Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study

Duncan Wilson, Gareth Ambler, Clare Shakeshaft, Martin M Brown, Andreas Charidimou, Rustam Al-Shahi Salman, Gregory Y H Lip, Hannah Cohen, Gargi Banerjee, Henry Houlden, Mark J White, Tarek A Yousry, Kirsty Harkness, Enrico Flossmann, Nigel Smyth, Louise J Shaw, Elizabeth Warburton, Keith W Muir, Hans Rolf Jäger, David J Werring, CROMIS-2 collaborators, John Aeron-Thomas, Prasanna Aghoram, Elaine Amis, Peter Anderton, Sreeman Andole, Ijaz Anwar, John Bamford, Azra Banaras, Aian Barry, Ruth Bellfied, Aienne Benford, Ajay Bhalla, Maneesh Bhargava, Biju Bhaskaran, Neelima Bhupathiraju, Jonathan Birns, Aian Blight, Angie Bowring, Ellen Brown, David Bruce, Amanda Buck, Kerry Bunworth, Ilse Burger, Laura Burgess, Mathew Burn, Evelyn Burssens, Mauian Burton, Nicola Butler, Denise Button, Michael Carpenter, Dinesh Chadha, Kausik Chatterjee, Lillian Choy, David Cohen, Lynne Connell, Martin Cooper, John Corrigan, Donna Cotterill, Gillian Courtauld, Susan Crawford, Claire Cullen, Krishna Dani, Amelia Daniel, Prabel Datta, Michelle Davis, Nicola Day, Mandy Doherty, Catherine Douglas, Karen Dunne, Collette Edwards, Charlotte Eglinton, Abduelbaset Elmarimi, Hedley Emsley, Timothy England, Daniel Epstein, Renuka Erande, Bernard Esisi, Rachel Evans, Pamela Farren, Pauline Fitzell, Glyn Fletcher, Rachel Gallifent, Rachel Gascoyne, Elio Giallombardo, Bindu Gregary, Gunaratam Gunathilagan, Paul Guyler, Brigid Hairsine, Michael Haley, Anne Hardwick, David Hargroves, Frances Harrington, Amanda Hedstrom, Clare Holmes, Senussi Hussein, Tanya Ingram, Sissi Ispoglou, Liz Iveson, Venetia Johnson, Frances Justin, Shahid Kausar, Karen Kee, Michael Keeling, Shagufta Khan, Agnieszka Kieliszkowska, Hayley Kingwell, Vinodh Krishnamurthy, Sagal Kullane, Balakrishna Kumar, Simon Leach, Sana Leason, Paula Lopez, Robert Luder, Barbara Madigan, Stuart Maguire, Holly Maguire, Karim Mahawish, Linetty Makawa, Maam Mamun, Dulka Manawadu, David Mangion, Aravindakshan Manoj, Syed Mansoor, Tracy Marsden, Rachel Marsh, Sheila Mashate, Michael McCormick, Clare McGolick, Madeleine McKee, Emma Mckenzie, Sanjeevikumar Meenakishundaram, Zoe Mellor, Amulya Misra, Amit Mistri, Azlisham Mohd Nor, Mushiya Mpelembue, Peter Murphy, Arumug Nallasivam, Ann Needle, Vinh Nguyen, Janice O'Connell, Paul O'Mahony, James Okwera, Chukwuka Orefo, Peter Owusu-Agyei, Anthea Parry, Adrian Parry-Jones, Kath Pasco, Chris Patterson, Cassilda Peixoto, Jane Perez, Nicola Persad, Mia Porteous, Michael Power, Christopher Price, Harald Proschel, Shuja Punekar, Janet Putterill, Marc Randall, Ozlem Redjep, Habib Rehman, Emma Richards, Victoria Riddell, Christine Roffe, Gill Rogers, Anthony Rudd, Kari Saastamoinen, Mahmud Sajid, Banher Sandhu, Christine Schofield, Jon Scott, Lakshmanan Sekaran, Pankaj Sharma, Jagdish Sharma, Simon Sharpe, Matthew Smith, Anew Smith, Nikola Sprigg, Julie Staals, Amy Steele, Gail Storey, Kelley Storey, Santhosh Subramonian, Jane Sword, Grainne Tallon, Garryck Tan, Margaret Tate, Jennifer Teke, Natalie Temple, Teresa Thompson, Sharon Tysoe, Djamil Vahidassr, Anouk van der Kwaak, Roland Veltkamp, Deborah Walstow, Caroline Watchurst, Fran Watson, Dean Waugh, Peter Wilkinson, David Wilson, Sarah Wilson-Owen, Belinda Wroath, Inez Wynter, Emma Young, Duncan Wilson, Gareth Ambler, Clare Shakeshaft, Martin M Brown, Andreas Charidimou, Rustam Al-Shahi Salman, Gregory Y H Lip, Hannah Cohen, Gargi Banerjee, Henry Houlden, Mark J White, Tarek A Yousry, Kirsty Harkness, Enrico Flossmann, Nigel Smyth, Louise J Shaw, Elizabeth Warburton, Keith W Muir, Hans Rolf Jäger, David J Werring, CROMIS-2 collaborators, John Aeron-Thomas, Prasanna Aghoram, Elaine Amis, Peter Anderton, Sreeman Andole, Ijaz Anwar, John Bamford, Azra Banaras, Aian Barry, Ruth Bellfied, Aienne Benford, Ajay Bhalla, Maneesh Bhargava, Biju Bhaskaran, Neelima Bhupathiraju, Jonathan Birns, Aian Blight, Angie Bowring, Ellen Brown, David Bruce, Amanda Buck, Kerry Bunworth, Ilse Burger, Laura Burgess, Mathew Burn, Evelyn Burssens, Mauian Burton, Nicola Butler, Denise Button, Michael Carpenter, Dinesh Chadha, Kausik Chatterjee, Lillian Choy, David Cohen, Lynne Connell, Martin Cooper, John Corrigan, Donna Cotterill, Gillian Courtauld, Susan Crawford, Claire Cullen, Krishna Dani, Amelia Daniel, Prabel Datta, Michelle Davis, Nicola Day, Mandy Doherty, Catherine Douglas, Karen Dunne, Collette Edwards, Charlotte Eglinton, Abduelbaset Elmarimi, Hedley Emsley, Timothy England, Daniel Epstein, Renuka Erande, Bernard Esisi, Rachel Evans, Pamela Farren, Pauline Fitzell, Glyn Fletcher, Rachel Gallifent, Rachel Gascoyne, Elio Giallombardo, Bindu Gregary, Gunaratam Gunathilagan, Paul Guyler, Brigid Hairsine, Michael Haley, Anne Hardwick, David Hargroves, Frances Harrington, Amanda Hedstrom, Clare Holmes, Senussi Hussein, Tanya Ingram, Sissi Ispoglou, Liz Iveson, Venetia Johnson, Frances Justin, Shahid Kausar, Karen Kee, Michael Keeling, Shagufta Khan, Agnieszka Kieliszkowska, Hayley Kingwell, Vinodh Krishnamurthy, Sagal Kullane, Balakrishna Kumar, Simon Leach, Sana Leason, Paula Lopez, Robert Luder, Barbara Madigan, Stuart Maguire, Holly Maguire, Karim Mahawish, Linetty Makawa, Maam Mamun, Dulka Manawadu, David Mangion, Aravindakshan Manoj, Syed Mansoor, Tracy Marsden, Rachel Marsh, Sheila Mashate, Michael McCormick, Clare McGolick, Madeleine McKee, Emma Mckenzie, Sanjeevikumar Meenakishundaram, Zoe Mellor, Amulya Misra, Amit Mistri, Azlisham Mohd Nor, Mushiya Mpelembue, Peter Murphy, Arumug Nallasivam, Ann Needle, Vinh Nguyen, Janice O'Connell, Paul O'Mahony, James Okwera, Chukwuka Orefo, Peter Owusu-Agyei, Anthea Parry, Adrian Parry-Jones, Kath Pasco, Chris Patterson, Cassilda Peixoto, Jane Perez, Nicola Persad, Mia Porteous, Michael Power, Christopher Price, Harald Proschel, Shuja Punekar, Janet Putterill, Marc Randall, Ozlem Redjep, Habib Rehman, Emma Richards, Victoria Riddell, Christine Roffe, Gill Rogers, Anthony Rudd, Kari Saastamoinen, Mahmud Sajid, Banher Sandhu, Christine Schofield, Jon Scott, Lakshmanan Sekaran, Pankaj Sharma, Jagdish Sharma, Simon Sharpe, Matthew Smith, Anew Smith, Nikola Sprigg, Julie Staals, Amy Steele, Gail Storey, Kelley Storey, Santhosh Subramonian, Jane Sword, Grainne Tallon, Garryck Tan, Margaret Tate, Jennifer Teke, Natalie Temple, Teresa Thompson, Sharon Tysoe, Djamil Vahidassr, Anouk van der Kwaak, Roland Veltkamp, Deborah Walstow, Caroline Watchurst, Fran Watson, Dean Waugh, Peter Wilkinson, David Wilson, Sarah Wilson-Owen, Belinda Wroath, Inez Wynter, Emma Young

Abstract

Background: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack.

Methods: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316.

Findings: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0-20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1-5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27-10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29-0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53-0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60-0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07-0·43, p=0·0065; and 0·33, 0·14-0·51, p=0·00059, respectively).

Interpretation: In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation.

Funding: The Stroke Association and the British Heart Foundation.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Participant flow
Figure 2
Figure 2
Probability of symptomatic intracranial haemorrhage according to the presence or absence of cerebral microbleeds The hazard ratio (HR) and 95% CI are derived from the model adjusted for hypertension and age.

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Source: PubMed

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