Hrev_master Abstract The effects of Oral Anticoagulation Therapy (OAT) in older patients who suffered a mild Traumatic Brain Injury (mTBI) are widely debated but still strong guidelines are lacking and clinical approaches and management are sometimes heterogeneous. Different predictors of adverse outcomes were identified in the lit- erature but their use in the decision-making process is unclear. Moreover, there is no consensus on the appropriate length of stay in the Observation Unit nor on the continuation of OAT, even if the diagnosis of life-threatening delayed post-traumatic Intracranial Hemorrhage is rare. The recurrence of a control CT scan is often needless. This review aims to summarize recent scientific literature focusing on patients with mTBI taking OAT and to identify crucial questions on the topic to suggest a best clinical practice. Introduction Mild Traumatic Brain Injury (mTBI) in patients taking Oral Anticoagulation Therapy (OAT) represents an increasingly com- mon cause of presentation to the Emergency Department (ED), especially among older individuals. The median age of traumatic admission has risen over the years1 due to increased life expectan- cy. Low-energy falls are the most common mechanism of injury in the geriatric population.2 On the other hand, the use of OAT to pre- vent and treat thromboembolic complications of atrial fibrillation, deep venous thrombosis, valvular heart disease, and surgically placed cardiac valves is constantly growing.3,4 Although mTBI has a generally favorable prognosis,2,3 morbid- ity and mortality after falls appear to increase with age5 being asso- ciated with a higher risk of Intracranial Hemorrhage (ICH) and a higher mortality rate in patients on OAT.3,4,6-8 Whilst several guide- lines recommend discharging patients who are asymptomatic and stable and whose Glasgow Coma Scale (GCS) score is 15 after 24 hours of observations,9,10 difficulty in clinical decision-making often persists, since few randomized controlled trials have been performed in this setting, and bleeding risk predictors are not yet clearly identified. The purpose of this review is to analyze the recent scientific literature for assessing the state of art in the management of adult patients with mTBI taking OAT and giving clinical guidance for diagnosis and treatment to cover clinical questions from the patient’s admission to the Emergency Department (ED) discharge. Materials and Methods The target of this review is adult patients receiving OAT who suffer mTBI. Both treatments with Direct Oral Anticoagulants (DOACs) and Vitamin K Antagonists (VKAs) were considered. MTBI in defined as blunt head injury associated with a GCS score of 13-15. PubMed literature research was performed using the MeSH database with the searching tags [traumatic brain injury] and [anti- coagulants]. Studies were selected if the following inclusion crite- ria were met: i) cohort study of adult patients with mTBI; ii) pre- injury use of oral anticoagulation (DOACs vs/or VKAs cohorts); iii) reporting on pre-injury patient demography and comorbidity; iv) reporting on bleeding complications, treatment and outcomes; v) written in English. Emergency Care Journal 2022; volume 18:10640 Correspondence: Naria Park, Medicina d’Urgenza Universitaria Azienda Ospedaliera Universitaria Pisana, Pisa, Italy. Address:Via del Rio 273, 55054 Massarosa (Lucca, Italy) Tel.: +39.3475157599 E-mail: nariapark01@gmail.com Key words: Mild traumatic brain injury; oral anticoagulation therapy. Contributions: NP, GT, AZ, AC conceived the project. NP, GT, AZ, AC wrote the manuscript. All authors have read and approved the manu- script. Conflict of interest: The authors declare no conflict of interest. Availability of data and materials: All data generated or analyzed during this study are included in this published article. Ethics approval and consent to participate: Not applicable. Informed consent: Not applicable. Received for publication: 25 May 2022. Revision received: 14 June 2022. Accepted for publication: 14 June 2022. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2022 Licensee PAGEPress, Italy Emergency Care Journal 2022; 18:10640 doi:10.4081/ecj.2022.10640 Publisher's note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organiza- tions, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its man- ufacturer is not guaranteed or endorsed by the publisher. [Emergency Care Journal 2022; 18:10640] [page 37] The state of the art of the management of anticoagulated patients with mild traumatic brain injury in the Emergency Department Naria Park,1 Gianni Turcato,2 Arian Zaboli,2 Massimo Santini,3 Alessandro Cipriano3 1Medicina d’Urgenza Universitaria Azienda Ospedaliera Universitaria Pisana, Pisa; 2Dipartimento di Emergenza Ospedale di Merano, Merano; 3Medicina d’Urgenza e Pronto Soccorso Azienda Ospedaliera Universitaria Pisana, Pisa, Italy Non -co mmerc ial us e o nly For clarity and pragmatism, topical issues were addressed by answering the following questions: i) should all anticoagulated patients with mTBI undergo a head CT scan? ii) Which are the pos- sible predictors of ICH after mTBI? iii) Are DOACs safer than VKAs? iv) Should the head CT scan be repeated? We also selected some unsolved questions from the literature. Results Should all anticoagulated patients undergo a head CT scan? OAT is considered a risk factor for bleeding complications by several international guidelines (Table 1).9-13 For this reason, well- established clinical practice suggests performing a head CT scan in all anticoagulated patients with mTBI. Different clinical decision rules for deciding to perform cranial tomography in patients with head trauma exist.12,14,15 The Canadian CT Head Rule, which is very sensitive for the detection of intracranial pathologies requir- ing surgical intervention, indicates performing head CT imaging in all patients on OAT. However, it is notable that, although prior studies and meta- analyses demonstrated an association between traumatic ICH and anticoagulation or antiplatelet agents in patients with head trau- ma,16-19 some recent studies did not demonstrate such an associa- tion.20-24 In a retrospective cohort analysis of 2567 patients, Lampart et al. did not find a significant relationship between traumatic ICH and any anticoagulant/antiplatelet agents, although combination therapy was associated with an increase in hospital mortality.25 Similarly, Uccella et al. found that patients taking OAT with GCS 15 after blunt head trauma did not have a higher risk for intracranial hemorrhage than the general population.26 These new observations could be due to the different cohorts of patients. Indeed, when prior studies about TBI in OAT compre- hended a more heterogeneous casuistry concerning age and dynamics of trauma, recent literature is often focused on low ener- gy falls in older adults. Considering these heterogenous data we could conclude that anticoagulation with VKAs and DOACs are possible strong risk factors for post-traumatic ICH with a risk of complication of less than 15%27,28 depending on the type of anticoagulation. In the next future, the management of these patients could be based on clinical and trauma-related risk factors rather than anticoagulation therapy alone as proposed in some recent trials.22,29,30 Which are possible predictors of ICH after mTBI? A central issue of clinical management of such a growing pop- ulation is identifying the possible risk factors associated with adverse outcomes (neurosurgery, death, etc.), and providing a deci- sion-making instrument for clinical and radiological monitoring (Table 2). Some authors even suggest that these predictors could be use- ful to choose eventually for omitting routine CT head scanning, according to the low prevalence of traumatic ICH, particularly in patients treated with DOACs.27-29 Several prediction rules and guidelines for the detection of intracranial lesions and the necessity for neurosurgical intervention after mTBI in adults included items that have been examined for the specific case of anticoagulated subjects as well. The AHEAD multicenter observational study by Mason et al. showed that post-traumatic vomiting, amnesia, headache and loss of consciousness were associated with a greater risk of adverse outcomes in warfarin patients following mTBI.31 In a 6-year retrospective analysis, Riccardi et al. found a sig- nificant increased risk of post-traumatic intracranial bleeding in patients with loss of consciousness, headache, vomiting, or neuro- logical signs.19 Post-traumatic amnesia, evidence of trauma above the clavi- cles, high blood glucose, high blood pressure at arrival to the ED, and low prothrombin activity were predictors for ICH in patients suffering mTBI while OAT in a recent study by Cipriano et al.30 In a retrospective observational study above patients taking DOACs, Turcato et al.29 found that major dynamics, post-traumatic loss of consciousness, post-traumatic amnesia, GCS<15, post-trau- matic headache, and visible trauma above the clavicles were asso- Review [page 38] [Emergency Care Journal 2022; 18:10640] Table 1. Should all anticoagulated patients with mTBI undergo a Head CT scan? Evidence Y N Note GL EFNS guideline9 x Guidelines and Rules suggest performing a head CT scan in all patients treated with blood thinners within 8 hours of trauma GL NICE guideline10 x GL NEXUS II11 x CR CHIP prediction rule12 x CR Canadian CT Head Rule14 x CR New Orleans Criteria15 x RCS Jeffree et al.18 x SR Minhas et al.16 x RCS Riccardi et al.19 x RCS Lampart et al.25 ? No relationship between OAT and tICH risk RCS Uccella et al.26 ? Only patients with GCS 15 PCS Nishijima et al.21 ? No relationship between OAT and tICH risk RCS Alrajhi et al.24 ? Low bleeding risk in minimal (4.8%) vs minor (21.9%) head trauma in warfarinized patients PCS Kuczawski et al.23 x RCS Turcato et al.22 x In absence of predictors CR: clinical rule; GL: guideline; PCS: prospective cohort study; RCS: retrospective cohort study; SR: systematic review; CT: computed tomography; OAT: oral anticoagulation therapy; tICH: traumatic intracranial hemor- rhage; CGS: Glasgow Coma Scale; LOC: loss of consciousness. Non -co mmerc ial us e o nly ciated with a higher likelihood of ICH. Nishijima et al.21 recently conducted a prospective multicentric study where history of vomiting, evidence of trauma above the clavicles, or an abnormal GCS score are more predictive of trau- matic ICH than anticoagulant or antiplatelet use; mechanism of injury other than ground-fall and a history of loss of consciousness or amnesia were independent risk factors for the incidence of trau- matic ICH on initial cranial CT scan as well. In a recent trial, Turcato et al.22 proposed to collect these pre- dictors in a “decision tree analyses” in which data mining tech- niques allow the visualization of relationships between many vari- ables by defining explicit rules for their classification and their influence on the dependent variable. Despite this study having a retrospective observational design requiring to be confirmed in prospective trials, the hypothesis that the introduction of these techniques into clinical practice would reduce the number of CT scans for anticoagulated patients with mTBI is intriguing. Are DOACs safer than VKAs? In the last years, many authors focused on the comparison between direct anticoagulants and warfarin regarding their effec- tiveness in preventing thromboembolic illness and their respective hemorrhagic risk. Several studies demonstrated a safer profile of DOACs both in the setting of spontaneous and traumatic ICH (Table 3).27,29,30,32-40 A systematic review by Fuller et al. of seven observational studies estimates that the prevalence of adverse outcomes (death, intracranial hematoma, or neurosurgery) after mTBI in patients taking DOACs ranged from 0.0% to 8.3%.27 This value is almost half of the rate of traumatic ICH above patients in OAT with VKAs, as documented in several other studies.30,34,35,41,42 Further retrospective studies confirmed these data emphasizing the better safety profile compared to warfarin.42,43 Conversely, Zeeshan et al. found an increased risk of progres- sion, neurosurgical intervention and mortality among the DOAC cohort when compared to warfarin.44 However, falls caused only 42% of TBI while motor vehicle collisions accounted for a third of patients, leading to a lower GCS at admission. These differences make it difficult to compare Zeeshan’s study with others focused on blunt head trauma in the elderly. In conclusion, the evidence seems to sustain that DOACs are safer than VKAs, but it is also true that warfarin is sometimes the obvious choice for frail patients due to their comorbidities. To rule out the possibility of bias, further studies will be needed to confirm the better safety profile of DOACs even in patients with frailty. Should the head CT scan be repeated? The practice of routinely repeating head CT in anticoagulated patients within 24 hours after their first negative CT scan to assess for delayed ICH (dICH) has been widely shared in the past years and it is still currently applied in some countries.45 Nevertheless, a growing number of evidence suggests that the risk of developing a dICH is very low and when present did not require neurosurgical intervention (Table 4). The prevalence rate of dICH ranges between 1%- 4.5%.29,30,34,42,46-48 A similar incidence is described in the subgroup of patients treated with DOACs (0.95%-2.1%).49,50 In a recent publication by Soleimani et al., only 3 patients above 314 experienced a dICH and they have all been discharged in a week at most.51 The authors con- cluded that, in absence of concomitant antiplatelet medication, a confirming head CT scan after initial negative is not necessary. In a study published in 2019, Cohan et al. found that the inci- dence of dICH in patients on warfarin to those on DOACs was similar (2.6% vs 2.1%) and administration of reversal agents, neu- rosurgical interventions, or deaths never occurred.50 Even data from a 2020 publication by Savioli et al. are in line (3.2% vs 1.3%).42 Many more trials confirmed this evidence in the last peri- od.52-63 Anyway, comparison between the two categories of oral anticoagulants is hard due to the small number of patients suffering dICH observed. These data do not support routinely obtaining a repeat CT head after a negative initial CT scan since the risk of complications in asymptomatic anticoagulated head trauma patient is negligible when an initial CT scan is negative. In a recent study by Turcato et al.,22 patients without risk factors for bleeding were free from bad outcomes linked to trauma. However, the decision if and when to schedule the control imaging may be influenced by Review [Emergency Care Journal 2022; 18:10640] [page 39] Table 2. Which are possible predictors of ICH after mTBI? In this table, items considered by most used prediction rules (CHIP prediction tule, Canadian CT Head rule, New Orleans Head CT rule) are shown by colored boxes. In lines below, “*” indicates those predictors of tICH for the authors. GCS: Glasgow Come Scale; EAC: evidence of trauma above clavicles; Sk F: skull fractures; PTA: post-traumatic amnesia; MT: major trauma; Vom: vomiting; PTS: posttraumatic seizures; LOC: (post- traumatic) loss of consciousness; Nrl D: neurologic disabilities; HA: (post-traumatic) headache; Glc: elevated blood glucose at arrival; BP: elevated blood pressure at arrival. Non -co mmerc ial us e o nly the findings of the initial CT, underlying risk factors, and the evo- lution of neurological examination. Unsolved questions How long patient’s neurological state should be monitored? Due to the possibility of developing dICH in anticoagulated mTBI patients with normal initial neurological examination and negative head CT scan, clinical observation for at least 24 hours after the traumatic event is recommended.52,59,64 However, as already commented, many authors report that diagnoses of ICH in control head CT are rare and rarely require neurosurgical interven- tion. At the time of discharge, it is essential to provide mTBI patients with an information sheet on what to do at home and which are the red flags for coming to medical attention. Interestingly, some studies indicate that household observation is effective as the CT in presence of a caregiver and a patient able to understand home instruction.42,65 These data, along with the very small incidence of dICH, suggest that routinely performing control CT scan in not indicated nor cost-effective and new models of shorter observation should be designed.66 Considering the lack of strong evidence supporting the risk of delayed complication in the first 24 hours and some trials reporting the absence (0%) of adverse events in that short period,22,30 a short- er period of observation, such as 6 hours, after a negative head CT scan performed at least 2-6 hour far from the trauma could be rea- sonable. This observational period together with clear patients’ home information seems to be the best choice in terms of safety and cost-effectiveness. When and how long to discontinue OAT after mTBI? Considering risk/benefit balance, it is widely shared that patients without hemorrhagic complications after head trauma will continue to take OAT, as previously indicated. Conversely, the choice to switch oral anticoagulant to subcutaneous antithrombotic prophylaxis, despite being frequently adopted, is without strong evidence-based experiences and is still debated, especially in those subjects with minimal lesions at CT scan. This group of patients has good outcomes and rarely needs surgery. Therefore, switching to Low-Molecular Wight Heparin (LMWH) does not give any ben- efit in patients premedicated with DOACs since it has a similar duration of action but less evidence of safety and efficacy. Finally, clear indications about the timing to restart OAT are lacking and the incidence of thromboembolic adverse events, while anticoagu- lation is discontinued, is not clearly described in the literature. Review Table 3. Are DOACs safer than VKAs? Evidence Y N Note SR Fuller et al.27 x PCS Cipriano et al.40 x RCS Prexl et al.35 x RCS Spinola et al.34 x RCS Savioli et al.42 x PCS Zeeshan et al.44 x All TBI; 1/3 motor vehicle crush, only 42% ground falls PCS Wilson et al.41 x PCS: prospective cohort study; RCS: retrospective cohort study; SR: systematic review; TBI: traumatic brain injury Table 4. Should the head CT scan be repeated? Evidence Y N Note RCS Reynolds et al.45 x PCS Kaen et al.46 x Control CT scan NOT indicated if normal neurological exam and in absence of symptoms onset RCS Peck et al.52 x PCS Nishijima et al.53 x SR Cohn et al.54 x RCS McCammack et al.61 x SR Chauny et al.55 x RCS Uccella et al.56 x RCS Lim et al.57 x RCS Campiglio et al.58 x PCS Huang et al.62 x RCS Verschoof et al.59 x RCS Barmparas et al.49 x RCS Afaneh et al.60 x RCS Mann et al.48 x PCS Cipriano et al.30 x RCS Mourad et al.47 x RCS Turcato et al.22 x RCS Cohan et al.50 x RCS Soleimani et al.51 x SR Hickey et al.63 x PCS: prospective cohort study; RCS: retrospective cohort study; SR: systematic review; CT: computed tomography. [page 40] [Emergency Care Journal 2022; 18:10640] Non -co mmerc ial us e o nly Discussion This review aims to collect recent data on patients suffering mTBI while treated with OAT and to suggest a shared model of their clinical management. Our proposal is shown in Figure 1. Due to the increasing life expectancy, ground-falls in older people are the most common phenotype in this setting. Considering mTBI in the elderly, GCS deserves a particular focus. In fact, despite several authors emphasizing the worse outcome for patients presenting to the ED with GCS less than 15, older patients with traumatic ICH are reported to have higher GCS level com- pared with younger patients with equivalent injury.67 Moreover, GCS variation from baseline can be uncertain and slow, and even determining the baseline condition can be difficult in patients with dementia. Recently, new scores for the evaluation of older adults after head trauma such as eTBI68 have been proposed. Certain aspects related to trauma such as amnesia, lesions above the clavicles or different dynamics from ground level falls seem to correlate with major risk to develop hemorrhagic compli- cations; further studies will assess if other significant clinical pre- dictors exist. Strong recommendations for clinical management of anticoag- ulated patients with blunt trauma after an initial negative head CT scan are still lacking. If the avoidance of a second CT scan in those patients with normal neurological exam and without symptoms is well established in clinical practice, it is not clear how long the observation period should last but a 6 hours period seems safe. Although rare, dICH can occur several days after trauma. Therefore, the best cost-effective approach seems to be an ultra- short period in Observation Unit, then providing patients and care- givers with clear indications for household monitoring for the next month. Conclusions Patients in OAT suffering a TBI require an initial head CT scan to evaluate the presence of traumatic ICH. DOACs have a better safety profile compared to VKAs. Post- traumatic amnesia, evidence of trauma above the clavicles, major dynamics, post-traumatic loss of consciousness, and GCS<15 are the strongest risk factors for t-ICH. Delayed ICH is rare and repeating a head CT exam is not indi- cated unless evolution of the neurological state. For those patients with GCS 15, minor trauma dynamic (e.g., ground falls) and in absence of risk factors a short period of clinical–or even household when possible–observation is recommended. The present review collects expert opinions in the field of MTBI and OAT. At the same time, we have reviewed the best sci- entific literature available on this topic, these scientific papers are not all of excellent quality but they are what we currently have available. The main limitation of the study is the potential selection bias. In the next future, randomized controlled trials are required to give strong recommendations in this setting. References 1. Gelbard R, Inaba K, Okoye OT, et al. 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