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Randomized Controlled Trial
. 2024 Jul 2;150(1):19-29.
doi: 10.1161/CIRCULATIONAHA.124.069324. Epub 2024 May 16.

Early Versus Late Initiation of Direct Oral Anticoagulants After Ischemic Stroke in People With Atrial Fibrillation and Hemorrhagic Transformation: Prespecified Subanalysis of the Randomized Controlled ELAN Trial

Roman Rohner #  1 , Markus Kneihsl #  2   3   4 , Martina B Goeldlin  5 , Arsany Hakim  1 , Mattia Branca  6 , Stefanie Abend  5   6 , Waldo Valenzuela Pinilla  7 , Sabine Fenzl  1 , Beata Rezny-Kasprzak  1 , Daniel Strbian  8 , Sven Trelle, Maurizio Paciaroni  9 , Götz Thomalla  10 , Patrik Michel  11 , Krassen Nedeltchev  12 , Thomas Gattringer  2   3 , Else C Sandset  13 , Leo Bonati  4   14 , Diana Aguiar de Sousa  15 , P N Sylaja  16 , George Ntaios  17 , Masatoshi Koga  18 , Zuzana Gdovinova  19 , Robin Lemmens  20 , Natan M Bornstein  21 , Peter Kelly  22 , Mira Katan  4 , Thomas Horvath  5 , Jesse Dawson #  23 , Urs Fischer #  5   4 ; ELAN Investigators
Affiliations
Free article
Randomized Controlled Trial

Early Versus Late Initiation of Direct Oral Anticoagulants After Ischemic Stroke in People With Atrial Fibrillation and Hemorrhagic Transformation: Prespecified Subanalysis of the Randomized Controlled ELAN Trial

Roman Rohner et al. Circulation. .
Free article

Erratum in

Abstract

Background: Whether hemorrhagic transformation (HT) modifies the treatment effect of early compared with late initiation of direct oral anticoagulation in people with ischemic stroke and atrial fibrillation is unknown.

Methods: This is a post hoc analysis of the ELAN trial (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation). The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, major extracranial bleeding, systemic embolism, or vascular death within 30 days. Secondary outcomes were the individual components, 30- and 90-day functional outcome. We estimated outcomes based on HT, subclassified as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) on prerandomization imaging (core laboratory rating) using adjusted risk differences between treatment arms.

Results: Overall, 247 of 1970 participants (12.5%) had HT (114 HI 1, 77 HI 2, 34 PH 1, 22 PH 2). For the primary outcome, the estimated adjusted risk difference (early versus late) was -2.2% (95% CI, -7.8% to 3.5%) in people with HT (HI: -4.7% [95% CI, -10.8% to 1.4%]; PH: 6.1% [95% CI, -8.5% to 20.6%]) and -0.9% (95% CI, -2.6% to 0.8%) in people without HT. Numbers of symptomatic intracranial hemorrhage were identical in people with and without HT. With early treatment, the estimated adjusted risk difference for poor 90-day functional outcome (modified Rankin Scale score, 3-6) was 11.5% (95% CI, -0.8% to 23.8%) in participants with HT (HI: 7.4% [95% CI, -6.4% to 21.2%]; PH: 25.1% [95% CI, 0.2% to 50.0%]) and -2.6% (95% CI, -7.1% to 1.8%) in people without HT.

Conclusions: We found no evidence of major treatment effect heterogeneity or safety concerns with early compared with late direct oral anticoagulation initiation in people with and without HT. However, early direct oral anticoagulation initiation may worsen functional outcomes in people with PH.

Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT03148457.

Keywords: anticoagulants; ischemic stroke; therapeutics.

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Conflict of interest statement

Disclosures Dr Goeldlin reports grants from the Swiss Academy of Medical Sciences/Bangerter-Rhyner-Foundation (for the submitted work), Swiss Stroke Society, European Stroke Organization, Mittelbauvereinigung der Universität Bern, and Inselgruppe AG, as well as Congress grants from the European Academy of Neurology and Pfizer (outside the submitted work). Dr Hakim received a research grant from the Swiss Heart Foundation for the ELAN study. Drs Branca and Trelle are 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 the 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. Dr Strbian reports advisory board participation for AstraZeneca and an unrestricted educational grant from Boehringer Ingelheim. Dr Paciaroni served on the speakers bureau for Daiichi Sankyo, Sanofi, iRhythm, Pfizer, and Bristol Myers Squibb. Dr Thomalla received fees as a consultant or lecturer from Acandis, Alexion, Amazon, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Portola, and Stryker, as well as grant support from the European Union, German Research Foundation (DFG), German Federal Ministry of Education and Research (BMBF), and the German Innovation Fund, all outside the submitted work. Dr Nedeltchev served on advisory board for Bayer, Boehringer Ingelheim, Daiichi Sankyo, and BMS/Pfizer and received unrestricted educational grants from Bayer, Daiichi Sankyo, BMS/Pfizer, and Alexion. Dr Gattringer received a research grant from the Austrian Science Fund and Austrian Neurological Society; speaker honoraria and travel support from BMS Pfizer and Bayer; speaker honoraria, travel support, and advisory board fees from Boehringer Ingelheim; advisory board fees from Novartis; and speaker honoraria from Amgen. Dr Sandset received speaker honoraria from Daiichi Sankyo and Boston Scientific. Dr Bonati has received an unrestricted research grant from AstraZeneca; consultancy or advisory board fees or speaker honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Claret Medical, and InnovHeart; and travel grants from AstraZeneca and Bayer. Dr Aguiar de Sousa received speaker fees or honoraria for advisory board participation from Organon, Bial, AstraZeneca, Bayer, and Johnson & Johnson, outside the submitted work, and reports data safety monitor board participation for the SECRET trial (University of British Columbia). Dr Ntaios reports speaker fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Elpen, Ferrer, Javelin, Novartis, and Sanofi. Dr Koga received honoraria from Bayer Yakuhin, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, BMS/Pfizer, BMS/Janssen Pharmaceuticals, and Otsuka Pharmaceutical, as well as research support from Daiichi Sankyo and Nippon Boehringer Ingelheim, all of which are outside of the submitted work. Dr Gdovinova received fees as a consultant or lecturer from Biogen, Boehringer Ingelheim, MSD, Novartis, Pfizer, Sandoz, Schwabe, and TEVA. Dr Lemmens has no personal disclosures but reports institutional fees for consultancy from BMS, Boehringer Ingelheim, Medtronic, and Pfizer. Dr Katan reports research support of the SNF, principal investigator of the MOSES trial (182267), the Crescendo ERA NET Neuron (213471), co-applicant of the DISTAL (198783) and TECNO (204977) randomized controlled trials, and the AGLESS study (200573); grants from the Swiss Heart Foundation; and participation on advisory boards and/or speaker honoraria from Medtronic, BMS Pfizer/Jansen, and AstraZeneca. Dr Kelly served on the advisory board for Alexion and Novo Nordisk; Daiichi Sankyo, BMS/Pfizer, and Bayer have provided unrestricted grant funding for education and research to the Stroke Clinical Trials Network Ireland; and grant funding was received from the Health Research Board Ireland. Dr Dawson reports speaker fees from Pfizer, BMS, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, and Bayer, as well as research funding from Pfizer, BMS, and the Stroke Association. Dr Fischer received research support from the Swiss National Science Foundation and the Swiss Heart Foundation; served as a principal investigator for the ELAN trial and coprincipal investigator of the DISTAL, TECNO, SWIFT DIRECT, and SWITCH trials; received research grants from Medtronic (BEYOND SWIFT, and SWIFT DIRECT) and Stryker, Rapid Medical, Penumbra, and Phenox (DISTAL); received consultancy fees from Medtronic, Stryker, and CSL Behring (fees paid to institution); participated on an advisory board for Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera (fees paid to institution); was a member of a clinical event committee of the COATING study (Phenox) and a member of the data and safety monitoring board of the TITAN, LATE_MT, and IN EXTREMIS trials; and served as president of the Swiss Neurological Society. The other authors report no conflicts.

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