Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants

David J Seiffge, Duncan Wilson, Gareth Ambler, Gargi Banerjee, Isabel Charlotte Hostettler, Henry Houlden, Clare Shakeshaft, Hannah Cohen, Tarek A Yousry, Rustam Al-Shahi Salman, Gregory Lip, Martin M Brown, Keith Muir, H R Jäger, David J Werring, David J Seiffge, Duncan Wilson, Gareth Ambler, Gargi Banerjee, Isabel Charlotte Hostettler, Henry Houlden, Clare Shakeshaft, Hannah Cohen, Tarek A Yousry, Rustam Al-Shahi Salman, Gregory Lip, Martin M Brown, Keith Muir, H R Jäger, David J Werring

Abstract

Objective: We investigated the contribution of small vessel disease (SVD) to anticoagulant-associated intracerebral haemorrhage (ICH).

Methods: Clinical Relevance of Microbleeds in Stroke-2 comprised two independent multicentre observation studies: first, a cross-sectional study of patients with ICH; and second, a prospective study of patients taking anticoagulants for atrial fibrillation (AF) after cerebral ischaemia. In patients with ICH, we compared SVD markers on CT and MRI according to prior anticoagulant therapy. In patients with AF and cerebral ischaemia treated with anticoagulants, we compared the rates of ICH and ischaemic stroke according to SVD burden score during 2 years follow-up.

Results: We included 1030 patients with ICH (421 on anticoagulants), and 1447 patients with AF and cerebral ischaemia. Medium-to-high severity SVD was more prevalent in patients with anticoagulant-associated ICH (CT 56.1%, MRI 78.7%) than in those without prior anticoagulant therapy (CT 43.5%, p<0.001; MRI 64.5%, p=0.072). Leukoaraiosis and atrophy were more frequent and severe in ICH associated with prior anticoagulation. In the cerebral ischaemia cohort (779 with SVD), during 3366 patient-years of follow-up the rate of ICH was 0.56%/year (IQR 0.27-1.03) in patients with SVD, and 0.06%/year (IQR 0.00-0.35) in those without (p=0.001); ICH was independently associated with severity of SVD (HR 5.0, 95% CI 1.9 to 12.2,p=0.001), and was predicted by models including SVD (c-index 0.75, 95% CI 0.63 to 0.85).

Conclusions: Medium-to-high severity SVD is associated with ICH occurring on anticoagulants, and independently predicts ICH in patients with AF taking anticoagulants; its absence identifies patients at low risk of ICH. Findings from these two complementary studies suggest that SVD is a contributory factor in ICH in patients taking anticoagulants and suggest that anticoagulation alone should no longer be regarded as a sufficient 'cause' of ICH.

Trial registration: NCT02513316.

Conflict of interest statement

Competing interests: DJS: Scientific advisory boards: Bayer and Pfizer. Compensation for educational efforts: Stago. DJW: speaking honoraria: Bayer. DJW: personal fees from Bayer and Portola.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Study flow chart. AF, atrialfibrillation; CROMIS-2, Clinical Relevance of Microbleedsin Stroke; ICH, intracerebral haemorrhage; SVD, small vessel disease; OAC, oral anticoagulation.
Figure 2
Figure 2
Small vessel disease burden on MRI in patients with intracerebral haemorrhage (ICH) with prior anticoagulation therapy compared with those without prior anticoagulation therapy.
Figure 3
Figure 3
Kaplan-Meier curves of intracerebral haemorrhage (A, C) and recurrent ischaemic (B, D) stroke according to small vessel disease (SVD) burden (A, B), the HAS-BLED score (for intracerebral haemorrhage) (C) and the CHA2DS2-VASc (for recurrent ischaemic stroke) (D).

References

    1. Hilkens NA, van Asch CJJ, Werring DJ, et al. . Predicting the presence of macrovascular causes in non-traumatic intracerebral haemorrhage: the diagram prediction score. J Neurol Neurosurg Psychiatry 2018;89:674–9. 10.1136/jnnp-2017-317262
    1. van Asch CJJ, Velthuis BK, Greving JP, et al. . External validation of the secondary intracerebral hemorrhage score in the Netherlands. Stroke 2013;44:2904–6. 10.1161/STROKEAHA.113.002386
    1. Hart RG, Pearce LA, Aguilar MI. Meta-Analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. 10.7326/0003-4819-146-12-200706190-00007
    1. Hart RG. What causes intracerebral hemorrhage during warfarin therapy? Neurology 2000;55:907–8. 10.1212/WNL.55.7.907
    1. Hart RG. Making anticoagulation safer. Neurology 2002;59:153. 10.1212/wnl.59.2.153
    1. O'Donnell MJ, Xavier D, Liu L, et al. . Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010;376:112–23. 10.1016/S0140-6736(10)60834-3
    1. O'Donnell MJ, Chin SL, Rangarajan S, et al. . Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet 2016;388:761–75. 10.1016/S0140-6736(16)30506-2
    1. Rosand J, Hylek EM, O'Donnell HC, et al. . Warfarin-Associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology 2000;55:947–51. 10.1212/WNL.55.7.947
    1. Seiffge DJ, Kägi G, Michel P, et al. . Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage. Ann Neurol 2018;83:451–9. 10.1002/ana.25165
    1. Martí-Fàbregas J, Prats-Sánchez L, Guisado-Alonso D, et al. . SMASH-U versus H-ATOMIC: a head-to-head comparison for the etiologic classification of intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2018;27:2375–80. 10.1016/j.jstrokecerebrovasdis.2018.04.026
    1. Martí-Fàbregas J, Prats-Sánchez L, Martínez-Domeño A, et al. . The H-ATOMIC criteria for the etiologic classification of patients with intracerebral hemorrhage. PLoS One 2016;11:e0156992. 10.1371/journal.pone.0156992
    1. Meretoja A, Strbian D, Putaala J, et al. . SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage. Stroke 2012;43:2592–7. 10.1161/STROKEAHA.112.661603
    1. Wilson D, Ambler G, Shakeshaft C, et al. . 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. Lancet Neurol 2018;17:539–47. 10.1016/S1474-4422(18)30145-5
    1. Wilson D, Charidimou A, Werring DJ. Advances in understanding spontaneous intracerebral hemorrhage: insights from neuroimaging. Expert Rev Neurother 2014;14:661–78. 10.1586/14737175.2014.918506
    1. Wilson D, Werring DJ. Antithrombotic therapy in patients with cerebral microbleeds. Curr Opin Neurol 2017;30:38–47. 10.1097/WCO.0000000000000411
    1. Wardlaw JM, Smith EE, Biessels GJ, et al. . Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822–38. 10.1016/S1474-4422(13)70124-8
    1. Klarenbeek P, van Oostenbrugge RJ, Rouhl RPW, et al. . Ambulatory blood pressure in patients with lacunar stroke: association with total MRI burden of cerebral small vessel disease. Stroke 2013;44:2995–9. 10.1161/STROKEAHA.113.002545
    1. Staals J, Makin SDJ, Doubal FN, et al. . Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 2014;83:1228–34. 10.1212/WNL.0000000000000837
    1. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–300. 10.1177/003591576505800503
    1. Charidimou A, Wilson D, Shakeshaft C, et al. . The clinical relevance of microbleeds in stroke study (CROMIS-2): rationale, design, and methods. Int J Stroke 2015;10:155–61. 10.1111/ijs.12569
    1. van Swieten JC, Hijdra A, Koudstaal PJ, et al. . Grading white matter lesions on CT and MRI: a simple scale. J Neurol Neurosurg Psychiatry 1990;53:1080–3. 10.1136/jnnp.53.12.1080
    1. Charidimou A, Schmitt A, Wilson D, et al. . The cerebral haemorrhage anatomical rating inStrument (charts): development and assessment of reliability. J Neurol Sci 2017;372:178–83. 10.1016/j.jns.2016.11.021
    1. Pasquier F, Leys D, Weerts JG, et al. . Inter- and intraobserver reproducibility of cerebral atrophy assessment on MRI scans with hemispheric infarcts. Eur Neurol 1996;36:268–72. 10.1159/000117270
    1. Fazekas F, Chawluk JB, Alavi A, et al. . Mr signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol 1987;149:351–6. 10.2214/ajr.149.2.351
    1. Gregoire SM, Chaudhary UJ, Brown MM, et al. . The microbleed anatomical rating scale (MARS): reliability of a tool to map brain microbleeds. Neurology 2009;73:1759–66. 10.1212/WNL.0b013e3181c34a7d
    1. Harper L, Barkhof F, Fox NC, et al. . Using visual rating to diagnose dementia: a critical evaluation of MRI atrophy scales. J Neurol Neurosurg Psychiatry 2015;86:1225–33. 10.1136/jnnp-2014-310090
    1. Doubal FN, MacLullich AMJ, Ferguson KJ, et al. . Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 2010;41:450–4. 10.1161/STROKEAHA.109.564914
    1. Banerjee G, Wilson D, Ambler G, et al. . Cognitive impairment before intracerebral hemorrhage is associated with cerebral amyloid angiopathy. Stroke 2018;49:40–5. 10.1161/STROKEAHA.117.019409
    1. Charidimou A, Linn J, Vernooij MW, et al. . Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions. Brain 2015;138:2126–39. 10.1093/brain/awv162
    1. Fazekas F, Kleinert R, Offenbacher H, et al. . Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993;43:1683–9. 10.1212/WNL.43.9.1683
    1. Sandercock P, Wardlaw JM, IST-3 collaborative group, et al. . The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352–63. 10.1016/S0140-6736(12)60768-5
    1. Arba F, Mair G, Carpenter T, et al. . Cerebral white matter hypoperfusion increases with small-vessel disease burden. data from the third International stroke trial. J Stroke Cerebrovasc Dis 2017;26:1506–13. 10.1016/j.jstrokecerebrovasdis.2017.03.002
    1. Maclullich AMJ, Wardlaw JM, Ferguson KJ, et al. . Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J Neurol Neurosurg Psychiatry 2004;75:1519–23. 10.1136/jnnp.2003.030858
    1. Wilson D, Charidimou A, Shakeshaft C, et al. . Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type. Neurology 2016;86:360–6. 10.1212/WNL.0000000000002310
    1. Lip GYH, Nieuwlaat R, Pisters R, et al. . Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro heart survey on atrial fibrillation. Chest 2010;137:263–72. 10.1378/chest.09-1584
    1. Pisters R, Lane DA, Nieuwlaat R, et al. . A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro heart survey. Chest 2010;138:1093–100. 10.1378/chest.10-0134
    1. Seiffge DJ, Curtze S, Dequatre-Ponchelle N, et al. . Hematoma location and morphology of anticoagulation-associated intracerebral hemorrhage. Neurology 2019;92:e782-e791. 10.1212/WNL.0000000000006958
    1. Wilson D, Ambler G, Lee KJ. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies. Lancet Neurol 2019.
    1. van Veluw SJ, Biessels GJ, Klijn CJM, et al. . Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy. Neurology 2016;86:867–71. 10.1212/WNL.0000000000002419
    1. Nandigam RNK, Viswanathan A, Delgado P, et al. . Mr imaging detection of cerebral microbleeds: effect of susceptibility-weighted imaging, section thickness, and field strength. AJNR Am J Neuroradiol 2009;30:338–43. 10.3174/ajnr.A1355

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅