Abstract
Background
With increasing use of direct oral anticoagulants (DOACs) and availability of new reversal agents, the risk of traumatic intracranial hemorrhage (tICH) requires better understanding. We compared hemorrhage expansion rates, mortality, and morbidity following tICH in patients treated with vitamin k antagonists (VKA: warfarin) and DOACs (apixaban, rivaroxaban, dabigatran).
Methods
Retrospective chart review of patients from 2010 to 2017 was performed to identify patients with imaging diagnosis of acute traumatic intraparenchymal, subdural, subarachnoid, and epidural hemorrhage with preadmission use of DOACs or VKAs. We identified 39 patients on DOACs and 97 patients on VKAs. Demographic information, comorbidities, hemorrhage size, and expansion over time, as well as discharge disposition and Glasgow Outcome Scale (GOS) were collected. Primary outcome was development of new or enlargement of tICH within the first 48 h of initial CT imaging.
Results
Of 136 patients with mean (SD) age 78.7 (13.2) years, most common tICH subtype was subdural hematoma (N = 102/136; 75%), and most common mechanism was a fall (N = 130/136; 95.6%). Majority of patients in the DOAC group did not receive reversal agents (66.7%). Hemorrhage expansion or new hemorrhage occurred in 11.1% in DOAC group vs. 14.6% in VKA group (p = 0.77) at a median of 8 and 11 h from initial ED admission, respectively (p = 0.82). Patients in the DOAC group compared to VKA group had higher median discharge GOS (4 vs. 3 respectively, p = 0.03), higher percentage of patients with good outcome (GOS 4–5, 66.7% vs. 40.2% respectively, p = 0.005), and higher rate of discharge to home or rehabilitation (p = 0.04).
Conclusions
We report anticoagulation-associated tICH outcomes predominantly due to fall-related subdural hematomas. Patients on DOACs had lower tICH expansion rates although not statistically significantly different from VKA-treated patients. DOAC-treated patients had favorable outcomes versus VKA group following tICH despite low use of reversal strategies. DOAC use may be a safer alternative to VKA in patients at risk of traumatic brain hemorrhage.
Similar content being viewed by others
References
Biondi-Zoccai G, Malavasi V, D’Ascenzo F, et al. Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. HSR Proc Intensive Care Cardiovasc Anesth. 2013;5(1):40–54.
Kwong JS, Lam YY, Yan BP, et al. Bleeding of new oral anticoagulants for stroke prevention in atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiovasc Drugs Ther. 2013;27(1):23–35.
Sardar P, Chatterjee S, Wu WC, et al. New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons. PLoS ONE. 2013;8(10):e77694.
Chatterjee S, Sardar P, Biondi-Zoccai G, et al. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol. 2013;70(12):1486–90.
Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128–39.
Rogers KC, Finks SW. A new option for reversing the anticoagulant effect of factor Xa inhibitors: andexanet alfa (ANDEXXA). Am J Med. 2019;132(1):38–41.
Joppa SA, Salciccioli J, Adamski J, et al. A practical review of the emerging direct anticoagulants, laboratory monitoring, and reversal agents. J Clin Med. 2018. https://doi.org/10.3390/jcm7020029
Martin AC, Le Bonniec B, Fischer AM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168(4):4228–33.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9.
Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102.
Kobayashi L, Barmparas G, Bosarge P, et al. Novel oral anticoagulants and trauma: the results of a prospective american association for the surgery of trauma multi-institutional trial. J Trauma Acute Care Surg. 2017;82(5):827–35.
Simonsen CZ, Steiner T, Tietze A, et al. Dabigatran-related intracerebral hemorrhage resulting in hematoma expansion. J Stroke Cerebrovasc Dis. 2014;23(2):e133–4.
Purrucker JC, Capper D, Behrens L, et al. Secondary hematoma expansion in intracerebral hemorrhage during rivaroxaban therapy. Am J Emerg Med. 2014;32(8):947 e3-5.
Wassef SN, Abel TJ, Grossbach A, et al. Traumatic intracranial hemorrhage in patients taking dabigatran: report of 3 cases and review of the literature. Neurosurgery. 2013;73(2):E368–73 (discussion E73-4).
Feeney JM, Neulander M, DiFiori M, et al. Direct oral anticoagulants compared with warfarin in patients with severe blunt trauma. Injury. 2017;48(1):47–50.
Riccardi A, Spinola B, Minuto P, et al. Intracranial complications after minor head injury (MHI) in patients taking vitamin K antagonists (VKA) or direct oral anticoagulants (DOACs). Am J Emerg Med. 2017;35(9):1317–9.
Ganetsky M, Lopez G, Coreanu T, et al. Risk of intracranial hemorrhage in ground-level fall with antiplatelet or anticoagulant agents. Acad Emerg Med. 2017;24(10):1258–66.
Scotti P, Seguin C, Lo BWY, et al. Antithrombotic agents and traumatic brain injury in the elderly population: hemorrhage patterns and outcomes. J Neurosurg. 2019;1:1–10.
Romero JM, Kelly HR, Delgado Almandoz JE, et al. Contrast extravasation on CT angiography predicts hematoma expansion and mortality in acute traumatic subdural hemorrhage. AJNR Am J Neuroradiol. 2013;34(8):1528–34.
Kleinman JT. Hillis AEJordan LC ABC/2: estimating intracerebral haemorrhage volume and total brain volume, and predicting outcome in children. Dev Med Child Neurol. 2011;53(3):281–4.
Zumkeller M, Behrmann R, Heissler HE, et al. Computed tomographic criteria and survival rate for patients with acute subdural hematoma. Neurosurgery. 1996;39(4):708–12 (discussion 12-3).
Klein AM, Howell K, Vogler J, et al. Rehabilitation outcome of unconscious traumatic brain injury patients. J Neurotrauma. 2013;30(17):1476–83.
Paiva WS, de Andrade AF, de Amorim RL, et al. The prognosis of the traumatic subarachnoid hemorrhage: a prospective report of 121 patients. Int Surg. 2010;95(2):172–6.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.
Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104.
Hankey GJ, Stevens SR, Piccini JP, et al. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke. 2014;45(5):1304–12.
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(2):222–5.
Hagii J, Tomita H, Metoki N, et al. Characteristics of intracerebral hemorrhage during rivaroxaban treatment: comparison with those during warfarin. Stroke. 2014;45(9):2805–7.
Di Minno G, Martinez J, McKean ML, et al. Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med. 1985;79(5):552–9.
Powers AY, Pinto MB, Aldridge AM, et al. Factors associated with the progression of conservatively managed acute traumatic subdural hemorrhage. J Crit Care. 2018;48:243–50.
Parra MW, Zucker L, Johnson ES, et al. Dabigatran bleed risk with closed head injuries: are we prepared? J Neurosurg. 2013;119(3):760–5.
Stollberger C, Finsterer J. Reservations against new oral anticoagulants after stroke and cerebral bleeding. J Neurol Sci. 2013;330(1–2):16–7.
Awad AJ, Walcott BP, Stapleton CJ, et al. Dabigatran, intracranial hemorrhage, and the neurosurgeon. Neurosurg Focus. 2013;34(5):E7.
Sheikh-Taha M Idarucizumab for Reversal of Dabigatran: Single-Center Real-World Experience. Am J Cardiovasc Drugs 2018.
Edwards G, Roman C, Jithoo R, et al. Use of Idarucizumab for dabigatran reversal: emergency department experience in two cases with subdural haematoma. Trauma Case Rep. 2018;13:46–9.
Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med. 2017;377(5):431–41.
Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–24.
Kleinow ME, Garwood CL, Clemente JL, et al. Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic. J Manag Care Pharm. 2011;17(7):523–30.
Gehrie E, Tormey C. Novel oral anticoagulants: efficacy, laboratory measurement, and approaches to emergent reversal. Arch Pathol Lab Med. 2015;139(5):687–92.
Siegal D, Lu G, Leeds JM, et al. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv. 2017;1(21):1827–38.
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(12):1131–41.
Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326–35.
Funding
Dr. Hanley was awarded significant research support through grant numbers 5U01NS062851 for Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III and for Minimally Invasive Surgery Plus r-tPA for Intracerebral Hemorrhage Evacuation (MISTIE) III 1U01NS080824. Dr. Ziai is supported by grants 5U01NS062851 and 1U01NS080824. Dr. Ziai reports personal fees from CR Bard, Inc. and Portola Pharmaceuticals, outside the submitted work.
Author information
Authors and Affiliations
Contributions
Each of the authors contributed uniquely to the preparation of this manuscript: SS was involved in imaging analysis, data collection, and manuscript preparation; EBM helped in editing and data interpretation; HA contributed to imaging analysis; PAN helped in editing and data interpretation; DFH and MD contributed to editing and data interpretation; WZ was involved in studying concept, statistical analysis, and data interpretation, and he is a senior author.
Corresponding author
Ethics declarations
Conflict of interest
Dr. Marsh reports sponsored research from the American Heart Association. Dr. Hanley reports sponsored research support from the NIH, and has consulted for BrainScope, Neurotrope, Portola, and Op2Lysis. Dr. Ziai reports sponsored research support from the NIH and has consulted for Bard, Inc. and Portola Pharmaceuticals.
Ethical Approval/Informed Consent
This retrospective study was approved by Johns Hopkins Institutional Review Board. As it was a retrospective data collection, no direct consent was obtained from individual patients.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Shin, S.S., Marsh, E.B., Ali, H. et al. Comparison of Traumatic Intracranial Hemorrhage Expansion and Outcomes Among Patients on Direct Oral Anticoagulants Versus Vitamin k Antagonists. Neurocrit Care 32, 407–418 (2020). https://doi.org/10.1007/s12028-019-00898-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12028-019-00898-y