Rivaroxaban Effective for Secondary Stroke Prevention in AF

Daniel M. Keller, PhD

May 27, 2011

May 27, 2011 (Hamburg, Germany) — Subgroup analysis of the ROCKET-AF trial, a large phase 3 trial of stroke prevention in patients with atrial fibrillation (AF), shows a lower risk for recurrent stroke in patients with a history of prior stroke with rivaroxaban (Xarelto, Bayer/Johnson & Johnson) vs warfarin.

Speaking here at the XX European Stroke Conference, Werner Hacke, MD, PhD, professor and chairman of the Department of Neurology at the University of Heidelberg in Germany, said this benefit in secondary prevention occurred without any excess bleeding in the rivaroxaban arm.

"My final conclusion was that rivaroxaban can be used in primary and in secondary prevention based on the overall results that clearly indicate that it is at least equivalent to (warfarin) and has less severe side effects," Professor Hacke told Medscape Medical News.

In this secondary prevention cohort, "which could have had the risk of more bleeding complication because the brain is already injured, it was very reassuring to see that there is absolute homogeneity in the results and that it really can also be used in those severely affected patients with the very high CHADS score based on those results."

Main ROCKET-AF Trial

Rivaroxaban, a direct factor Xa inhibitor, is one of a handful of new oral anticoagulant agents for the prevention of stroke in patients with AF. Although vitamin K inhibitors are very effective in preventing ischemic stroke, their use is limited by side effects, including intracranial hemorrhage (ICH), their narrow therapeutic range, drug and food interactions, and the need for continual monitoring to keep patients in the therapeutic range.

Dr. Werner Hacke

ROCKET-AF (Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) was a randomized, double-blind trial involving patients with AF at moderate to high risk for stroke. It recruited patients with a high CHADS2 score, a clinical predictor tool to estimate the risk of stroke in patients with AF. Patients in each arm of the trial had a CHADS2 score of approximately 3.5 (of a possible 6), and almost 55% of patients had a history of stroke, transient ischemic attack (TIA), or systemic embolism.

Patients were randomly assigned to rivaroxaban, 20 mg/day (15 mg/day if the creatinine clearance rate was 30-49 mL/min) (n = 6958), or to dose-adjusted warfarin (n = 7004) to maintain an international normalized ratio target of 2.5. Study subjects were monitored monthly.

For the entire study population, rivaroxaban was noninferior to warfarin for the prevention of stroke and non–central nervous system (CNS) embolism but did not achieve statistical superiority. It was associated with a 21% event rate reduction compared with warfarin.

The cumulative rate of stroke or non-CNS embolism at just more than 2.5 years of follow-up was 1.71% with rivaroxaban vs 2.16% with warfarin (hazard ratio, 0.79; 95% confidence interval, 0.66 – 0.96; P < .001 for noninferiority). At the same time, a safety analysis favored rivaroxaban (P = .015 for superiority to warfarin). Notably, the risk of ICH was reduced by 33% and the risk of fatal bleeding by 50% with the new agent.

Secondary Stroke Prevention

The trial protocol prespecified an analysis of safety and efficacy endpoints for the secondary prevention cohort (ie, those study participants who had a history of stroke or TIA). Patients with a history of stroke or TIA are considered at high risk for stroke recurrence and for intracranial hemorrhagic complications.

The prior stroke cohort (n = 7468) was significantly younger (69.7 vs 72.9 years, respectively) and had a higher CHADS2 score (3.93 vs 2.97) than those without a history of stroke. The group without prior stroke had significantly more hypertension, congestive heart failure, and diabetes.

In this trial, with the highest number of AF patients with prior stroke ever studied, rivaroxaban was associated with a 13% lower risk of recurrent stroke or systemic embolism compared with warfarin.

Table 1. ROCKET-AF Subanalysis: Secondary Stroke Prevention

Endpoint Rivaroxaban Warfarin Hazard Ratio (95% Confidence Interval)
Recurrent stroke or systemic embolism (events per 100 patient-years) 2.26 2.60 0.87 (0.69 – 1.10)


These results are similar to those for the overall ROCKET-AF population. Again, rates of bleeding were similar for the 2 treatment groups, although fatal bleeding and ICH events were lower in the rivaroxaban treatment arm. However, the differences were not statistically significant because the subgroup population was not powered to detect differences in these endpoints.

Table 2. ROCKET-AF Subanalysis: Safety Endpoints

Endpoint Rivaroxaban Warfarin Hazard Ratio (95% Confidence Interval)
Safety outcome events (events per 100 patient-years) 13.31 13.87 0.96 (0.87 – 1.07)
Intracerebral hemorrhage (events per 100 patient-years) 0.59 0.8 0.74 (0.47 – 1.15)


Professor Hacke noted that this trial, with about 55% of subjects having a history of AF and stroke or TIA, reflects neurologists' clinical practice better than many previous studies, where only about 15% of subjects had AF and prior events. "This trial has the largest number of those patients that we see," he said. "This represents our daily real life."

Dog-Fight Ahead

In an interview with Medscape Medical News, Professor Peter Sandercock, MA, DM, professor of medical neurology at the University of Edinburgh and director of Edinburgh Neuroscience in the United Kingdom, pointed out that there are 2 other new anticoagulant agents in development or on the market: apixaban (Pfizer/Bristol-Myers Squibb), a factor Xa inhibitor, and dabigatran (Pradaxa, Boehringer Ingelheim), a direct thrombin inhibitor.

"Clearly the new agents offer quite a lot in terms of safety, tolerability, ease of taking, and greater compliance in some senses, but then there is still some concern about their long-term safety because they've only been tested in relatively short term," he said. "And really, these are going to be agents that need to be taken life-long."

One currently cited advantage of the new agents, including rivaroxaban, is that they do not interact with other drugs. "I think we'll need to see what happens in the real clinical world," Professor Sandercock advised and suggested postmarketing studies "to try and understand whether they really are as good as they are said to be."

Many patients doing well with warfarin will, appropriately, continue to take it. But "there are a few folks that just can't get into the therapeutic range [or] for whatever reason can't take warfarin, and for them these new agents are helpful," he said.

Looking beyond the science, Prof. Sandercock predicted "a bit of a dog fight between the drug companies to sort out who can market their product most aggressively, and each of the agents has some pluses and minuses."

ROCKET-AF was funded by Johnson & Johnson and Bayer HealthCare. Professor Hacke is a member of the ROCKET-AF Executive Steering Committee, for which he has been reimbursed for his time and activities. He is a speaker for Bayer-Schering and Boehringer Ingelheim. Professor Sandercock, who had no relation to the trial, was a member of the independent Data and Safety Monitoring Board for the RE-LY trial of dabigatran. Fees and expenses were credited to his department and not to him personally. He has no other disclosures.

XX European Stroke Conference (ESC). Presented May 25, 2011.


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