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An earlier start to anticoagulation after an acute ischemic stroke for patients found to have atrial fibrillation appeared safe and possibly improved outcomes, according to the randomized ELAN trial.

Starting a direct oral anticoagulant (DOAC) within 48 hours for mild or moderate stroke or on day 6 or 7 in those with major stroke resulted in a 2.9% composite rate of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days.

That rate was 4.1% more typical strategy of initiation at day 3 or 4 after minor stroke, day 6 or 7 after moderate stroke, and day 12-14 after major stroke, researchers led by Urs Fischer, MD, of University Hospital Basel in Switzerland, reported in the . The trial was also presented at the European Stroke Organization Conference in Munich, Germany.

While the trial had no formal hypothesis testing for superiority or even noninferiority, the 95% confidence interval for a difference between groups was consistent with anywhere from a 30-day risk reduction of 2.84 percentage points to an increase of about 0.5 percentage points with early anticoagulation.

"Early treatment initiation can therefore be supported if indicated or if desired," the researchers concluded. "The rates of the outcomes increased only slightly more at 90 days than at 30 days, findings that suggest there was not an excessive risk associated with early anticoagulation through that period."

Current clinical practice is to delay the initiation of anticoagulation after ischemic stroke, with the American Heart Association–American Stroke Association calling for waiting more than 14 days if there is a high risk of hemorrhagic transformation or starting anywhere from day 2 to day 14 if that risk is low.

"We're always trying to prevent recurrent stroke, but we don't want to cause hemorrhagic transformation," commented Geoffrey Barnes, MD, of the University of Michigan Frankel Cardiovascular Center in Ann Arbor. "There was a concern that with the direct oral anticoagulants, becoming essentially fully anticoagulated within just a couple of hours, there could be that risk of causing hemorrhagic transformation shortly after an ischemic stroke."

Along with the somewhat similarly designed but smaller trial, the findings "really provide us reassurance that the direct oral anticoagulants are not significantly increasing the risk of hemorrhagic transformation and may even be leading to fewer recurrent strokes," said Barnes, who was not involved in either trial.

The 30-day recurrent ischemic stroke rate was 1.4% with early treatment compared with 2.5% in the later-treatment group and 1.9% versus 3.1% at 90 days, which was not statistically significant in either case (OR 0.57, 95% CI 0.29-1.07, and 0.60, 95% CI 0.33-1.06).

"For everyday clinicians, this looks pretty similar to other randomized trials," said Barnes, pointing to the stroke risk curves that "clearly are trending towards favoring early treatment is better."

With meta-analysis potentially providing the odds ratios and hazard ratios for the primary endpoint that people are used to seeing, Barnes predicted that the "clear consistency" would be persuasive to guidelines committees too.

Perhaps most reassuring, though, according to Barnes, were the "very low" symptomatic intracranial hemorrhage rates of just 0.2% in both groups by 30 days.

"That goes along with everything seen from initial phase III of the direct oral anticoagulants to many of the real-world data studies we've seen, just showing that these drugs are remarkably safe when it comes to the risk of intracranial hemorrhage," he said. "So I was very much reassured by those data that we saw in a group of patients that are, I would think, very high risk."

The trial randomized 2,013 acute ischemic stroke patients (median age 77, 45% female) at 103 sites in 15 countries to open-label treatment with a DOAC in the two time frames. Of them, 37% had minor stroke (≤1.5 cm), 40% had moderate stroke (an infarct in the distribution of a cortical superficial branch of the middle, anterior, or posterior cerebral artery), and 23% had major stroke (≤1.5 cm in the distribution of these arteries, the brain stem, or cerebellum).

Stroke magnitude was determined by the site investigators on the basis of a standardized visual rating scheme for magnetic resonance imaging or computed tomography imaging performed before randomization. Median National Institutes of Health Stroke Scale (NIHSS) score was 5 at admission and 3 at randomization.

Study limitations included the exclusion of patients already receiving therapeutic anticoagulation at baseline and the low median NIHSS score at baseline. The trial also lacked demographic data for the participants; while they were enrolled from Europe, the Middle East, and Asia, the majority of the trial population came from predominantly white European areas.

The -- Optimal Timing of Anticoagulation after Acute Ischaemic Stroke -- trial is ongoing in in the United Kingdom to add to the evidence.

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