Intracranial Bleed Risk Higher in Warfarin Than Rivaroxaban Users

View on the News

Premature to Shift Away From Warfarin

Although rivaroxaban is another tool in our armamentarium for patients at risk of stroke, I think it’s premature to make a paradigm shift away from warfarin.

Clearly, ROCKET-AF showed us that rivaroxaban was noninferior to warfarin. This subanalysis showed that rivaroxaban also had a decreased rate of intracranial hemorrhage, compared with warfarin, but we must keep in mind that the drug did not affect the ROCKET-AF trial’s primary end points of stroke or systemic embolism, nor did it decrease mortality, compared with warfarin.

One of the biggest concerns about rivaroxaban and some of the other new antithrombotic agents is that we have no established protocol to deal with bleeding, should it occur, as we do with warfarin. At this point, we really don’t know the best way to deal with a bleed. This is something we will learn only with more time. And, compared with the other new-generation anticoagulants apixaban and dabigatran, rivaroxaban seems to have a few more side effects, such as nausea and increased liver enzymes.

Rivaroxaban and these other drugs do have benefit of being fixed-dose medications taken once or twice a day, and which don’t require the monitoring that warfarin does. But they are going to be more expensive.

If a patient is under treatment with warfarin and is stable, and if the monitoring schedule is acceptable and there are no major INR fluctuations, I don’t think there is any indication to shift treatment. If the patient has difficulty maintaining a therapeutic INR or if the monitoring is inconvenient, then I suspect patients might welcome the use of one of these fixed-dose agents.

Dr. José Biller is chairman of neurology at Loyola University, Maywood, Ill. He is the lead author on a recently published review of the new-generation anticoagulation drugs (Expert Rev. Neurother. 2012;12:179-90). He had no disclosures.



NEW ORLEANS – Compared with warfarin, the new-generation anticoagulant rivaroxaban was associated with a 40% lower risk of intracranial hemorrhage in patients with atrial fibrillation who were taking the agents to prevent stroke.

Since its approval by the Food and Drug Administration last fall, rivaroxaban has been deemed an alternative to warfarin, especially among those patients who have trouble maintaining a stable international normalized ratio, who have warfarin side effects, or who find the constant warfarin monitoring untenable, Dr. Graeme Hankey said at an international stroke conference.

Rivaroxaban also doesn’t involve the medication and food interactions that can make warfarin problematic, said Dr. Hankey, head of the stroke unit at Royal Perth Hospital, Western Australia.

"Many patients don’t want to take warfarin for these reasons," he said in an interview. "Rivaroxaban doesn’t have these interactions. It has a stable, predictable effect with once-a-day dosing and doesn’t require this constant monitoring."

Dr. Hankey’s subanalysis of the pivotal ROCKET-AF study, which compared rivaroxaban with warfarin, also determined that some patients had up to a 4-fold increased risk of an intracranial bleed while taking either of the anticoagulants.

The initial study – Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation or ROCKET AF – included 14,264 patients with atrial fibrillation; a history of stroke, TIAs, or systemic embolism; and at least two of the following stroke risk factors: heart failure or a left ventricular ejection fraction of 35% or less; hypertension; an age of 75 years or more; or the presence of diabetes mellitus. Patients were randomized to receive dose-adjusted warfarin or rivaroxaban. Those with normal creatinine clearance received 20 mg daily of the study drug; those with a decreased clearance received 15 mg rivaroxaban daily.

The study’s main end point – a combination of stroke or systemic embolism – was similar in both groups (about 2% per year). The rates of myocardial infarction, and major bleeding also were not significantly different. Vascular mortality and all-cause mortality were nearly identical. However, there was a significant difference in intracranial hemorrhage, favoring rivaroxaban (0.8%; 55 vs. 1.2%; 84) (N. Engl. J. Med 2011;365:883-91). Fatal bleeding occurred in less than 1% of each group.

Dr. Hankey’s subanalysis examined the drug’s effect on intracranial hemorrhage, "probably the most-feared complication of anticoagulation," according to the investigator. It also examined independent risk factors for intracranial hemorrhage regardless of which drug the study patients took.

He and his colleagues found 172 intracranial hemorrhages in ROCKET-AF – a rate of about 7% per year. Of these bleeds, 128 were intracerebral, 5 subarachnoid, 38 subdural, and 1 extradural. Patients taking rivaroxaban were 40% less likely to have an intracranial hemorrhage than were those taking warfarin.

The subanalysis identified factors that significantly increased the risk of an intracranial bleed. The largest by far were race and concomitant use of clopidogrel. Compared with whites, blacks were more than 400% more likely to have a brain bleed (odds ratio, 4.2), while Asians were 200% more likely. Those taking clopidogrel plus either warfarin or rivaroxaban were 250% more likely to have a bleed than were those not taking an additional anticoagulant (OR, 2.50).

Other significant associations with brain bleeds were as follows:

• High diastolic blood pressure – 21% increased risk for every 10 mm/Hg above normal.

• Poor kidney function – 10% increased risk for every 10 mL/min decrease in creatinine clearance.

• History of stroke or transient ischemic attack – 55% increased risk.

• Low platelets – 8% increased risk;

• Low albumin – 37% increased risk.

The FDA approved rivaroxaban in 2011, to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

ROCKET-AF was supported by Johnson & Johnson Pharmaceutical Researchand Development and by Bayer HealthCare. Dr. Hankey was an investigator on the trial and has received honoraria for speaking on the study drug. He is also a consultant for Boehringer Ingelheim and Bayer, which make dabigatran and rivaroxaban, respectively.

Recommended Reading

Aortic Regurgitation After TAVR Poses Threat
MDedge Cardiology
PCI Trial Halted After FFR's Benefit Shown
MDedge Cardiology
Risk Factors, Not Race, Determine Lifetime Heart Risks
MDedge Cardiology
Trauma Risk in Oral Anticoagulant Users Prompt Search for Antidotes
MDedge Cardiology
Feds Bar Generic Drug Maker Ranbaxy
MDedge Cardiology
Vytorin Falls Short of New Indication for CKD Patients
MDedge Cardiology
Lifestyle Changes Cut Heart and Cancer Risks
MDedge Cardiology
Blood Pressure Differences Between Arms Flags Vascular Disease
MDedge Cardiology
Updated Criteria Revisit PCI Appropriateness Scenarios
MDedge Cardiology
Longer Monitoring Needed to Detect Cause of Cryptogenic Stroke
MDedge Cardiology