbuminuria has been associated with both intracerebral hemorrhage and hematuria.[21,22] Hypertension was not found to be an independent predictor of major hemorrhage in ARISTOTLE, which may reflect the degree of blood pressure control achieved among trial participants. The lower rate of major bleeding in females has not been previously reported and warrants further study. Only 8 patients with liver dysfunction experienced a major hemorrhage, precluding any definitive conclusion regarding this patient subgroup.

Study Limitations

The objective of a randomized trial is to provide the most valid, unbiased estimate of medication effect. For this reason, individuals with anticipated difficulty with study protocols or with heightened risk of short exposures (adherence, excessive risk of hemorrhage) may be underrepresented. Thus, extrapolation of trial results to these populations should be done cautiously. However, rates of major hemorrhage associated with warfarin in contemporary AF trials are 2- to 3-fold higher than the rates reported in earlier studies, likely reflecting the older age of today's trial participants, the higher prevalence of chronic disease and concomitant aspirin use, and the overall broader prescription of anticoagulant medications in current AF populations.[23–24] Thus, we believe our trial participants are representative of most patients with AF in clinical practice.