People with atrial fibrillation (AF) who have a stroke could benefit from receiving blood-thinning treatments—known as direct oral anticoagulants (DOACs)—at an earlier stage than is currently recommended, as per a new study led by researchers from University College London (UCL; London, UK) as well as other findings presented recently at the 16th World Stroke Congress (WSC; 23–26 October, Abu Dhabi, United Arab Emirates).
Results from the British Heart Foundation-funded OPTIMAS study are now published in The Lancet, having been delivered for the first time by chief investigator David Werring (UCL Queen Square Institute of Neurology, London, UK) at WSC 2024. The study ultimately found that it is safe and effective to give blood-thinning treatments to AF patients within four days of them having a stroke, rather than waiting for the traditionally recommended timeframe of up to 14 days.
“There are concerns that starting anticoagulants too early might increase the risk of bleeding into the area of the brain damaged by the stroke—especially in people with more severe strokes,” Werring noted. “However, starting them too late might leave the patient at risk of stroke due to further clots from the heart.”
A recent UCL press release states that more than 1.6 million people in the UK alone have been diagnosed with AF, and they are five times more likely to have a stroke than people without AF. In addition, AF patients who have had a stroke have an increased risk of having another—a risk that can be reduced by taking anticoagulants.
However, anticoagulants come with the rare but dangerous side-effect of bleeding into the brain, and there is a lack of evidence about when is best to start taking them after a stroke. Current UK guidelines are varied, suggesting that patients who have had a moderate or severe stroke should wait at least five days before being started on blood-thinning treatments, the release adds.
With these uncertainties in mind, a research team led by Werring investigated the impact of early versus delayed anticoagulant treatment via the OPTIMAS study—a multicentre randomised controlled trial (RCT) with blinded-outcome adjudication.
OPTIMAS saw 3,648 patients with acute ischaemic stroke and AF assigned 1:1 to either early (≤4 days after stroke) or delayed (7–14 days after stroke) DOAC therapy across 100 UK hospitals. The two groups had mean DOAC initiation times of 3.3 days and 8.4 days, respectively. OPTIMAS’ primary endpoint was a composite of recurrent stroke—ischaemic stroke or symptomatic intracranial haemorrhage (ICH)—and systemic arterial embolism within 90 days, while secondary outcomes included major bleeding, functional status, anticoagulant adherence, quality of life, and use of health and social care resources.
Analyses of a total of 3,621 AF patients who had had a stroke between 2019 and 2024 revealed that the trial’s early and late DOAC groups experienced a similar number of recurrent strokes, and early treatment was found to be effective without increasing the risk of a brain bleed. The researchers hope that these findings will enable patients to benefit from blood-thinning treatments in a more timely manner—as well as preventing patients from missing out on them altogether.
“People have delayed giving these drugs previously and OPTIMAS provides reassurance that this isn’t necessary, regardless of stroke severity,” Werring said. “This should lead to a rapid change in clinical practice, particularly for people with more severe strokes.”
Nick Freemantle, senior investigator and director of the UCL Comprehensive Clinical Trials Unit (CCTU) that co-ordinated the trial, added: “The benefits are that patients are quickly given the definitive and effective long-term stroke prevention treatment instead of waiting—which could lead to the treatments not being started at all, especially if patients are discharged from hospital.”
Bryan Williams, chief scientific and medical officer of the British Heart Foundation, who is also based at the UCL Institute of Cardiovascular Science, commented: “When treating strokes in people with AF, clinicians must strike a delicate balance to ensure swift treatment while minimising risk of potentially harmful side-effects. This important study reveals that taking blood-thinning medication within the first few days of a stroke does not come with heightened risk, as previously thought. These results could be transformative, making the case for earlier treatment that could help more people with AF avoid having another stroke, and the associated complications.”
Evidence favouring early DOAC initiation proliferates
In addition to the late-breaking findings of the OPTIMAS study, two other key pieces of evidence on the timing of DOAC initiation were presented at WSC 2024.
The first of these presentations saw Signild Åsberg (Uppsala University, Uppsala, Sweden) and UCL’s Hakim-Moulay Dehbi relay results from CATALYST—a collaboration involving a prospective individual participant data meta-analysis (IPDMA) of all the available RCTs evaluating the optimal timing of anticoagulation after ischaemic stroke and AF.
The IPDMA included the aforementioned OPTIMAS trial, as well as the ELAN, START and TIMING studies, which were conducted across a total of 17 countries in Europe, the Middle East, Asia, and the USA, and included more than 6,700 participants recruited between 2017 and 2024. The analysis defined early DOAC therapy as initiation within four days of stroke onset, and later therapy as initiation at five days or later. Its primary endpoint was the occurrence of stroke—including ischaemic stroke, ICH or unclassified stroke—within 30 days after randomisation.
Åsberg, Dehbi and colleagues have shown that earlier initiation (<4 days) ultimately demonstrated a clear benefit compared to later initiation (≥5 days), with their primary endpoint measure revealing a significant reduction in the early group versus the later group (2.12% vs 3.02%; odds ratio, 0.7) at 30 days. This finding was consistent across all key subgroups, each of which suggested advantages with early DOAC initiation. Further analyses also showed a clear benefit with early DOAC initiation in ischaemic stroke specifically, while rates of symptomatic ICH and extracranial haemorrhage were found to be low in both the early and late groups. Analyses at 90 days indicated that, while event rates remained lower in the early group versus the late group, this difference was no longer statistically significant.
The researchers have stated that these findings support the approach of starting DOACs early—within four days—in clinical practice, with the CATALYST IPDMA providing the highest quality evidence that is currently available on the superiority of early versus late initiation of anticoagulation treatment in patients with acute ischaemic stroke and AF.
A second presentation at WSC 2024 was given by Alexandros Polymeris (University of Basel, Basel, Switzerland) and pertained to the ‘net clinical benefit’ of early versus late DOAC initiation in patients with AF and ischaemic stroke. Outlining findings from an analysis of ELAN, Polymeris noted that this trial and other, similar studies have focused on endpoints combining ischaemic and haemorrhagic events without considering the contrasting levels of severity carried by these different event types.
Polymeris and colleagues’ post-hoc analysis therefore sought to estimate net clinical effects linked to early versus late anticoagulation treatment within 30 days by subtracting the rate of excess major bleeding events (both intracranial and extracranial) attributable to early treatment from the rate of excess ischaemic events (recurrent ischaemic stroke and systemic embolism) prevented by early treatment. This approach included weighting haemorrhagic events according to their varying impacts on death and disability relative to ischaemic events. Ancillary analyses included net clinical benefit calculations within 90 days, in subgroups according to infarct size, and after inclusion of non-major bleeding events.
The analysis ultimately showed, when DOAC treatment is initiated in the earlier versus later timeframe, the potentially increased risk for bleeding-related complications is more than compensated for by a reduced risk of thrombotic events, as measured by outcomes including disability and death. These findings were generated via clinical data from the 958 patients randomised to early anticoagulation and 959 patients randomised to late anticoagulation in ELAN—two groups between which baseline characteristics did not differ significantly. Polymeris reported that the result of no potential for a net increase in major harm between early and late DOAC initiation was consistent at both 30 and 90 days of follow-up.
The investigators for this analysis have concluded that their findings effectively eliminate the possibility for net clinical harm being caused by early DOAC initiation, and should ease concerns regarding the impact of iatrogenic bleeding events associated with this approach as well as overcoming one of the key previously suggested limitations of the original ELAN trial.
