Acute Therapies Research Articles

Oxygen Therapy in Cluster Headache, Migraine, and Other Headache Disorders

Oxygen therapy (OT) can relieve head pain in certain primary headache disorders, including cluster headache (CH). The exact underlying mechanism is currently uncertain, but suggested mechanisms include inhibition of the trigeminoautonomic reflex, modulation of neurotransmitters, and cerebral vasoconstriction. OT is the standard for acute treatment of CH, but patients with CH often experience considerable difficulties accessing home OT due to problems with insurance coverage. Inhalation of 100% oxygen at 6–12 L/min for 15–30 min using a non-rebreather face mask is one of the most effective acute therapies for CH, but several trials have indicated the superiority of higher oxygen flow rates of up to 15 L/min and/or using a demand-valve oxygen mask that can produce very high flow rates. Two randomized controlled trials have demonstrated the efficacy of OT in migraine, but obtaining reliable evidence is considered difficult because of different inhalation protocols, varying outcome measures, and small samples. There are some reports on the efficacy of OT as an adjuvant therapy in hypnic headache, primary headache in the emergency department, and even postdural puncture headache. The goal of this review article is to expand the knowledge regarding the use of oxygen in the treatment of headache disorders.

Early Termination of Acute Stroke Randomized Controlled Trials Published Between 2013 and 2020: A Systematic Review.

Termination of a clinical trial before the maximum planned sample size is accrued can occur for multiple valid reasons but has implications for the interpretation of results. We undertook a systematic review of contemporary acute stroke trials to document the prevalence of and reasons for early termination. We searched MEDLINE for randomized controlled trials of acute stroke therapies published between 2013 and 2020 in 9 major clinical journals. Manuscripts describing the primary results of phase 2 and phase 3 trials of acute stroke care were included. Data on study characteristics and adherence to CONSORT reporting guidelines were abstracted and summarized using descriptive statistics. Where feasible, we compared treatment effect sizes between trials terminated early and those not terminated early. Of 96 randomized controlled trials, 39 (41%) were terminated early, 84 (88%) had a data and safety monitoring board, and 57 (59%) reported a prespecified statistical stopping rule. Among the 39 trials terminated early, 10 were discontinued for benefit, 10 due to logistical issues, 8 for futility, 6 because of newly available evidence, 1 for harm, and 4 for other or a combination of reasons. The median percentage of the maximum planned sample size accrued among trials terminated early was 63% (range, 8%-89%). Only 55% of trials (53 of 96) reported whether interim efficacy analyses were conducted, as recommended by the CONSORT guidelines. When 10 endovascular therapy trials were compared according to early termination status, the effect sizes of trials terminated early for benefit were only modestly larger than those not terminated early. The high prevalence of early termination in combination with the wide variety of reasons underscores the necessity of meticulous trial planning and adherence to methodological and reporting guidelines for early termination. Registration: URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42019128727.

Thrombus Composition, Imaging, and Outcome Prediction in Acute Ischemic Stroke

New imaging techniques have advanced our ability to capture thrombus characteristics and burden in real time. An improved understanding of recanalization rates with thrombolysis and endovascular thrombectomy based on thrombus characteristics has spurred interest in new therapies for acute stroke. This article reviews the biochemical, structural, and imaging characteristics of intracranial thrombi in acute ischemic stroke; the relationship between thrombus composition and response to lytic and endovascular therapies; and current and future directions for improving outcomes in patients with acute stroke based on thrombus characteristics. Thrombus composition, size, location, and timing from stroke onset correlate with imaging findings in acute ischemic stroke and are associated with clinical outcome. Further research across multiple domains could assist in better applying our knowledge of thrombi to patient selection and individualization of acute therapies.

Safety and Risk of Medication Overuse Headache in Lasmiditan and Second-Generation Gepants: A Rapid Review

The treatment of migraine is often complicated by insufficient headache relief, a miscellany of side effects and the risk of developing Medication Overuse Headache (MOH). Novel acute therapies have been recently developed and are now in the early post-marketing phase. Lasmiditan is a highly selective serotonin receptor agonist that binds to the 5-HT1F receptor, while ubrogepant and rimegepant antagonize the calcitonin gene-related peptide receptor. All three medications are now prescribed in a real-world setting, and an adequate level of knowledge is the starting point for rational use. In this rapid systematic review, we have established what is known about lasmiditan, ubrogepant and rimegepant, highlighting the most relevant safety aspects available from published studies and speculating about their risk of MOH.

Abstract 1122‐000237: Prior Vascular Risk Factors Affecting Presentation Time and Utilization of Acute Ischemic Stroke Therapies

Introduction : Multiple factors have been reported to influence the time between onset of symptoms in acute ischemic stroke and hospital presentation. Although education level is one independent factor in presentation, as we previously reported, health literacy has not been fully assessed regarding specific patient knowledge on stroke or its known risk factors. This study aims to determine whether having a history of vascular risk factors such as prior stroke, coronary artery disease (CAD), or atrial fibrillation (AF) influence presentation time and acute ischemic stroke therapy utilization. Methods : This study included 250 acute ischemic stroke patients presenting to a large academic community hospital from February to December 2018. Educational level was defined within four categories: Grade School, High School, College or Higher, and Unknown. Last seen normal, symptom onset, and arrival times were acquired. Vascular risk factors chosen for this study included prior stroke, CAD, and AF. History of vascular risk factors was verified by medical documentation showing prior diagnosis by physician. Initial NIH Stroke Scale score, stroke location, vessel involved, LDL, hemoglobin A1c, gender, and race were also obtained. Patients were categorized based on their level of education, the presence or absence of vascular risk factors, and utilization of tPA or thrombectomy (MT). The primary outcomes were onset‐to‐arrival time (OTA), in minutes, and utilization rates of acute ischemic stroke therapies (either tPA, MT, or both). Subgroup analysis was conducted to associate education level with each vascular risk factor, comparing OTA and acute ischemic stroke therapy utilization rate. Results : As previously reported, educational level was inversely associated with OTA and positively associated with utilization of at least one acute ischemic stroke therapy. Prior stroke, CAD, and AF showed a substantial OTA decrease for all education groups except for College. Prior stroke decreased OTA in Grade School by 24% (764 vs. 579); High School by 30% (222 vs. 154) and College by 20% (52 vs. 41). CAD decreased OTA in Grade School by 65% (734 vs. 253), High School by 14% (209 vs. 180), and College by 3% (50 vs 49). AF decreased OTA in Grade School by 88% (764 vs. 91) and High School by 56% (216 vs. 95), but increased in College by 35% (47 vs. 64). History of prior stroke decreased utilization of both tPA and MT by 14%; CAD increased tPA use by 8% and MT by 5%; while AF increased tPA use by 9% and MT by 12%. Conclusions : Having at least one prior vascular risk factor (prior stroke, CAD, AF), diagnosed by a physician, was associated with lower OTA in Grade School and High School educated patients. A history of prior stroke was associated with lower acute stroke therapy utilization (tpa and MT), while both CAD and AF were associated with increased acute stroke therapy utilization.

The Effect and Safety of 5-HT1F Receptor Agonist Lasmiditan on Migraine: A Systematic Review and Meta-Analysis.

Background Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT1F receptor agonist appears more promising for aborting migraine attacks. Objective To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks. Methods The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model. Results Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92), P = 0.007; 200 mg: RR = 0.81, 95% CI (0.66, 0.99), P = 0.04) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs (RR = 2.75, 95% CI (0.81, 9.37), P = 0.11). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose (RR = 0.83, 95% CI (0.74, 0.94), P = 0.004) but associated with a higher risk of reporting at least one TEAE (RR = 0.88, 95% CI (0.81, 0.96), P = 0.006). Conclusions Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

Suppression of collagen IV alpha-2 subunit by prolyl hydroxylase domain inhibition via hypoxia-inducible factor-1 in chronic kidney disease.

Elevation of hypoxia‐inducible factor 1 protein has been shown to be protective in acute kidney injury and HIF1α enhancing drug therapies are currently in clinical trials for the treatment of anemia of chronic kidney disease. Despite its benefits, long‐term HIF1 elevation seems to be associated with additional effects in the kidneys such as tubulointerstitial fibrosis. To better understand the effects of prolonged HIF1 exposure, assessment of baseline and post‐therapy levels of HIF1α and other related biomarkers is essential. In this study, we assessed the effect of HIF1α enhancement using prolyl hydroxylase inhibitor (PHD‐I) DMOG, on a key profibrotic marker of kidney disease. In specific, we examined the change in expression of Collagen 4 subunit A2 in cultured urinary cells of CKD patients pre and post 24‐hour exposure to 1mM DMOG. Our results show that besides HIF1α enhancement, COL4A2 protein is suppressed in presence of DMOG. To determine if this effect is mediated by HIF1, we used HIF1α gene silencing in HEK293 cells and examined the effect of DMOG on protein and gene expression of COL4A2 post 24‐hour exposure. We showed that silencing HIF1α reverses and amplifies the expression of COL4A2 in HEK293 cells. Our data suggest that HIF1 directly regulates the expression of COL4A2 in kidney cells and that HIF1α enhancing therapy has suppressive effects on COL4A2 that may be clinically relevant and must be considered in determining the safety and efficacy of these drugs in the treatment of anemia.

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.

Chronic Migraine Pathophysiology and Treatment: A Review of Current Perspectives.

Chronic migraine is a disabling neurological disorder that imposes a considerable burden on individual and socioeconomic outcomes. Chronic migraine is defined as headaches occurring on at least 15 days per month with at least eight of these fulfilling the criteria for migraine. Chronic migraine typically evolves from episodic migraine as a result of increasing attack frequency and/or several other risk factors that have been implicated with migraine chronification. Despite this evolution, chronic migraine likely develops into its own distinct clinical entity, with unique features and pathophysiology separating it from episodic migraine. Furthermore, chronic migraine is characterized with higher disability and incidence of comorbidities in comparison to episodic migraine. While existing migraine studies primarily focus on episodic migraine, less is known about chronic migraine pathophysiology. Mounting evidence on aberrant alterations suggest that pronounced functional and structural brain changes, central sensitization and neuroinflammation may underlie chronic migraine mechanisms. Current treatment options for chronic migraine include risk factor modification, acute and prophylactic therapies, evidence-based treatments such as onabotulinumtoxinA, topiramate and newly approved calcitonin gene-related peptide or receptor targeted monoclonal antibodies. Unfortunately, treatments are still predominantly ineffective in aborting migraine attacks and decreasing intensity and frequency, and poor adherence and compliance with preventative medications remains a significant challenge. Novel emerging chronic migraine treatments such as neuromodulation offer promising therapeutic approaches that warrant further investigation. The aim of this narrative review is to provide an update of current knowledge and perspectives regarding chronic migraine background, pathophysiology, current and emerging treatment options with the intention of facilitating future research into this debilitating and largely indeterminant disorder.

Comparison of aspiration thrombectomy to other endovascular therapies for proximal upper extremity deep venous thrombosis

ObjectiveCatheter-directed thrombolysis (CDT) provides an effective method for clearing deep venous thrombosis (DVT). Unfortunately, CDT is associated with hemorrhagic complications. This study evaluated the technical success of the various endovascular therapies including a new mechanical aspiration thrombectomy (AT) device for the treatment of acute upper extremity DVT (UEDVT). MethodsThis single-center retrospective review included patients with acute symptomatic proximal UEDVT secondary to venous thoracic outlet syndrome. Undergoing endovascular therapy from December 2013 to June 2019. Patients were treated with a variety of methods including CDT, ultrasound-assisted thrombolysis (USAT), rheolytic thrombectomy, and AT. We evaluated outcomes for patients undergoing AT compared with nonaspiration thrombectomy (NAT) techniques. The primary outcome was technical success, defined as resolution of more than 70% of the thrombus. The secondary end point was the ability to complete the therapy in a single session. ResultsThere were 22 patients who had endovascular management of their symptomatic proximal UEDVT. All 22 patients (100%) were successfully treated with more than a 70% thrombus resolution. Ten patients underwent AT, of which 50% (5/10) had single session therapies. Twelve patients underwent NAT (three had CDT or USAT alone; three had USAT with rheolytic thrombectomy; and six had CDT followed by rheolytic thrombectomy), with single session therapy occurring in only 8.3% of the NAT group (1/12). The average total dose of thrombolytics was 12.6 ± 9.65 mg in the AT group compared with 19.0 ± 5.78 mg in the NAT group (mean difference, –6.4; 95% confidence interval, –1.1 to 13.9). All but one of the patients in the AT group went on to have successful first rib resections. All NAT patients had successful first rib resections. A venogram was not performed at the time of decompression. All patients except one underwent resection via the infraclavicular approach, with rib removal posterior to the brachial plexus, a median of 8.0 (interquartile range, 6.0-12.0) days after DVT therapy. ConclusionsIn this study, a technical success rate of 100% was achieved for acute symptomatic proximal UEDVT therapies. AT technology allows for higher rates of treatment in a single session, thereby minimizing a patient's risks of bleeding complications. More research is needed to further define the role of this new technology in the treatment paradigm of UEDVT management.

Acute Reperfusion Therapies for Acute Ischemic Stroke.

The field of acute stroke treatment has made tremendous progress in reducing the overall burden of disability. Understanding the pathophysiology of acute ischemic injury, neuroimaging to quantify the extent of penumbra and infarction, and acute stroke reperfusion therapies have together contributed to these advancements. In this review we highlight advancements in reperfusion therapies for acute ischemic stroke.

New Therapies to Modulate Post-Infarction Inflammatory Alterations in the Myocardium: State of the Art and Forthcoming Applications.

Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. AMI causes necrosis of cardiac cells and triggers a complex inflammatory response, affecting infarct size, cardiac function and clinical outcomes. This inflammatory response can be divided into 3 phases: 1) the pro-inflammatory phase, in which the release of damage-associated molecular patterns from necrotic cells triggers the secretion of pro-inflammatory mediators and attracts immune cells to clean the debris, further damaging viable myocardium, 2) the reparative phase, in which anti-inflammatory signals activate immune-modulating cells and trigger the production of a stable scar, 3) the maturation phase, in which inflammatory and fibrotic signals are suppressed, but may persist, leading to left ventricular adverse remodelling. Thus, the inflammatory response is an appealing therapeutic target to improve the outcomes of patients with AMI. Numerous anti-inflammatory therapies have shown potential in animal models, but the translation to human trials exhibited limited benefit. Glucocorticoids and non-steroidal anti-inflammatory drugs showed signals of harm due to their non-specific effects. Other broad inhibitors, e.g., methotrexate, cyclosporine, or colchicine, did not improve clinical outcomes as acute therapies for MI. Specific inhibitors of the complement cascade, adhesion molecules, or inflammatory mediators were mostly disappointing in humans. However, an interleukin-1 inhibitor (anakinra) and a matrix metalloproteinase inhibitor (doxycycline) improved clinical outcomes in patients with AMI. Promising RNAse1, anti-toll-like receptor 2 antibodies, and inflammasome inhibitors still need to be tested in humans. Finally, positive results should be replicated in large clinical trials before they can be implemented into the standard AMI therapy.

Increased Relative Functional Gain and Improved Stroke Outcomes: A Linked Registry Study of the Impact of Rehabilitation

ObjectivesIt is unclear how acute care influences patient outcomes in those who receive rehabilitation. We aimed to determine the associations between acute stroke therapies, outcomes during inpatient rehabilitation and self-reported outcomes at 90-180 days after stroke. Materials and MethodsPatient-level data from adults with acute stroke registered in the Australian Stroke Clinical Registry (AuSCR, 2014–2017) were linked with data from the Australasian Rehabilitation Outcomes Centre (AROC). The main outcome was relative function gain (RFG), which is a measure of the FIM change achieved between admission to discharge as a proportion of the total gain possible based on admission FIM, relative to the maximum achievable score. Multilevel logistic/median regression analyses were used to investigate the association between RFG achieved in rehabilitation and (1) acute stroke therapies; (2) 90–180 day outcomes (health-related quality of life using EuroQoL-5D-3L; independence according to modified Rankin Scale (score 0–2) and self-reported hospital readmission). ResultsOverall, 8397/8507 eligible patients from the AuSCR were linked with corresponding AROC data (95% linkage rate; median age 75 years, 43% female); 4239 had 90–180 days survey data. Receiving thrombolysis (16% of the cohort) had a minimal association with RFG in rehabilitation (coefficient: 0.03; 95% Confidence Interval [CI]: 0.01, 0.05). Greater RFG achieved whilst in in-patient rehabilitation was associated with better longer-term HR-QoL (coefficient 21.77, 95% CI 17.8, 25.8) including fewer problems with mobility, self-care, pain, usual activities and anxiety/depression; greater likelihood of independence (adjusted Odds Ratio: 10.66; 95% CI 7.86, 14.45); and decreased odds of self-reported hospital readmission (adjusted Odds Ratio: 0.53; 95% CI 0.41, 0.70) within 90-180 days post-stroke. ConclusionsStroke survivors who achieved greater RFG during inpatient rehabilitation had better HR-QoL and were more likely to be independent at follow-up. Acute care processes did not appear to impact RFG or long-term outcomes for those who accessed inpatient rehabilitation.

Health Equity.

Health Equity.

Association between acute myocardial infarction and death in 386 patients with a thrombus straddling a patent foramen ovale

BackgorundRight atrial thrombi are rarely found straddling a patent foramen ovale (PFO). A thrombus straddling a PFO (TSPFO), also known as impending paradoxical embolism, is a medical emergency associated with up to 11.5% risk of death within 24 h of being diagnosed. We hypothesized that acute myocardial infarction (MI) and ischemic stroke (IS) diagnosed upon the admission of patients with TSPFO are associated with increased risk of death. We also investigated if specific acute therapies are associated with reduced in-hospital mortality. MethodsWe performed a systematic search including case reports and series of adult patients with TSPFO published from 1950 to October 30, 2020. We gathered patient-level data and we applied a logistic regression model to evaluate on the risk of in-hospital death. We performed time-trends and several sensitivity analyses. ResultsWe included 386 cases with a TSPFO comprised in 359 publications. The median age was 61 years and 51.2% were females. Fifty (13.0%) patients died during hospital stay, 82 (21.2%) had an acute IS, and 18 (4.6%) had an acute MI diagnosed upon admission. Acute MI (OR 7.83, 95%CI 2.70–22.7; P < 0.0001), but not IS, was associated with increased risk of death. Right atrial thrombectomy was associated with a 65% decreased in-hospital mortality (OR 0.35, 95%CI 0.18–0.70, P = 0.003). Results remained unchanged on sensitivity analyses. ConclusionIn this systematic review of 386 cases of TSPFO, acute MI but not IS was associated with 8-fold increased risk of death, while surgical thrombectomy was associated with a significant 65% reduction of in-hospital mortality.

PRIMED2 Preclinical Evidence Scoring Tool to Assess Readiness for Translation of Neuroprotection Therapies

Many neuroprotective and other therapies for treatment of acute ischemic stroke have failed in translation to human studies, indicating a need for more rigorous, multidimensional quality assessment of the totality of preclinical evidence supporting a therapy prior to conducting human trials. A consensus panel of stroke preclinical model and human clinical trial experts assessed candidate items for the translational readiness scale, compiled from prior instruments (STAIR, ARRIVE, CAMARADES, RoB 2) based on importance, reliability, and feasibility. Once constructed, the tool was applied by two independent raters to four current candidate acute stroke therapies, including two pharmacologic agents [nerinetide and trans-sodium crocetinate] and two device interventions [cathodal transcranial direct current stimulation and fastigial nucleus stimulation]. The Preclinical evidence of Readiness In stroke Models Evaluating Drugs and Devices (PRIMED2) assessment tool rates the totality of evidence available from all reported preclinical animal stroke model studies in 11 domains related to diversity of tested animals, time windows, feasibility of agent route of delivery, and robustness of effect magnitude. Within each content domain, clearly operationalized rules assign strength of evidence ratings of 0–2. When applied to the four assessed candidate agents, inter-rater reliability was high (kappa = 0.88), and each agent showed a unique profile of evidentiary strengths and weaknesses. The PRIMED2 assessment tool provides a multidimensional assessment of the cumulative preclinical evidence for a candidate acute stroke therapy on factors judged important for successful basic-to-clinical translation. Further evaluation and refinement of this tool is desirable to improve successful translation of therapies for acute stroke.

Outcomes of different acute mesenteric ischemia therapies in the last 20 years: A meta-analysis and systematic review.

Acute mesenteric ischemia is a disease with high morbidity and mortality, and it is traditionally treated with open surgery. Endovascular therapy and hybrid techniques are alternative treatments that are also currently available. We performed a meta-analysis to evaluate the outcomes of the different treatment approaches in the last 20years. Studies on acute mesenteric ischemia that were indexed in PubMed, Embase, and MEDLINE databases (from January 1, 2000, to April 1, 2021) were reviewed. All related retrospective observational studies and case series were included. A random-effects model was used to calculate pooled estimates, and the results were reported as proportions and 95% confidence intervals (CIs). In our study, a total of 2369 patients (in 39 studies) underwent endovascular, open surgery, or retrograde open mesenteric stenting. The pooled mortality estimates for open surgery, endovascular therapy, and retrograde open mesenteric stenting were 40% (95% CI, 0.33-0.47; I2 = 84%), 26% (95% CI, 0.19-0.33; I2 = 33%), and 32% (95% CI, 0.21-0.44; I2 = 26%), respectively. The mortality associated with open surgical treatment, endovascular therapy, and retrograde open mesenteric stenting tend to be similar in the last 20years.

Ischemic stroke in Morocco: Prehospital delay and associated factors

ObjectivesThis study aimed to estimate prehospital delay and to identify the factors associated with the late arrival of patients with ischemic stroke at the Souss Massa Regional Hospital Center in Morocco. Patients and methodsAn observational, prospective, cross-sectional study was conducted from March 2019 to September 2019 in the Souss Massa regional hospital center, which is a public hospital structure. A questionnaire was administered to patients with ischemic stroke and to bystanders (family or others), while clinical and paraclinical data were collected from medical records. Univariate and multivariate logistic regression analyses were used to identify the factors associated with delayed arrival at emergency department. ResultsA total of 197 patients and 197 bystanders who fulfilled the criteria for the study were included. The median time from symptom onset to hospital arrival was 6hours (IQR, 4–16). Multiple regression analysis showed that illiteracy (OR 38.58; CI95%: 3.40–437.27), waiting for symptoms to disappear (patient behavior) (OR 11.24; CI95%: 1.57–80.45), deciding to go directly to the hospital (patient behavior) (OR 0.07; CI95%: 0.01–0.57), bystander's knowledge that stroke is a disease requiring urgent care within a limited therapeutic window (OR 0.005; CI95%: 0.00–0.36), and direct admission without reference (OR 0.005; CI95%: 0.00–0.07), were independently associated with late arrival (>4.5hours) of patients with acute ischemic stroke. In addition, illiteracy (OR 24.62; CI95%: 4.37–138.69), vertigo and disturbance of balance or coordination (OR 0.14; CI95%: 0.03–0.73), the relative's knowledge that stroke is a disease requiring urgent care and within a limited therapeutic window (OR 0.03; CI95%: 0.00–0.22), calling for an ambulance (relative's behavior) (OR 0.16; CI95%: 0.03–0.80), distance between 50 and 100km (OR 10.16; CI95%: 1.16–89.33), and direct admission without reference (OR 0.03; CI95%: 0.00–0.14), were independently associated with late arrival (>6hours) of patients with acute ischemic stroke. ConclusionPatient behavior, bystander knowledge and direct admission to the competent hospital for stroke care are modifiable factors potentially useful for reducing onset-to-door time, and thereby increasing the implementation rates of acute stroke therapies.

A Framework for Estimating the Eligible Patient Population for New Migraine Acute Therapies in the United States.

IntroductionMigraine is associated with considerable disability for patients not adequately managed with current standards of care. New acute therapies may offer relief for this population of patients; however, population size and associated potential costs of new therapies are unclear. In this study, a conceptual framework was developed to estimate anticipated use of new acute therapies.MethodsTargeted literature review (TLR) was conducted to identify factors affecting access to migraine-specific acute therapies, and characteristics of individuals who would be eligible for new acute therapies. Findings from the TLR were combined to create a framework for estimating the size of the eligible patient population. This framework was used to calculate two estimates of the eligible patient population by applying parameters (i) identified in the TLR and (ii) from a recent budget-impact analysis (BIA).ResultsThe primary factors affecting access to migraine-specific acute therapies identified in the TLR were consulting a healthcare professional for headache, receiving a migraine diagnosis, and receiving a prescription for migraine-specific treatment. Characteristics of individuals likely to use new acute therapies reflected in the TLR were contraindication to triptans, or failure to respond to/tolerate at least two oral triptans. Application of the framework suggested that 15–25% of individuals with migraine would be eligible for new acute therapies.ConclusionA limited number of patients currently use migraine-specific acute therapies. Among such patients, a significant proportion do not have adequate symptom control. Accordingly, a minority of individuals with migraine may be expected to use new acute therapies. The framework developed in this study is intended to facilitate estimating the eligible patient population in assessments of costs of new acute therapies. Such assessments should also consider recommendations that patients have access to multiple types of acute therapies, which may yield savings from reduced medication-overuse headache (MOH), progression to chronic migraine, and urgent-care costs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01781-z.

Sex Disparities in Enrollment in Recent Randomized Clinical Trials of Acute Stroke

The underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments. To determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations. MEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020. Eligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset. Data extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database. The primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates. The search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was -0.053 (95% CI, -0.065 to -0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was -0.067 (95% CI, -0.078 to -0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6-percentage point decrease in the enrollment of women. Further research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.