Trauma Surg Acute Care Open: first published as 10.1136/tsaco-2020-000605 on 3 December 2020. Downloaded from Open access Review Restarting and timing of oral anticoagulation after traumatic intracranial hemorrhage: a review and summary of ongoing and planned prospective randomized clinical trials Ben King ,1 Truman Milling,2 Byron Gajewski,3 Todd W Costantini,4 Jo Wick,3 Michelle A Price ,5 Dinesh Mudaranthakam,3 Deborah M Stein,6 Stuart Connolly,7 Alex Valadka,8 Steven Warach9 1College of Medicine, SUMMARY cease or reverse anticoagulation to stabilize the Department of Health Systems Anticoagulant- associated traumatic intracranial patient. At some time point, most patients with and Population Health Sciences, University of Houston, Houston, hemorrhage (tICrH) is a devastating injury with high tICrH return to a state which again favors antico- Texas, USA morbidity and mortality. For survivors, treating clinicians agulation. A survey of neurosurgeons found nearly 2Seton Dell Medical School face the dilemma of restarting oral anticoagulation half encounter the tICrH restart question once a Stroke Institute, Ascension with scarce evidence to guide them. Thromboembolic week or more.4 There is already broad consensus Seton, Austin, Texas, USA 3 4 3 risk is high from the bleeding event, patients’ high that most patients with tICrH should be restarted. Department of Biostatistics 3 4 and Data Science, University of baseline risks, that is, the pre- existing indication for The unanswered question is when. In the absence Kansas Medical Center, Kansas anticoagulation, and the risk of immobility after the of randomized trials and a definitive time target, City, Kansas, USA bleeding episode. This must be balanced with potentially restart practice in tICrH is highly variable—from 4 Division of Trauma, Surgical devastating hematoma expansion or new hemorrhagic 3 days to several months to never.5 Cumulative Critical Care, Burns and Acute Care Surgery, UC San Diego lesions. Retrospective evidence and expert opinion thromboembolic risk rises with time and is a combi- Health, San Diego, California, support restarting oral anticoagulants in most patients nation of baseline risk, the bleeding episode itself, USA with tICrH, but timing is uncertain. Researchers have any reversal agents used and immobility afterwards. copyright. 5Coalition for National Trauma failed to make clear distinctions between tICrH and Rebleeding risk is high early when clots are forming Research, San Antonio, Texas, spontaneous intracranial hemorrhage (sICrH), which have and stabilizing and falls with increasing time (see USA 6Department of Surgery, differing natural histories. While both appear to benefit figure 1), eventually to a baseline, which may be University of California- San from restarting, sICrH has a higher rebleeding risk and informed/adjusted by the type of index bleeding Francisco, School of Medicine, similar or lower thrombotic risk. Clinical equipoise episode for any additional rebleeding risk. Impor- San Francisco, California, USA on restarting is also divergent. In sICrH, equipoise is tantly, ICrH is at least two diseases with different 7Population Health Research Institute, McMaster University, centered on whether to restart. In tICrH, it is centered on natural histories. Spontaneous intracerebral hemor- Hamilton, Ontario, Canada when. Several prospective randomized clinical trials are rhage (sICH), such as lobar ICH with cerebral 8Department of Neurosurgery, ongoing or about to start to examine the risk–benefit of amyloid angiopathy, may heighten the patient’s risk Virginia Commonwealth restarting. Most of them are restricted to patients with for recurrent bleeding and alter the baseline risk– University, Richmond, Virginia, sICrH, with antiplatelet control groups. Most are also benefit for anticoagulation.6 In contradistinction, USA http://tsaco.bmj.com/ 9Department of Neurology, The restricted to direct oral anticoagulants (DOACs), as they after tICrH, the index hemorrhage is less likely to University of Texas at Austin are associated with a lower overall risk of ICrH. There is affect the patient’s baseline bleeding risk.7 Several Dell Medical School, Austin, some overlap with tICrH via subdural hematoma, and trials are in planning or actively enrolling to address Texas, USA one trial is specific to restart timing with DOACs in only anticoagulation restart and restart timing ques- traumatic cases. This is a narrative review of the current tions. Numerous retrospective cohorts have found Correspondence to evidence for restarting anticoagulation and restart timing benefit with minimal increased risk of recurrent Dr Ben King; kingb@ uh. edu after tICrH along with a summary of the ongoing and hemorrhage in patients with restarted tICrH.5 7–11 Received 2 October 2020 planned clinical trials. This narrative review summarizes the retrospective on September 24, 2021 by guest. Protected Revised 18 November 2020 evidence for restart and timing of restart of oral Accepted 19 November 2020 anticoagulants after tICrH, the guidelines and the prospective trials on this topic. BACKGROUND US trauma centers care for >18 000 anticoagulated traumatic intracranial hemorrhages (tICrHs) per METHODS © Author(s) (or their year,1 although this likely understates the disease The evidence for this review was obtained through employer(s)) 2020. Re- use permitted under CC BY-NC . No scope as many tICrH cases are cared for in non- searches of PubMed between January 1, 2010 and commercial re-use . See rights trauma centers.2 Failure to restart anticoagulation in January 1, 2020, supplemented with a review using and permissions. Published tICrH survivors contributes to an enormous throm- Google Scholar (Alphabet). The systematic search by BMJ. boembolic burden in strokes, venous thromboem- excluded evidence from prior to 2010 because 3–5 To cite: King B, Milling T, bolism (VTE) and other events. The risk–benefit this evidence would focus almost exclusively on Gajewski B, et al. Trauma in the naïve state usually favors anticoagulation by treatment and reversal with vitamin K antagonist Surg Acute Care Open an order of magnitude, but this relationship shifts (VKA) treatment. The searches were conducted 2020;5:e000605. once ICrH has occurred,3 5 when clinicians must using the structured search terms: traumatic AND King B, et al. Trauma Surg Acute Care Open 2020;5:e000605. doi:10.1136/tsaco-2020-000605 1 Trauma Surg Acute Care Open: first published as 10.1136/tsaco-2020-000605 on 3 December 2020. Downloaded from Open access Figure 1 Conceptual representation of stratified results of secondary Figure 2 Overall response from survey participants on timing of oral 4 risks of restarting anticoagulation following a bleeding event, over time anticoagulant re- initiation across 11 clinical scenarios. Reproduced 4 to restart. AC: anticoagulation. with open access from Xu et al. 2018 Public Library of Science under CC BY 4.0. DOAC, direct oral anticoagulant; HTN, hypertension; ICH, intracerebral hemorrhage; IPH, intraparenchymal hemorrhage. (intracranial OR intracerebral) AND hemorrhage OR “traumatic brain injury” AND anticoagulation within all available search- able fields. longer) in central nervous system hemorrhage.3 The differing Titles and abstracts were reviewed for inclusion in the review equipoise in sICrH and tICrH is illustrated in the prospective based on relevance to the central research questions. Included trial designs (see ‘Prospective randomized trials’ section for articles addressed anticoagulation- associated ICrH presenta- details). The one tICrH trial is focused on timing of restart tions and treated the question of treatment reinitiation within without a non- anticoagulated control, while the several sICrH the results reported in the abstract. The review excluded search trials all have a control group. results that did not address the principle questions in this review, addressed conditions other than ICrH without stratified analysis Clinical guidelines of this condition, did not consider anticoagulation or exclusively Current trauma guidelines do not address the use of antico- considered antiplatelet treatments or did not evaluate treatment agulant treatment after ICrH. The 2014 update to the Amer- reinitiation (either decision or timing). The review excluded case ican Heart Association/American Stroke Association guidelines studies, series, and qualitative research studies as well. for stroke prevention in stroke and temporary ischemic attack In addition, PubMed and Google Scholar were searched for includes a special section on the use of antithrombotic therapy clinical guidelines relevant to the clinical topic. This search was after ICrH.13 These guidelines clearly demonstrate shortcomings conducted using the structured search terms: “guidelines”[Title] of the available evidence as they endorse individualized assess- copyright. AND (“intracranial hemorrhage” OR “intracerebral hemor- ment of the restart decision. To this end, they advise consid- rhage” OR “traumatic brain injury”). Guidelines obtained were eration of the risks of subsequent thromboembolism, recurrent reviewed to confirm that they represented national or inter- ICrH and overall ‘patient status’. It subsequently suggests that national experts and that the committees were represented by cases with higher risk of recurrent ICH relative to cerebral appropriate professional organizations. Trials were identified infarction may consider antiplatelet therapy instead of antico- at international meetings