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


As previously reported, the ARISTOTLE trial enrolled 18,201 patients from 1,034 clinical sites in 39 countries. The on-treatment safety population included 18,140 patients. The median follow-up time was 20.5 months. Major hemorrhage occurred in 789 patients (4.3%) overall; 327 in the apixaban group (2.13% per year) compared with 462 in the warfarin group (3.09% per year; HR 0.69, 95% confidence interval [CI]: 0.60 to 0.80; p < 0.001). Patients who sustained a major bleed were older (74 vs. 70 years, respectively), more commonly had a history of myocardial infarction, prior hemorrhage, impaired renal function, and a fall within the previous year compared with patients without ISTH major hemorrhage ( Table 1 ). They also weighed less and had a lower hematocrit level at baseline. Among the qualifying risk factors, patients who sustained a major hemorrhage were more likely to have a history of stroke, transient ischemic attack (TIA) or systemic embolism, diabetes, or hypertension. They were also more likely to use aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs, statins, and gastric antacid drugs at baseline.

Location of Hemorrhage

The most frequent sites of major hemorrhage were gastrointestinal (31%; n = 248), intracranial (22%; n = 171), and soft tissue (10%; n = 75) ( Table 2 ). Two-thirds of the gastrointestinal bleeds involved the upper tract. Apixaban was associated with fewer gastrointestinal hemorrhages than warfarin, but this difference did not achieve statistical significance (HR 0.89, 95% CI: 0.70 to 1.14). There were also fewer soft tissue hematomas associated with apixaban that met the criteria for ISTH major hemorrhage (HR 0.46, 95% CI: 0.29 to 0.74). In addition, apixaban was associated with fewer major hemorrhages related to trauma: 37 in the apixaban group (0.24% per year) compared with 60 in the warfarin group (0.40% per year; HR 0.60, 95% CI: 0.40 to 0.91; p = 0.015). As previously reported, apixaban was associated with fewer intracranial hemorrhages than warfarin (HR 0.42, 95% CI: 0.30 to 0.58).

Severity and Short-term Consequences of Hemorrhage

Major extracranial hemorrhage-associated adverse consequences occurred less frequently in the apixaban group than in the warfarin group, including fewer hospitalizations (HR: 0.75, 95% CI: 0.61 to 0.92), fewer medical or surgical interventions to stop the bleeding (HR: 0.72, 95% CI: 0.56 to 0.93), fewer transfusions (HR: 0.71, 95% CI: 0.57 to 0.89), and fewer changes in antithrombotic therapy (HR: 0.78, 95% CI: 0.64 to 0.95) ( Table 3 ). Major ISTH hemorrhage criteria followed by death within 30 days occurred half as often in the apixaban group compared with the warfarin group, with 36 and 71 events, respectively (HR: 0.50, 95% CI: 0.33 to 0.74; p < 0.001) (Figure 1).

Figure 1.

Major Bleeding Following by Death Within 30 Days
CI = confidence interval; HR = hazard ratio.

Independent Factors Associated With First Major Hemorrhage

Older age, prior hemorrhage, prior stroke or TIA, diabetes, lower creatinine clearance,[5] and decreased hematocrit level were independently associated with an increased risk of major hemorrhage ( Table 4 ). Use of aspirin and nonsteroidal anti-inflammatory drugs also independently increased the risk of major bleeding by approximately 30%. In the multivariable models, randomization to apixaban, compared with warfarin, was associated with a lower risk of major hemorrhage (HR: 0.69, 95% CI: 0.60 to 0.72), as was female sex and liver disease.

In an exploratory analysis of subgroup by treatment interactions, we found a differential effect by treatment according to 3 variables: baseline renal function, weight, and diabetes. For patients with renal dysfunction and low body weight, the reduction in bleeding with apixaban appeared to be greater than in patients with normal renal function and higher body weight than in patients taking warfarin. For patients with diabetes, the reduction in bleeding with apixaban appeared to be less than for patients without diabetes.