Meurer, William J.

Abstract This third Guideline for Reasonable and Appropriate Care in the Emergency Department (GRACE‐3) from the Society for Academic Emergency Medicine is on the topic adult patients with acute dizziness and vertigo in the emergency department (ED). A multidisciplinary guideline panel applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding five questions for adult ED patients with acute dizziness of less than 2 weeks' duration. The intended population is adults presenting to the ED with acute dizziness or vertigo. The panel derived 15 evidence‐based recommendations based on the timing and triggers of the dizziness but recognizes that alternative diagnostic approaches exist, such as the STANDING protocol and nystagmus examination in combination with gait unsteadiness or the presence of vascular risk factors. As an overarching recommendation, (1) emergency clinicians should receive training in bedside physical examination techniques for patients with the acute vestibular syndrome (AVS; HINTS) and the diagnostic and therapeutic maneuvers for benign paroxysmal positional vertigo (BPPV; Dix–Hallpike test and Epley maneuver). To help distinguish central from peripheral causes in patients with the AVS, we recommend: (2) use HINTS (for clinicians trained in its use) in patients with nystagmus, (3) use finger rub to further aid in excluding stroke in patients with nystagmus, (4) use severity of gait unsteadiness in patients without nystagmus, (5) do not use brain computed tomography (CT), (6) do not use routine magnetic resonance imaging (MRI) as a first‐line test if a clinician trained in HINTS is available, and (7) use MRI as a confirmatory test in patients with central or equivocal HINTS examinations. In patients with the spontaneous episodic vestibular syndrome: (8) search for symptoms or signs of cerebral ischemia, (9) do not use CT, and (10) use CT angiography or MRI angiography if there is concern for transient ischemic attack. In patients with the triggered (positional) episodic vestibular syndrome, (11) use the Dix–Hallpike test to diagnose posterior canal BPPV (pc‐BPPV), (12) do not use CT, and (13) do not use MRI routinely, unless atypical clinical features are present. In patients diagnosed with vestibular neuritis, (14) consider short‐term steroids as a treatment option. In patients diagnosed with pc‐BPPV, (15) treat with the Epley maneuver. It is clear that as of 2023, when applied in routine practice by emergency clinicians without special training, HINTS testing is inaccurate, partly due to use in the wrong patients and partly due to issues with its interpretation. Most emergency physicians have not received training in use of HINTS. As such, it is not standard of care, either in the legal sense of that term (“what the average physician would do in similar circumstances”) or in the common parlance sense (“the standard action typically used by physicians in routine practice”).

Background and Purpose: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. Methods: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. Results: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09–1.21]; P =0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32–1.34]; P =0.25) among noncarriers. There was no significant interaction by genotype for major ischemia ( P =0.36) or stroke ( P =0.33). Conclusions: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00991029.

Background and Purpose— Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The c ombined approach to l ysis utilizing e ptifibatide a nd r ecombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination. Methods— The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke–funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 μg/kg bolus followed by 0.75 μg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy. Results— Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 ( P =0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 ( P =0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA–only arm ( P =0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group. Conclusions— The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.