More Support for Early DOACs After AF-Related Stroke

ABU DHABI, UAE — One day after two new datasets seemed to remove any doubt that essentially all patients with atrial fibrillation (AF) should receive a direct oral anticoagulant (DOAC) soon after an acute stroke, the exact same message was reinforced by a novel risk-weighted analysis of last year’s landmark trial.

For those still concerned about iatrogenic bleeding events from early DOAC use, “I would argue that our findings essentially rule out net harm from early initiation of anticoagulation,” said study investigator Alexandros A. Polymeris, MD, PhD, Department of Neurology and Stroke Center, University of Basel, Basel, Switzerland.

The results were presented as a late breaking study on October 25 at the 16th World Stroke Congress (WSC) 2024.

Best Way to Reduce Complications

Just over a year ago, the 2000-patient ELAN trial, published in The New England Journal of Medicine, supported a net benefit from early DOAC, defined as within 28 hours of an AF-related stroke, relative to late DOAC, defined variably as 3-4 days after a minor stroke, 6-7 days after a moderate stroke, and 12-14 days after a major stroke.

The net benefit was based on the composite event list of ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial bleeding, or vascular death. At 30 days, any primary outcome event was less frequent after early than late DOAC (2.9% vs 4.1%), but the 95% CI included a 0.5% increased risk for events, and the events were treated equally.

Treating these events equally is a problem, said Polymeris. In particular, it does not rule out the increased risk for the most catastrophic events.

“We all know that these events [included in the composite endpoint] are not equivalent. They are not equally deadly. They are not equally disabling,” he said.

This was the premise of a new post hoc analysis of ELAN, conducted for those still concerned that early DOAC might create an increased risk for the most devastating complications following stroke.

In this post hoc analysis, weights were given to the specific events. With weights reflecting the relative risk for major harm, the study was able to show no potential for net increased major harm, not just reduced risk for events of any kind, for early vs late DOAC therapy within a range of 95% intervals.

The finding was entirely consistent with the 3468-patient randomized OPTIMAS study and the CATALYST meta-analysis of four major studies, including ELAN, that addressed this question. Both OPTIMAS and CATALYST were presented sequentially at the WSC just 1 day earlier.

In remarks following the plenary session where the OPTIMAS trial and CATALYST meta-analysis were presented, session moderator, Craig Anderson, MD, The George Institute for Global Health, Sydney, Australia, described the results as “practice changing.”

Contrary to some guidelines that have suggested late start of DOACs after an AF-related stroke is better than an early start, he suggested the cumulative data now establish early start DOACs as the best way to reduce post-stroke complications.

Intracranial Hemorrhage (ICH) Risk Should Not Overshadow Net Benefit

The data presented by Polymeris make this story even more compelling. Despite the randomized trials, he pointed out that this might still leave a shadow of doubt if the most severe consequences are not weighted.

In other words, this new analysis shows that the trade of an increased risk for ICH or bleeding is more than compensated by a reduced risk for thrombotic events on the basis of outcomes such as disability or death.

Many clinicians recognize that “ICH is known to carry a much higher risk of disability and mortality” than milder strokes and systemic thromboembolism, said Polymeris. It’s for this reason that he and his coinvestigators embarked on a comprehensive weight-based analysis.

The net benefit analysis was drawn from outcomes in 958 patients randomized to early DOAC and 959 patients randomized to late DOAC in ELAN. Baseline characteristics did not differ significantly. Outcomes were evaluated at both 30 and 90 days.

Using a formula from published methodology and adjusted for variables such as age, severity as measured with the National Institutes of Health Stroke Scale, and infarct size, the events were weighted for the risk they posed. For example, while ischemic events were given a value of 1.0, extracranial bleeding, a lower risk event, was given a weight of 0.7, but ICH, often the most feared complication, was weighted at 1.5.

After subtracting the rate of excess major bleeding events attributable to early treatment from the rate of recurrent ischemic events prevented by early treatment in the context of these weighted risk equivalents, there was a consistent advantage for early DOAC, reported Polymeris. This was true at both 30 and 90 days.

When all events are expressed at ischemic-event equivalents per 100 persons, “we estimate that early DOAC initiation prevents two to three events,” Polymeris reported. When assessed across a wide adjusted 95% CI employed, Polymeris said a neutral effect is statistically unlikely while the possibility of a harmful effect from early DOAC is essentially eliminated.

Though the current guidelines regarding early use of DOACs have been mixed, the ELAN post hoc analysis, along with the new data from OPTIMAS and the CATALYST meta-analysis, establish early DOAC as a standard of care for most patients with an AF-related acute stroke, according to Polymeris.

He acknowledged that exceptions should be considered for patients at a particularly high risk for bleeding risk, but these conclusions are applicable in real-world practice.

In his remarks, Anderson also suggested that there might be exceptions, such as patients who are frail or have other risk factors for increased bleeding, but he called the combined results of OPTIMAS and CATALYST convincing for the management of most AF patients with an acute stroke.

Anderson, like Polymeris the following day, said these data should be reassuring for those clinicians who have been reluctant to use early DOACs after an AF-related stroke due to the fear of ICH.

The ELAN study received funding from governmental and nonprofit organizations. Polymeris reported no relevant financial relationships. Anderson reported financial relationships with Penumbra and Takeda China.