Reduction in the severity and duration of headache following fremanezumab treatment in patients with episodic and chronic migraine.

OBJECTIVE: To evaluate the impact of fremanezumab on the severity and duration of remaining migraine attacks in patients with chronic migraine (CM) or episodic migraine (EM). BACKGROUND: Fremanezumab is a fully humanized monoclonal antibody (IgGΔa) that selectively targets calcitonin gene-related peptide and is efficacious in reducing migraine frequency. METHODS: This exploratory post hoc analysis included data from three randomized, double-blind, 12-week, phase 3 studies (HALO CM, HALO EM, and FOCUS). In all three studies, patients with CM or EM were randomized 1:1:1 to receive subcutaneous quarterly fremanezumab (month 1/2/3: 675 mg/placebo/placebo), monthly fremanezumab (month 1/2/3: 675 mg [CM], 225 mg [EM]/225 mg/225 mg), or matched monthly placebo. Changes from baseline were evaluated in the proportion of headache days of at least moderate severity, peak severity of headache days, mean monthly headache hours (of any severity and at least moderate severity), and mean headache hours per headache day of any severity. RESULTS: A total of 2843 patients were randomized with 2823 patients included in the efficacy analyses across all studies (HALO CM, N = 1121; HALO EM, N = 865; FOCUS, N = 837). At study baseline, mean (standard deviation [SD]) monthly number of headache days rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 13.2 (5.5), 12.8 (5.8), and 13.3 (5.8) in HALO CM; 7.2 (3.1), 6.8 (2.9), and 6.9 (3.1) in HALO EM; and 12.4 (5.8), 12.7 (5.8), and 12.8 (5.9) in FOCUS. Patients experienced significant least-squares mean (LSM; 95% confidence interval) percent reductions from baseline in monthly number of headache days rated moderate or severe during the 12 weeks: HALO CM, quarterly fremanezumab, 34.5% (-39.8, -29.2) and monthly fremanezumab, 36.2% (-41.4, -31.0) vs. placebo, 19.6% (-20.0, -14.3); HALO EM, quarterly fremanezumab, 40.7% (-47.8, -33.5) and monthly fremanezumab, 43.4% (-50.4, -36.3) vs. placebo, 17.9% (-24.9, -11.0); and FOCUS, quarterly fremanezumab, 36.5% (-41.9, -31.1) and monthly fremanezumab, 38.6% (-44.0, -33.3) vs. placebo, 3.5% (-8.9, 1.8); all p < 0.0001. At study baseline, mean (SD) number of monthly headache hours rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 66.4 (58.8), 68.0 (53.9), and 68.5 (57.0) in HALO CM; 33.3 (25.4), 31.7 (23.7), and 31.6 (23.2) in HALO EM; and 59.2 (54.7), 64.3 (65.2), and 65.9 (70.2) in FOCUS. Significant reductions were observed in LSM (standard error) number of monthly headache hours of at least moderate severity: HALO CM, quarterly fremanezumab, 24.4 (2.5) and monthly fremanezumab, 26.4 (2.3) vs. placebo, 14.1 (2.5); HALO EM, quarterly fremanezumab, 14.5 (1.4) and monthly fremanezumab, 15.5 (1.3) vs. placebo, 8.1 (1.3); and FOCUS, quarterly fremanezumab, 16.8 (3.0) and monthly fremanezumab, 18.3 (3.0) vs. placebo, 2.3 (3.0); all p < 0.001. CONCLUSION: These analyses demonstrated that quarterly or monthly treatment with fremanezumab significantly reduced headache severity and duration in patients with CM or EM, including in patients with documented inadequate response to two to four prior migraine preventive medication classes.

Treatment benefit among migraine patients taking fremanezumab: results from a post hoc responder analysis of two placebo-controlled trials.

BACKGROUND: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials? METHODS: We included subjects with episodic migraine (EM) or chronic migraine (CM) who received fremanezumab quarterly (675 mg/placebo/placebo) or monthly (EM: 225 mg/225 mg/225 mg; CM: 675 mg/225 mg/225 mg) during the 12-week randomized, double-blind, placebo-controlled HALO EM and HALO CM clinical trials. EM and CM responders were defined as participants with a reduction of ≥ 2 or ≥ 4 monthly migraine days, respectively. Treatment benefits evaluated included reductions in monthly migraine days, acute headache medication use, and headache-related disability, and changes in health-related quality of life (HRQoL). RESULTS: Overall, 857 participants from the HALO trials were identified as responders (EM: 429 [73.8%]; CM: 428 [56.7%]). Reductions in the monthly average number of migraine days were greater among EM (quarterly: 5.4 days; monthly: 5.5 days) and CM (quarterly: 8.7 days; monthly: 9.1 days) responders compared with the overall population. The proportion of participants achieving ≥ 50% reduction in the average monthly number of migraine days was also greater in responders (EM: quarterly, 59.8%; monthly, 63.7%; CM: quarterly, 52.8%; monthly, 59.0%) than in the overall population. Greater reductions in the average number of days of acute headache medication use, greater reductions in headache-related disability scores, and larger improvements in HRQoL were observed among EM and CM responders compared with the overall populations. CONCLUSIONS: Fremanezumab responders achieved clinically meaningful improvements in all outcomes. The magnitude of improvements with fremanezumab across efficacy outcomes was far greater in responders than in the overall trial population, providing insight into expected treatment benefits in participants who respond to fremanezumab in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02629861 (HALO EM) and NCT02621931 (HALO CM).

Variability in Blood Eosinophil Counts in Patients with Eosinophilic Asthma.

BACKGROUND: Blood eosinophil (EOS) counts are critical to the accurate identification of asthma phenotypes. However, there are few long-term data on intraindividual EOS count variability among patients with eosinophilic asthma. OBJECTIVE: This post hoc analysis of 2 phase III clinical trials from the reslizumab BREATH program explored the variability of blood EOS counts in patients with eosinophilic asthma receiving placebo. METHODS: Pooled data from study participants receiving placebo (previously randomized 1:1 to receive reslizumab or placebo) were analyzed for blood EOS count variability over 52 weeks. EOS counts were measured up to twice during screening, every 4 weeks from randomization to the end of treatment and at the 90-day follow-up visit. RESULTS: Of 476 included patients, 31 (6.5%), 38 (8.0%), 55 (11.6%), and 352 (73.9%) patients had baseline blood EOS counts of <150, ≥150 to <300, ≥300 to <400, and ≥400 cells/µL, respectively. Patients frequently shifted between EOS count categories during the 52-week treatment period, most often moving to the highest EOS category. Among patients in each of the lower 3 EOS categories, 27% to 56% of patients shifted to the ≥400 cells/µL category at some point during the treatment period. CONCLUSION: Intraindividual variability in blood EOS count was high among patients with eosinophilic asthma receiving placebo, with shifts to ≥400 cells/µL from lower categories frequently observed. Repeat determinations of blood EOS count may be important to ensure appropriate selection of therapy in patients with severe asthma.

In patients with severe asthma with eosinophilia in reslizumab clinical trials, high peripheral blood eosinophil levels are associated with low FEV1 reversibility.

BACKGROUND: A post hoc analysis of two randomized, placebo-controlled, Phase 3 trials of intravenous reslizumab, an anti-interleukin-5 (IL-5) biologic for severe eosinophilic asthma. METHODS: Relationships between baseline blood eosinophil levels (EOS), forced expiratory volume in 1 s (FEV1) reversibility to ß2-agonists and treatment outcomes were assessed. RESULTS: Mean baseline FEV1 reversibility was numerically lower among patients with high (≥ 400 cells/µL) versus low baseline EOS. Reslizumab produced clinically significant improvement in FEV1, exacerbation rates and patient-reported outcomes after 52 weeks, including in patients with high EOS and low FEV1 reversibility (≤ 14%) to ß2-agonists at baseline. CONCLUSIONS: Clinical trial eligibility criteria stipulating minimum FEV1 reversibility to ß2-agonists of ≥ 12% might exclude patients who would benefit from treatment with anti-IL-5 biologics.

Teaching residents to work with torture survivors: experiences from the Bronx Human Rights Clinic.

INTRODUCTION: Despite the 1984 United Nations's Convention Against Torture calling to train doctors to work with torture survivors, many physicians are unaware of their obligation and few are taught the requisite clinical skills. AIM: To describe the development, implementation, and evaluation of a curriculum to teach residents to work with torture survivors. PARTICIPANTS: Medicine residents in New York City PROGRAM DESCRIPTION: A 2-component curriculum consisting of a series of workshops and clinical experiences, which provide content, skills, and practices regarding the medical, psychological, ethical, and legal aspects of evaluating and caring for torture survivors. CURRICULUM EVALUATION: All 22 trainees received surveys before and after training. Surveys assessed residents' relevant prior experience, beliefs, skills, and attitudes regarding working with torture survivors. At baseline, 23% of residents described previous human rights trainings and 17% had work experiences with torture survivors. Before the curriculum, 81% of residents reported doctors should know how to evaluate survivors, although only 5% routinely screened patients for torture. After the curriculum, residents reported significant improvements in 3 educational domains-general knowledge, sequelae, and self-efficacy to evaluate torture survivors. DISCUSSION: This curriculum addresses the disparity between doctors' obligations, and training to work with torture survivors. It is likely to achieve its educational goals, and can potentially be adapted to other residencies.

The effect of race on provider decisions to test for illicit drug use in the peripartum setting.

BACKGROUND: Testing for illicit drugs may expose women who test positive to severe legal and social consequences. It is unknown whether racial disparities in drug testing practices underlie observed disparities in legal and social consequences of positive tests. METHODS: Using administrative hospital and birth certificate data, we analyzed factors associated with both receipt and results of illicit drug testing among women with live births during 2002-2003. We assessed the independent association of race and other sociodemographic factors with both receipt of a drug test by the mother or her newborn infant and positive maternal or neonatal toxicology results, after controlling for obstetrical conditions and birth outcomes associated with maternal substance abuse. RESULTS: Of the 8487 women with live births, 244 mother-newborn pairs (3%) were tested for illicit drug use. Black women and their newborns were 1.5 times more likely to be tested for illicit drugs as nonblack women in multivariable analysis. However, race was not independently associated with a positive result. CONCLUSIONS: We identified racial differences in rates of testing for illicit drug use between black and nonblack women. We found equivalent positivity rates among tested black and nonblack women. The prevalence of drug use among untested women is unknown, however, so although tested women had equivalent rates of substance use detected, whether black and nonblack substance users are equally likely to be identified in the course of peripartum care remains uncertain.

Effects of pegylated interferon alfa-2b on the pharmacokinetic and pharmacodynamic properties of methadone: a prospective, nonrandomized, crossover study in patients coinfected with hepatitis C and HIV receiving methadone maintenance treatment.

BACKGROUND: Hepatitis C virus (HCV) infection is common among methadone-maintained HIV-positive individuals. Pegylated interferon (pegIFN) used in combination with ribavirin is conventional treatment for HCV. However, pegIFN has been associated with adverse effects (AEs) that may simulate opioid withdrawal and be confused with insufficient methadone dosage. OBJECTIVE: The aim of this study was to determine, using methadone pharmacokinetic properties, whether methadone dosage adjustments are needed on initiation of treatment with pegIFN alfa-2b for HCV in methadone-maintained HIV-positive patients. METHODS: This prospective, nonrandomized, crossover study was conducted at the Albert Einstein College of Medicine and Montefiore Medical Center (Bronx, New York). Patients who were aged > or =18 years, coinfected with chronic HCV and HIV, and had been receiving methadone maintenance treatment (dosage, 40-200 mg/d PO) for at least 8 weeks prior to enrollment were eligible. We determined mean methadone C(max), T(max), Cn,in, AUC, and oral clearance (CL/F) values over a 24-hour period before (baseline) and after the administration of pegIFN alfa-2b 1.5 microg/kg SC (2 doses given 1 week apart). To determine differences in opiate withdrawal symptoms, one of the primary investigators administered the Subjective Opiate Withdrawal Scale (SOWS) and Objective Opiate Withdrawal Scale (OOWS) at baseline and 7, 14, and 21 days after the administration of the first dose. Study participants underwent weekly clinical evaluation for signs and symptoms of methadone withdrawal and for AEs of pegIFN. RESULTS: Nine patients were included in the study (7 men, 2 women; 7 Hispanic, 2 black; mean [SD] age, 41 [8.3] years; mean [SD] weight, 75.0 [12.3] kg). We did not observe any significant changes from baseline in mean C(max), T(max), C(min), AUC, and CL/F values despite 80% power to detect a 30% change in either direction. Changes from baseline in SOWS and OOWS scores were not statistically significant. The only AEs reported were mild and consistent with those expected after pegIFN alfa-2b administration, such as inflammation at the injection site and mild, brief, flu-like symptoms. CONCLUSION: Based on the results of this small, prospective, nonrandomized study, pegIFN alfa-2b did not appear to precipitate opioid withdrawal in this sample of methadone-maintained persons with HIV and chronic HCV coinfection; methadone dosage adjustments were unlikely to be needed.

A randomized, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients.

OBJECTIVE: To determine whether ketamine administration affects markers of inflammation in cardiac surgery with cardiopulmonary bypass (CPB) and to investigate differences between 2 low-dose ketamine regimens. DESIGN: Prospective, randomized, placebo-controlled trial. SETTING: Single-center university hospital. PARTICIPANTS: Patients undergoing cardiac surgery with CPB. INTERVENTION: Patients (n = 50) were randomized to 1 of 3 groups: ketamine, 0.25 mg/kg (n = 15); ketamine, 0.5 mg/kg (n = 18);or placebo (n = 17) in a double-blind manner at the time of induction of general anesthesia. MEASUREMENTS AND MAIN RESULTS: Serum C-reactive protein (CRP) and interleukin (IL)-6, IL-8, and IL-10 were measured at baseline, on intensive care unit (ICU) arrival, and on the first postoperative day (POD 1). Both ketamine doses decreased the serum IL-6 response at ICU arrival and POD 1 compared with placebo (p < 0.05). CRP was lower in the 0.5-mg/kg group than placebo on POD 1 (p = 0.003). IL-10 was lower in the ketamine groups (p = 0.01) at POD 1 compared with placebo; IL-8 levels were not affected by ketamine. Mean arterial pressure and systemic vascular resistance were higher at the end of surgery, arrival in the ICU, and POD 1 in the ketamine groups (p < 0.05). CONCLUSION: Low-dose ketamine (0.5 mg/kg) attenuates increases in CRP, IL-6, and IL-10 while decreasing vasodilatation after CPB.

Quantitative continuous EEG for detecting delayed cerebral ischemia in patients with poor-grade subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI) due to vasospasm is often undetected by clinical exam in patients with poor-grade subarachnoid hemorrhage (SAH). The purpose of this study was to identify quantitative EEG (qEEG) parameters that are most sensitive and specific for the detection of DCI in stuporous or comatose SAH patients. METHODS: Of 78 consecutive Hunt-Hess grade 4 or 5 SAH patients admitted to our Neuro-ICU over a 2-year period, 48 were eligible for participation and 34 were enrolled. Continuous EEG monitoring was performed from post-operative day 2 to post-SAH day 14. In each patient, 20 artifact-free, 1 min EEG-clips following an alerting stimulus were analyzed: 10 clips were obtained on monitoring day 1 (baseline), and 10 on days 4-6 (follow-up). In DCI patients, follow-up clips were obtained after the onset of deterioration and before infarction had occurred. Twelve qEEG parameters were calculated using fast Fourier transformation; generalized estimating equations were used to compare ratios of change in qEEG parameters in patients with and without DCI. RESULTS: Nine of 34 patients (26%) developed DCI. The alpha/delta ratio (alpha power/delta power; ADR) demonstrated the strongest association with DCI. The median decrease of ADR for patients with DCI was 24%, compared to an increase of 3% for patients without DCI (Z=4.0, P<0.0001). Clinically useful cut-offs included 6 consecutive recordings with a >10% decrease in ADR from baseline (sensitivity 100%, specificity 76%) and any single measurement with a >50% decrease (sensitivity 89%, specificity 84%). CONCLUSIONS: A decrease in the ADR may be a sensitive method of detecting DCI, with reasonable specificity. This post-stimulation qEEG parameter may supplement the clinical exam in poor-grade SAH patients and may prove useful for the detection of DCI. SIGNIFICANCE: Following ADRs may allow earlier detection of DCI and initiation of interventions at a reversible stage, thus preventing infarction and neurological morbidity.

Effect of acute physiologic derangements on outcome after subarachnoid hemorrhage.

OBJECTIVE: To determine the effect that acute physiologic derangements have on outcome after subarachnoid hemorrhage (SAH) and to design a composite score summarizing these abnormalities. DESIGN: Prospective observational study. SETTING: Neuroscience intensive care unit in a tertiary care academic center. PATIENTS: Consecutive cohort of 413 patients with SAH admitted within 3 days of SAH onset with 3-month modified Rankin Scale scores. INTERVENTIONS: None. RESULTS: Among 20 physiologic variables assessed within 24 hrs of admission, four were independently associated with death or severe disability (modified Rankin Scale score, 4-6) at 3 months in a multivariate analysis: arterio-alveolar gradient of >125 mm Hg (odds ratio [OR], 4.5; 95% confidence interval [CI], 2.7-7.6), serum bicarbonate of <20 mmol/L (OR, 2.9; 95% CI, 1.6-5.6), serum glucose of >180 mg/dL (OR, 2.8; 95% CI, 1.6-4.8), and mean arterial pressure of <70 or >130 mm Hg (OR, 1.7; 95% CI, 1.0-2.9). Based on their proportional contribution to outcome, we constructed the SAH Physiologic Derangement Score (SAH-PDS; range, 0-8) by assigning the following weights for abnormal findings: arterio-alveolar gradient, 3 points; bicarbonate, 2 points; glucose, 2 points; and mean arterial pressure, 1 point. After controlling for known predictors of death or severe disability (age, admission neurologic status, loss of consciousness, aneurysm size, intraventricular hemorrhage, and rebleeding), the SAH Physiologic Derangement Score was independently associated with poor outcome (OR, 1.3 for each point increase; 95% CI, 1.1-1.6). By contrast, the systemic inflammatory response syndrome score and the Acute Physiology and Chronic Health Evaluation II physiologic subscore did not add predictive value to the model. CONCLUSION: Acute interventions specifically targeting hypoxemia, metabolic acidosis, hyperglycemia, and cardiovascular instability may improve the outcome of SAH patients. The SAH Physiologic Derangement Score may prove useful for rapidly quantifying the severity of important physiologic derangements in acute SAH.

Failure of intraoperative jugular bulb S-100B and neuron-specific enolase sampling to predict cognitive injury after carotid endarterectomy.

OBJECTIVE: Cognitive decline occurs in 25% of patients after carotid endarterectomy (CEA). Elevated serum concentrations of S-100B and neuron-specific enolase (NSE) occur after stroke, and serum S-100B levels at 24 hours are associated with clinical outcome after both stroke and CEA. We hypothesized that we could detect acute elevations in serum levels of these markers obtained intraoperatively from the jugular bulb (JB) and that these elevations would predict cognitive dysfunction postoperatively as measured by neuropsychometric test performance. METHODS: Forty-three patients scheduled for elective CEA were assessed with a battery of neuropsychometric tests before and 1 day after surgery. Before the carotid artery was clamped, a 6-French Fogarty catheter was inserted into the facial vein and threaded 6 cm rostrally into the JB. Serum samples were withdrawn from this catheter and simultaneously from a radial arterial catheter (A-line) at three time points: before clamping, 15 minutes into clamping, and after unclamping the carotid artery. Concentrations between groups were compared by analysis of variance and paired t tests. RESULTS: Total deficit scores were significantly worse in 13 (30%) of the 43 patients 1 day after surgery. There was a trend toward elevations in JB concentrations of S-100B relative to A-line levels 15 minutes after cross-clamping (11% elevation, P = 0.079, paired t test). In addition, 15 minutes after clamping of the carotid artery, levels of S-100B from the JB were significantly elevated compared with levels at baseline (P = 0.040, one-way analysis of variance). No significant changes were found between any time point in levels of S-100B from the A-line blood or of NSE from either the JB or the A-line. Subtle cognitive decline after CEA was not correlated with intraoperative levels of S-100B or NSE, but there was a weak, statistically nonsignificant, association between a rise in 15-minute S-100B levels and cognitive injury that was not seen with JB samples. CONCLUSION: Although intraoperative levels of S-100B and NSE from the JB failed to predict cognitive injury, carotid cross-clamping, independent of injury, seems to be associated with early elevations in S-100B.

Piloting web-based NAMCS data collection for nurse-managed centers.

Research consistently has shown that Nurse Practitioners (NPs) provide health care equivalent to that of physicians, and especially excel in patient education and case management, essential interventions to promote self-care in chronically ill ambulatory patients. Yet large-scale national studies have not been done. Nurse-managed centers are not included in the sampling frame of the National Ambulatory Medical Care Survey (NAMCS) and only 2.1% of the 2000 sample was from patient encounters with NPs.1 The aims of this pilot study were to create a web-based format for the NAMCS; to expand it by adding selected nursing diagnoses, interventions, and outcomes; and to pilot-test it with 300 patient encounters in 5 nurse-managed centers.

Global cerebral edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome.

BACKGROUND AND PURPOSE: Cerebral edema visualized by CT is often seen after subarachnoid hemorrhage (SAH). Inflammatory or circulatory mechanisms have been postulated to explain this radiographic observation after SAH. We sought to determine the frequency, causes, and impact on outcome of early and delayed global cerebral edema after SAH. METHODS: We evaluated the presence of global edema on admission and follow-up CT scans in 374 SAH patients admitted within 5 days of onset to our Neurological Intensive Care Unit between July 1996 and February 2001. Using multivariate analysis, we identified predictors of global cerebral edema and evaluated the impact of global edema on outcome 3 months after onset with the modified Rankin Scale. RESULTS: Global edema was present on admission CT scans in 8% (n=29) and developed secondarily in 12% (n=44) of the patients. Global edema on admission was predicted by loss of consciousness at ictus and increasing Hunt-Hess grade. Delayed global edema was predicted by aneurysm size >10 mm, loss of consciousness at ictus, use of vasopressors, and increased SAH sum scores. Thirty-seven percent (n=137) of the patients were dead or severely disabled (modified Rankin Scale 4 to 6) at 3 months. Death or severe disability was predicted by any global edema, aneurysm size >10 mm, loss of consciousness at ictus, increased National Institutes of Health Stroke Scale scores, and older age. CONCLUSIONS: Global edema is an independent risk factor for mortality and poor outcome after SAH. Loss of consciousness, which may reflect ictal cerebral circulatory arrest, is a risk factor for admission global edema, and vasopressor-induced hypertension is associated with the development of delayed global edema. Critical care management strategies that minimize edema formation after SAH may improve outcome.