Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

David J Werring; Hakim-Moulay Dehbi; Norin Ahmed; Liz Arram; Jonathan G Best; Maryam Balogun; Kate Bennett; Ekaterina Bordea; Emilia Caverly; Marisa Chau; Hannah Cohen; Mairead Cullen; Caroline J Doré; Stefan T Engelter; Robert Fenner; Gary A Ford; Aneet Gill; Rachael Hunter; Martin James; Archana Jayanthi; Gregory Y H Lip; Sue Massingham; Macey L Murray; Iwona Mazurczak; Philip S Nash; Amalia Ndoutoumou; Bo Norrving; Hannah Sims; Nikola Sprigg; Tishok Vanniyasingam; Nick Freemantle; OPTIMAS investigators

doi:10.1016/S0140-6736(24)02197-4

Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

Lancet. 2024 Oct 23:S0140-6736(24)02197-4. doi: 10.1016/S0140-6736(24)02197-4. Online ahead of print.

Authors

David J Werring¹, Hakim-Moulay Dehbi², Norin Ahmed², Liz Arram³, Jonathan G Best³, Maryam Balogun², Kate Bennett², Ekaterina Bordea², Emilia Caverly², Marisa Chau², Hannah Cohen⁴, Mairead Cullen², Caroline J Doré², Stefan T Engelter⁵, Robert Fenner², Gary A Ford⁶, Aneet Gill², Rachael Hunter², Martin James⁷, Archana Jayanthi², Gregory Y H Lip⁸, Sue Massingham³, Macey L Murray⁹, Iwona Mazurczak², Philip S Nash³, Amalia Ndoutoumou², Bo Norrving¹⁰, Hannah Sims², Nikola Sprigg¹¹, Tishok Vanniyasingam², Nick Freemantle²; OPTIMAS investigators

Collaborators

OPTIMAS investigators:
Benjamin Jelley, Tom Hughes, Mim Evans, Diego Garcia Esteban, Lucy Knibbs, Lauren Broad, Rebecca Price, Liz Hamer Griebel, Sian Hewson, Kamy Thavanesan, Louise Mallon, Anna Smith, Miranda White, Liqun Zhang, Brian Clarke, Youssif Abousleiman, Lauren Binnie, Cai Hua Sim, Margarida Castanheira, Fiona Humphries, Sabaa Obarey, Shez Feerick, Yee Chin Lee, Alex Lewis, Riham Muhammad, Nina Francia, Ndifreke Atang, Azra Banaras, Marilena Marinescu, Philip Ferdinand, Resti Varquez, Ida Ponce, Surabhi Saxena, Eoin O'Brien, Juliana Delos Reyes, Jennifer Mitchell-Douglas, Jobbin Francis, Soma Banerjee, Vaishali Dave, Sheila Mashate, Tulsi Patel, Lakshmanan Sekaran, Wahid Murad, Asokanathan Asaipillai, Sethuraman Sakthivel, Margaret Tate, Jane Angus, Lisa Reid, Caroline Fornolles, Saul Sundayi, Lincy Poolon, Francis Justin, Sophy Hunte, Mohit Bhandari, Jules Kho, Vera Cvoro, Ruwan Parakramawansha, Mandy Couser, Hannah Hughes, Aaizza Naqvi, Kirsty Harkness, Emma Richards, Jo Howe, Chris Kamara, Jon Gardner, Harjit Bains, Rachel Teal, Jeethu Joseph, Jithen Benjamin, Samer Al-Hussayni, George Thomas, Faye Robinson, Lynn Dixon, Manju Krishnan, Peter Slade, Tal Anjum, Sharon Storton, Katja Adie, Keren Northcott, Katie Morgan, Emilie Williams, Harinath Chanashekar, Holly Maguire, Claire Gabriel, Deborah Maren, Hannah David, Sheron Clarke, Kiruba Nagaratnam, Varun Nelatur, Neelima Mannava, Lara Blasco, Joseph Devine, Rajaram Bathula, Parvathy Gopi, Niharika Mehta, Sreena Sreedevi Raj, James Teo, Laszio Sztriha, Yee Mah, Sandeep Ankolekar, Beatrix Sari, Maria Tibajai, Alicia Morgan, Maria Recaman, Samantha Bayhonan, Caroline Belo, Sharon Finch, Samantha Keenan, Angie Bowring, Ashit Shetty, Siang Chan, Lucy Gray, Thomas Harrison, Oliver Spooner, Edward Kinsella-Perks, Esther Erumere, Brittany Sanders, Don Sims, Mark Willmot, Edward Littleton, Elaine Spruce, Lisa Moody, Christopher Sheriden, Scott Luxmore-Brown, Aoife Neal, Sophie Beddows, Maria Assuncao Tuna, Amulya Misra, Ruth Penn, Sonia Mariampillai, Ijaz Anwar, Arunkumar Annamalai, Sarah Whitehouse, Lorna Shepherd, Elaine Siddle, Kausik Chatterjee, Sandra Leason, Angela Davies, Richard James Marigold, Sarah Frank, Alix Baird, Tomas Hannam-Penfold, Liliana Inacio, Simon Smith, David Eveson, Kashif Musarrat, Shagufta Khan, Tracy Harris, Muhibbur Chowdhury, Sajid Alam, Elena Jamieson, Ebitare Anyankpele, Farah Al Shalchi, Vanessa Rivers, Stephanie Bell, Rebecca Francis, Deborah Beeby, Jenny Finch, Mary Joan Macleod, German Guzman-Gutierrez, Karla Carter, Janice Irvine, Lukuman Gbadamoshi, Telma Costa, Sarah Heirons, Hayley Stoney, Louise Shaw, James Choulerton, Darwin Catibog, Naweed Sattar, Min Myint, Andy Smith, Kwin Serac, Hedley Emsley, Sulaiman Sultan, Bindu Gregary, Allan Brown, Afzal Mahmood, Navraj Chattha, William Old, Claire Pegg, Miriam Davey, Michelle Page, Banher Sandhu, Emily Phiri, Khalid Rashed, Elisabeth Wilson, Esther Hindley, Sarah Board, Sherly Antony, Alfonso Tanate, Michelle Davis, Beth Holland, Victoria Slater, Michelle Fawcett, Tim England, James Scott, Jessica Beavan, Amanda Hedstrom, Dumin Karunatilake, Kimberley Gillmain, Nishy Singh, Tracy Hallows, Mark Barber, Luke Yates, Clayton Micallef, Derek Esson, Wai Meng Yu, Benjamin Jaa Ming New, Alexandre Matos, Clare Burt, Louise Cabrelli, Gillian Wilkie, Madana Meegada, Ramanathan Kirthivasan, Caroline Fox, Victoria Mead, Amanda Lyle, Rajesh Saksena, Aashima Bakshi, Alison O'Kelly, Jahanzeb Rehan, Osaretin Ebueka, Martin Cooper, Inez Wynter, Susan Smith, Senthil Kumar, Linda O'Brien, Cerrys Parker, Emma Parker, Numan Khan, Christopher Patterson, Stuart Maguire, Outi Quinn, Ruth Bellfield, Yousif Behnam, Janet Costa, Cheryl Padilla-Harris, Louise Moram, Syed Abid Raza, Helen Tench, Tanya Sims, Heather McGuinness, Ronda Loosley, Rebecca Wolf-Roberts, Sandeep Buddha, Irmak Salt, Kerry Lewis, Sunanda Mavinamne, Coleen Ditchfield, Sharon Dealing, Alexander Shah, Ginette Crossingham, Memory Mwadeyi, Anthony Kenton, Faith Omoregie, Saidu Abubakar, Allison Warwick, Gemma Hector, Ahamad Hassan, Emelda Veraque, Michelle Farman, Linetty Makawa, Anthony Byrne, Jackie Kirkham, Gareth Blayney, Jey Selwyn, Puneet Kakar, Mohammed Al Khaddour, Reena Dhami, Emelda Baker, Bernard Esisi, Emma Clarkson, Dominic Fellowes, Jergovic Kresmir, Paul Guyler, David Ngo, Indunil Wijenayake, Sharon Tysoe, Joanne Galliford, Paula Harman, Mark Garside, Madhava Badanahatti, Anna Smith, Victoria Riddell, Gita Gramizadeh, Dipankar Dutta, Milda Bajoriene, Hulya Erdogan, Deborah Ward, Fergus Doubal, Neshika Samarasekera, Sarah Risbridger, Allan MacRaild, Abul Azim, Lisa Wood, Ruth Tampset, Raj Shekhar, Umesh Rai, Tracy Fuller, Aricsa Joshy, Evelyn Nadar, Manohar Kini, Syed Ahmad, Matthew Robinson, Lucia King, Venkatesan Srinivasan, Magdalena Karwacka-Cichomska, Vicki Moore, Kate Smith, Bincy Kariyadil, Kelvin Kong, Kelly Hubbard, Sarwat Arif, Muhammad Hasan, Natalie Temple, Daniele Arcoria, Zoey Horne, Thandar Soe, Hilary Wyllie, Christian Hacon, Helen Sutherland, Brian Menezes, Venetia Johnson, Nigel Smyth, Zehra Mehdi, Ela Tone, Arian Bradley, Emma Levell, Aleksandra Ekkert, Sara Mazzucco, Laura McCafferty, Linda Vonoven, Suprita Dewan, Pagadala Sridhar, Jayne Thomas, Samantha Coetzee, Becky Icke, Jill Williams, Narayanamoorthi Saravanan, Pamela Bradley, Rebecca Marie Gibson, Jijimol Antony, Imran Ashraf, Jose Mabuti, Charlotte Kamundi, Prasanna Patiola, Naomi Oakley, Harold Proeschel, Debs Kelly, Wendy Longley, Ashleigh Cave, Carla Ambrico, Toby Black, Elisa Porretta, Alpha Anthony, Suzanne Ragab, Judith Dube, Shahid Kausar, Abdullah Gujjar, Mohammad Abdullah, Daljit Kaur, Naveen Gadapa, Sumita Choudhary, Nabeela Nisar, Grace Fawehinmi, Karen Dunne, Sam King, Amit Kishore, Stephanie Lee, Tracy Marsden, Melanie Slaughter, Kathryn Cawley, Jane Perez, Peter Anderton, Salem Soussi, Deborah Walstow, Rebecca Pugh, Aravind Manoj, Glynn Fletcher, Paula Lopez, Michael McCormick, Michael Magee, Grainne Tallon, Denise McFarland, Denise Cosgrove, Naval Shinh, Kneale Metcalf, Alina Kostyuk, Susan McDonald, Sophie Sayers, Walee Sayed, Sam Abraham, Gemma Szabo, Gareth Crosbie, Jim McIlmoyle, Patricia Fearon, Kerry Courtney, Suzanne Tauro, Arun Singh, Anand Nair, Stephen Duberley, Sheeba Philip, Cath Curley, Wendy Goddard, Luke Bridge, Paul Willcoxson, Peter Wanklyn, Jennifer Owen, John France, Bryony Reed, Angie Foulds, Bella Richard, Louise Parfitt, Brendan Affley, Cristina Russo, Margaret Dsouza, Elizabeth Cruddas, David Hargroves, James Rand, Som Shekar, Yaqoob Bhat, Gail Marshall, Maxine Nash, Nasar Ahmad, Blessing Oduh Okoko, Rachel Evans, Tegan Taylor, Jesse Dawson, Elizabeth Colquhoun, Christopher James, Carlos Aguirre, Catherine MacPhee, Janet Phipps, Sissi Ispoglou, Anne Hayes, Rachel Evans

Affiliations

¹ Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, London, UK; Comprehensive Stroke Service, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK. Electronic address: d.werring@ucl.ac.uk.
² Comprehensive Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
³ Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, London, UK.
⁴ Research Department of Haematology, University College London, London, UK; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK.
⁵ Neurology and Neurorehabilitation, University Department of Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland.
⁶ Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Medical Sciences Division, University of Oxford, Oxford, UK.
⁷ Royal Devon and Exeter Hospital, Exeter, UK; University of Exeter Medical School, Exeter, UK.
⁸ Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK; Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁹ MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.
¹⁰ Department of Clinical Sciences and Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
¹¹ Stroke Trials Unit, Division of Mental Health and Clinical Neuroscience, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK.

PMID: 39491870
DOI: 10.1016/S0140-6736(24)02197-4

Abstract

Background: The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation.

Methods: We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7-14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing.

Findings: Between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI -0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (p_{non-inferiority}=0·0003). Superiority was not identified (p_superiority=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, -0·004 to 0·006; p=0·78).

Interpretation: Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation.

Funding: British Heart Foundation.

Associated data

ClinicalTrials.gov/NCT03759938