Dabigatran Slashes Risk of Brain Bleeding in Patients with Prior Stroke

Neurology Today
1 April 2010; Volume 10(7); p 8

SUSMAN, E D

In a large trial, dabigatran was found to be at least as effective as warfarin in preventing strokes and reducing the risk of intracranial hemorrhage among patients who had had a prior transient ischemic attack or stroke.

SAN ANTONIO, TX—Treatment of patients who have experienced a transient ischemic attack (TIA) or a stroke with the oral anticoagulant dabigatran showed that the investigational drug was at least a good as warfarin in preventing strokes and it reduced the risk of intracranial bleeding.

“In patients who already had a TIA or stroke and suffer from atrial fibrillation, dabigatran is as effective as warfarin,” said study author Hans-Cristoph Diener, MD, PhD, professor and chairman of neurology at University Hospital in Essen, Germany. Dr. Diener described the results of the phase 3 RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy Warfarin Compared to Dabigatran) here at the International Stroke Conference, which was sponsored by the American Stroke Association, in February.

“The problem with warfarin is that it is difficult to handle. You have to keep patients in a very narrow range of anticoagulation, which is measured by the INR (International Normalized Ratio),” he explained. “If people are below the therapeutic range they have an increased risk of ischemic stroke, and if they are above the therapeutic range they have an increased risk of hemorrhage. Warfarin also has interactions with other drugs and food. There is a continuous need for monitoring.”

“Dabigatran is much easier to handle because it is given in a fixed dose and does not require checking on anticoagulation and it has a significantly lower rate of serious bleeding events, including intracerebral hemorrhage,” he said.

Dr. Diener noted that people who have atrial fibrillation have a five-time higher risk of suffering a stroke. He said that currently warfarin is the treatment of choice to prevent stroke, having shown in clinical trials that the Vitamin K antagonist reduces the risk of stroke compared to placebo by about 70 percent compared with about 40 percent for aspirin.

In the RE-LY study, researchers randomized more than 18,113 people to either warfarin or two different doses of dabigatran —110 mg twice a day (low-dose), or 150 mg (high-dose) twice a day and followed patients an average of two years.

Figure. DR. HANS-CRISTOPH DIENER:“Dabigatran is much easier to handle [than warfarin] because it is given in a fixed dose and does not require checking on anticoagulation and it has a significantly lower rate of serious bleeding events, including intracerebral hemorrhage.”

[ Click here to enlarge ]

Dr. Diener reported on the subgroup of 3,623 patients who already had a TIA or stroke when they entered the trial. The primary endpoint was the incidence of ischemic strokes and systemic embolism. “For this outcome there was no difference between the two doses of dabigatran and warfarin,” he said in a news briefing. [For more study statistics, see “RE-LY Study Data.”]

“In regard to major bleeds, the low dose of dabigatran was significantly superior to warfarin,” Dr. Diener said. “It caused fewer major hemorrhages. The high dose of dabigatran had an equivalent bleeding rate. Most important for the neurologist is the risk of cerebral hemorrhages. People with warfarin have a higher risk of hemorrhages.”

There were 30 intracranial bleeding events in patients with previous TIA or strokes among those on warfarin compared with six events in patients on the low dose of dabigatran (p<0.001) and 13 events in the high dose dabigatran patients (p=0.007).

“Across the study period, people who received warfarin had 18 hemorrhagic strokes and people who had lose dose dabigatran had two hemorrhagic strokes (p=0.003) and people on high dose dabigatran had five (p=0.009),” Dr. Diener said. “This translates to a relative risk reduction of hemorrhagic strokes to between 73- and 89-percent.”

“In terms of practical use, if a patient is on warfarin and is doing very well because the INR is kept very strict and the patient is very compliant and the risk factors are controlled, I can't see a reason why one should change,” Dr. Diener said. “But there are many patients who have INRs that are all over the place or it is difficult for them to have coagulation tests when they travel, for example — these would be good candidates for dabigatran,” he said.

Dabigatran is marketed in Europe and Canada for prevention of venous thrombosis. Its approval is pending in the United States.

Thomas G. Brott, MD, professor of neurology and director for research at the Mayo Clinic in Jacksonville, FL, agreed with Dr. Diener regarding who should take dabigatran once the drug receives approval in the United States. People who are doing well on warfarin should remain on that drug, he said. Dr. Brott suggested that doctors would seek to put new patients on dabigatran if it is approved, even though it is likely to be more expensive than warfarin.

He did not think that the hints about possible heart attacks with dabigatran would cause neurologists to refrain from prescribing dabigatran since dabigatran has shown that its use can reduce the incidence of intracranial hemorrhage — the bane of treatment with warfarin. “Neurosurgeons hate warfarin,” Dr. Brott said, in commenting on the RE-LY study. He did not participate in that research.

The RE-LY trial was funded by Boehringer-Ingelheim.•

Hans-Cristoph Diener, MD, PhD, professor and chairman of neurology at University Hospital in Essen, Germany, said that in the overall RE-LY study there was a slight increase in the numbers of people in the overall study who had a myocardial infarction with dabigatran.

“In the subgroup [the 3,623 patients who already had a TIA or stroke] there was no difference. The rate of myocardial infarction was absolutely identical in the three treatment groups,” he said.

In those with prior events, the risk of a heart attack was 0.63 per 100 patients years in the low dose dabigatran group; 0.81 per 100 patient years in the high dose dabigatran patients and 0.64 in the warfarin patients.

In an earlier study, reported at at the European Society of Cardiology meeting in Barcelona in 2009, 6,015 patients with non-vavular atrial fibrillation and one other risk factor for stroke were assigned to treatment with dabigatran 110 mg daily. After more than two years of follow-up, 182 patients experienced a stroke, an annual rate of 1.53 percent.

Another group of 6,076 patients were assigned to receive dabigatran 150 mg a day: 134 had strokes at an annual rate of 1.11 percent.

The final group of 6,022 patients, who received open-label warfarin, had 199 strokes, an annual rate of 1.69 percent.

The heart attack rate was 0.51 per 100 patient years with warfarin; 0.75 in the low dose dabigatran and 0.71 in the high dose dabigatran.

Dr. Diener speculated that there might be something in warfarin that protected patients better against heart attacks that was not in dabigatran, which accounted for overall lower rates of heart attacks in the warfarin group in the overall study.•

Primary endpoint: ischemic stroke or systemic embolism

* 64 of 1,195 subjects assigned to warfarin —a rate of 2.74 events per year.

* 55 of the 1,195 subjects assigned to the low dose dabigatran — a rate of 2.32 events per year (p=0.37)

* 51 of the 1,233 subjects assigned to high-dose dabigatran — a rate of 2.07 (p=0.14).•