Clinical and Radiological Characteristics of Vitamin K Versus Non-Vitamin K Antagonist Oral Anticoagulation-Related Intracerebral Hemorrhage

  • Małgorzata M. MillerEmail author
  • Jessica Lowe
  • Muhib Khan
  • Muhammad U. Azeem
  • Susanne Muehlschlegel
  • Adalia H. Jun-O’Connell
  • Richard P. GoddeauJr.
  • Majaz Moonis
  • Danielle Gritters
  • Brian Silver
  • Nils Henninger
Original Article



Recent studies indicated that functional outcome after intracranial hemorrhage (ICH) related to direct oral anticoagulation (DOAC-ICH) is similar, if not better, than vitamin K antagonist (VKA)-related ICH (VKA-ICH) due to a smaller initial hematoma volume (HV). However, the association with hematoma expansion (HE) and location is not well understood.


We retrospectively analyzed 102 consecutive patients with acute non-traumatic ICH on oral anticoagulation therapy to determine HV and HE stratified by hematoma location, and the relation to the 90-day outcome.


DOAC-ICH (n = 25) and VKA-ICH (n = 77) had a similar admission HV and HE (unadjusted p > 0.05, each). Targeted reversal strategies were used in 93.5% of VKA-ICH versus 8% of DOAC-ICH. After adjustment, an unfavorable 90-day functional outcome (modified Rankin scale score 4–6) was independently associated with a lower admission Glasgow Coma Scale score (OR 1.63; 95% CI 1.26–2.10; p < 0.001) and greater HV (OR 1.03; 95% confidence interval (CI) 1.00–1.05; p = 0.046). After exclusion of patients without follow-up head computed tomography to allow for adjustment by occurrence of HE, VKA-ICH was associated with an approximately 3.5 times greater odds for a poor 90-day outcome (OR 3.64; 95% CI 1.01–13.09; p = 0.048). However, there was no significant association of the oral anticoagulant strategy with 90-day outcome in the entire cohort (OR 2.85; 95% CI 0.69–11.86; p = 0.15).


DOAC use did not relate to worse HE, HV, and functional outcome after ICH, adding to the notion that DOAC is a safe alternative to VKA even in the absence of access to targeted reversal strategies (which are still not universally available).


Warfarin Direct oral anticoagulants Intracranial hemorrhage 


Author Contributions

MMM was involved in the study design, data acquisition, data analysis and interpretation, and drafting the article; JL and MK were involved in data acquisition, data interpretation, and revision of the manuscript; MUA and DG performed data acquisition and revision of the manuscript; SM, AHJO, RPG, MM, and BS were involved in interpretation of data and revision of the manuscript; NH was involved in the study design, data acquisition, statistical analysis of the data, interpretation of data, and drafting the article. All authors have read and approved the submitted manuscript.

Sources of Support

Dr. Henninger is supported by K08NS091499 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. Dr. Muehlschlegel is supported by K23HD080971 from the NIH/National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Dr. Henninger reports grants from NINDS, personal fees from Omniox, Inc, personal fees from Portola Pharmaceuticals, Inc, outside the submitted work. Dr. Muehlschlegel reports grants from NIH/NICHD, other from BARD Inc, outside the submitted work. Dr. Silver reports other from Joint Commission, other from Women’s Health Initiative, other from NIH, personal fees from Medicolegal malpractice reviews, personal fees from Ebix, personal fees from MedLink, personal fees from Medscape, outside the submitted work. Dr. Miller, Dr. Lowe, Dr. Khan, Dr. Azeem, Dr. Jun-O’Connell, Dr. Goddeau, Dr. Moonis, Dr. Gritters have nothing to disclose.

Ethical Approval

Our investigation was approved by institutional review boards, and we were granted a Health Insurance Portability and Accountability Act waiver of informed consent at the University of Massachusetts and Spectrum Health.


  1. 1.
    Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace. 2016;18:1609–78.CrossRefGoogle Scholar
  2. 2.
    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.CrossRefGoogle Scholar
  3. 3.
    Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology. 2008;71:1084–9.CrossRefGoogle Scholar
  4. 4.
    Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(638–45):e4.Google Scholar
  5. 5.
    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;383:955–62.CrossRefGoogle Scholar
  6. 6.
    Ansell J. New oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation. Circulation. 2012;125:165–70 (discussion 70).CrossRefGoogle Scholar
  7. 7.
    Wilson D, Seiffge DJ, Traenka C, et al. Outcome of intracerebral hemorrhage associated with different oral anticoagulants. Neurology. 2017;88:1693–700.CrossRefGoogle Scholar
  8. 8.
    Marques-Matos C, Alves JN, Marto JP, et al. POST-NOAC: Portuguese observational study of intracranial hemorrhage on non-vitamin K antagonist oral anticoagulants. Int J Stroke. 2017;12:623–7.CrossRefGoogle Scholar
  9. 9.
    Boulouis G, Morotti A, Pasi M, Goldstein JN, Gurol ME, Charidimou A. Outcome of intracerebral haemorrhage related to non-vitamin K antagonists oral anticoagulants versus vitamin K antagonists: a comprehensive systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2018;89:263–70.Google Scholar
  10. 10.
    Takahashi H, Jimbo Y, Takano H, et al. Intracerebral hematoma occurring during warfarin versus non-vitamin K antagonist oral anticoagulant therapy. Am J Cardiol. 2016;118:222–5.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    Hagii J, Tomita H, Metoki N, et al. Characteristics of intracerebral hemorrhage during rivaroxaban treatment: comparison with those during warfarin. Stroke. 2014;45:2805–7.CrossRefGoogle Scholar
  13. 13.
    Kawabori M, Niiya Y, Iwasaki M, et al. Characteristics of symptomatic intracerebral hemorrhage in patient receiving direct oral anticoagulants: comparison with warfarin. J Stroke Cerebrovasc Dis. 2018;27:1338–42.CrossRefGoogle Scholar
  14. 14.
    Tsivgoulis G, Lioutas VA, Varelas P, et al. Direct oral anticoagulant- vs vitamin K antagonist-related nontraumatic intracerebral hemorrhage. Neurology. 2017;89:1142–51.CrossRefGoogle Scholar
  15. 15.
    Sheth KN, Cushing TA, Wendell L, et al. Comparison of hematoma shape and volume estimates in warfarin versus non-warfarin-related intracerebral hemorrhage. Neurocrit Care. 2010;12:30–4.CrossRefGoogle Scholar
  16. 16.
    Webb AJ, Ullman NL, Morgan TC, et al. Accuracy of the ABC/2 score for intracerebral hemorrhage: systematic review and analysis of MISTIE, CLEAR-IVH, and CLEAR III. Stroke. 2015;46:2470–6.CrossRefGoogle Scholar
  17. 17.
    Khan M, Baird GL, Elias R, et al. Comparison of intracerebral hemorrhage volume calculation methods and their impact on scoring tools. J Neuroimaging. 2017;27:144–8.CrossRefGoogle Scholar
  18. 18.
    Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20:1183–97.CrossRefGoogle Scholar
  19. 19.
    Bruno A, Akinwuntan AE, Lin C, et al. Simplified modified Rankin scale questionnaire: reproducibility over the telephone and validation with quality of life. Stroke. 2011;42:2276–9.CrossRefGoogle Scholar
  20. 20.
    Henninger N, Lin E, Baker SP, Wakhloo AK, Takhtani D, Moonis M. Leukoaraiosis predicts poor 90-day outcome after acute large cerebral artery occlusion. Cerebrovasc Dis. 2012;33:525–31.CrossRefGoogle Scholar
  21. 21.
    Helenius J, Henninger N. Leukoaraiosis burden significantly modulates the association between infarct volume and national institutes of health stroke scale in ischemic stroke. Stroke. 2015;46:1857–63.CrossRefGoogle Scholar
  22. 22.
    Woo D, Broderick JP, Kothari RU, et al. Does the National Institutes of Health Stroke Scale favor left hemisphere strokes? NINDS t-PA Stroke Study Group. Stroke. 1999;30:2355–9.CrossRefGoogle Scholar
  23. 23.
    von der Brelie C, Doukas A, Naumann R, et al. Clinical and radiological course of intracerebral haemorrhage associated with the new non-vitamin K anticoagulants. Acta Neurochir (Wien). 2017;159:101–9.CrossRefGoogle Scholar
  24. 24.
    Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke. 2000;31:2558–62.CrossRefGoogle Scholar
  25. 25.
    Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993;24:987–93.CrossRefGoogle Scholar
  26. 26.
    Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;32:891–7.CrossRefGoogle Scholar
  27. 27.
    Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med. 2017;377:431–41.CrossRefGoogle Scholar
  28. 28.
    Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375:1131–41.CrossRefGoogle Scholar
  29. 29.
    Faine BA, Amendola J, Homan J, Ahmed A, Mohr N. Factors associated with availability of anticoagulation reversal agents in rural and community emergency departments. Am J Health Syst Pharm. 2018;75:72–7.CrossRefGoogle Scholar
  30. 30.
    Lauer A, Cianchetti FA, Van Cott EM, et al. Anticoagulation with the oral direct thrombin inhibitor dabigatran does not enlarge hematoma volume in experimental intracerebral hemorrhage. Circulation. 2011;124:1654–62.CrossRefGoogle Scholar
  31. 31.
    Zhou W, Zorn M, Nawroth P, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–8.CrossRefGoogle Scholar
  32. 32.
    Pollack CV Jr, Bernstein R, Dubiel R, et al. Healthcare resource utilization in patients receiving idarucizumab for reversal of dabigatran anticoagulation due to major bleeding, urgent surgery, or procedural interventions: interim results from the RE-VERSE AD study. J Med Econ. 2017;20:435–42.CrossRefGoogle Scholar
  33. 33.
    van der Wall SJ, van Rein N, van den Bemt B, et al. Performance of idarucizumab as antidote of dabigatran in daily clinical practice. Europace 2018. Scholar
  34. 34.
    Ko D, Razouki Z, Otis J, Marulanda-Londono E, Hylek EM. Anticoagulation reversal in vitamin K antagonist-associated intracerebral hemorrhage: a systematic review. J Thromb Thrombolysis. 2018;46:227–37.CrossRefGoogle Scholar
  35. 35.
    Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032–60.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society 2019

Authors and Affiliations

  • Małgorzata M. Miller
    • 1
    Email author
  • Jessica Lowe
    • 2
  • Muhib Khan
    • 2
  • Muhammad U. Azeem
    • 1
  • Susanne Muehlschlegel
    • 1
    • 3
    • 4
  • Adalia H. Jun-O’Connell
    • 1
  • Richard P. GoddeauJr.
    • 1
  • Majaz Moonis
    • 1
  • Danielle Gritters
    • 5
  • Brian Silver
    • 1
  • Nils Henninger
    • 1
    • 6
  1. 1.Department of NeurologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Division of Neurology, Neuroscience InstituteSpectrum HealthGrand RapidsUSA
  3. 3.Department of SurgeryUniversity of Massachusetts Medical SchoolWorcesterUSA
  4. 4.Department of Anesthesia and Critical CareUniversity of Massachusetts Medical SchoolWorcesterUSA
  5. 5.Spectrum Health Office of ResearchSpectrum HealthGrand RapidsUSA
  6. 6.Department of PsychiatryUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations