NEW ORLEANS—Rivaroxaban is associated with a 40% lower risk of intracranial hemorrhage than warfarin among patients with atrial fibrillation and a moderate to high risk of stroke, according to research presented at the 2012 International Stroke Conference. In addition, patients with poor renal functioning, previous stroke, and high blood pressure are more likely to experience intracerebral hemorrhage, said Graeme J. Hankey, MD, consultant neurologist and head of the Stroke Unit at Royal Perth Hospital in Australia.
Dr. Hankey and his colleagues conducted a subanalysis of the Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. In the main study, patients who took rivaroxaban were 12% less likely to experience a stroke than patients who took warfarin. For the subanalysis, Dr. Hankey and his colleagues sought to determine the independent, significant predictors of intracranial hemorrhage among patients with atrial fibrillation. The trial followed 14,264 patients with atrial fibrillation who were randomly assigned to take an adjusted dose of warfarin or 20 mg of rivaroxaban daily.
The investigators followed up with patients at one, two, and four weeks, and at monthly intervals thereafter. The median follow-up time was 1.9 years. The study’s overall primary outcome was stroke or systemic embolism, and Dr. Hankey chose intracranial hemorrhage as the primary outcome of the substudy.
Warfarin and Rivaroxaban May Entail Different Levels of Bleeding Risk
During the follow-up, 172 patients had an intracerebral hemorrhage, 414 had a nonhemorrhagic stroke, and 13,678 had no intracerebral hemorrhage or stroke. The average annual rate of intracerebral hemorrhage was 0.68 per 100 patient years. Patients taking rivaroxaban were 40% less likely to have an intracerebral hemorrhage than patients taking warfarin.
The drugs’ pharmacodynamics may explain the difference between their associated risks of intracerebral hemorrhage. “The brain is incredibly rich in a substance called tissue factor,” said Dr. Hankey. “If there’s any slight leakage of blood, tissue factor will … form a clot so you don’t have a nasty bleed. Warfarin interferes with that coagulation mechanism. Tissue factor binds to factor VII to make the blood clot. Warfarin inhibits factor VII,” but rivaroxaban does not, Dr. Hankey explained.
Medical and Geographic Risk Factors
The investigators also found that for every 10-mm reduction in renal filtration rate, the risk of bleeding to the brain increased. Every 10-mm Hg increase in diastolic blood pressure augmented the risk of bleeding by 21%. Previous stroke increased the risk by 55%. In addition, patients from the Asia Pacific region, North America, Western Europe, and Latin America had a higher risk of intracerebral hemorrhage than patients from Eastern Europe.
Patients taking more than one blood thinner had two and a half times the risk of intracerebral hemorrhage as patients taking one blood thinner. Also, persons with a platelet count lower than 210 × 109/L at baseline had an increased risk of intracerebral hemorrhage. Patients with low serum albumin and those with low creatinine clearance also had a high risk of bleeds to the brain.
On the other hand, patients who take warfarin continuously for a long period may have a low risk of intracerebral hemorrhage. “This is a recognized phenomenon,” said Dr. Hankey. “If you started anticoagulation a few months before, you survived a warfarin stress test, haven’t had a bleed on it, and you’re still taking it, then that’s a good predictor that you’re unlikely to bleed in the future,” he added.
—Erik Greb