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Apixaban lowers risk for intracranial hemorrhages in patients with atrial fibrillation
Patients with atrial fibrillation demonstrated substantially lower risk for intracranial hemorrhage with the anticoagulant apixaban than with warfarin, according to a randomized study published in Blood.
Further, aspirin may increase the risk for brain bleeds, especially in older patients.
“Intracranial hemorrhage has high morbidity and high mortality and is the most severe and most feared complication among physicians prescribing oral anticoagulants,” Renato D. Lopes, MD, MHS, PhD, cardiologist at Duke Clinical Research Institute, said in a press release. “This study shows apixaban is a better option for oral anticoagulation than warfarin because it reduces stroke while substantially reducing intracranial hemorrhage.”
Atrial fibrillation affects between 2.7 and 6.1 million Americans and can lead to blood clots that cause strokes. According to the CDC, patients with atrial fibrillation are five times more likely to experience a stroke. Anticoagulants substantially lower the risk for stroke, but also increase the risk for uncontrolled bleeding.
Intracranial hemorrhages occur in approximately 1% of patients receiving anticoagulants for atrial fibrillation and can occur spontaneously or after trauma, such as a fall.
Brain bleeds have been associated with a 30-day mortality rate of 50%. Symptoms include headaches, vomiting, seizures and coma.
Warfarin — a vitamin K antagonist — has been a standard oral anticoagulation therapy. Researchers compared warfarin with apixaban — a non–vitamin K antagonist — in patients with atrial fibrillation.
The ARISTOTLE trial including 18,201 patients from North America, Latin America, Europe and Asia with atrial fibrillation and at least one other additional risk factor for stroke, such as age older than 75 years, having a previous stroke or transient ischemic attack, symptomatic heart failure or left ventricular ejection fraction of less than 40%, diabetes or hypertension.
Researchers randomly assigned patients to receive apixaban (5 mg twice daily) or dose-adjusted warfarin with a targeted international normalized ratio of 2 to 3. Patients aged older than 80 years, with a weight less than 132 pounds, and creatinine greater than 1.5 mg/dL received a reduced dose of apixaban.
The number of intracranial hemorrhages on each anticoagulant medication served as the primary endpoint. Median follow-up was 1.8 years.
Patients assigned apixaban achieved a lower rate of intracranial hemorrhages than those assigned warfarin (29.9% vs. 70.1%). Patients assigned apixaban also experienced a longer median time to intracranial hemorrhage (348 days; range 41-563 vs. 279 days; range 113-455 days).
The majority of intracranial hemorrhages were spontaneous (71.2%; n = 116) compared with traumatic (28.8%; n = 47). The primary locations of the hemorrhages were intraparenchymal (64.4%; n = 105), subdural (27%; n = 44) and subarachnoid (8.6%; n = 14).
Patients with intracranial hemorrhage tended to be older (median, 74 years), weigh less (median, 168 pounds) and have a higher frequency of falls (7.6% vs. 4.5%, P = .068). Researchers also noted that, of the patients assigned to warfarin who had intracranial hemorrhage, 80% had a pre- intracranial hemorrhage international normalized ratio within or below therapeutic range (2.6) less than 2 weeks before the event, suggesting that better control of international normalized ratio might not necessarily have a significant impact on reducing intracranial hemorrhages.
Further, aspirin use was independently associated with increased risk for intracranial hemorrhage. Of those with an event, 37.9% (n = 66) took aspirin at baseline and 31% took aspirin the day before intracranial hemorrhage.
“We know that aspirin has only a modest effect in preventing stroke in atrial fibrillation patients, yet it was one of the top predictors in intracranial hemorrhage,” Lopes said. “Our finding demonstrates that aspirin is not as safe as one might think.”
Mortality rates following intracranial hemorrhage were 43.3% at 30 days, 45.3% at 90 days and 47.6% at 6 months. Of the 66 patients who died before discharge, 71.2% (n = 47) had intraparenchymal hemorrhages, 22.7% (n = 15) had subdural hematomas and 6.1% (n = 4) had subarachnoid hemorrhages. – by Chuck Gormley
Disclosure: Bristol-Myers Squibb and Pfizer funded the study. Lopes reports research funding from Bristol-Myers Squibb and Glaxo Smith Kline; and consultant roles with Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Pfizer and Portola. Please see the full study for a list of all other researchers’ relevant financial disclosures.