a b s t r a c t

Background: Clopidogrel is an adenosine diphosphate receptor antagonist. The risk of intracranial hemorrhage following minor head trauma in patients with pre-injury use of clopidogrel has not been fully determined. Methods: This case-controlled study examined the effects of pre-injury use of clopidogrel in adult (age 14 years and older) patients with minor head trauma.

Results: During the study period, 1660 patients head computed tomography scans were performed in the emergency department, of which 658 met inclusion criteria. Intracranial hemorrhage was noted in 30% of patients on clopidogrel, compared with 2.2% of those patients without pre-injury use of clopidogrel. After performing a logistic regression analysis for confounders, the pre-injury use of clopidogrel was significantly associated with intracranial hemorrhage in this study population (OR 16.7; 95% CI 1.71-162.7).

Conclusion: The use of clopidogrel is associated with a significantly increased risk of developing intracranial hemorrhage following minor trauma.

(C) 2013

Background

In North America, head trauma accounts for more than one million emergency department (ED) visits annually, with most of these visits being the result of minor head trauma [1,2]. Decision rules have been developed to determine which patients with minor head trauma need neuro-imaging [1,3]. While these decision rules exclude patients on oral anticoagulants (eg, warfarin), they do not specifically address patients on anti-platelet agents like clopidogrel.

Clopidogel, a second-generation thienopyridine, is a noncompetitive antagonist of the P2Y12 ADP receptor that prevents platelet activation and subsequent aggregation [4,5]. The American College of Cardiology Foundation, American Heart Association, and the European Society of Cardiology all recommend dual anti-platelet therapy with aspirin and an ADP receptor antagonist in patients with acute coronary syndromes [6,7]. Furthermore, even in the absence of an acute coronary syndrome,

? There are no financial, litigational, or other conflicts of interest to disclose.

?? The data have been previously published as an abstract at the Society of

Emergency Medicine’s Annual Meeting, 2013.

? Author contribution statement: All authors provided meaningful contributions to the manuscript, and meet criteria for authorship. Michael Levine takes responsibility for

the manuscript in its entirety. There are no financial, litigational, or other conflicts of interest to disclose.

* Corresponding author. Department of Emergency Medicine, University of Southern California, Los Angeles, CA 90033, USA. Tel.: +1 44018184260300.

E-mail address: [email protected] (M. Levine).

such therapy is also routine for patients undergoing percutaneous coronary intervention [8]. In addition to its cardiac indications, clopidogrel is being used for prevention of cerebrovascular attacks in patients with carotid atherosclerotic disease [9] and in the medical management of patients with peripheral artery disease [10].

However, this very effective platelet inhibition comes at a cost and it has been demonstrated that patients with pre-injury use of Antiplatelet agents who develop intracranial hemorrhages have higher morbidity and mortality that those who were not on the agents [11]. Most of the previous studies examining the effect of preinjury use of clopidogrel in patients with head trauma included patients with any traumatic injury (rather than isolated minor head trauma) and analyzed their data by grouping both antiplatelet agents (eg, clopidogrel) and anticoagulants (eg, warfarin) rather than focusing on antiplatelet agents alone, leaving the risk of Intracranial injury after minor head trauma in patients with pre-injury use of clopidogrel as yet undefined. This study sought to define this risk.

Methods

This institutional review board-approved retrospective case control study was performed at a tertiary care, level I adult and pediatric trauma center in Phoenix, AZ. The standard practice pattern at this center is to obtain a Computerized tomography scan on all patients who report pre-injury use of clopidogrel who sustain minor head trauma. This study included all patients over the age of 14 years who received a Head CT.in the ED for minor head trauma during a six

0735-6757/$ - see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2013.08.063

72 M. Levine et al. / American Journal of Emergency Medicine 32 (2014) 71-74

month span. Patients on clopidogrel were compared to those without pre-injury use of clopidogrel.

A list of all head CT scans performed from the ED during the time span was obtained. Investigators reviewed each of these records to determine the indication for neuroimaging (eg, medical versus traumatic etiologies), and subsequently assessed all scans performed for traumatic etiologies for study eligibility. Study eligibility was determined prior to reviewing the medication history or the results of Neuroimaging studies.

Subjects

All adult (age N 14) years who had a head CT for minor head trauma. Subjects may or may not have had a brief (b 1 minute) loss of consciousness. Subjects with a loss of consciousness greater than 1 minute were excluded, as were those who had focal neurologic findings or persistent altered mental status. The use of warfarin was an exclusion criteria, as pre-injury use of warfarin has been previously identified to be an independent risk factor for intracranial injury [12].

Data abstraction

Data abstracted from the medical records included age, sex, use of warfarin, clopidogrel, or aspirin, reason for head CT, loss of conscious- ness (and duration if present), mechanism of trauma, presence of trauma above the clavicles, results of neuroimaging, and outcome.

Prior to data abstraction each reviewer was given a brief training, and five “practice” chartswereabstractedforthepurposeofensuringuniform data abstraction. Data were collected on pre-designed data abstraction sheets, independently, by 2 investigators (ML, BW), and subsequently entered into a spreadsheet (Excel 2007; Microsoft Corp, Redmond, WA). Frequent meetings occurred among the investigators to resolve any differences in chart abstraction, maintain accuracy, and review abstrac- tion methods. Disagreements were resolved with consensus [13].

Definitions

Minor head trauma was defined as any blunt or penetrating head injury with or without a loss of consciousness in a patient who had a non-focal neurologic exam and a Glasgow Coma Scale (GCS) of 15 on first assessment by an emergency physician. If the trauma was unwitnessed, patients were considered to have had a brief loss of consciousness if they could not remember the Traumatic event, or if witnesses reported a loss of consciousness (for which the duration was either unknown or not documented) as long as the patients were awake upon the arrival of emergency medical services. Patients with a documented loss of consciousness greater than 1 minute or who remained unresponsive upon arrival of emergency medical service were considered to have had a Prolonged LOSs of consciousness, and were therefore excluded. Trauma above the clavicles was defined as any deformity, abrasion, laceration, hematoma, or contusion located at or cephalad to the clavicles.

Outcome parameters

The primary outcome was the development of any hemorrhage on head CT, including subdural, epidural, intra-parenchymal, or sub- arachnoid bleeding.

Statistics

For categorical variables, independent associations were assessed via ?² and Fisher Exact tests, as appropriate. Medians and inter- quartile ranges were used to assess non-normally distributed ordinal data. Nonparametric analysis was performed via a Mann-Whitney U test. Odds ratios and 95% confidence intervals were determined to assess the strength of the association between clopidogrel use and the development of head injury, and were calculated based on logistic regression analysis. All statistical analyses were performed using STATA 2007 (STATACorp, College Station, TX).

1660 subjects screened

900 scans done for traumatic indications

760 scans for medical indications

886 unique patient encounters

833 not on anticoagulants

175 with altered mental status

658 subjects meeting eligibility criteria

14 with pre-injury use of warfarin

39 pediatrics

847 adults

14 subjects with multiple visits during study period

Fig. Patient screening and exclusion by criteria.

M. Levine et al. / American Journal of Emergency Medicine 32 (2014) 71-74 73

Results

During the study period 1660 patients head CT scans were performed, of which 658 (39.6%) met inclusion criteria (Fig.). The median (IQR) age of the included patients was 37 (27-49) years and 482/658 (73.3%) were men. A known or presumed brief loss of consciousness was observed in 313 (47.6%) of 658 subjects, and 501 (76.1%) of 658 had evidence of trauma above the clavicles. The mechanisms of injury included falls (28.5%), Motor vehicle collisions (31.7%), assaults (35%), and other/miscellaneous traumas (4.8%). Nearly all patients were ultimately discharged to their home (98%), although 12 patients (1.8%) were ultimately discharged to a skilled nursing or rehabilitation facility. One patient (0.2%) died. The majority of the patients who needed ongoing care after discharge required therapy for their other traumatic injuries, rather than their head injuries. Nonetheless, three patients with head injury, including one with pre-injury use of aspirin and clopidogrel, were discharged to a rehabilitation center or a skilled nursing facility. A ? statistic was analyzed for each variable abstracted and was N 0.8 for each variable. Ten patients had pre-injury use of clopidogrel, of whom 3 (30%) sustained an intracranial hemorrhage. In contrast, of the 648 subjects not taking clopidogrel, 14 (2.2%) sustained an intracranial injury (OR 19.4; 95% CI 4.54-82.9; Pb.05). After adjusting for age, sex, presence of trauma above the clavicles, mechanism of injury, and pre-injury use of aspirin, only pre-injury use of clopidogrel remained statistically

significant (OR 16.7; 95% CI 1.71-162.7).

Discussion

This study is the first to examine patients with minor head trauma who have a GCS of 15 on arrival who had a history of pre- injury use of clopidogrel and compare them to those without pre- injury use of antiplatelet agents. The odds of sustaining an intracranial injury are significantly greater in those on clopidogrel and are also significantly greater than previously published estimates of intracranial injury in patients with minor head trauma not on antiplatelet agents [3].

Similar to studies involving New Orleans Criteria, this study required subjects to have a GCS of 15 on arrival to be defined as having had minor head trauma [3]. Both the current study and the New Orleans Criteria permitted patients to have altered mental status prior to arrival, but patients were considered “minor” so long as their GCS was 15 upon initial assessment by an emergency physician. Other studies, such as the Canadian CT Head rule, included patients with a GCS of 13-15 in their definition of minor trauma [1,14].

In 2011, Brewer and colleagues published their study of the incidence of intracranial hemorrhage after minor head trauma in patients with pre-injury use of either clopidogrel or warfarin at a level II trauma center over three years [15]. Similar to the current study, Brewer only included patients with a GCS of 15. However, the majority of their 141 patients were anticoagulated with warfarin. Of the 36 patients receiving clopidogrel with or without aspirin, 24/39 (61%) had negative head CTs, while 15/39 (38%) had abnormal head CT scans. The percentage of abnormal head CTs in patients on clopidogrel in their population was similar to that observed in this study.

The risks of immediate and delayed head injury in patients with pre-injury use of clopidogrel or warfarin was also recently examined by Nishijima and colleagues [16]. The authors enrolled 1064 patients at 6 hospitals, of whom 296 had pre-injury use of clopidogrel and of whom 276 (93.2%) received a head CT. In these 276 subjects on clopidogrel who had head CTs, 12% (33/276; 95% CI 8.4-16.4%) were found to have a traumatic intracranial hemorrhage. While 87.6% of all subjects in their study had a GCS of 15 on arrival, one third (11/33) of the subjects on clopidogrel who had intracranial hemorrhage did not have a normal mental status as defined by the New Orleans Criteria

[3]. The following year, the same group conducted a prospective, observational study in adult patients with mild Blunt head trauma (GCS 13-15) with preinjury use of warfarin or clopidogrel and were unable to identify any specific characteristics of such patients which would lead to a low-risk classification [17]. Consequently, the authors recommend all patients with pre-injury use of clopidogrel or warfarin obtain a CT in an urgent manner.

Fabri and colleagues examined 1,558 patients at 32 EDs in Italy with mild, moderate, and severe head injury [18]. In their study, 72% of patients had mild head injury (defined as GCS 14 or 15), 25% had moderate head injury (defined as GCS 9-13), and 1% of subjects had severe head injury (defined as GCS b 8). From this cohort, 537 subjects were identified with pre-injury use of aspirin ticlopidine, clopidogrel, or nonsteroidal anti-inflammatory drugs. In their study, the risk of developing a worsening intracranial injury on follow up head CT was twice as great in those patients on antiplatelet agents compared to those not on antiplatelet agents. Similar to the current study, Fabri et al noted an increased risk of intracranial injuries in those with pre- injury use of clopidogrel.

While several studies have examined the risk of head injury in those with pre-injury use of antiplatelet agents, this study was the first to limit the study population to those with a GCS of 15 on arrival to the ED. Despite more strict inclusion criteria than prior studies, the current study found a higher rate of intracranial injury compared with prior studies. While larger, prospective studies are likely needed to define the exact risk of traumatic intracranial hemorrhage in this study population, this study does demonstrate an increased risk of intracranial hemorrhage in patients on clopidogrel with minor head trauma and supports the recommendation by Nishijima and col- leagues [17] to urgently obtain neuroimaging in all patients on clopidogrel with minor head trauma.

The study is limited by its retrospective nature, and hence the conclusions are limited by the completeness and quality of the data and reliability of patient medication history as noted in the medical records. In an effort to reduce such a limitation, data abstracted were limited to categorical variables (eg, presence or absence of hemor- rhage on CT). The CT scans were not re-read for this study, but rather restricted to the final radiologist interpretations in an effort to maximize interrater reliability, as evidenced by the high ? score.

Overall, there were relatively few number of patients on

clopidogrel, and even fewer with intracranial injuries. These small numbers resulted in large confidence intervals, and thus may limit a true estimation of the effect of clopidogrel in patients with minor head trauma. Nonetheless, it is clear that such an effect exists.

Conclusion

In this study of patients with minor head trauma and a GCS of 15 on arrival to the ED, pre-injury use of clopidogrel was a statistically significant independent risk factor for the development of intracranial hemorrhage.

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