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Emergency medicine (EM) is the front line of research in neurologic emergencies. Entities such as stroke, traumatic brain injury, and nonconvulsive seizure are time-sensitive pathologies; a very narrow diagnostic and therapeutic window exists to prevent long-lasting sequelae. The pivotal role of EM in the treatment of such conditions has not gone unnoticed by the National Institutes of Health and has led to the development of the Neurological Emergencies Treatment Trials (NETT) network.[1]

Of critical interest to emergency physicians is the effect of antiplatelet or anticoagulant therapy on the management of patients suffering from head injury or stroke. Antiplatelet agents including aspirin, warfarin, thienopyridines (e.g., clopidogrel and ticolidine), and a wave of recent additions are regularly used alone or in combination for treating coronary syndromes, peripheral vascular disease, and stroke. While the combination of clopidogrel and aspirin is not recommended for prevention of cardiovascular events, even in high-risk patients (due to the lack of clear benefits),[2, 3] the use of this combination has shown early benefit during and after acute cardiovascular events (e.g., myocardial infarction) or in patients undergoing stenting or similar procedures.[4] Using this regimen in this particular patient population is associated with a number needed to treat of 50 for preventing new cardiovascular events (i.e., one new cardiovascular event will be prevented for every 50 patients treated), 77 for preventing nonfatal myocardial infarction, and 200 for nonfatal stroke prevention.[5] Unfortunately, these treatments are not without risk. The number needed to harm for this regimen is 400 for major bleeding events (event requiring hospitalization or transfusion), 71 for rash, and 91 for other side effects (e.g., diarrhea).[5] Currently, an ongoing multicenter trial (POINT trial) is assessing the benefits of early loading of clopidogrel in patients with transient ischemic attack.[6]

There has been a growing concern over the effect of antiplatelet agents in patients with head trauma, stroke, and intracranial hemorrhage (ICH). In a large multicenter trial (n = 1,064), Nishijima et al.[7] showed that the risk of immediate ICH in patients with head injury and preinjury antiplatelet use was even higher than in those on warfarin (12% in clopidogrel group vs. 5% in warfarin group; relative risk = 2.31; 95% confidence interval = 1.5 to 3.6).[7] In this issue of Academic Emergency Medicine, the same investigators show that the use of preinjury clopidogrel was associated with significantly higher risk of immediate ICH in a subgroup of patients with minor head trauma.[8] Unfortunately, these investigators were not able to create a clinical decision rule for predicting ICH in minor head trauma patients on antiplatelet agents.

While this study successfully attracts our attention to a serious and complex matter pertaining to the care of these patients, its observational nature warrants some caution in interpretation of the results. The highly plausible association between antiplatelet agents and ICH might not necessarily translate into causation. In addition, the small number of patients with ICH (primary outcome), and the relatively small total sample size for deriving a decision rule, prevented the authors from accounting for all possible confounding variables in their analysis.

In another research article published in this issue,[9] investigators assessed the risk of ICH in stroke patients taking antiplatelet agents and undergoing thrombolysis. This study reviewed data from 830 patients undergoing thrombolysis after stroke, with almost half of patients on preexisting antiplatelet treatment.[9] These investigators showed that in this population, prestroke use of antiplatelet agents was not associated with increased risk of ICH after thrombolysis. They then combined their results with those of other studies to perform a meta-analysis. This analysis suggested that there might be a small but statistically significant increase in the absolute risk of radiographic and symptomatic ICH in patients with preexisting antiplatelet use. The investigators further noted an increased bleeding rate in patients above the age of 80 on antiplatelet therapy. Unfortunately, this study was not able to investigate the effect of dose, timing, and dual antiplatelet therapy on outcomes.[9]

Moving forward, how do we balance the proven prophylactic benefit of these medications with the apparent increased bleeding risk? Reviewing the evidence for risk and benefit of antiplatelets indicates that these agents should be carefully selected for each individual and each indication. Joint research between EM, primary care, cardiology, neurology, surgery, and neurosurgery is needed to further guide the practice of prescribing these agents (single agent or combination therapy).

In patients with minor head trauma with preinjury use of antiplatelets, we do not have clear guidelines for identifying patients who require computed tomography (CT) scan or those who are low risk enough to allow forgoing the radiation. Furthermore, the current guidelines used to stratify the risk of ICH or the need for imaging do not take into consideration the use of antiplatelet agents. For example, using loss of consciousness as a criterion for ordering head CT would have missed many ICH in the study subjects enrolled in the two trials mentioned here. Given the real potential for poor outcomes, the threshold for imaging must remain low in this patient population. This approach is especially important considering that the available treatment options to decrease bleeding complications (e.g., platelet transfusion) in patients with traumatic ICH and preinjury antiplatelet have not been associated with improvement in clinically important outcomes.[10] There are ongoing studies looking into alternative options for improving the platelet function in such circumstances (e.g., using 1-deamino-8-d-arginine vasopressin, or DDAVP).[11]

We are still unclear on whether there are additional risks to consider in acute stroke patients on antiplatelet agents who are candidates for thrombolysis. The combined data suggest that there may be an increased risk of ICH after thrombolysis, albeit slight. While this may not necessarily change our treatment strategy, currently it is reasonable to further explore the potential risks, especially in those over the age of 80 years and on antiplatelet therapy. It may also be important to bring up this point when discussing thrombolysis option with the patients or their families.

The continuous development and approval of new oral direct thrombin and factor X inhibitors further escalate the challenges facing emergency physicians. Some of the unique characteristics of these new agents are the absence of effective reversal agents. A recent meta-analysis found a threefold increase in major bleeding events with the use of new-generation oral anticoagulants among patients receiving antiplatelet therapy after acute coronary syndrome.[12]

In summary, physicians should become familiar with the risks associated with the use of antiplatelet agents and should carefully consider the risk/benefit profile for each individual prior to starting antiplatelet therapy. We need to expeditiously gather data to define the effect of antiplatelet agents on the prevalence and morbidity of ICH and create a CT decision rule for patients with minor head injury who are on these agents. However, the work of Nishijima et al. presented here highlights the challenges ahead in achieving the latter goal. We also need to further investigate the role that antiplatelet agents may play in increasing postthrombolysis bleeding and in risk-stratifying stroke patients undergoing thrombolysis. Developing and implementing such plans to define and refine the role of antiplatelets in intracranial bleeding will require tremendous energy and effort, but will certainly result in improvement of patient-oriented outcomes. General George Patton once stated: “A good plan violently executed now is better than a perfect plan executed next week.”[13] He also rationalized, “A pint of sweat will save a gallon of blood.”[14]

References

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  2. References
  • 1
    University of Michigan Health System. Neurological Emergencies Treatment Trials. Available at: http://nett.umich.edu/nett/welcome. Accessed Nov 30, 2012.
  • 2
    Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354:170617.
  • 3
    Squizzato A, Keller T, Romualdi E, Middeldorp S. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane Database Syst Rev. 2011; (1):CD005158.
  • 4
    Bowry A, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J Cardiol. 2008; 101:9606.
  • 5
    The Number Needed to Treat (NNT). Clopidogrel to Prevent Cardiovascular Disease for People Who Have Had Heart Attacks or Strokes. Available at: http://www.thennt.com/clopidogrel-for-cardiovascular-prevention-after-prior-heart-attack-or-stroke. Accessed Nov 30, 2012.
  • 6
    Clinical Coordinating Center, NINDS NETT Network, Clinical Research Collaboration. Platelet-oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial. Available at: http://www.pointtrial.org. Accessed Nov 30, 2012.
  • 7
    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; 59:4608.
  • 8
    Nishijima DK, Offerman SR, Ballard DW, et al. Risk of intracranial hemorrhage in patients with minor head injury on antiplatelets and warfarin. Acad Emerg Med. 2013; 20:00000.
  • 9
    Meurer WJ, Kwok H, Skolarus LE, et al. Does preexisting antiplatelet treatment influence postthrombolysis intracranial hemorrhage in community treated ischemic stroke patients: an observational study. Acad Emerg Med. 2013; 20:00000.
  • 10
    Nishijima DK, Zehtabchi S, Berrong J, Legome E. Utility of platelet transfusion in adult patients with traumatic intracranial hemorrhage and preinjury antiplatelet use: a systematic review. J Trauma Acute Care Surg. 2012; 72:165863.
  • 11
    Levine M, Swenson S, McCormick T, Henderson SO, Thomas SH, Markland FS. Reversal of thienopyridine-induced platelet dysfunction following desmopressin administration. J Med Toxicol. 2012; [Epub ahead of print] doi 10.1007/s13181-012-0275–6.
  • 12
    Komocsi A, Vorobcsuk A, Kehl D, Aradi D. Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012; 172:153745.
  • 13
    Estate of General George S. Patton Jr. The Official Website of General George S. Patton, Jr. Available at: http://www.generalpatton.com/quotes/index.html. Accessed Nov 30, 2012.
  • 14
    Humes JC. Speak like Churchill, Stand Like Lincoln: 21 Powerful Secrets of History's Greatest Speakers. New York, NY: Three Rivers Press, 2002.