Pradaxa Fails to Prevent Recurrence After Cryptogenic Stroke

By Gene Emery

May 16, 2019

NEW YORK (Reuters Health) - Dabigatran, sold under the brand name Pradaxa by Boehringer Ingelheim to prevent stroke in people with atrial fibrillation, is no more effective than aspirin for preventing a subsequent stroke in patients who have experienced a cryptogenic stroke.

Such strokes account for 20% to 30% of ischemic strokes, researchers note in the May 16 New England Journal of Medicine.

The RE-SPECT ESUS trial showed that after a median of 19 months of follow-up, 6.6% of the 2,695 dabigatran recipients had a recurrent stroke (4.1% per year) versus 7.7% of the same number of participants who took aspirin (4.8% per year), a non-significant difference (P=0.10).

The rates of major bleeding were also not significantly different between the two groups, with Pradaxa patients seeing a slightly higher rate (1.7% vs. 1.4% per year).

But the rate of clinically relevant non-major bleeding was nearly double with dabigatran, seen in 1.6% of patients per year compared with 0.9% with aspirin, a significant difference.

The drug retails for about $500 per month, according to prices at Boehringer Ingelheim financed and supervised the study.

"Our hypothesis was that dabigatran would be more effective than aspirin for stroke prevention in patients with embolic stroke of undetermined source because many of these patients might have had an unrecognized source of cardiac embolism, including atrial fibrillation," write the researchers, led by Dr. Hans-Christoph Diener of University Duisburg-Essen in Germany.

When he and his colleagues looked at secondary outcomes of the risk of ischemic stroke or of a combination of nonfatal stroke, nonfatal myocardial infarction and death from cardiovascular causes, they also found no significant differences when dabigatran was used.

The annual ischemic stroke rate was 4.0% with the drug and 4.7% with aspirin, where the hazard ratio of 0.84 had a 95% confidence interval of 0.68 to 1.03.

For the combination of nonfatal stroke, nonfatal myocardial infarction and death from cardiovascular causes, the annual rates were 4.8% with dabigatran versus 5.4% for aspirin (hazard ratio 0.88 but a confidence interval of 0.73 to 1.06).

The aspirin dose was 100 mg once daily. Dabigatran recipients were given either 150 mg or, if they were over 74 or had an estimate creatinine clearance of 30 to 50 ml per minute, 110 mg twice daily.

Participants who got the lower dose saw significantly fewer events, but that was a post hoc analysis.

"It offers food for thought," coauthor Dr. Ralph Sacco, chairman of neurology at the University of Miami's Miller School of Medicine, told Reuters Health by phone. "But that's a subgroup analysis and that's always tricky."

The patients were treated at 564 sites in 42 countries. All received three tablets daily. Half the group took a placebo aspirin and their received dabigatran; the rest took real aspirin and placebo dabigatran.

Coronary heart disease patients assigned to the dabigatran group were allowed to keep taking aspirin. Dr. Sacco said he didn't think that hampers the relevance of the new findings.

"I don't think the effect of aspirin would be large enough to affect the results," he said. "Besides, we wanted the trial to reflect real-world conditions."

The discontinuation rates were 24.9% with dabigatran and 21.1% with aspirin, mostly because of adverse events.


N Engl J Med 2019.