Author: Gerrit M Grosse

Department of Neurology, Hannover Medical School, Hannover, Germany

Twitter: @gerritgrosse

Oral anticoagulants (OAC) are highly efficient in secondary prevention after ischaemic stroke or transient ischaemic attack (TIA) in patients with atrial fibrillation (AF). However, there was still uncertainty whether an early application of OAC does not only prevent recurrent ischaemic events but is also safe concerning haemorrhagic complications (1). Especially in patients with acute stroke of larger infarct sizes, haemorrhagic transformation is feared and thus it is common sense to delay starting OAC in these patients, although the evidence for this reasoning is low.

Randomized controlled trials (RCTs) that led to the approval of non-vitamin K antagonist oral anticoagulants (NOAC) excluded patients with recent ischemic stroke and observational studies on this topic yielded heterogonous findings. Thus, the international guidelines are currently based on expert opinions. One pragmatic and often applied approach is the 1 – 3 – 6 – 12 days rule which is based on the clinical stroke severity.

Four RCTs were initiated to provide us with evidence on the common dilemma of the timing of anticoagulation in the early phase of acute stroke due to AF: TIMING (2), START (3), OPTIMAS (4) and ELAN (5). The TIMING study has been presented at the European Stroke Organisation Conference (ESOC) in 2021 and was published in Circulation last year (6). Importantly, TIMING showed that an early initiation (i.e. ≤4 days) was noninferior to a later start (5–10 days) with NOACs. Moreover, none of the patients in both groups suffered a symptomatic intracranial haemorrhage (6).

At the recent ESOC 2023 in Munich, Professor Urs Fischer presented the results of the ELAN trial, which were simultaneously published in the New England Journal of Medicine (7). ELAN (“Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillation”) is an investigator-initiated, international RCT that enrolled 2,013 patients with recent ischaemic stroke and AF. The patients were randomised in a 1:1 fashion to an early start of anticoagulation depending on infarct size, i.e. within 48 hours after a minor or moderate stroke and on day 6-7 after a major stroke, respectively, or to a later start, i.e. on day 3-4 for minor, on day 6-7 for moderate or on day 12-14 after a major stroke (5). Importantly, the severity of stroke was assessed by imaging: Minor strokes were defined as lesions of ≤1.5 cm in the anterior or posterior circulation. Moderate strokes were defined as lesions in a cortical superficial branch of the anterior or posterior circulation or in the internal border zone and major strokes were defined as lesions involving a complete vascular territory, lesions of ≥1.5 cm in the brainstem or cerebellum or multiple moderate lesions. Of note, the study design did not incorporate a formal statistical test for superiority or non-inferiority but rather had a descriptive approach.

The primary outcome, which was defined as a composite of ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial haemorrhage, or vascular death within 30 days after randomisation, was observed in 29 (2.9%) of the patients in the early treatment and in 41 (4.1%) patients in the later treatment group, translating to a risk difference of −1.18 percentage points with a 95% confidence interval of −2.84 to 0.47. Two patients in each group suffered a symptomatic intracranial haemorrhage. The odds of a recurrent ischemic stroke by 30 days was almost halved in patients with an early application of anticoagulation (odds ratio, 0.57; 95% confidence interval: 0.29 to 1.07). Taken together, the trial found no evidence that initiation of a NOAC earlier than currently suggested by guidelines in patients with acute ischemic stroke and AF, based on a simple visual assessment of brain imaging, increases the risk of haemorrhagic complications. On the contrary, a clinically important reduction in the risk for the composite endpoint and, in particular, for recurrent ischemic events was found at 30 days after randomisation.

In conclusion, ELAN is a landmark trial that provides further evidence that an early initiation of NOACs after acute ischaemic stroke is likely safe and contributes to a reduction in recurrent ischemic events. It will be very exciting to see if START and OPTIMAS will show similar results. In addition to these RCTs, results from large observational studies like PRODAST (n=10,000) (8) and RASUNOA-prime (n=3,000) (9) will additionally provide us with “real-world” evidence on the ideal timing of anticoagulation following acute stroke due to AF.

  1. Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ, et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol. 2019;18(1):117-26.
  2. Åsberg S, Hijazi Z, Norrving B, Terént A, Öhagen P, Oldgren J. Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation: study protocol for a registry-based randomised controlled trial. Trials. 2017;18(1):581.
  3. King BT, Lawrence PD, Milling TJ, Warach SJ. Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial. International Journal of Stroke. 2019;14(9):977-82.
  4. Best JG, Arram L, Ahmed N, Balogun M, Bennett K, Bordea E, et al. Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial. Int J Stroke. 2022;17(5):583-9.
  5. Fischer U, Trelle S, Branca M, Salanti G, Paciaroni M, Ferrari C, et al. Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN (ELAN): Protocol for an international, multicentre, randomised-controlled, two-arm, open, assessor-blinded trial. European Stroke Journal. 2022;7(4):487-95.
  6. Oldgren J, Åsberg S, Hijazi Z, Wester P, Bertilsson M, Norrving B. Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study. Circulation. 2022;146(14):1056-66.
  7. Fischer U, Koga M, Strbian D, Branca M, Abend S, Trelle S, et al. Early versus Later Anticoagulation for Stroke with Atrial Fibrillation. N Engl J Med. 2023.
  8. Grosse GM, Weimar C, Kuklik N, Hüsing A, Stang A, Brinkmann M, et al. Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study. European Stroke Journal. 2021;6(4):438-44.
  9. Haas K, Purrucker JC, Rizos T, Heuschmann PU, Veltkamp R. Rationale and design of the Registry of Acute Stroke Under Novel Oral Anticoagulants-prime (RASUNOA-prime). Eur Stroke J. 2019;4(2):181-8.

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