HELSINKI, Finland — The pros and cons of early vs late initiation of a direct oral anticoagulant (OAC) after acute ischemic stroke in the setting of atrial fibrillation (AF) for secondary prevention was the topic of a lively debate at the Congress of the European Academy of Neurology 2024.
In an audience vote prior to the discussion, 77% voted yes to early anticoagulation, whereas 23% opted for no early anticoagulation.
Arguing for early anticoagulation, Urs Fischer, MD, professor of neurology at University Hospital Basel, Switzerland, told delegates that neurologists face a dilemma after stroke in patients with AF.
“We are scared of ischemic recurrence [if we don’t start oral anticoagulation early], but on the other hand, if we do, we risk hemorrhagic transformation (HT) and especially intracranial hemorrhage (ICH). There is a lot of anxiety about this.”
Still, recurrent ischemic stroke is less severe than an ICH is, he noted.
The answer to this conundrum essentially boils down to what the net benefit of either of the two strategies is in individual patients, Fischer added.
He went on to comprehensively review the literature in this space before concluding that “there is no reason to delay anticoagulation in people with acute ischemic stroke and AF.”
Opposing Fischer was Zuzana Gdovinova, MD, PhD, Department of Neurology, L. Pasteur University Hospital, P.J. Safarik University, Kosice, Slovakia.
“I will not speak about minor or moderate strokes as there is nothing to flag about early treatment, rather the fear of bleeding is in major strokes,” she said.
Compared with the world of clinical trials with centers of excellence in stroke, in the real-world, smaller hospitals are concerned about potential complications, so they usually initiate OAC later, said Gdovinova. Essentially, the clinical decision comes down to treating the individual, she said.
“We know that, in real life, we treat older patients [who are often excluded from clinical trials], and they have a higher risk [than younger patients do] because of comorbidities and polypharmacy. So, I think this is a group — older patients — who we should be very careful with in deciding on early anticoagulation,” Gdovinova added.
Session Chair Anita Arsovska, MD, PhD, head of Department for Urgent Neurology, University Clinic of Neurology, and professor of neurology at University Ss Cyril and Methodius, Skopje, North Macedonia, agreed and endorsed the idea of an individualized approach.
“We need to have more details on our patients, and in the future, we need to have more focused guidelines based on whether the stroke is severe or not, whether there is HT, etc.,” said Arsovska.
She believes that the current practice used by most stroke centers of initiating oral anticoagulation 3 or 4 days after minor stroke, 6 or 7 days after moderate stroke, and up to 14 days after a major stroke will be slowly abandoned.
Fischer summarized the latest literature in this space, starting with the TIMING study, which examined early vs delayed non–vitamin K antagonist OAC therapy after acute ischemic stroke in AF in patients from the Swedish Stroke Registry that was published in Circulation in 2022.
A total of 880 participants were randomly assigned to either early (within 4 days of stroke [n = 450]) or delayed (5-10 days after stroke [n = 438]) initiation of OAC therapy. The choice of anticoagulant was at the investigator’s discretion. The primary outcome was a composite of recurrent ischemic stroke, symptomatic ICH, or all-cause mortality at 90 days.
Numerically lower rates of ischemic stroke and death and the absence of symptomatic ICH suggests that early OAC initiation was safe and should be considered for acute secondary stroke prevention in eligible patients.
“There was a remarkable finding in TIMING: No single patient suffered a symptomatic ICH,” Fischer said.
Next, he discussed the ELAN randomized controlled trial, which was reported by Fischer at the European Stroke Organization Conference (ESOC) in Munich in May, and simultaneously published online in The New England Journal of Medicine. This study included just over 2000 patients with an acute ischemic stroke and AF.
The early treatment group started OAC within 48 hours of a minor or moderate stroke, whereas those with a major stroke started on day 6 or 7. The alternate later-treatment strategy started 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.
The ELAN results showed that OAC can be safely started much earlier than initiation generally occurs in current clinical practice, Fischer said. Starting treatment earlier was not associated with an increased risk for ICH but rather was linked to a lower rate of ischemic events.
“There is no reason to delay direct oral anticoagulant treatment in these patients,” Fischer said. “Early treatment initiation is probably better [at reducing ischemic events] and is unlikely to cause harm.”
However, he added, several unanswered questions remain.
For example, when to start oral anticoagulation in patients with severe stroke is still open to interpretation and in those with certain risk factors as well as when to restart OAC in those with hemorrhagic transformation or ICH.
A post hoc analysis of ELAN, published recently in JAMA Neurology, attempted to address the first issue. It showed “that in all infarct size groups, there were numerically fewer primary outcome events [composite of recurrent ischemic stroke, symptomatic ICH, extracranial bleeding, systemic embolism, or vascular death within 30 days] in those randomized to early anticoagulation,” Fischer noted.
Further, it demonstrated that those with major stroke may have the largest benefit of early anticoagulation, with a number needed to treat of 30 and a low risk for symptomatic ICH.
So the next question is whether the drive for early OAC could be pushed to as early as within 48 hours of a major stroke.
“We have been reluctant to start [this] early, as we thought we might kill the patients,” Fischer said.
Regarding the timing of restarting OAC after hemorrhage, his group has done more work on this, which will soon be published in Circulation.
The goal of this study was to assess whether the presence of HT on pre-randomization imaging in the ELAN study modified the estimated safety of early vs late initiation of OAC. They also reported on outcomes in patients with different HT subtypes, namely hemorrhagic infarction (HI) types 1 and 2 and parenchymal hemorrhage (PH) types 1 and 2.
“The results show no major treatment effect heterogeneity or safety concerns between patients with and without HT,” said Fischer. However, he added, there was one red flag. In those with PH, early anticoagulation increased the risk for a poor 90-day functional outcome with a probability of 25%.
The take-home message, said Fischer, is that “in HT types 1 and 2, there is no reason to delay oral anticoagulants in those with acute ischemic stroke and AF.
“In those with PH1, an individualized benefit-risk assessment should be applied and in those with PH2, early initiation of oral anticoagulation should be avoided.”
He concluded his talk by detailing several other randomized controlled trials that are ongoing or are completed but are still to report investigating stroke prevention in patients with AF and a history of ICH. These include: NASPAF-ICH, ENRICH-AF, ASPIRE, PRESTIGE-AF, STATICH, A3ICH, and STROKECLOSE.
Two trials, so-START and APACHE-AF, have already been reported but the results were “inconclusive,” he said.
Gdovinova then took podium and said that treating minor or moderate stroke is not the issue, rather, she added, “the fear of bleeding is in major stroke.”
In the TIMING trial, there were concerns about potential harm with early initiation of OAC only in the small group of patients who underwent thrombectomy or had National Institutes of Health Stroke Scores (NIHSS) > 15 on admission. She also noted that the lack of brain imaging in this study “may be considered a limitation.”
In the ELAN study, 23% of patients had major stroke, which was determined not with use of NIHSS but rather with imaging prior to randomization, which was most often performed after thrombolysis or thrombectomy.
The median age of patients in ELAN was 77 years, and the oldest patient was 84. Older patients in ELAN had a 2.5-fold increased risk for stroke or systemic embolism and major bleeding with OAC, which Gdovinova said reinforces her advice to carefully consider the risks vs benefits of early oral anticoagulation in older populations.
Turning to current guidelines, Gdovinova noted that the European Heart Rhythm Association (EHRA) recommends starting OAC after 12 or 14 days in major stroke. The 2020 European Society of Cardiology (ESC) guidelines on the diagnosis and management of AF don’t have timing recommendations. Neither do the 2019 guidelines from the European Stroke Organisation (ESO) “because of the low quality of evidence”; ESO recommends initiating OAC treatment after 14 days in patients with major ischemic stroke, she noted.
Gdovinova went on to point out some of ELAN’s limitations, notably the fact that people with PH type 1 or 2 at the time of random assignment were not included. However, in the substudy reported in Helsinki by Fischer and published in JAMA Neurology, PH was found in post hoc analysis likely because of mixed classification of patients with HT by local investigators, she said.
“This underscores the importance of careful neuroimaging interpretation in clinical practice because the result will influence future treatment,” Gdovinova noted.
The next question is when to reinitiate OAC treatment in patients who experience a brain hemorrhage after OAC.
An EHRA survey showed that most members started oral anticoagulation 30 days after brain hemorrhage, she said. A retrospective study from also showed that starting 15-30 days after the brain hemorrhage is best “because this is the period when there is benefit from anticoagulation but there is no increase in the risk of bleeding,” Gdovinova noted.
However, another observational study from the Swedish Registry recommended that the best time to start oral anticoagulation in this group of patients is between 7 and 8 weeks after brain hemorrhage.
Looking to the guidelines for this group of patients, those from EHRA, which were released in 2018 before results of the ELAN trial were reported, recommend starting OAC treatment between 4 and 8 weeks after surgical removal of a brain hematoma. They also recommend that brain imaging, CT or MRI, should be considered to determine resolution of the hematoma before reinitiation of oral anticoagulation.
The 2020 ESC guidelines recommend at least 4 weeks for this patient population, and the ESO guidance makes no specific recommendation about timing, but the decision to restart OAC can be considered after weighing the risks and benefits.
Guidelines from the American Heart Association/American Stroke Association are “interesting” on this point, said Gdovinova, because in 2015 the associations recommended starting OAC 4 weeks after anticoagulant-related ICH and in 2022, they recommended starting between 7 and 8 weeks.
Summing up, Gdovinova said that the issue of when to start OAC after acute stroke with AF remains an open question.
“We have groups of patients that should start later. These include older patients with comorbidities and polypharmacy, those with PH type 1 or 2, those with cerebral microbleeds — although there is not a recommendation in ischemic stroke to do screening for microbleeds, we do know this, and we must be careful with these patients and start later — and in those with an NIHSS > 15.”
Fischer said that he agreed with most of Gdovinova’s recommendations, barring the use of the NIHSS to direct treatment “as we looked at high and low NIH scores in ELAN and we couldn’t find any difference [in outcomes].”
“My advice is to give oral anticoagulation within 6 days of a major stroke in those with AF,” he said.
In the poll after the debate, the percentage of session attendees supporting early OAC increased from 77% to 87%, and those who do not support early initiation dropped from 23% to 13%.
Fischer reports research support of the Swiss National Science Foundation and the Swiss Heart Foundation; PI of the ELAN trial, Co-PI of the DISTAL, TECNO, SWIFT DIRECT, SWITCH, ELAPSE, and ICARUS trial; steering committee member of the DO_IT trial; research grants from Medtronic (BEYOND SWIFT, SWIFT DIRECT), Stryker, Rapid medical, Penumbra, Medtronic, Phenox (DISTAL), Boehringer Ingelheim (TECNO) (fees paid to the institution); consultancies for Medtronic, Stryker, and CSL Behring (fees paid to institution); participation in an advisory board for AstraZeneca (former Alexion/Portola), Boehringer Ingelheim, Biogen, AbbVie, and Acthera (fees paid to institution); member of a clinical event committee (CEC) of the COATING study (Phenox) and member of the data and safety monitoring committee (DSMB) of the TITAN, LATE_MT, and IN EXTREMIS trials; president of the Swiss Neurological Society; president-elect of the European Stroke Organisation.
