NEW ORLEANS—A sub–analysis of the pivotal ROCKET-AF trial of rivaroxaban versus warfarin found that use of clopidogrel, as well as increasing diastolic blood pressure, renal impairment, and low serum albumin, were among the risk factors associated with intracranial hemorrhage in patients with atrial fibrillation, regardless of which drug is used.
Baseline warfarin use and residence in Eastern Europe were associated with a lower risk of brain bleeding, Graeme J. Hankey, MBBS, MD, consultant neurologist and head of the Stroke Unit at the University of Western Australia in Perth, reported here at the American Stroke Association International Stroke Conference.
Of note, he said, was that hemorrhagic bleeding was a significant 40 percent less common with rivaroxaban than warfarin in patients with atrial fibrillation (p=0.002, 95% CI 0.44-0.83).
THE FIRST ANALYSIS
In the double-blind Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial, 14,264 high-risk patients with AF and either a prior stroke, transient ischemic attack or systemic embolus, or at least three high-risk factors for stroke, were randomized to either 20 mg daily of rivaroxaban (or 15 mg daily for those with impaired creatinine clearance) or warfarin with a target international normalized ratio (INR) of 2.0 to 3.0. The mean follow-up was 1.9 years.
The primary results, published last year in the New England Journal of Medicine, showed that the rate of stroke or systemic embolism was 1.7 percent per year in the rivaroxaban group and 2.2 percent per year in the warfarin group. This resulted in a p-value of less than 0.001 for noninferiority.
There were significant reductions in intracranial hemorrhage in the rivaroxaban group, but mortality rates were similar between the groups.
Based on the results, the FDA late last year approved rivaroxaban, a direct oral factor Xa inhibitor, to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. The sub-analysis sought to understand more about the independent significant predictors for intracranial bleeds among patients in the trial.
“ICH is the most feared complication of anticoagulation, with an incidence of about 1 percent per year. Identifying individuals with AF at risk of stroke who are likely to have an ICH if treated with anticoagulants remains a challenge,” Dr. Hankey said.
Studies that have previously attempted to examine risk factors for ICH were underpowered because “the condition is uncommon and the number of outcomes is small,” he said.
A NEW SUB-ANALYSIS
For this analysis, ICH was defined as symptomatic bleeding into the skull causing focal neurologic symptoms and diagnosed by CT or MRI imaging or autopsy.
A total of 13,833 of the patients in ROCKET-AF were used in the analysis due to missing data for some patients, Dr. Hankey said. Over a median follow-up period of 1.94 years, there were a total of 172 ICH events. Of those, 128 were intracerebral hemorrhages, 38 were subdural, five were subarachnoid, and one was an extradural hemorrhage.
The average annual rate of intracranial bleeds was 0.68 percent per 100 patient-years. Multivariate analysis showed that in addition to randomization to rivaroxaban, there were two other independent significant protective factors for intracranial hemorrhage: residence in Eastern Europe (versus West Europe, North American, Latin America, or Asia Pacific) was associated with a 66 percent lower risk. This could be due to lower numbers of blacks and Asians, both of which are highly associated with ICH, or to ascertainment bias, Dr. Hankey said.
In addition, baseline warfarin use was associated with a 38 percent lower risk. He speculated that this was because these participants “had already [taken] warfarin without an occult bleed.” (See “Six Factors Associated with ICH Risk.”)
Dr. Hankey said: “The message is that high-risk people may want to consider lowering their blood pressure, ask whether they need additional clopidogrel, and perhaps consider whether rivaroxaban might be a more appropriate treatment.”
“We have to be very careful about giving anticoagulants to patients at risk for bleeding into the brain, and therefore need to be able to identify who those patients are,” he continued. “The bottom line is we now have predictors of the risk of bleeding. The risk is not high, but some of the risk factors — e.g., blood pressure, kidney function, and use of antiplatelet agents — are modifiable,” he said.
ENOUGH TO REPLACE WARFARIN?
In brief interviews with nearly a dozen stroke neurologists at the meeting, it was clear that many are taking a cautious approach to replacing warfarin with the newer anticoagulants. Efficacy is seen as fairly comparable, they said, but safety is an issue, particularly in light of their irreversibility and bleeding risks.
Daniel T. Lackland, DrPH, professor of neuroscience and epidemiology at the Medical University of South Carolina, in Charleston, pointed to the wide confidence interval for rivaroxaban versus warfarin in the new analysis and said he will not be changing his practice at this point. Further studies are needed to validate these findings, he said.
Jeffrey L. Saver, MD, director of the University of California, Los Angeles Stroke Center, said: “For patients with difficulty taking warfarin or monitoring it closely, we now have options. But we need to watch for bleeding with these as well as with warfarin. It is an evolution, not a revolution. We want to be somewhat conservative and watch for rare side effects.
“The new data are important because when choosing between warfarin and the new anticoagulants, it is helpful to know which patients are at higher risk for brain bleeds and know which risk factors are modifiable,” he said.
Asked if he thought there was a class effect, Dr. Hankey said that the findings are consistent with those observed with the other warfarin alternatives, dabigatran and apixaban. That is probably because unlike warfarin, these newer agents do not interact with factor VII, he said.
The ROCKET-AF sub-analysis was funded by Johnson & Johnson Pharmaceutical Research and Development and by Bayer HealthCare AG. Dr. Hankey received honoraria as a member of the ROCKET-AF executive committee.•
FACTORS ASSOCIATED WITH ICH RISK
Six factors associated with increased ICH risk were:
- Cockcroft-Gault creatine clearance (10 percent increase in risk per 10-mL/min decrease). “This was closely associated with age,” the study author Graeme J. Hankey, MBBS, said.
- Lower platelet count (< 210 x 109/L).
- Low albumin levels (37 percent increase in risk per 0.5-g/dL decrease).
- History of stroke or TIA increased risk 55 percent.
- Baseline use of a thienopyridine such as clopidogrel raised risk 2.5-fold.
- Increasing diastolic blood pressure (21 percent increase in risk per 10-mm Hg increase).