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

Urs Fischer; Sven Trelle; Mattia Branca; Georgia Salanti; Maurizio Paciaroni; Cecilia Ferrari; Stefanie Abend; Seraina Beyeler; Daniel Strbian; Götz Thomalla; George Ntaios; Leo H Bonati; Patrik Michel; Krassen Nedeltchev; Thomas Gattringer; Else Charlotte Sandset; Peter Kelly; Robin Lemmens; Masatoshi Koga; Padmavathy N Sylaja; Diana Aguiar de Sousa; Natan M Bornstein; Zuzana Gdovinova; David J Seiffge; Jan Gralla; Thomas Horvath; Jesse Dawson

doi:10.1177/23969873221106043

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

Eur Stroke J. 2022 Dec;7(4):487-495. doi: 10.1177/23969873221106043. Epub 2022 Jun 15.

Authors

Urs Fischer^{1

2}, Sven Trelle³, Mattia Branca³, Georgia Salanti⁴, Maurizio Paciaroni⁵, Cecilia Ferrari², Stefanie Abend², Seraina Beyeler², Daniel Strbian⁶, Götz Thomalla⁷, George Ntaios⁸, Leo H Bonati^{1

9}, Patrik Michel¹⁰, Krassen Nedeltchev^{2

11}, Thomas Gattringer¹², Else Charlotte Sandset^{13

14}, Peter Kelly¹⁵, Robin Lemmens^{16

17}, Masatoshi Koga¹⁸, Padmavathy N Sylaja¹⁹, Diana Aguiar de Sousa²⁰, Natan M Bornstein²¹, Zuzana Gdovinova²², David J Seiffge², Jan Gralla²³, Thomas Horvath², Jesse Dawson²⁴

Affiliations

¹ Department of Neurology, University Hospital Basel, University of Basel, Switzerland.
² Department of Neurology, University Hospital Bern, and University of Bern, Bern, Switzerland.
³ CTU Bern, University of Bern, Bern, Switzerland.
⁴ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
⁵ Department of Medicine, University Hospital Perugia, Perugia, Italy.
⁶ Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁷ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸ Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
⁹ Research Department, Reha Rheinfelden, Rheinfelden, Switzerland.
¹⁰ Department of Neurology, Lausanne University Hospital, Lausanne, Switzerland.
¹¹ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
¹² Department of Neurology, and Division of Neuroradiology, Vascular and Interventional Radiology, Department of Radiology, Medical University of Graz, Graz, Austria.
¹³ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁴ The Norwegian Air Ambulance Foundation, Oslo, Norway.
¹⁵ Department of Neurology, Dublin Mater Misericordiae University Hospital, Dublin, Ireland.
¹⁶ Department of Neurology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
¹⁷ VIB Center for Brain and Disease Research, Department of Neurosciences, Experimental Neurology, Leuven, Belgium.
¹⁸ Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
¹⁹ Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Kerala, India.
²⁰ Stroke Center, Central Lisbon University Hospital Center, and University of LIsbon, Lisbon, Portugal.
²¹ Department of Neurology, Shaare-Zedek Medical Center, Jerusalem, Israel.
²² Department of Neurology, P.J. Safarik University and University Hospital L. Pasteur Kosice, Slovakia.
²³ Department of Diagnostic and Interventional Neuroradiology, University Hospital Bern, and University of Bern, Bern, Switzerland.
²⁴ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK.

Abstract

Rationale: Direct oral anticoagulants (DOAC) are highly effective in preventing ischaemic strokes in people with atrial fibrillation (AF). However, it is unclear how soon they should be started after acute ischaemic stroke (AIS). Early initiation may reduce early risk of recurrence but might increase the risk of haemorrhagic complications.

Aim: To estimate the safety and efficacy of early initiation of DOACs compared to late guideline-based initiation in people with AIS related to AF.

Methods and design: An international, multicentre, randomised (1:1) controlled, two-arm, open, assessor-blinded trial is being conducted. Early treatment is defined as DOAC initiation within 48 h of a minor or moderate stroke, or at day 6-7 following major stroke. Late treatment is defined as DOAC initiation after day 3-4 following minor stroke, after day 6-7 following moderate stroke and after day 12-14 following major stroke. Severity of stroke is defined according to imaging assessment of infarct size.

Sample size: ELAN will randomise 2000 participants 1:1 to early versus late initiation of DOACs. This assumes a risk difference of 0.5% favouring the early arm, allowing an upper limit of the 95% confidence interval up to 1.5% based on the Miettinen & Nurminen formula.

Outcomes: The primary outcome is a composite of symptomatic intracranial haemorrhage, major extracranial bleeding, recurrent ischaemic stroke, systemic embolism or vascular death at 30 ± 3 days after randomisation. Secondary outcomes include the individual components of the primary outcome at 30 ± 3 and 90 ± 7 days and functional status at 90 ± 7 days.

Discussion: ELAN will estimate whether there is a clinically important difference in safety and efficacy outcomes following early anticoagulation with a DOAC compared to late guideline-based treatment in neuroimaging-selected people with an AIS due to AF.

Keywords: Atrial fibrillation; DOAC; acute ischaemic stroke; anticoagulation; timing.