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^{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.

PMID: 36478762
PMCID: PMC9720853
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

Urs Fischer et al. Eur Stroke J. 2022 Dec.

. 2022 Dec;7(4):487-495.

doi: 10.1177/23969873221106043. Epub 2022 Jun 15.

Authors

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.

PMID: 36478762
PMCID: PMC9720853
DOI: 10.1177/23969873221106043

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.

PubMed Disclaimer

Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This is an academic investigator-initiated trial. Urs Fischer: Research support of the Swiss National Science Foundation (32003B_197009; 32003B_169975) and the Swiss Heart Foundation for the ELAN trial. Conflicting interests and disclosures outside the ELAN trial: research grants from Medtronic and Stryker; consultancy for Medtronic, CSL Behring, Alexion/Portola; Speakers honorarium from Abbott and Medtronic; DSMB member in the TITAN and IN EXTREMIS trials; Vice President of the Swiss Neurological Society Sven Trelle: ST is affiliated with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up-to-date list of CTU Bern’s conflicts of interest see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html Mattia Branca: MB is affiliated with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up-to-date list of CTU Bern’s conflicts of interest see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html Georgia Salanti: None. Maurizio Paciaroni: honoraria as a member of the speaker bureau of Sanofi-Aventis, Bristol-Myers Squibb, Daiiki Sankyo and Pfizer. Cecilia Ferrari: None. Stefanie Abend: None. Seraina Beyeler: None. Daniel Strbian: Unrestricted educational grant from Boehringer Ingelheim. Goetz Thomalla: received fees as a consultant or lecturer from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb / Pfizer, Daiichi Sanyo, Portola, and Stryker, all outside the submitted work. George Ntaios: reports speaker fees/advisory boards/research support from Abbott, Amgen, Bayer, Boehringer Ingelheim, BMS, and Pfizer; all paid to the University of Thessaly. Leo H Bonati: has received an unrestricted research grant from AstraZeneca, and consultancy or advisory board fees or speaker’s honoraria from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Claret Medical, and InnovHeart, and travel grants from AstraZeneca and Bayer. Patrik Michel: no disclosures/conflicts of interest. Krassen Nedeltchev: Advisory boards: Bayer, Boehringer Ingelheim, Daichii Sankyo, BMS/Pfizer, unrestricted educational grants: Bayer, Daichii Sankyo, BMS/Pfizer, Alexion. Thomas Gattringer: BMS Pfizer: speakers’ honoraria, travel support; Bayer: speakers’ honoraria, travel support; Boehringer Ingelheim: speakers’ honoraria, travel support, advisory board Else C Sandset: Speaker Honoraria from Boston Scientific. Peter Kelly: Advisory boards – Alexion, Novo Nordisk. Daichii Sankyo, BMS/Pfizer, Bayer have provided unrestricted grant funding for education and research to the Stroke Clinical Trials Network Ireland; Grant funding: Health Research Board Ireland. Robin Lemmens: No personal disclosures but reports institutional fees for consultancy from BMS, Boehringer Ingelheim, Genentech, Ischemaview, Medpass, Medtronic and Pfizer. Masatoshi Koga: honoraria from Daiichi-Sankyo, and research support from Daiichi-Sankyo and Nippon Boehringer Ingelheim. Padmavathy N Sylaja: PN Sylaja – Funding for the RESTORE trial from Indian Council of Medical Research, Advisory board member of Medtronic PRAAN study, Steering committee member of the Angels initiative. Diana Aguiar de Sousa: personal fees for AstraZeneca advisory board participation, travel support from Boehringer Ingelheim, DSMB participation for the SECRET trial (University of British Columbia), and speaking fees from Bayer outside the submitted work. Natan M Bornstein: Pfizer Israel consultation fees and International speaker bureau; Bayer Israel –consultation fees; Boehringer Ingelheim – consultation fees and International speaker bureau. Zuzana Gdovinova: received fees as a consultant or lecturer from Biogen, Boehringer-Ingelheim, MSD, Novartis, Pfizer, Sandoz, Schwabe, TEVA. David Seiffge: reports travel support from Boehringer Ingelheim, advisory board fees from AstraZeneca, and DSMB participation for the SECRET trial (University of British Columbia). Speaker fees from Bayer. Jan Gralla: Global PI of STAR (NCT01327989) and Swift Direct (NCT03192332) (Medtronic), Consultancy: CEC member of the Promise Study (Penumbra), Consultancy; Swiss National Foundation SNF grant for MRI in stroke. Thomas Horvath: None. Jesse Dawson: Speaker fees – Pfizer, BMS, Boeringher Inhgelheim, Daicchi Sankyo, Medtronic, Bayer Research funding – Pfizer, BMS.

Figures

**Figure 1.**
Stroke size classification.

**Figure 2.**
Trial schedule. DOAC, direct oral anticoagulants; Tel., telephone; h, hours; d, days.

See this image and copyright information in PMC

References

1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955–962. - PubMed
1. Seiffge DJ, Werring DJ, Paciaroni M, et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol 2019; 18: 117–126. - PMC - PubMed
1. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094–2106. - PubMed
1. Paciaroni M, Agnelli G, Ageno W, et al. Timing of anticoagulation therapy in patients with acute ischaemic stroke and atrial fibrillation. Thromb Haemost 2016; 116: 410–416. - PubMed
1. Paciaroni M, Agnelli G, Falocci N, et al. Early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with non-vitamin-K oral anticoagulants (RAF-NOACs) study. J Am Heart Assoc 2017; 6: e007034. - PMC - PubMed

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources