Risk of Intracranial Hemorrhage Lower With Apixaban Than Warfarin

Author’s Perspective

Lead author Renato D. Lopes, MD, PhD, MHS: “In patients with atrial fibrillation (AF) requiring oral anticoagulation therapy, we can reduce intracranial hemorrhage (ICH) by using apixaban rather than warfarin (regardless of the type and location of the ICH), and by avoiding concomitant aspirin, especially in patients who are older in age. Concomitant aspirin use was independently associated with increased risk of ICH, which suggests that avoiding unnecessary aspirin use could be a strategy to reduce ICH risk.”

Patients with atrial fibrillation (AF) who received the direct factor Xa inhibitor apixaban had a significantly lower incidence of intracranial hemorrhage (ICH) than patients who received warfarin (0.33% per year vs. 0.8% per year; p<0.001), according to an analysis of the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. The authors, led by Renato D. Lopes, MD, PhD, MHS, from the Duke Clinical Research Institute in Durham, North Carolina, noted that this reduction occurred regardless of ICH type or location.

The ARISTOTLE trial enrolled 18,140 patients who had nonvalvular AF and at least one additional risk factor for stroke (including ≥75 years old, previous stroke/transient ischemic attack, symptomatic heart failure or left ventricular ejection fraction <40%, diabetes, or hypertension). Patients were excluded if they had clinically significant mitral stenosis, prosthetic mechanical heart valve, previous ICH, severe renal insufficiency, recent stroke, or a need for dual antiplatelet therapy.

Patients were randomized to receive:

  • apixaban 5 mg twice daily (reduced dose of 2.5 mg was given to patients with ≥2 of the following: ≥80 years old, body weight ≤60 kg, and creatinine ≥1.5 mg/dL)
  • dose-adjusted warfarin with a target international normalized ratio (INR) of 2.0-3.0

The overall incidence of ICH was 0.57 per 100 patient-years of follow-up (n=174). More patients with ICH received warfarin (70.1%) than apixaban (29.9%).

The most common locations of ICH included intraparenchymal (n=105; 64.4%), subdural (n=44; 27%), and subarachnoid (n=14; 8.6%). Warfarin-treated patients were more likely to experience intraparenchymal (0.47% per year vs. 0.21% per year) and subdural hemorrhages (0.22% per year vs. 0.07% per year), compared with those receiving apixaban.

No patients had more than one ICH event during the study, but 19 patients presented with ICH at >1 site – 11 of which were traumatic. Most ICHs were spontaneous (n=116; 71.2%) and traumatic (n=47; 28.8%). A total of 107 ICH events (61.5%) fulfilled the criteria for hemorrhagic stroke.

Treatment with apixaban was associated with less:

  • overall ICH (hazard ratio [HR] = 0.42; 95% CI 0.30-0.58; p<0.0001)
  • spontaneous ICH (HR=0.52; 95% CI 0.35-0.75; p=0.0006)
  • traumatic ICH (HR=0.26; 95% CI 0.13-0.53; p=0.0002)

“Nearly 80 percent of the warfarin-treated patients with ICH had an INR within or below therapeutic range around two weeks before the event (INR=2.6; range = 2.1-3.0), demonstrating that most of the risk of ICH among patients taking warfarin is not related to the dose of warfarin,” Dr. Lopes told ASH Clinical News. “This finding also suggests that better control of INR might not necessarily have a significant impact on reducing ICH in the warfarin population.”

Mortality rates at 30 days, 90 days, and six months following ICH were 43.3 percent, 45.3 percent, and 47.6 percent, respectively. Overall mortality rates were similar in both treatment cohorts: 45.4 percent in the apixaban cohort and 42.6 percent in the warfarin cohort.

Dr. Lopes and colleagues also noted that aspirin use was prevalent among patients who experienced ICH: 66 (37.9%) were receiving aspirin at baseline and 54 (31%) were receiving aspirin the day prior to the ICH event. “Concomitant aspirin use was independently associated with increased risk of ICH,” the authors wrote, adding that “only half of the patients using aspirin had a formal indication for its use.”  The ARISTOTLE protocol did not require or restrict aspirin use.

“Our findings highlight the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in [older patients],” the authors concluded.

The study is limited in that it was a secondary analysis from a clinical trial that was designed to assess a different primary outcome, thus some residual confounding is likely present, according to Dr. Lopes.

Source: Lopes RD, Guimarães PO, Kolls BJ, et al. Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy: clinical characteristics, predictors, management, and clinical outcomes. Blood. 2017 March 28. [Epub ahead of print]