Cardiovascular safety of dihydroergotamine mesylate delivered by precision olfactory delivery (INP104) for the acute treatment of migraine.

OBJECTIVE: To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials. BACKGROUND: Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug-device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®). METHODS: The STOP 101 was a Phase 1 open-label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria. RESULTS: In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9-15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4-17.1) at 5 min post-dose, persisting up to 30 min post-dose for systolic BP (6.3 mmHg; 95% CI 3.0-9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9-11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non-serious, vascular treatment-emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off-protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs. CONCLUSION: In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV-related contraindications.

Headache due to Vascular Disorders.

Headache and cerebrovascular disease (CVD) are inextricably linked. Although in some cases headache complicating CVD may be little more than a symptomatic afterthought, in other cases, early recognition of headache's role in the CVD process is critical to effective management. In other words, headaches secondary to CVD span a spectrum, and in this article, we will review that spectrum.

Headache secondary to cerebrovascular disease.

OBJECTIVES: To discuss headache secondary to cerebrovascular disease. BACKGROUND: Headache is an important symptom in cerebrovascular diseases. In some conditions, headache is the leading symptom. Migraine is associated with an increased risk of stroke. METHODS: The authors undertook a literature search for the terms "headache" and "cerebrovascular diseases". RESULTS: We report studies on headache in subarachnoidal hemorrhage, intracerebral hemorrhage, ischemic stroke, TIA, basilar artery thrombosis, cervical artery dissection, cerebellar stroke, arteritis and cerebral sinus venous thrombosis. In addition, we discuss migraine and stroke and thunderclap headache. CONCLUSIONS: Headache is a leading symptom in many cerebrovascular diseases. Headache in combination with focal neurological deficits requires immediate diagnosis and treatment.

Patient-Reported Outcomes from a 1-Year, Real-World, Head-to-Head Comparison of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine.

INTRODUCTION/OBJECTIVE: Chronic migraine (CM) is associated with impaired health-related quality of life and substantial socioeconomic burden, but many people with CM are underdiagnosed and do not receive appropriate preventive treatment. OnabotulinumtoxinA and topiramate have demonstrated efficacy (treatment benefit under ideal conditions) for the prevention of headaches in people with CM in clinical trials, but real-world studies suggest markedly different clinical effectiveness (treatment benefit based on a blend of efficacy and tolerability). This study sought to evaluate patient-reported outcomes (PROs) of onabotulinumtoxinA versus topiramate immediate release for people with CM. METHODS: FORWARD was a prospective, multicenter, randomized, parallel-group, open-label, phase 4 study comparing onabotulinumtoxinA 155 U every 12 weeks with topiramate 50 to 100 mg/day for ≤36 weeks in people with CM. PROs measured included the Headache Impact Test (HIT-6), 9-item Patient Health Questionnaire Quick Depression Assessment (PHQ-9), Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP), and Functional Impact of Migraine Questionnaire (FIMQ). RESULTS: A total of 282 patients were randomized and treated with onabotulinumtoxinA (n = 140) or topiramate (n = 142). From baseline to week 30, mean HIT-6 test scores improved significantly in patients taking onabotulinumtoxinA compared with topiramate (P < .001). Improvements in depression over time were observed via larger changes in PHQ-9 scores with onabotulinumtoxinA than topiramate (P < .001). Work productivity assessed via WPAI:SHP scores revealed significant improvements with onabotulinumtoxinA versus topiramate in Work Productivity Loss (P = .024) and Activity Impairment (P < .001) domains. Results from the FIMQ also revealed a larger reduction from baseline with onabotulinumtoxinA vs topiramate (P < .0001). CONCLUSION: OnabotulinumtoxinA treatment had more favorable real-world effectiveness than topiramate on depression, headache impact, functioning and daily living, activity, and work productivity. The overall study results suggest that the beneficial effects on a range of PROs are the result of improved effectiveness when onabotulinumtoxinA is used as preventive treatment for CM. TRIAL REGISTRATION: CLINICALTRIALS.GOV: NCT02191579; https://clinicaltrials.gov/ct2/show/NCT02191579.

FORWARD Study: Evaluating the Comparative Effectiveness of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine.

OBJECTIVE: To compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention. BACKGROUND: The efficacy* of onabotulinumtoxinA and topiramate has been established in placebo-controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive treatments, however, has not been established (*the benefit of treatment under real-world conditions, representing a blend of efficacy and tolerability). METHODS: In this multicenter, randomized, parallel-group, post-authorization, open-label prospective study (FORWARD; ClinicalTrials.gov, NCT02191579), we randomized adults with CM (1:1) to onabotulinumtoxinA 155 U every 12 weeks for 3 cycles or topiramate "immediate release" 50-100 mg/day to week 36. Primary outcome measure was proportion of patients achieving ≥50% reduction in headache days (weeks 29-32). Missing values were imputed using baseline observation carried forward (BOCF) methodology. After 12 weeks, patients initially randomized to topiramate could cross over to onabotulinumtoxinA treatment. We monitored and recorded all adverse events (AEs). RESULTS: We enrolled 282 patients (onabotulinumtoxinA, n = 140; topiramate, n = 142) and 148 patients completed randomized treatment (onabotulinumtoxinA, n = 120 [86%]; topiramate, n = 28 [20%]). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n = 7 [5%]; topiramate, n = 27 [19%]) and AEs (onabotulinumtoxinA, n = 5 [4%]; topiramate, n = 72 [51%]). Eighty topiramate patients crossed over to onabotulinumtoxinA. In the BOCF analysis, a significantly higher proportion of patients randomized to onabotulinumtoxinA experienced ≥50% reduction in headache frequency compared with those randomized to topiramate (40% [56/140] vs 12% [17/142], respectively; adjusted OR, 4.9 [95% CI, 2.7-9.1]; P < .001). OnabotulinumtoxinA was superior to topiramate in meeting secondary endpoints. In a post hoc analysis using observed data, the 50% responder rates at week 12 were 45.6% for onabotulinumtoxinA (n = 125) and 29.4% for topiramate (n = 109) (P = .015). AEs were reported by 48% (105/220) of onabotulinumtoxinA and 79% (112/142) of topiramate patients. Results were similar in those who crossed over to onabotulinumtoxinA. CONCLUSIONS: While using imputation methods of accounting for differences in discontinuation rates, we found onabotulinumtoxinA to have greater clinical utility than topiramate, largely because of tolerability issues associated with the latter and a relatively higher number of onabotulinumtoxinA patients remaining on treatment.

Effects of onabotulinumtoxinA treatment in chronic migraine patients with and without daily headache at baseline: results from the COMPEL Study.

BACKGROUND: OnabotulinumtoxinA is effective in preventing chronic migraine (CM); however, the benefit of onabotulinumtoxinA in patients with CM with daily headache is unknown because these patients are typically excluded from clinical trials. This subanalysis of the COMPEL Study assessed the efficacy and safety of onabotulinumtoxinA in people with CM with and without daily headache. METHODS: In total, 715 patients received onabotulinumtoxinA 155 U with or without concomitant oral preventive treatment. Patients who had complete daily diary records for the 28 days of the baseline period were stratified based on daily headache status. The primary outcome variable was reduction in headache-day frequency per 28-day period at 108 weeks (after 9 treatment cycles) relative to baseline. Exploratory outcomes included moderate to severe headache days, migraine disability (using the Migraine Disability Assessment [MIDAS] questionnaire), and health-related quality of life (Migraine-Specific Quality-of-Life Questionnaire v2 [MSQ]). Adverse events and their relatedness were recorded. RESULTS: Overall, 641 patients had complete daily diary records at baseline. In patients with daily headache (n = 138) versus without (n = 503), treatment with onabotulinumtoxinA was associated with a significant mean (SD) reduction in 28-day headache-day frequency relative to baseline at week 108 (- 10.5 [9.2] vs - 12.2 [6.7], respectively; both P < 0.001) with no significant between-group difference (P = 0.132). The mean (SD) reduction in moderate to severe headache days at week 108 was significant in patients with and without daily headache (- 11.5 [9.4] and - 9.9 [6.4]; P < 0.001) with no significant between-group difference (P = 0.153). Mean (SD) MIDAS scores significantly improved from baseline at week 108 (- 43.3 [73.4] and - 43.6 [46.7]; both P < 0.001), with no significant between-group difference (P = 0.962). Similarly, mean (SD) MSQ subscale scores significantly improved from baseline at week 108 for patients with and without daily headache. OnabotulinumtoxinA was well tolerated in patients with and without daily headache. CONCLUSION: Results indicate that onabotulinumtoxinA is associated with reductions from baseline in headache-day frequency and improvements in disability and quality of life for up to 108 weeks in people with CM with daily headache; however, a longer duration of treatment was required to fully realize the treatment effect on headache. No new safety concerns were identified.

Effects of onabotulinumtoxinA treatment in patients with and without allodynia: results of the COMPEL study.

BACKGROUND: OnabotulinumtoxinA is effective in treating chronic migraine (CM), but there are limited data assessing how allodynia affects preventive treatment responses. This subanalysis of the 108-week, multicenter, open-label COMPEL Study assessed the efficacy and safety of onabotulinumtoxinA in people with CM with and without allodynia. METHODS: Patients (n = 715) were treated with onabotulinumtoxinA 155 U every 12 weeks for 9 treatment cycles. The Allodynia Symptom Checklist was used to identify patients with allodynia (scores ≥3). The primary outcome for this subanalysis was reduction in monthly headache days from baseline for weeks 105 to 108 in groups with and without allodynia. Other outcomes included assessments of moderate to severe headache days, disability (using the Migraine Disability Assessment [MIDAS] questionnaire), and health-related quality of life (Migraine-Specific Quality-of-Life Questionnaire [MSQ] v2). Adverse events and their relation to treatment were recorded. RESULTS: OnabotulinumtoxinA was associated with a significant mean (SD) reduction in headache day frequency at week 108 relative to baseline in patients with (n = 289) and without (n = 426) allodynia (- 10.8 [7.1] and - 12.5 [7.4], respectively; both P < 0.001) that was significantly greater in patients without allodynia (P = 0.044 between-subgroup comparison). Moderate to severe headache days were significantly reduced at week 108 in patients with and without allodynia (- 9.6 [6.9] and - 10.5 [7.2]; both P < 0.001); reduction was similar between groups. MIDAS scores improved significantly at week 108 (- 53.0 [50.3] and - 37.7 [53.0]; both P < 0.001), with a significant between-group difference in favor of those with allodynia (P = 0.005). Similarly, MSQ subscale scores (Role Function Preventive, Role Function Restrictive, Emotional Function) significantly improved at week 108 for patients with and without allodynia: 20.6 (21.9) and 16.9 (20.7), 28.0 (23.3) and 24.7 (22.7), and 27.6 (26.5) and 24.9 (26.1), respectively (all P < 0.001). OnabotulinumtoxinA was well tolerated in patients with and without allodynia. CONCLUSION: Results indicate that onabotulinumtoxinA is associated with reductions from baseline in multiple efficacy outcomes for up to 108 weeks whether or not allodynia is present. The allodynia group showed a smaller treatment response for reduction in headache days, but a similar or greater treatment response for improvement in other measures. No new safety concerns were identified.

An academic debate: OnabotulinumtoxinA for chronic migraine: PREEMPT-derived vs "customized" dosing/injection paradigm.

In 2010 onabotulinumtoxinA (OnabotA) was approved by the United States Food and Drug Administration for the treatment of chronic migraine (CM). Data supporting approval were derived primarily from two parallel placebo-controlled trials, the PREEMPT studies. Many clinicians and research investigators critical of those data have recommended that the dosing/injection paradigm for treating CM be "customized" to the needs of the individual patient rather than administered in a uniform fashion conforming to the methodology utilized in the PREEMPT studies. In this paper the authors debate the issue of whether treatment of CM with OnabotA should be standardized versus customized.

Inpatient versus Outpatient Management of TIA or Minor Stroke: Clinical Outcome.

BACKGROUND: The management of patients with acute transient ischemic attack (TIA) or minor stroke is highly variable. Whether hospitalization of such patients significantly improves short-term clinical outcome is unknown. We assessed the short-term clinical outcome associated with inpatient versus outpatient management of patients with TIA or minor stroke. METHODS: We evaluated a consecutive series of patients with acute TIA or minor ischemic stroke (NIH Stroke Scale score ≤ 3) presenting to a single emergency department (ED). We randomized patients to either hospital-based or outpatient-based management. All patients underwent interview and examination 7-10 days following the index event. RESULTS: This study included 100 patients, 41 with TIA and 59 with minor stroke. Nineteen (46%) of the TIA patients and 29 (49%) of the minor stroke patients randomized to hospital management, and the remaining 22 TIA patients and 30 minor stroke patients randomized to outpatient-based management. In the patients with a minor stroke, neurologic worsening occurred in 6 out of 29 (21%) in the inpatient arm compared with 3 out of 30 (10%) in the outpatient arm (p = 0.3). In none of these cases was acute interventional therapy or need for urgent admission considered medically appropriate. In the patients with a TIA, recurrence of a TIA occurred in 2 out of 19 (11%) in the inpatient arm compared with 2 out of 22 (9%) in the outpatient arm (p = 1). None of the patients with a TIA randomized to the inpatient arm experienced a stroke compared with 1 out of 22 in the outpatient arm (p = 1). There were no deaths in either group. CONCLUSION: Routine hospitalization of all patients with TIA or minor ischemic stroke may not positively affect short-term clinical outcome.

Cerebral Sinus Thrombosis.

BACKGROUND: Although cerebral venous thrombosis/cerebral sinus thrombosis (CVT/CST) remains a relatively uncommon cause of stroke and other neurologic complications, the widespread availability of noninvasive brain imaging has led to an increase in its diagnosis. PURPOSE: Through a review and description of its epidemiology, clinical features and treatment, to heighten awareness of CVT/CST. METHODOLOGY: Via a systematic review of the more recently published medical literature relevant to the topic and focusing in particular on primary sources, we compiled data related to the incidence of CVT/CST and its diagnosis, treatment and prognosis. RESULTS: Thrombosis of a cerebral vein or sinus may occur in individuals of any age and may be caused by a myriad of prothrombotic conditions, both primary and acquired. The clinical presentation of CVT/CST is widely variable, but headache is present in the great majority of cases, and the predominant symptom in many. The headache associated with CVT/CST may be acute, severe, and even "thunderclap" in character, or it may be chronic, pervasive, and of lower intensity. CONCLUSIONS: Given its eclectic epidemiology, its potential to produce a highly unfavorable clinical outcome, and evidence suggesting that specific treatment improves outcome, CVT/CST is a disorder whose salient features should be familiar to virtually all clinicians.

Hemiplegia and headache: a review of hemiplegia in headache disorders.

The most common scenario wherein the practicing neurologist is likely to encounter a patient with headache and hemiplegia will vary depending on his/her specific type of practice. A neurologist providing consultative service to an emergency department is far more likely to see patients with "secondary" headache and hemiplegia in the setting of either ischemic or hemorrhagic stroke than hemiplegia as a transient feature of a primary headache disorder. Neurologists subspecializing in headache medicine who practice in a tertiary referral headache clinic are more likely to encounter hemiplegic migraine, but even in that clinical setting hemiplegic migraine is by no means a frequent diagnosis. The acute onset of hemiplegia can be very frightening not only to the patient but also to the medical personnel. Given the abundance of mimicry, practitioners must judiciously ascertain the correct diagnosis as treatment may greatly vary depending on the cause of both headache and hemiplegia. In this review, we will address the most common causes of hemiplegia associated with headache.

Real-world economic impact of onabotulinumtoxinA in patients with chronic migraine.

OBJECTIVE: To determine whether the utilization of healthcare resources is reduced after chronic migraine patients are treated for 6 months with onabotulinumtoxinA. BACKGROUND: OnabotulinumtoxinA is indicated for headache prophylaxis in patients with chronic migraine, but its effect on healthcare resource use is unknown. METHODS: We analyzed data from an open-label study of 230 chronic migraine patients refractory to ≥2 oral prophylactics who presented to a headache specialty clinic and who were treated with two cycles of onabotulinumtoxinA. Frequency and cost of migraine-related healthcare resource use, including visits to emergency departments, urgent care, or hospitalization, were compared for the 6 months before and after initial treatment. Costs were based on publicly available sources. RESULTS: Compared with the 6 months predating initial treatment, patients had 55% fewer emergency department visits (174 vs 385), 59% fewer urgent care visits (61 vs 150), and 57% fewer hospitalizations (19 vs 45) during the 6-month treatment period (P < .01 for all). Analysis of treatment-related costs yielded an average reduction of $1219.33/patient, off-setting 49.7% of the total estimated cost for 6 months of treatment with onabotulinumtoxinA. CONCLUSIONS: Although we are unable to distinguish onabotulinumtoxinA's treatment effect from other potential confounding variables, our analysis showed that severely afflicted, treatment-refractory patients with chronic migraine experienced a significant cost-offset through reduced migraine-related emergency department visits, urgent care visits, and hospitalizations in the 6 months following treatment initiation of onabotulinumtoxinA. Future analyses will assess the longer-term effect of onabotulinumtoxinA treatment and the potential contribution of regression to the mean.

Headaches caused by vascular disorders.

The clinical association between stroke and headache is complex, ranging from the largely irrelevant to the highly specific. The incidence and clinical relevance of acute headache are highly dependent on stroke subtype and etiology. In this article the issue of headache accompanying acute stroke is addressed in some detail.

A review of needle-free sumatriptan injection for rapid control of migraine.

The treatment of migraine was transformed in 1992 with the introduction of the first triptan-based therapy, subcutaneous (SC) sumatriptan. SC sumatriptan has high efficacy and a rapid onset of action compared with other available triptans and formulations presumably because of its short Tmax, high Cmax, and avoidance of enteral absorption. Because of these characteristics, SC sumatriptan is still considered the most reliably and rapidly effective self-administered medication available for acute migraine. Even so, it is relatively little used possibly in part because of patient "needle-phobia." The needle-free sumatriptan injection system (Sumavel DosePro) was developed to address this concern. Clinical trials have shown that the needle-free system is bioequivalent to needle-based injection systems, easy to use, and capable of providing rapid and effective symptom relief for many migraine episodes. Sumavel DosePro is an effective treatment for migraine and should be part of the therapeutic armamentarium, particularly in cases where a rapid onset of action is critical or where oral administration is problematic.