Encouraging Early Safety Data for Dabigatran in Stroke

May 30, 2018

GOTHENBURG, Sweden — Results of a preliminary study show promising indications of safety for the use of the new oral anticoagulant drugs in patients with transient ischemic attack (TIA) or minor stroke.  

The Dabigatran following Acute Transient ischemic Attack and minor Stroke (DATAS II) study showed no increase in symptomatic hemorrhagic transformation with dabigatran vs aspirin.

The study was presented at the recent 4th European Stroke Organisation Conference (ESOC) 2018.

"At present early recurrent stroke prevention is focused on use of antiplatelet drugs but that will not be sufficient to prevent certain types of strokes, particularly cardioembolic strokes, which represent at least 20% of patients with recurrent stroke," said lead investigator Ken Butcher, MD, University of Alberta, Edmonton, Canada.

Dr Ken Butcher

DATAS II was designed specifically to look at the safety of using one of the new oral anticoagulant drugs in the acute stroke setting, since there is no information on this as yet.

Previous studies have not supported the use of older anticoagulants in acute stroke because of a high risk for hemorrhagic transformation seen with unfractionated and low-molecular-weight heparin, Butcher noted.

The DATAS II study included 301 patients with high-risk TIA or minor stroke (National Institutes of Health Stroke Scale [NIHSS] score, 0 to 9) who presented within 72 hours of symptom onset. They underwent MRI, and those with diffusion-weighted imaging (DWI) lesions greater than  25 mL were excluded.

Anyone with an indication or contraindication for anticoagulation were excluded so that patients with known atrial fibrillation were not enrolled. But Butcher noted that one in four patients in the study had evidence of large-artery atherosclerotic disease.

The patients were randomly assigned to dabigatran (150/110 mg twice daily) or aspirin (81 mg daily) for 30 days. 

The primary endpoint was symptomatic hemorrhagic transformation — parenchymal hemorrhage type 2 with blood occupying more than 30% of the original infarct volume and associated with clinical deterioration of more than 4 points on the NIHSS scale occurring within 5 weeks of randomization.

There were zero primary endpoints in either the dabigatran or aspirin group. No parenchymal hemorrhages occurred in either group. "This obviously simplified the statistical analysis," Butcher quipped. 

Asymptomatic hemorrhagic transformation occurred in 7.8% of the dabigatran group vs 3.5% of the aspirin group (relative risk, 2.2; 95% CI, 0.79 - 6.21).   

While the study was not powered for efficacy, there were numerically fewer ischemic events in the dabigatran group: recurrent ischemic lesions on DWI or fluid-attenuated inversion recovery (FLAIR) MRI at 30 days were seen in 9 patients (6.3%) in the dabigatran group and 14 (9.9%) in the aspirin group (relative risk, 0.64; 95% CI, 0.29 - 1.44).

"This doesn't translate into a significant risk reduction, but the trend is going the right way," Butcher commented.

He explained that the DATAS II study is an intermediate between the NAVIGATE ESUS and POINT trials, both of which were presented for the first time at this ESOC meeting.

"What has become clear is that the longer patients are on more aggressive antithrombotic therapy, whether that is dual antiplatelet drugs or an anticoagulant, then the greater the risk of hemorrhagic complications," he said. "NAVIGATE was disappointing, but it was looking at a very different population over an expanded time period. I don't think it closes the door at all to short-term anticoagulation in the acute setting."

POINT involved a patient population similar to that of DATAS II and "shows that we can reduce recurrent strokes with dual antiplatelet therapy but that is also not without risk," Butcher added. "You could argue that the risks seen with dual antiplatelet therapy in POINT were higher than we saw with dabigatran in DATAS II over that short period of time. So I still think there is room for further trials of these novel anticoagulants in this setting."   

He stressed that the DATAS II trial did not select patients on the infarct pattern but took all comers.

"One of the more interesting secondary observations that comes out of our study is that patients that show an initial stroke with a lacunar pattern can go on to have a recurrent stroke with an embolic pattern. Our current approach to infer etiology of stroke based on infarct pattern could be oversimplistic. It might be better to take a broader brush to antithrombotic therapy."

Butcher and colleagues are keen to pursue further trials with anticoagulation in this population.

"It is clear that after the POINT trial the guidelines will now change — the standard of care will become dual antiplatelet therapy probably for 30 days so that will have to be the new control group in any future trials," he commented. "But we have a shown good safety data on dabigatran and we would like to now pursue a larger efficacy trial."

 Commenting on the DATAS II study, Urs Fischer, University Hospital (Inselspital), Bern, Switzerland, said, "This is exciting information.

"The use of these new oral anticoagulant drugs in stroke is an important question. It is great that it is being addressed in new trials."    

4th European Stroke Organisation Conference (ESOC) 2018. Presented May 16, 2018.

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