Earlier Anticoagulation Safe in Stroke With AF: ELAN

Patients presenting with an acute ischemic stroke and found to have atrial fibrillation (AF) can be safely started on a direct oral anticoagulant (DOAC) much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH) but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel, Switzerland, commented to theheart.org | Medscape Cardiology.

“This trial will change clinical practice in that we can feel much more reassured that starting DOAC treatment early in these patients will not cause harm,” he said.

Senior investigator, Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, United Kingdom, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Fischer presented the results of the ELAN trial at the European Stroke Organisation Conference (ESOC) in Munich, Germany, on May 24. The trial was also simultaneously published online in The New England Journal of Medicine (NEJM).

He explained that patients presenting with acute ischemic stroke who are found to have atrial fibrillation need to be started on anticoagulation to reduce the risk for a recurrent stroke. But there are no clear guidelines on when to start anticoagulation in these patients at present, with concerns that starting very early may increase the risk for hemorrhagic transformation and ICH.

Based on observations that patients with larger strokes have a higher risk for ICH in the early post-stroke period, some guidelines advise different times for starting anticoagulation for different stroke severities: 1 day for a transient ischemic attack, 3 days for a minor stroke, 6 days for a moderate stroke, and 12 days for a severe stroke — known as the 1-, 3-, 6-, 12-day rule.

“But this is not based on evidence – just on expert opinion,” Fischer noted. “The ELAN trial was conducted to obtain more solid information on optimal timing for starting anticoagulation and whether we can safely start a DOAC earlier than these guidelines currently advise.”

For the trial, which was conducted in 15 countries, 2013 patients with an acute ischemic stroke and found to have AF were randomly selected to start DOAC treatment earlier or later.

The later-treatment strategy followed the current approach of starting treatment at day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke, whereas the earlier-treatment group started DOAC treatment within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke.

In terms of stroke severity, which was defined on imaging-based criteria, 37% of patients had a minor stroke, 40% had a moderate stroke, and 23% had a major stroke.

The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.

Results showed that this occurred in 2.9% in the early-treatment group and 4.1% in the later-treatment group (risk difference, -1.18 percentage points; 95% CI, -2.84 to 0.47) by 30 days.

Recurrent ischemic stroke occurred in 1.4% in the early-treatment group and 2.5% in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29-1.07). Symptomatic intracranial hemorrhage occurred in two participants (0.2%) in both groups by 30 days.

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,” the researchers report in the NEJM paper.

“Early treatment initiation can therefore be supported if indicated or if desired,” they conclude.

“The most important finding was that among 2000 patients randomized, there was a very low rate of bleeding complications, and no increase in any bleeding complication in the early DOAC group. This has been a major worry about starting anticoagulation early,” Fischer commented.

“These are very practical findings in that we can keep things simple,” Dawson added. “If the patient has a big stroke, anticoagulation with a DOAC can now be started at 6 days. For everyone else, we can start DOAC treatment as soon as possible without fear of causing harm. So, we can now confidently give patients with a minor or moderate stroke, as defined by imaging, a beneficial treatment as soon as we establish they are having an ischemic stroke and have AF.”

Dawson pointed out that about 25% of patients with ischemic stroke are found to have AF on admission ECG, and in another 4%-5%, AF is found in the first 48 hours. “These are the patients we are targeting in this study.”

The researchers note that the trial did not have a statistical superiority or noninferiority design but rather aimed to estimate the treatment effects of early initiation vs later initiation of DOACs.

“This trial was slightly different in that we weren’t testing a strict statistical hypothesis because we didn’t have any data with which to formulate what sort of effect size to aim for, so we performed a qualitative trial to look at what the event rates were with the two approaches,” Fischer explained. “Our main findings are that ICH rates were not increased with early DOAC treatment, and that ischemic event rates were numerically reduced, but because we didn’t have strict statistical limits, we can only say this is a high probability but not a certainty.”

Dawson added: “We can say from these results that there is a high level of probability that early DOAC treatment does not cause harm and a reasonable probability that it reduces risks of a recurrent stroke or other ischemic event.”

The researchers give an estimate of the effect size for the primary composite endpoint, which combines the major ischemic and bleeding events, ranging from a 2.8% lower risk to a 0.5% higher risk with early DOAC treatment.

“So, it is very likely that the composite endpoint would be lower,” Dawson said.

Fischer noted that a previous study (TIMING) tried to address the issue of earlier vs later anticoagulation in these patients but was stopped early after 880 patients had been enrolled because of slow recruitment.

“Results from this study failed to show superiority of early vs late DOAC treatment but they did suggest noninferiority, and they also found no increase in major bleeding complications, which is an added reassurance,” he commented.

Another trial looking at early vs late anticoagulation in these patients, OPTIMAS, is ongoing in the United Kingdom and is aiming to randomize 3500 patients.

Imaging-Based Assessment of Stroke Severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

“We took a cautious approach by using imaging to define stroke severity. So, when using these results in clinical practice, it is important that patients are selected for the timing of DOAC treatment based on the imaging results,” Dawson explained. “This is very straightforward as the size of the stroke can be seen clearly on the routine CT imaging that all patients receive up front. This is a very pragmatic and simple protocol. And advanced imaging is not required.”

He noted that though clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, Greece, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

“There was a very low ICH rate with only two events in each group. And then there was above a 1% reduction in the composite outcome including ischemic vascular events and bleeding,” he noted.

“This is important because there are many thousands of patients with acute ischemic stroke and AF and now, we have a large study showing we can treat them with a DOAC early and this appears to be safe and it appears also be more effective in terms of outcome events,” Tsivgoulis said.

But he highlighted one important caveat: that the majority of patients had mild or moderate stroke.

European Stroke Organisation Conference 2023. Presented May 24.  

N Eng J Med. Published online May 24, 2023. Abstract

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