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Can Anticoagulated Patients be Discharged Home Safely from the Emergency Department after Minor Head Injury?
The Journal of Emergency Medicine, Vol. 46, No. 3, pp. 410–417, 2014 Copyright Ó 2014 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2013.08.107
Evidence Based Medicine CAN ANTICOAGULATED PATIENTS BE DISCHARGED HOME SAFELY FROM THE EMERGENCY DEPARTMENT AFTER MINOR HEAD INJURY? Brian Cohn, MD,* Samuel M. Keim, MD, MS,† and Arthur B. Sanders, MD, MHA† *Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri and †Department of Emergency Medicine, University of Arizona College of Medicine, Phoenix, Arizona Reprint Address: Samuel M. Keim, MD, MS, Department of Emergency Medicine, University of Arizona College of Medicine, P.O. Box 245057, Tucson, AZ 85724-5057
, Abstract—Background: Anticoagulated patients have increased risk for bleeding, and serious outcomes could occur after head injury. Controversy exists regarding the utility of head computed tomography (CT) in allowing safe discharge dispositions for anticoagulated patients suffering minor head injury. Clinical Question: What is the risk of delayed intracranial hemorrhage in anticoagulated patients with minor head injury and a normal initial head CT scan? Evidence Review: Four observational studies were reviewed that investigated the outcomes of anticoagulated patients who presented after minor head injury. Results: Overall incidence of death or neurosurgical intervention ranged from 0 to 1.1% among the patients investigated. The studies did not clarify which patients were at highest risk. Conclusion: The literature does not support mandatory admission for all anticoagulated patients after minor head injury, but further studies are needed to identify the higher-risk patients for delayed bleeding to determine appropriate management. Ó 2014 Elsevier Inc. , Keywords—head imaging; prognosis
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ing height. He struck his forehead on the concrete but suffered no loss of consciousness (LOC). He has a mild headache, has had no nausea or vomiting, and his wife states that he has had no altered mental status since the fall. On examination, he has a Glasgow Coma Scale (GCS) score of 15, a superficial abrasion to his forehead, no cervical spine pain or tenderness, and a normal neurologic examination. His international normalized ratio (INR) is 2.8. His head computed tomography (CT) scan is normal. After updating the patient’s tetanus immunization, you discharge him home in the care of his wife. That night after your shift you recall that in Italy, standard of care in patients with head injury on anticoagulation is 24 h of observation followed by a repeat CT scan. You consider the efficacy of such a protocol, and begin asking yourself about the patient’s risk of delayed intracranial hemorrhage (ICH). CLINICAL QUESTION
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What is the risk of delayed ICH in anticoagulated patients with minor head injury and a normal initial head CT scan? CASE REPORT CONTEXT A 68-year-old man with a history of atrial fibrillation, for which he takes warfarin for anticoagulation, presents to your Emergency Department (ED) after a fall from stand-
Traumatic brain injury results in just over 1.3 million ED visits, 275,000 hospitalizations, and 52,000 deaths
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annually in the United States (US) alone, with an increase in ED visits and hospitalization of 14.4% and 19.5%, respectively, from 2002 to 2006 (1). In elderly patients suffering a fall, long-term anticoagulation has been shown to increase not only the incidence of ICH compared to those not on anticoagulation (8.0% vs. 5.3%, p < 0.0001), but to also increase mortality in those with ICH (21.9% vs. 15.2%, p = 0.04) (2). Additionally, the use of warfarin prior to blunt head trauma has been shown to increase mortality compared to those not taking anticoagulants, with an odds ratio of 2.008 (95% confidence interval [CI] 1.634–2.467) (3). Unfortunately, the rate of preinjury warfarin use has been increasing in trauma patients in the US, from 2.3% in 2002 to 4.0% in 2006 (p < 0.001); in patients older than 65 years, use increased from 7.3% in 2002 to 12.8% in 2006 (p < 0.001) (4). Patients older than 65 years account for approximately 10% of ED visits and 30% of admissions for traumatic brain injury (5). The projected growth of our elderly population will likely lead to a significant increase in the number of ED visits for head injury from this group of patients (6). Given the increasing number of head injury patients seen in the ED, and the increase in concomitant anticoagulant use, the clinical dilemmas surrounding these patients have become more and more relevant. Although clinical decision rules such as the Canadian CT Head Rule, the New Orleans criteria, and the NEXUS-II criteria exist to help determine which head injury patients require a head CT scan, these rules do not apply to anticoagulated patients (7–9). Studies in patients taking warfarin who suffer minor head injury have shown incidences of ICH ranging from 6.2% to 29%, leading some authors to conclude that most, if not all, such patients should undergo routine cranial CT scanning on presentation (8,10–14). One important question surrounds the prognostic implications of a normal cranial CT scan in head injury patients on anticoagulant therapy. Although some European guidelines suggest that all anticoagulated patients with head injury should be admitted for a period of routine observation, these recommendations are not based on studies of the prevalence of delayed ICH (15,16). The question remains whether a period of observation or routine serial CT scanning is warranted in such patients.
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EVIDENCE REVIEW The Value of Sequential Computed Tomography Scanning in Anticoagulated Patients Suffering from Minor Head Injury (17) Population. The study population was patients presenting to Hospital 12 de Octubre in Madrid, Spain within 48 h of minor head injury on anticoagulant therapy. A total of 137 patients presented during the study period, mean age 76 years, 33% men, with a median interval from trauma to CT scan of 3.2 h. Study design. This was a prospective observational study performed from October 2005 to December 2006. Patients with a negative initial CT scan were admitted for 24 h of observation, with serial neurologic examinations performed every 4–6 h. A control CT scan was performed 20–24 h after the initial scan. Demographic data and subsequent examination data were obtained by neurosurgical residents. CT scans were interpreted by radiology or neurosurgery staff. Findings on control CT scans were compared to the initial CT scan and classified as unchanged or worsened (defined as the presence of any sign of ICH). Primary outcome. Incidence of ICH on control CT scan. Inclusion criteria. Patients aged older than 16 years, suffering head injury within 48 h of presentation, with GCS score of 14–15, currently treated with heparin or warfarin, with a normal initial CT scan, were included. Main results.The mean INR was 3.8, and the median time to control CT scan was 20 h. Delayed ICH was observed in 2 of 137 patients, for an incidence of 1.5% (95% CI 0.4–5%); both of these were among the 3 patients in the study who were also on an antiplatelet agent and were among the 10% with LOC. No patients required change in management based on control CT scan findings (0%; 95% CI 0–3%). The difference in incidence of bleeding between patients with and without concomitant antiplatelet use was statistically significant (absolute risk reduction [ARR] 67%; p = 0.01) as was the difference between patients with and without LOC (ARR 14%; p = 0.004).
EVIDENCE SEARCH Using PUBMED, a search strategy of ‘‘warfarin’’ OR ‘‘Coumadin’’ OR ‘‘anticoagulation’’ AND ‘‘trauma’’ AND ‘‘intracranial hemorrhage’’ was entered on September 12, 2012, resulting in 279 articles. This strategy identifies four articles relevant to the clinical question. The bibliographies of the selected articles were reviewed but revealed no further relevant articles.
Delayed Intracranial Hemorrhage after Blunt Trauma: Are Patients on Preinjury Anticoagulants and Prescription Antiplatelet Agents at Risk? (18) Population. The study population was patients presenting to Scripps Mercy Hospital in San Diego, CA, a Level I trauma center, suffering head injury while taking anticoagulant of antiplatelet agents. Five hundred patients
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qualified for the study, of whom 424 (85%) had a negative initial head CT scan. The average age was 75.0 years; 49.5% were male, 289 (68.2%) were taking warfarin, 103 (24.3%) were on clopidogrel, 7 (1.7%) were taking ‘‘other’’ anticoagulant or antiplatelet agents, and 25 (5.9%) were taking a combination of agents. Study design. This was a retrospective chart review of patients presenting between January 1, 2006 and August 31, 2009. Patients with a negative initial CT scan were admitted for 6 h of observation, followed by repeat CT scan. Medical records were reviewed for age, gender, injury mechanism, history of LOC, Injury Severity Score (ISS), head Abbreviated Injury Scale, admission GCS score, length of hospital stay, intensive care unit length of stay, and neurologic deterioration during observation (Table 1). Head CT results were classified as positive if they demonstrated any ICH (subarachnoid hemorrhage, intraparenchymal hemorrhage, parenchymal contusion, subdural hematoma, or epidural hematoma). Any equivocal study was considered positive. All positive repeat head CT scans were reviewed by a radiologist experienced in trauma radiology who was blinded to the imaging results and clinical details. Review of the hospital trauma registry and inquiry of the San Diego County Medical Audit Committee were undertaken to identify patients with unexpected deterioration or readmission after discharge. Primary outcome. Primary outcome was the incidence of ICH on repeat CT scan. Inclusion criteria. Patients aged $ 15 years with blunt mechanism of injury and preinjury use of an anticoagulant or antiplatelet agent (warfarin, clopidogrel, heparin, enoxaparin, or dipyridamole and aspirin in combination) were included. Aspirin use alone was not sufficient for inclusion. Patients taking warfarin with INR < 1.3 were excluded.
Table 1. Injury Severity Score (ISS) Region
AIS Score
AIS Meaning
Head, neck, and cervical spine Face Thorax, thoracic spine, diaphragm Abdomen and lumbar spine Extremities including pelvis External soft tissue injury
1 2 3 4 5 6
Minor Moderate Serious Severe Critical Unsurvivable
AIS = Abbreviated Injury Scale. Injury Severity Score is calculated by the sum of the squares of the three highest scores. The ISS takes a value of 75 if any system receives an AIS score of 6.
Main results. Of 424 patients enrolled with negative initial CT scan, 62 (14.6%) refused the second CT. There were four (1%; 95% CI 0.4–2.4%) positive repeat CT scans in patients with normal initial CT scan. Of 289 patients on warfarin, there were four (1.4%; 95% CI 0.5–3.5%) positive repeat CT scans (representing all positive cases). None of these patients (0%; 95% CI 0–1%) required neurosurgical intervention. No patients who had a change in mental status after the first CT had an ICH on the second CT. Management of Minor Head Injury in Patients Receiving Oral Anticoagulant Therapy: a Prospective Study of a 24-H Observation Protocol (19) Population. The study population comprised patients presenting to Academic Hospital, a Level II trauma center in Ancona, Italy, suffering minor head injury while receiving warfarin therapy for at least 1 week. There were 116 patients identified, of whom 97 (84%) had an initial negative CT scan. Ten of these patients later refused a second CT scan and were excluded from analysis. For the 87 remaining patients, median age was 82 years and 37% were male. Study design. This was a prospective case series conducted between January 2007 and March 2010. Patients meeting inclusion criteria with a negative initial head CT scan were admitted to an ED observation unit for 24 h, followed by a repeat head CT scan. All CT scans were interpreted by staff neuroradiologists. A CT scan was considered positive if any of the following were present: subdural, epidural, or parenchymal hematoma; subarachnoid hemorrhage, cerebral contusion; or depressed skull fracture. During the period of observation, patients received neurologic evaluation every 4–6 h. Treating emergency physicians used a specialized data collection form to document inclusion/exclusion criteria, demographics, GCS score, mechanism of injury, sensory or motor deficits, indication for anticoagulation, INR, and concomitant antiplatelet therapy. The medical records were reviewed by two investigators for the presence or absence of: acute traumatic intracranial lesion on the repeat CT scan, death, admission for any CT abnormality, operative neurosurgery, or readmission within 30 days. Primary outcome. Primary outcome was the incidence of ICH on repeat CT scan. Also considered was neurologic deterioration during observation and need for neurosurgical intervention. Inclusion criteria. Patients aged $ 14 years with minor head injury, a GCS score of 14–15, and an ISS < 15, presenting within 48 h of injury, on anticoagulant therapy with warfarin for at least 1 week.
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Main results. Of 97 patients enrolled with a normal initial CT scan, 10 refused the second CT scan, leaving 87 patients in the analysis. Of these, 5 (6%; 95% CI 1– 11%) patients had ICH noted on the repeat CT scan. Only 1 (1%; 95% CI 0.2–6.2%) of these patients required neurosurgical intervention. Two (2%; 95% CI 0.5–5%) additional patients with subdural hematoma were identified in follow-up. The greatest predictor of delayed ICH was an INR $ 3 (relative risk = 14; 95% CI 4–49). Immediate and Delayed Traumatic Intracranial Hemorrhage in Patients with Head Trauma and Preinjury Warfarin or Clopidogrel Use (20) Population. The population comprised patients in the ED at one of two trauma centers or four community hospitals in Northern California with blunt head trauma while taking warfarin or clopidogrel. There were 1064 eligible patients with an average age of 75.4 years, of whom 47.1% were male. Ground-level fall accounted for 83.3% of injuries. Of 1000 eligible patients who underwent an initial CT scan, 930 had no ICH. Of these, 687 (74%) were on warfarin and 243 (26%) were on clopidogrel. Study design. This was a prospective, observational, multicenter study performed between April 2009 and January 2011. Using a standardized data form, treating ED faculty recorded patient history, injury mechanism, clinical examination, and GCS score prior to initial head CT scan, which was obtained at the discretion of the treating physician. Immediate ICH was defined as the presence of any ICH or contusion. Delayed ICH was defined as ICH on CT scan occurring within 14 days of the initial, normal CT scan in the absence of repeated trauma. All head CT scans were interpreted by faculty radiologists. Neurosurgical intervention was defined as use of intracranial pressure monitor or brain tissue oxygen probe, placement of a burr hole, craniotomy, craniectomy, intraventricular catheter or subdural drain, or the use of mannitol or hypertonic saline. Delayed ICH was assessed by electronic medical record review in the case of patients admitted for at least 14 days, or standardized telephone survey at least 14 days after the ED visit for all others. Primary outcome. The primary outcomes were the incidence of immediate and delayed ICH in patients receiving warfarin or clopidogrel suffering minor head injury. Inclusion criteria. Patients aged $ 18 years presenting with blunt head trauma and warfarin or clopidogrel use within the previous 7 days were included. Patients were excluded if they were transferred from other facilities or if they were taking both warfarin and clopidogrel.
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Main results. The prevalence of immediate ICH in patients taking clopidogrel and warfarin was 12.0% (95% CI 8.4–16.4%) and 5.1% (95% CI 3.6–7.0%), respectively. The relative risk of clopidogrel compared to warfarin was 2.31 (95% CI 1.48–3.63). Delayed ICH was identified in 0 (0%; 95% CI 0–1.5%) patients receiving clopidogrel and 4 (0.6%; 95% CI 0.2–1.5%) patients receiving warfarin. Of the 4 patients with delayed ICH, 2 died and 2 required no neurosurgical intervention. In patients on warfarin, ICH requiring neurosurgical intervention occurred in 2 (0.3%; 95% CI 0.1–1.1%) patients. Most immediate ICH had GCS 15 (64%) and a few had no LOC (11% warfarin, 18% clopidogrel). The raw agreement for individual predictor variables was good (87–100% agreement), but no kappa values were reported. CONCLUSION In the four studies reviewed, the incidence of delayed ICH after normal CT scan ranged from 0.6% to 6%. However, if a diagnosed ICH has no effect on the patient’s outcome or treatment, then it would be considered a surrogate outcome, which is often used as a substitute for a clinically meaningful end point that measures directly how a patient feels, functions, or survives (21,22). As such outcomes are often found to be clinically insignificant, their use has been questioned in the literature, and the incidence of patient important outcomes should be considered instead (Table 2) (23). In these studies, the majority of patients found to have delayed ICH required no neurosurgical intervention and had no adverse outcome documented. The incidence of death or neurosurgical intervention ranged from 0 to 1.1%. The authors of one of the articles suggest that ‘‘our data support the general effectiveness of the European Federation of Neurological Societies’ recommendations for 24-hour observation followed by a repeated head CT scan for anticoagulated patients with a minor head injury’’ (19). However, this conclusion is based on the incidence of delayed ICH (6%) rather than the incidence of clinically important outcomes (1.1%). In this study, only one patient out of 87 suffered clinically significant delayed ICH. It is mentioned in the study that one patient showed signs of neurologic deterioration, however, they do not say if this was the same patient who required neurosurgical intervention. If so, this would suggest that observation alone would suffice to detect any clinically significant delayed ICH. Additionally, the authors do not perform a costeffectiveness analysis to support their conclusion. In a subsequent editorial appearing in the same journal, it is suggested that a protocol of 24-h observation and routine repeat CT scanning would cost an average of just over $1
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Table 2. Evidence-Based Medicine Teaching Points Case Series A study that reports a consecutive collection of patients with the same or very similar condition, for example, patients with minor head injury while receiving anticoagulation. Problems associated with this study design include potential for selection bias and lack of a comparison or control group. No causal linkage can therefore be assumed between risk factors and outcomes. Confidence Interval (CI) The CI is an indicator of the precision of a study result or estimate. It is a range between two values within which it is probable that the true value lies for the whole population of patients from which the study patients were selected. With a 95% CI, the true value can be expected to be within that interval with 95% confidence. Patient-important Outcomes Not all outcomes reported in the medical literature are meaningful to actual patient care, nor to patients themselves. Outcomes that patients value directly are typically outcomes that should also be important to clinical practice. Frequently, physicians value physiologic outcomes that may not be clearly associated with increasing length or quality of life. Prospective Cohort The cohort study is typically a prospective investigation of a key outcome in a group of individuals who do not have the outcome in which some have a known risk factor compared to others that do not have the exposure. Both groups are followed to compare the incidence of the outcome of interest. The prospective cohort design is the preferred method for investigating prognosis and relative risk. A retrospective cohort might start by identifying a group of individuals with the disease in question, and the investigators study a medical record database, for example, trauma registry, for the group-specific risk factors or outcomes. For example, anticoagulated patients with minor head injury and an initial negative head computed tomography scan are investigated for deterioration after admission. These studies are known to be susceptible to problems such as selection and information bias. Risk There are several standard measures used in the medical literature to explicitly define risk. The value of the measure is linked to the quality of the study design that created it. As mentioned above, the prospective cohort design is the strongest design. It therefore produces the strongest measure, relative risk (RR). The odds ratio (OR) is an estimate of the RR and typically is produced by retrospective designs, for example, case control studies. Descriptive statistics, such as frequency of occurrence, are not nearly as strong as the RR and OR in describing risk.
million per patient saved (24). The author of the editorial suggests that home observation and telephone call follow-up would be more cost-effective, and likely as safe, though this has not been studied. One difficulty in studies of prognosis involves homogeneity. It would be unfair to say that all head injury patients on warfarin carry the same risk for delayed ICH. There are many risk factors that need to be considered, and a one-size-fits-all approach may not be warranted. A prior study on warfarin use in head trauma showed that the degree of anticoagulation was predictive of risk of ICH, rather than the use of warfarin alone, with an odds ratio of 2.59 in patients with an INR $ 2.0 (25). Another retrospective study of 1493 patients admitted for traumatic brain injury with preinjury warfarin use showed that both the risk of ICH and mortality were increased with higher INR (26). Whether this association can be applied to the risk of delayed ICH remains to be shown, however, one of the articles reviewed here suggests an increased risk in patients with an INR $ 3 (relative risk = 14; 95% CI 4–49) (19). An additional prognostic factor to consider is concomitant antiplatelet therapy. The risk of major bleeding is known to increase for those on combined anticoagulant– antiplatelet therapy, with hazard ratios of 1.83 (95% CI 1.72–1.96) and 3.08 (95% CI 2.32–3.91) for combined warfarin–aspirin and warfarin–clopidogrel use, respectively, compared to warfarin therapy alone (27). It seems reasonable to assume that combined therapy would lead to increased rates of both initial and delayed ICH in head injury patients, and in one of the studies that identi-
fied 2 patients with delayed ICH, both were taking aspirin in addition to warfarin (17). Concomitant antiplatelet therapy in three of the studies ranged from 0 to 5.9%, and the fourth paper specifically excluded such patients (17–20). Studies in the US have demonstrated much higher rates of concomitant antiplatelet therapy in patients taking warfarin, ranging from 19.4% to 38.5% (28,29). It is important to recognize the populations to whom the evidence applies. The current studies were predominantly (>80%) geriatric patients who had suffered a standinglevel fall. These were not young adults who were the victims of violence or motor vehicle accidents, so the evidence should not be applied to younger populations. Elderly adults are not a homogenous population. Numerous occult geriatric syndromes exist that differentiate biological age from physiological age, most of which are unrecognized in today’s ED (30). Geriatric syndromes include frailty, dementia, delirium, falls, functional status, and social isolation (31–36). As with any predictor variable, if one cannot measure a phenomenon, then one cannot study or understand that phenomenon. In anticoagulated head injury patients, the decision to obtain a repeat CT scan or observe for a prolonged period of time incorporates clinicians’ gestalt for many of these geriatric syndromes, and future elderly patient head injury research will need to adjust prognostic models for these confounding variables. Although the current literature does not support routine hospital observation for 24 h or repeat cranial CT scans in all anticoagulated patients with head injury, this may be warranted in those at increased risk of
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delayed bleeding, such as those with supratherapeutic INR levels or concomitant antiplatelet therapy. Further studies are needed to identify these higher-risk patients for delayed bleeding to determine appropriate management. Furthermore, as a result of the inherent difficulties in warfarin administration, including the need for strict dietary compliance and routine INR monitoring, attempts have been made to find alternative anticoagulants. As newer agents enter the market and begin to replace warfarin, such as the anti-Xa agents dabigatran and rivaroxaban, further studies on the risk of delayed hemorrhage may be necessary to determine the best management strategy for patients on these medications. COMMENTARY BY ARTHUR B. SANDERS, MD, MHA Minor head injury and the use of anticoagulants, especially in older patients, is a frequent clinical scenario in emergency medicine. The studies reviewed and the recent commentary by Li make a strong case for emergency physicians to strongly consider an initial head CT scan for patients with minor closed head injury (CHI) who are taking warfarin or clopidogrel, even if there are no focal neurologic deficits or loss of consciousness (24). It is well known that older patients can present with atypical symptoms even with severe ICH. The excellent analysis presented in this article addresses the secondary clinical question for patients on anticoagulants who suffer CHI: what is the risk of delayed ICH if the initial scan is normal? Do patients need admission and a second CT scan in 24 h, as recommended in some European guidelines? In the review of four studies, clinically significant ICH requiring neurosurgical intervention is rare and ranged from 0 to 1.1%. The prospective, observational study by Nishijima et al. is informative in that 3 of the 4 patients who had delayed ICH, including the 2 who died, had their repeat CT scans 3–7 days after their trauma (20). This brings up the key question of when, if at all, should a second scan be done assessing for delayed ICH: after 24 h, 72 h, 7 days, 14 days, or only if symptoms arise? We also note that 10–15% of patients who were admitted for observation and repeat scans refused the second scan; apparently, these patients felt well and did not want to incur the risks and costs of a second CT scan. Indeed, it is estimated that 24-h observation and repeat CT scan would cost over 1 million dollars per patient undergoing neurologic intervention (24). It is not clear if mortality is impacted at all by this recommended strategy. It is important that we realize the importance of clinical judgment and treat each patient as an individual. Perfect is the enemy of good. Trying to detect every patient who will experience a delayed ICH may be an admirable
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but unrealistic goal. It is not necessarily a medical error to have a patient return to the ED with a delayed bleed. Patients can be educated and asked to return, just as we do for many other medical conditions diagnosed in the ED. Each patient presents a unique clinical scenario and risk profile for delayed bleed. What was the mechanism of injury? What is the clinical examination like? Does the patient have a social support system for neuro checks at home? Can they return if needed? Are there other underlying medical conditions? What is the INR level for the patient on warfarin? The 85-year-old man with multiple comorbidities who lives alone would be more likely to benefit from a 24-h observation period than a 67-yearold man who got elbowed playing basketball and whose wife is a physician. Significant clinical questions remain that were not addressed in this important analysis. Should anticoagulation be reversed, if possible, to prevent delayed ICH? What anticoagulation conditions put patients at risk for delayed bleeds–aspirin, low-molecular-weight heparin, thrombin inhibitors, chemotherapy, or combinations of medications? What about patients who have clinical conditions that predispose them to coagulation problems, such as the alcoholic with cirrhosis and minor CHI? Should all these patients be admitted and have repeat CT scans? In conclusion, emergency physicians need to understand the increased risks of immediate and delayed bleeds with patients who have clinical states of anticoagulation. We assess and educate the patient about the risks and use our clinical judgment to determine the disposition for each individual patient. We understand that we will never be perfect, but strive to be good. REFERENCES 1. Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths 2002–2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010. 2. Pieracci FM, Eachempati SR, Shou J, Hydo LJ, Barie PS. Use of long-term anticoagulation is associated with traumatic intracranial hemorrhage and subsequent mortality in elderly patients hospitalized after falls: analysis of the New York State Administrative Database. J Trauma 2007;63:519–24. 3. Batchelor JS, Grayson A. A meta-analysis to determine the effect of anticoagulation on mortality in patients with blunt head trauma. Br J Neurosurg 2012;26:525–30. 4. Dossett LA, Riesel JN, Griffin MR, Cotton BA. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Arch Surg 2011;146:565–70. 5. Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010. 6. Eliastam M. Elderly patients in the emergency department. Ann Emerg Med 1989;18:1222–9. 7. Stiell IG, Wells GA, Vandemheen K, et al. The Canadian CT Head Rule for patients with minor head injury. Lancet 2001;357: 1391–6.
416 8. Haydel MJ, Preston CA, Mills TJ, Luber S, Blaudeau E, DeBlieux PM. Indications for computed tomography in patients with minor head injury. N Engl J Med 2000;343:100–5. 9. Mower WR, Hoffman JR, Herbert M, Wolfson AB, Pollack CV Jr, Zucker MI. Developing a decision instrument to guide computed tomographic imaging of blunt head injury patients. J Trauma 2005;59:954–9. 10. Li J, Brown J, Levine M. Mild head injury, anticoagulants and risk of intracranial injury. Lancet 2001;357:771. 11. Gittleman AM, Ortiz AO, Keating DP, Katz DS. Indications for CT in patients receiving anticoagulation after head trauma. AJNR Am J Neuroradiol 2005;26:603–6. 12. Brewer ES, Reznikov B, Liberman RF, et al. Incidence and predictors of intracranial hemorrhage after minor head trauma in patients taking anticoagulant and antiplatelet medication. J Trauma 2011; 70:E1–5. 13. Cohen DB, Rinker C, Wilberger JE. Traumatic brain injury in anticoagulated patients. J Trauma 2006;60:553–7. 14. Fabbri A, Vandelli A, Servadei F, Marchesini G. Coagulopathy and NICE recommendations for patients with mild head injury. J Neurol Neurosurg Psychiatry 2004;75:1787. 15. Vos PE, Battistin L, Birbamer G, et al. EFNS guideline on mild traumatic brain injury: report of an EFNS task force. Eur J Neurol 2002; 9:207–19. 16. Ingebrigtsen T, Romner B, Kock-Jensen C. Scandinavian guidelines for initial management of minimal, mild, and moderate head injuries. The Scandinavian Neurotrauma Committee. J Trauma 2000;48:760–6. 17. Kaen A, Jimenez-Roldan L, Arrese I, et al. The value of sequential computed tomography scanning in anticoagulated patients suffering from minor head injury. J Trauma 2010;68:895–8. 18. Peck KA, Sise CB, Shackford SR, et al. Delayed intracranial hemorrhage after blunt trauma: are patients on preinjury anticoagulants and prescription antiplatelet agents at risk? J Trauma 2011;71:1600. 19. Menditto VG, Lucci M, Polonara S, Pomponio G, Gabrielli A. Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. Ann Emerg Med 2012;59:451–5. 20. Nishijima DK, Offerman SR, Ballard DW, et al. Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and preinjury warfarin or clopidogrel use. Ann Emerg Med 2012;59:460–8. 21. Temple RJ. A regulatory authority’s opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, eds. Clinical measurement in drug evaluation. New York: John Wiley & Sons; 1995:3–22. 22. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled. Ann Intern Med 1996;125:605–13.
B. Cohn et al. 23. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines 2. Framing the question and deciding on important outcomes. J Clin Epidemiol 2011;64:395–400. 24. Li J. Admit all anticoagulated head-injured patients? A million dollars versus your dime. You make the call. Ann Emerg Med 2012;59: 457–9. 25. Pieracci FM, Eachempati SR, Shou J, Hydo LJ, Barie PS. Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients. J Trauma 2007;63:525–30. 26. Franko J, Kish KJ, O’Connell BG, Subramanian S, Yuschak JV. Advanced age and preinjury warfarin anticoagulation increase the risk of mortality after head trauma. J Trauma 2006;61:107–10. 27. Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170: 1433–41. 28. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004;35:2362–7. 29. Johnson SG, Witt DM, Eddy TR, Delate T. Warfarin and antiplatelet combination use among commercially insured patients enrolled in an anticoagulation management service. Chest 2007; 131:1500–7. 30. Carpenter CR, Griffey RT, Stark S, Coopersmith CM, Gage BF. Physician and nurse acceptance of technicians to screen for geriatric syndromes in the emergency department. West J Emerg Med 2011; 12:489–95. 31. Sternberg SA, Wershof Schwartz A, Karunananthan S, Bergman H, Mark Clarfield A. The identification of frailty: a systematic literature review. J Am Geriatr Soc 2011;59:2129–38. 32. Carpenter CR, DesPain B, Keeling TN, Shah M, Rothenberger M. The six-item screener and AD8 for the detection of cognitive impairment in geriatric emergency department patients. Ann Emerg Med 2011;57:653–61. 33. Han JH, Wilson A, Ely EW. Delirium in the older emergency department patient: a quiet epidemic. Emerg Med Clin North Am 2010;28:611–31. 34. Carpenter CR. Evidence-based emergency medicine/rational clinical examination abstract. Will my patient fall? Ann Emerg Med 2009;53:398–400. 35. Caterino JM, Murden RA, Stevenson KB. Functional status does not predict complicated clinical course in older adults in the emergency department with infection. J Am Geriatr Soc 2012;60:304–9. 36. Hastings SN, George LK, Fillenbaum GG, Park RS, Burchett BM, Schmader KE. Does lack of social support lead to more ED visits for older adults? Am J Emerg Med 2008;26:454–61.
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ARTICLE SUMMARY 1. Why is this topic important? Anticoagulated patients frequently present to the emergency department after head injury. 2. What is the clinical question? What is the risk of delayed intracranial hemorrhage in anticoagulated patients with minor head injury and a normal initial head computed tomography scan? 3. Search strategy Using PubMed, a search strategy of ‘‘warfarin’’ OR ‘‘Coumadin’’ OR ‘‘anticoagulation’’ AND ‘‘trauma’’ AND ‘‘intracranial hemorrhage.’’ 4. Citations appraised The value of sequential computed tomography scanning in anticoagulated patients suffering from minor head injury. 2010 (17) Delayed intracranial hemorrhage after blunt trauma: are patients on preinjury anticoagulants and prescription antiplatelet agents at risk? 2011 (18) Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. 2012 (19) Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and preinjury warfarin or clopidogrel use. 2012 (20) 5. Are the results valid? Overall, yes, but further research is needed to identify the highest-risk groups. 6. Can I apply the results to my practice? Yes.
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http://dx.doi.org/10.1016/j.jemermed.2013.08.107
Evidence Based Medicine CAN ANTICOAGULATED PATIENTS BE DISCHARGED HOME SAFELY FROM THE EMERGENCY DEPARTMENT AFTER MINOR HEAD INJURY? Brian Cohn, MD,* Samuel M. Keim, MD, MS,† and Arthur B. Sanders, MD, MHA† *Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri and †Department of Emergency Medicine, University of Arizona College of Medicine, Phoenix, Arizona Reprint Address: Samuel M. Keim, MD, MS, Department of Emergency Medicine, University of Arizona College of Medicine, P.O. Box 245057, Tucson, AZ 85724-5057
, Abstract—Background: Anticoagulated patients have increased risk for bleeding, and serious outcomes could occur after head injury. Controversy exists regarding the utility of head computed tomography (CT) in allowing safe discharge dispositions for anticoagulated patients suffering minor head injury. Clinical Question: What is the risk of delayed intracranial hemorrhage in anticoagulated patients with minor head injury and a normal initial head CT scan? Evidence Review: Four observational studies were reviewed that investigated the outcomes of anticoagulated patients who presented after minor head injury. Results: Overall incidence of death or neurosurgical intervention ranged from 0 to 1.1% among the patients investigated. The studies did not clarify which patients were at highest risk. Conclusion: The literature does not support mandatory admission for all anticoagulated patients after minor head injury, but further studies are needed to identify the higher-risk patients for delayed bleeding to determine appropriate management. Ó 2014 Elsevier Inc. , Keywords—head imaging; prognosis
injury;
anticoagulation;
ing height. He struck his forehead on the concrete but suffered no loss of consciousness (LOC). He has a mild headache, has had no nausea or vomiting, and his wife states that he has had no altered mental status since the fall. On examination, he has a Glasgow Coma Scale (GCS) score of 15, a superficial abrasion to his forehead, no cervical spine pain or tenderness, and a normal neurologic examination. His international normalized ratio (INR) is 2.8. His head computed tomography (CT) scan is normal. After updating the patient’s tetanus immunization, you discharge him home in the care of his wife. That night after your shift you recall that in Italy, standard of care in patients with head injury on anticoagulation is 24 h of observation followed by a repeat CT scan. You consider the efficacy of such a protocol, and begin asking yourself about the patient’s risk of delayed intracranial hemorrhage (ICH). CLINICAL QUESTION
medical
What is the risk of delayed ICH in anticoagulated patients with minor head injury and a normal initial head CT scan? CASE REPORT CONTEXT A 68-year-old man with a history of atrial fibrillation, for which he takes warfarin for anticoagulation, presents to your Emergency Department (ED) after a fall from stand-
Traumatic brain injury results in just over 1.3 million ED visits, 275,000 hospitalizations, and 52,000 deaths
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annually in the United States (US) alone, with an increase in ED visits and hospitalization of 14.4% and 19.5%, respectively, from 2002 to 2006 (1). In elderly patients suffering a fall, long-term anticoagulation has been shown to increase not only the incidence of ICH compared to those not on anticoagulation (8.0% vs. 5.3%, p < 0.0001), but to also increase mortality in those with ICH (21.9% vs. 15.2%, p = 0.04) (2). Additionally, the use of warfarin prior to blunt head trauma has been shown to increase mortality compared to those not taking anticoagulants, with an odds ratio of 2.008 (95% confidence interval [CI] 1.634–2.467) (3). Unfortunately, the rate of preinjury warfarin use has been increasing in trauma patients in the US, from 2.3% in 2002 to 4.0% in 2006 (p < 0.001); in patients older than 65 years, use increased from 7.3% in 2002 to 12.8% in 2006 (p < 0.001) (4). Patients older than 65 years account for approximately 10% of ED visits and 30% of admissions for traumatic brain injury (5). The projected growth of our elderly population will likely lead to a significant increase in the number of ED visits for head injury from this group of patients (6). Given the increasing number of head injury patients seen in the ED, and the increase in concomitant anticoagulant use, the clinical dilemmas surrounding these patients have become more and more relevant. Although clinical decision rules such as the Canadian CT Head Rule, the New Orleans criteria, and the NEXUS-II criteria exist to help determine which head injury patients require a head CT scan, these rules do not apply to anticoagulated patients (7–9). Studies in patients taking warfarin who suffer minor head injury have shown incidences of ICH ranging from 6.2% to 29%, leading some authors to conclude that most, if not all, such patients should undergo routine cranial CT scanning on presentation (8,10–14). One important question surrounds the prognostic implications of a normal cranial CT scan in head injury patients on anticoagulant therapy. Although some European guidelines suggest that all anticoagulated patients with head injury should be admitted for a period of routine observation, these recommendations are not based on studies of the prevalence of delayed ICH (15,16). The question remains whether a period of observation or routine serial CT scanning is warranted in such patients.
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EVIDENCE REVIEW The Value of Sequential Computed Tomography Scanning in Anticoagulated Patients Suffering from Minor Head Injury (17) Population. The study population was patients presenting to Hospital 12 de Octubre in Madrid, Spain within 48 h of minor head injury on anticoagulant therapy. A total of 137 patients presented during the study period, mean age 76 years, 33% men, with a median interval from trauma to CT scan of 3.2 h. Study design. This was a prospective observational study performed from October 2005 to December 2006. Patients with a negative initial CT scan were admitted for 24 h of observation, with serial neurologic examinations performed every 4–6 h. A control CT scan was performed 20–24 h after the initial scan. Demographic data and subsequent examination data were obtained by neurosurgical residents. CT scans were interpreted by radiology or neurosurgery staff. Findings on control CT scans were compared to the initial CT scan and classified as unchanged or worsened (defined as the presence of any sign of ICH). Primary outcome. Incidence of ICH on control CT scan. Inclusion criteria. Patients aged older than 16 years, suffering head injury within 48 h of presentation, with GCS score of 14–15, currently treated with heparin or warfarin, with a normal initial CT scan, were included. Main results.The mean INR was 3.8, and the median time to control CT scan was 20 h. Delayed ICH was observed in 2 of 137 patients, for an incidence of 1.5% (95% CI 0.4–5%); both of these were among the 3 patients in the study who were also on an antiplatelet agent and were among the 10% with LOC. No patients required change in management based on control CT scan findings (0%; 95% CI 0–3%). The difference in incidence of bleeding between patients with and without concomitant antiplatelet use was statistically significant (absolute risk reduction [ARR] 67%; p = 0.01) as was the difference between patients with and without LOC (ARR 14%; p = 0.004).
EVIDENCE SEARCH Using PUBMED, a search strategy of ‘‘warfarin’’ OR ‘‘Coumadin’’ OR ‘‘anticoagulation’’ AND ‘‘trauma’’ AND ‘‘intracranial hemorrhage’’ was entered on September 12, 2012, resulting in 279 articles. This strategy identifies four articles relevant to the clinical question. The bibliographies of the selected articles were reviewed but revealed no further relevant articles.
Delayed Intracranial Hemorrhage after Blunt Trauma: Are Patients on Preinjury Anticoagulants and Prescription Antiplatelet Agents at Risk? (18) Population. The study population was patients presenting to Scripps Mercy Hospital in San Diego, CA, a Level I trauma center, suffering head injury while taking anticoagulant of antiplatelet agents. Five hundred patients
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qualified for the study, of whom 424 (85%) had a negative initial head CT scan. The average age was 75.0 years; 49.5% were male, 289 (68.2%) were taking warfarin, 103 (24.3%) were on clopidogrel, 7 (1.7%) were taking ‘‘other’’ anticoagulant or antiplatelet agents, and 25 (5.9%) were taking a combination of agents. Study design. This was a retrospective chart review of patients presenting between January 1, 2006 and August 31, 2009. Patients with a negative initial CT scan were admitted for 6 h of observation, followed by repeat CT scan. Medical records were reviewed for age, gender, injury mechanism, history of LOC, Injury Severity Score (ISS), head Abbreviated Injury Scale, admission GCS score, length of hospital stay, intensive care unit length of stay, and neurologic deterioration during observation (Table 1). Head CT results were classified as positive if they demonstrated any ICH (subarachnoid hemorrhage, intraparenchymal hemorrhage, parenchymal contusion, subdural hematoma, or epidural hematoma). Any equivocal study was considered positive. All positive repeat head CT scans were reviewed by a radiologist experienced in trauma radiology who was blinded to the imaging results and clinical details. Review of the hospital trauma registry and inquiry of the San Diego County Medical Audit Committee were undertaken to identify patients with unexpected deterioration or readmission after discharge. Primary outcome. Primary outcome was the incidence of ICH on repeat CT scan. Inclusion criteria. Patients aged $ 15 years with blunt mechanism of injury and preinjury use of an anticoagulant or antiplatelet agent (warfarin, clopidogrel, heparin, enoxaparin, or dipyridamole and aspirin in combination) were included. Aspirin use alone was not sufficient for inclusion. Patients taking warfarin with INR < 1.3 were excluded.
Table 1. Injury Severity Score (ISS) Region
AIS Score
AIS Meaning
Head, neck, and cervical spine Face Thorax, thoracic spine, diaphragm Abdomen and lumbar spine Extremities including pelvis External soft tissue injury
1 2 3 4 5 6
Minor Moderate Serious Severe Critical Unsurvivable
AIS = Abbreviated Injury Scale. Injury Severity Score is calculated by the sum of the squares of the three highest scores. The ISS takes a value of 75 if any system receives an AIS score of 6.
Main results. Of 424 patients enrolled with negative initial CT scan, 62 (14.6%) refused the second CT. There were four (1%; 95% CI 0.4–2.4%) positive repeat CT scans in patients with normal initial CT scan. Of 289 patients on warfarin, there were four (1.4%; 95% CI 0.5–3.5%) positive repeat CT scans (representing all positive cases). None of these patients (0%; 95% CI 0–1%) required neurosurgical intervention. No patients who had a change in mental status after the first CT had an ICH on the second CT. Management of Minor Head Injury in Patients Receiving Oral Anticoagulant Therapy: a Prospective Study of a 24-H Observation Protocol (19) Population. The study population comprised patients presenting to Academic Hospital, a Level II trauma center in Ancona, Italy, suffering minor head injury while receiving warfarin therapy for at least 1 week. There were 116 patients identified, of whom 97 (84%) had an initial negative CT scan. Ten of these patients later refused a second CT scan and were excluded from analysis. For the 87 remaining patients, median age was 82 years and 37% were male. Study design. This was a prospective case series conducted between January 2007 and March 2010. Patients meeting inclusion criteria with a negative initial head CT scan were admitted to an ED observation unit for 24 h, followed by a repeat head CT scan. All CT scans were interpreted by staff neuroradiologists. A CT scan was considered positive if any of the following were present: subdural, epidural, or parenchymal hematoma; subarachnoid hemorrhage, cerebral contusion; or depressed skull fracture. During the period of observation, patients received neurologic evaluation every 4–6 h. Treating emergency physicians used a specialized data collection form to document inclusion/exclusion criteria, demographics, GCS score, mechanism of injury, sensory or motor deficits, indication for anticoagulation, INR, and concomitant antiplatelet therapy. The medical records were reviewed by two investigators for the presence or absence of: acute traumatic intracranial lesion on the repeat CT scan, death, admission for any CT abnormality, operative neurosurgery, or readmission within 30 days. Primary outcome. Primary outcome was the incidence of ICH on repeat CT scan. Also considered was neurologic deterioration during observation and need for neurosurgical intervention. Inclusion criteria. Patients aged $ 14 years with minor head injury, a GCS score of 14–15, and an ISS < 15, presenting within 48 h of injury, on anticoagulant therapy with warfarin for at least 1 week.
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Main results. Of 97 patients enrolled with a normal initial CT scan, 10 refused the second CT scan, leaving 87 patients in the analysis. Of these, 5 (6%; 95% CI 1– 11%) patients had ICH noted on the repeat CT scan. Only 1 (1%; 95% CI 0.2–6.2%) of these patients required neurosurgical intervention. Two (2%; 95% CI 0.5–5%) additional patients with subdural hematoma were identified in follow-up. The greatest predictor of delayed ICH was an INR $ 3 (relative risk = 14; 95% CI 4–49). Immediate and Delayed Traumatic Intracranial Hemorrhage in Patients with Head Trauma and Preinjury Warfarin or Clopidogrel Use (20) Population. The population comprised patients in the ED at one of two trauma centers or four community hospitals in Northern California with blunt head trauma while taking warfarin or clopidogrel. There were 1064 eligible patients with an average age of 75.4 years, of whom 47.1% were male. Ground-level fall accounted for 83.3% of injuries. Of 1000 eligible patients who underwent an initial CT scan, 930 had no ICH. Of these, 687 (74%) were on warfarin and 243 (26%) were on clopidogrel. Study design. This was a prospective, observational, multicenter study performed between April 2009 and January 2011. Using a standardized data form, treating ED faculty recorded patient history, injury mechanism, clinical examination, and GCS score prior to initial head CT scan, which was obtained at the discretion of the treating physician. Immediate ICH was defined as the presence of any ICH or contusion. Delayed ICH was defined as ICH on CT scan occurring within 14 days of the initial, normal CT scan in the absence of repeated trauma. All head CT scans were interpreted by faculty radiologists. Neurosurgical intervention was defined as use of intracranial pressure monitor or brain tissue oxygen probe, placement of a burr hole, craniotomy, craniectomy, intraventricular catheter or subdural drain, or the use of mannitol or hypertonic saline. Delayed ICH was assessed by electronic medical record review in the case of patients admitted for at least 14 days, or standardized telephone survey at least 14 days after the ED visit for all others. Primary outcome. The primary outcomes were the incidence of immediate and delayed ICH in patients receiving warfarin or clopidogrel suffering minor head injury. Inclusion criteria. Patients aged $ 18 years presenting with blunt head trauma and warfarin or clopidogrel use within the previous 7 days were included. Patients were excluded if they were transferred from other facilities or if they were taking both warfarin and clopidogrel.
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Main results. The prevalence of immediate ICH in patients taking clopidogrel and warfarin was 12.0% (95% CI 8.4–16.4%) and 5.1% (95% CI 3.6–7.0%), respectively. The relative risk of clopidogrel compared to warfarin was 2.31 (95% CI 1.48–3.63). Delayed ICH was identified in 0 (0%; 95% CI 0–1.5%) patients receiving clopidogrel and 4 (0.6%; 95% CI 0.2–1.5%) patients receiving warfarin. Of the 4 patients with delayed ICH, 2 died and 2 required no neurosurgical intervention. In patients on warfarin, ICH requiring neurosurgical intervention occurred in 2 (0.3%; 95% CI 0.1–1.1%) patients. Most immediate ICH had GCS 15 (64%) and a few had no LOC (11% warfarin, 18% clopidogrel). The raw agreement for individual predictor variables was good (87–100% agreement), but no kappa values were reported. CONCLUSION In the four studies reviewed, the incidence of delayed ICH after normal CT scan ranged from 0.6% to 6%. However, if a diagnosed ICH has no effect on the patient’s outcome or treatment, then it would be considered a surrogate outcome, which is often used as a substitute for a clinically meaningful end point that measures directly how a patient feels, functions, or survives (21,22). As such outcomes are often found to be clinically insignificant, their use has been questioned in the literature, and the incidence of patient important outcomes should be considered instead (Table 2) (23). In these studies, the majority of patients found to have delayed ICH required no neurosurgical intervention and had no adverse outcome documented. The incidence of death or neurosurgical intervention ranged from 0 to 1.1%. The authors of one of the articles suggest that ‘‘our data support the general effectiveness of the European Federation of Neurological Societies’ recommendations for 24-hour observation followed by a repeated head CT scan for anticoagulated patients with a minor head injury’’ (19). However, this conclusion is based on the incidence of delayed ICH (6%) rather than the incidence of clinically important outcomes (1.1%). In this study, only one patient out of 87 suffered clinically significant delayed ICH. It is mentioned in the study that one patient showed signs of neurologic deterioration, however, they do not say if this was the same patient who required neurosurgical intervention. If so, this would suggest that observation alone would suffice to detect any clinically significant delayed ICH. Additionally, the authors do not perform a costeffectiveness analysis to support their conclusion. In a subsequent editorial appearing in the same journal, it is suggested that a protocol of 24-h observation and routine repeat CT scanning would cost an average of just over $1
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Table 2. Evidence-Based Medicine Teaching Points Case Series A study that reports a consecutive collection of patients with the same or very similar condition, for example, patients with minor head injury while receiving anticoagulation. Problems associated with this study design include potential for selection bias and lack of a comparison or control group. No causal linkage can therefore be assumed between risk factors and outcomes. Confidence Interval (CI) The CI is an indicator of the precision of a study result or estimate. It is a range between two values within which it is probable that the true value lies for the whole population of patients from which the study patients were selected. With a 95% CI, the true value can be expected to be within that interval with 95% confidence. Patient-important Outcomes Not all outcomes reported in the medical literature are meaningful to actual patient care, nor to patients themselves. Outcomes that patients value directly are typically outcomes that should also be important to clinical practice. Frequently, physicians value physiologic outcomes that may not be clearly associated with increasing length or quality of life. Prospective Cohort The cohort study is typically a prospective investigation of a key outcome in a group of individuals who do not have the outcome in which some have a known risk factor compared to others that do not have the exposure. Both groups are followed to compare the incidence of the outcome of interest. The prospective cohort design is the preferred method for investigating prognosis and relative risk. A retrospective cohort might start by identifying a group of individuals with the disease in question, and the investigators study a medical record database, for example, trauma registry, for the group-specific risk factors or outcomes. For example, anticoagulated patients with minor head injury and an initial negative head computed tomography scan are investigated for deterioration after admission. These studies are known to be susceptible to problems such as selection and information bias. Risk There are several standard measures used in the medical literature to explicitly define risk. The value of the measure is linked to the quality of the study design that created it. As mentioned above, the prospective cohort design is the strongest design. It therefore produces the strongest measure, relative risk (RR). The odds ratio (OR) is an estimate of the RR and typically is produced by retrospective designs, for example, case control studies. Descriptive statistics, such as frequency of occurrence, are not nearly as strong as the RR and OR in describing risk.
million per patient saved (24). The author of the editorial suggests that home observation and telephone call follow-up would be more cost-effective, and likely as safe, though this has not been studied. One difficulty in studies of prognosis involves homogeneity. It would be unfair to say that all head injury patients on warfarin carry the same risk for delayed ICH. There are many risk factors that need to be considered, and a one-size-fits-all approach may not be warranted. A prior study on warfarin use in head trauma showed that the degree of anticoagulation was predictive of risk of ICH, rather than the use of warfarin alone, with an odds ratio of 2.59 in patients with an INR $ 2.0 (25). Another retrospective study of 1493 patients admitted for traumatic brain injury with preinjury warfarin use showed that both the risk of ICH and mortality were increased with higher INR (26). Whether this association can be applied to the risk of delayed ICH remains to be shown, however, one of the articles reviewed here suggests an increased risk in patients with an INR $ 3 (relative risk = 14; 95% CI 4–49) (19). An additional prognostic factor to consider is concomitant antiplatelet therapy. The risk of major bleeding is known to increase for those on combined anticoagulant– antiplatelet therapy, with hazard ratios of 1.83 (95% CI 1.72–1.96) and 3.08 (95% CI 2.32–3.91) for combined warfarin–aspirin and warfarin–clopidogrel use, respectively, compared to warfarin therapy alone (27). It seems reasonable to assume that combined therapy would lead to increased rates of both initial and delayed ICH in head injury patients, and in one of the studies that identi-
fied 2 patients with delayed ICH, both were taking aspirin in addition to warfarin (17). Concomitant antiplatelet therapy in three of the studies ranged from 0 to 5.9%, and the fourth paper specifically excluded such patients (17–20). Studies in the US have demonstrated much higher rates of concomitant antiplatelet therapy in patients taking warfarin, ranging from 19.4% to 38.5% (28,29). It is important to recognize the populations to whom the evidence applies. The current studies were predominantly (>80%) geriatric patients who had suffered a standinglevel fall. These were not young adults who were the victims of violence or motor vehicle accidents, so the evidence should not be applied to younger populations. Elderly adults are not a homogenous population. Numerous occult geriatric syndromes exist that differentiate biological age from physiological age, most of which are unrecognized in today’s ED (30). Geriatric syndromes include frailty, dementia, delirium, falls, functional status, and social isolation (31–36). As with any predictor variable, if one cannot measure a phenomenon, then one cannot study or understand that phenomenon. In anticoagulated head injury patients, the decision to obtain a repeat CT scan or observe for a prolonged period of time incorporates clinicians’ gestalt for many of these geriatric syndromes, and future elderly patient head injury research will need to adjust prognostic models for these confounding variables. Although the current literature does not support routine hospital observation for 24 h or repeat cranial CT scans in all anticoagulated patients with head injury, this may be warranted in those at increased risk of
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delayed bleeding, such as those with supratherapeutic INR levels or concomitant antiplatelet therapy. Further studies are needed to identify these higher-risk patients for delayed bleeding to determine appropriate management. Furthermore, as a result of the inherent difficulties in warfarin administration, including the need for strict dietary compliance and routine INR monitoring, attempts have been made to find alternative anticoagulants. As newer agents enter the market and begin to replace warfarin, such as the anti-Xa agents dabigatran and rivaroxaban, further studies on the risk of delayed hemorrhage may be necessary to determine the best management strategy for patients on these medications. COMMENTARY BY ARTHUR B. SANDERS, MD, MHA Minor head injury and the use of anticoagulants, especially in older patients, is a frequent clinical scenario in emergency medicine. The studies reviewed and the recent commentary by Li make a strong case for emergency physicians to strongly consider an initial head CT scan for patients with minor closed head injury (CHI) who are taking warfarin or clopidogrel, even if there are no focal neurologic deficits or loss of consciousness (24). It is well known that older patients can present with atypical symptoms even with severe ICH. The excellent analysis presented in this article addresses the secondary clinical question for patients on anticoagulants who suffer CHI: what is the risk of delayed ICH if the initial scan is normal? Do patients need admission and a second CT scan in 24 h, as recommended in some European guidelines? In the review of four studies, clinically significant ICH requiring neurosurgical intervention is rare and ranged from 0 to 1.1%. The prospective, observational study by Nishijima et al. is informative in that 3 of the 4 patients who had delayed ICH, including the 2 who died, had their repeat CT scans 3–7 days after their trauma (20). This brings up the key question of when, if at all, should a second scan be done assessing for delayed ICH: after 24 h, 72 h, 7 days, 14 days, or only if symptoms arise? We also note that 10–15% of patients who were admitted for observation and repeat scans refused the second scan; apparently, these patients felt well and did not want to incur the risks and costs of a second CT scan. Indeed, it is estimated that 24-h observation and repeat CT scan would cost over 1 million dollars per patient undergoing neurologic intervention (24). It is not clear if mortality is impacted at all by this recommended strategy. It is important that we realize the importance of clinical judgment and treat each patient as an individual. Perfect is the enemy of good. Trying to detect every patient who will experience a delayed ICH may be an admirable
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but unrealistic goal. It is not necessarily a medical error to have a patient return to the ED with a delayed bleed. Patients can be educated and asked to return, just as we do for many other medical conditions diagnosed in the ED. Each patient presents a unique clinical scenario and risk profile for delayed bleed. What was the mechanism of injury? What is the clinical examination like? Does the patient have a social support system for neuro checks at home? Can they return if needed? Are there other underlying medical conditions? What is the INR level for the patient on warfarin? The 85-year-old man with multiple comorbidities who lives alone would be more likely to benefit from a 24-h observation period than a 67-yearold man who got elbowed playing basketball and whose wife is a physician. Significant clinical questions remain that were not addressed in this important analysis. Should anticoagulation be reversed, if possible, to prevent delayed ICH? What anticoagulation conditions put patients at risk for delayed bleeds–aspirin, low-molecular-weight heparin, thrombin inhibitors, chemotherapy, or combinations of medications? What about patients who have clinical conditions that predispose them to coagulation problems, such as the alcoholic with cirrhosis and minor CHI? Should all these patients be admitted and have repeat CT scans? In conclusion, emergency physicians need to understand the increased risks of immediate and delayed bleeds with patients who have clinical states of anticoagulation. We assess and educate the patient about the risks and use our clinical judgment to determine the disposition for each individual patient. We understand that we will never be perfect, but strive to be good. REFERENCES 1. Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths 2002–2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010. 2. Pieracci FM, Eachempati SR, Shou J, Hydo LJ, Barie PS. Use of long-term anticoagulation is associated with traumatic intracranial hemorrhage and subsequent mortality in elderly patients hospitalized after falls: analysis of the New York State Administrative Database. J Trauma 2007;63:519–24. 3. Batchelor JS, Grayson A. A meta-analysis to determine the effect of anticoagulation on mortality in patients with blunt head trauma. Br J Neurosurg 2012;26:525–30. 4. Dossett LA, Riesel JN, Griffin MR, Cotton BA. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Arch Surg 2011;146:565–70. 5. Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010. 6. Eliastam M. Elderly patients in the emergency department. Ann Emerg Med 1989;18:1222–9. 7. Stiell IG, Wells GA, Vandemheen K, et al. The Canadian CT Head Rule for patients with minor head injury. Lancet 2001;357: 1391–6.
416 8. Haydel MJ, Preston CA, Mills TJ, Luber S, Blaudeau E, DeBlieux PM. Indications for computed tomography in patients with minor head injury. N Engl J Med 2000;343:100–5. 9. Mower WR, Hoffman JR, Herbert M, Wolfson AB, Pollack CV Jr, Zucker MI. Developing a decision instrument to guide computed tomographic imaging of blunt head injury patients. J Trauma 2005;59:954–9. 10. Li J, Brown J, Levine M. Mild head injury, anticoagulants and risk of intracranial injury. Lancet 2001;357:771. 11. Gittleman AM, Ortiz AO, Keating DP, Katz DS. Indications for CT in patients receiving anticoagulation after head trauma. AJNR Am J Neuroradiol 2005;26:603–6. 12. Brewer ES, Reznikov B, Liberman RF, et al. Incidence and predictors of intracranial hemorrhage after minor head trauma in patients taking anticoagulant and antiplatelet medication. J Trauma 2011; 70:E1–5. 13. Cohen DB, Rinker C, Wilberger JE. Traumatic brain injury in anticoagulated patients. J Trauma 2006;60:553–7. 14. Fabbri A, Vandelli A, Servadei F, Marchesini G. Coagulopathy and NICE recommendations for patients with mild head injury. J Neurol Neurosurg Psychiatry 2004;75:1787. 15. Vos PE, Battistin L, Birbamer G, et al. EFNS guideline on mild traumatic brain injury: report of an EFNS task force. Eur J Neurol 2002; 9:207–19. 16. Ingebrigtsen T, Romner B, Kock-Jensen C. Scandinavian guidelines for initial management of minimal, mild, and moderate head injuries. The Scandinavian Neurotrauma Committee. J Trauma 2000;48:760–6. 17. Kaen A, Jimenez-Roldan L, Arrese I, et al. The value of sequential computed tomography scanning in anticoagulated patients suffering from minor head injury. J Trauma 2010;68:895–8. 18. Peck KA, Sise CB, Shackford SR, et al. Delayed intracranial hemorrhage after blunt trauma: are patients on preinjury anticoagulants and prescription antiplatelet agents at risk? J Trauma 2011;71:1600. 19. Menditto VG, Lucci M, Polonara S, Pomponio G, Gabrielli A. Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. Ann Emerg Med 2012;59:451–5. 20. Nishijima DK, Offerman SR, Ballard DW, et al. Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and preinjury warfarin or clopidogrel use. Ann Emerg Med 2012;59:460–8. 21. Temple RJ. A regulatory authority’s opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, eds. Clinical measurement in drug evaluation. New York: John Wiley & Sons; 1995:3–22. 22. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled. Ann Intern Med 1996;125:605–13.
B. Cohn et al. 23. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines 2. Framing the question and deciding on important outcomes. J Clin Epidemiol 2011;64:395–400. 24. Li J. Admit all anticoagulated head-injured patients? A million dollars versus your dime. You make the call. Ann Emerg Med 2012;59: 457–9. 25. Pieracci FM, Eachempati SR, Shou J, Hydo LJ, Barie PS. Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients. J Trauma 2007;63:525–30. 26. Franko J, Kish KJ, O’Connell BG, Subramanian S, Yuschak JV. Advanced age and preinjury warfarin anticoagulation increase the risk of mortality after head trauma. J Trauma 2006;61:107–10. 27. Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170: 1433–41. 28. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004;35:2362–7. 29. Johnson SG, Witt DM, Eddy TR, Delate T. Warfarin and antiplatelet combination use among commercially insured patients enrolled in an anticoagulation management service. Chest 2007; 131:1500–7. 30. Carpenter CR, Griffey RT, Stark S, Coopersmith CM, Gage BF. Physician and nurse acceptance of technicians to screen for geriatric syndromes in the emergency department. West J Emerg Med 2011; 12:489–95. 31. Sternberg SA, Wershof Schwartz A, Karunananthan S, Bergman H, Mark Clarfield A. The identification of frailty: a systematic literature review. J Am Geriatr Soc 2011;59:2129–38. 32. Carpenter CR, DesPain B, Keeling TN, Shah M, Rothenberger M. The six-item screener and AD8 for the detection of cognitive impairment in geriatric emergency department patients. Ann Emerg Med 2011;57:653–61. 33. Han JH, Wilson A, Ely EW. Delirium in the older emergency department patient: a quiet epidemic. Emerg Med Clin North Am 2010;28:611–31. 34. Carpenter CR. Evidence-based emergency medicine/rational clinical examination abstract. Will my patient fall? Ann Emerg Med 2009;53:398–400. 35. Caterino JM, Murden RA, Stevenson KB. Functional status does not predict complicated clinical course in older adults in the emergency department with infection. J Am Geriatr Soc 2012;60:304–9. 36. Hastings SN, George LK, Fillenbaum GG, Park RS, Burchett BM, Schmader KE. Does lack of social support lead to more ED visits for older adults? Am J Emerg Med 2008;26:454–61.
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ARTICLE SUMMARY 1. Why is this topic important? Anticoagulated patients frequently present to the emergency department after head injury. 2. What is the clinical question? What is the risk of delayed intracranial hemorrhage in anticoagulated patients with minor head injury and a normal initial head computed tomography scan? 3. Search strategy Using PubMed, a search strategy of ‘‘warfarin’’ OR ‘‘Coumadin’’ OR ‘‘anticoagulation’’ AND ‘‘trauma’’ AND ‘‘intracranial hemorrhage.’’ 4. Citations appraised The value of sequential computed tomography scanning in anticoagulated patients suffering from minor head injury. 2010 (17) Delayed intracranial hemorrhage after blunt trauma: are patients on preinjury anticoagulants and prescription antiplatelet agents at risk? 2011 (18) Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. 2012 (19) Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and preinjury warfarin or clopidogrel use. 2012 (20) 5. Are the results valid? Overall, yes, but further research is needed to identify the highest-risk groups. 6. Can I apply the results to my practice? Yes.
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