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Background: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. Methods: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. Objective: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury. [ABSTRACT FROM AUTHOR]

The last three decades have produced several novel and efficient medications to treat migraine attacks and reduce attack frequency. Additionally, promising approaches for the development of acute therapy and migraine prophylaxis continue to be pursued. At the same time as we witness the development of better and more efficient medications with continuously fewer side effects, we also realise that the high cost of such therapies means that only a minority of migraine patients who could benefit from these medications can afford them. Furthermore, information on cost-effectiveness is still lacking. Here, we compare availiable data, highlight open questions and suggest trials to close knowledge gaps. With good reason, our medicine is evidence-based. However, if this evidence is not collected, our decisions will continue to be based on marketing and assumptions. At the moment, we are not doing justice to our patients. [ABSTRACT FROM AUTHOR]

Background: The optimal timing of initiating or resuming anticoagulation after acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with atrial fibrillation (AF) is debated. Dabigatran, a non-vitamin K oral anticoagulant (NOAC), has shown superiority against vitamin K antagonists (VKA) regarding hemorrhagic complications. Aims: In this registry study, we investigated the initiation of dabigatran in the early phase after AIS or TIA. Methods: PRODAST (Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA) is a prospective, multicenter, observational, post-authorization safety study. We recruited 10,039 patients at 86 German stroke units between July 2015 and November 2020. A total of 3,312 patients were treated with dabigatran or VKA and were eligible for the analysis that investigates risks for major hemorrhagic events within 3 months after early (⩽ 7 days) or late (> 7 days) initiation of dabigatran or VKA initiated at any time. Further endpoints were recurrent stroke, ischemic stroke, TIA, systemic embolism, myocardial infarction, death, and a composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. Results: Major bleeding event rates per 10,000 treatment days ranged from 1.9 for late administered dabigatran to 4.9 for VKA. Early or late initiation of dabigatran was associated with a lower hazard for major hemorrhages as compared to VKA use. The difference was pronounced for intracranial hemorrhages with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval (CI): 0.10–2.21) for early dabigatran use versus VKA use and an adjusted HR of 0.09 (95% CI: 0.00–13.11) for late dabigatran use versus VKA use. No differences were found between early initiation of dabigatran versus VKA use regarding ischemic endpoints. Conclusions: The early application of dabigatran appears to be safer than VKA administered at any time point with regards to the risk of hemorrhagic complications and in particular for intracranial hemorrhage. This result, however, must be interpreted with caution in view of the low precision of the estimate. [ABSTRACT FROM AUTHOR]

Background: Patients who had a cryptogenic stroke (CS) suspected to be causally related to a patent foramen ovale (PFO) are candidates for percutaneous PFO closure. In such patients, it is important to screen for atrial fibrillation (AF). Limited guidance is available regarding AF monitoring strategies in CS patients with PFO addressing optimal monitoring technology and duration. Aim: To provide a narrative review of cardiac rhythm monitoring in CS patients considered for PFO closure, including current practices, stroke recurrences after CS, findings from monitoring studies in CS patients, and predictors for AF detection published in the literature. To propose a personalized strategy for cardiac monitoring in CS patients, accounting for aspects predicting AF detection. Summary of review: AF detection in CS patients is predicted by age, left atrial enlargement, prolonged PR interval, frequent premature atrial contractions, interatrial conduction block, diabetes, prior brain infarctions, leukoaraiosis, elevated B-type natriuretic peptide (BNP)/N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and a family history of AF, as well as composed scores (e.g. CHA2DS2-VASc, atrial fibrillation in embolic stroke of undetermined source (AF-ESUS)). The causal role of the PFO may be accounted for by the risk of paradoxical embolism (RoPE) score and/or the PFO-Associated Stroke Causal Likelihood (PASCAL) classification. Conclusion: A personalized approach to AF detection in CS patients is proposed, accounting for the likelihood of AF detection and aimed at obtaining sufficient confidence regarding the absence of AF in patients considered for PFO closure. In addition, the impact of high-risk PFO features on the monitoring strategy is discussed. [ABSTRACT FROM AUTHOR]

Background: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has demonstrated efficacy for preventive treatment of episodic and chronic migraine. Since calcitonin gene-related peptide is expressed within the cardio- and cerebrovascular system and may have cardioprotective effects, it is critical to understand the cardio- and cerebrovascular safety of fremanezumab. Methods: This was a pooled analysis of three randomized, double-blind, placebo-controlled, phase 3, 12-week trials in which patients with episodic migraine or chronic migraine received quarterly fremanezumab, monthly fremanezumab, or placebo. Incidences of overall and serious adverse events were analyzed. Cardio- and cerebrovascular adverse events (CVAEs) were analyzed in subgroups stratified by cardio- and cerebrovascular medical history, cardiovascular risk factors (CVRFs), and use of cardio- and cerebrovascular medications or triptans. Results: Two thousand, eight hundred and forty-two patients were included in the study. Overall (58–65%) and serious adverse events (<1–2%) occurred in similar proportions across fremanezumab and placebo groups. CVAEs were infrequent, regardless of cardio- and cerebrovascular medical history (2–6%). CVAEs occurred in low, similar proportions of patients with CVRFs and those using cardio- and cerebrovascular medications or triptans. No cardio- and cerebrovascular signals were identified. Conclusion: Fremanezumab demonstrated a favorable overall and cardio- and cerebrovascular safety profile in more than 2800 patients with episodic migraine or chronic migraine, regardless of cardio- and cerebrovascular medical history, CVRFs, or medication use. Trial Registrations: NCT02629861 (HALO EM, https://clinicaltrials.gov/ct2/show/NCT02629861), NCT02621931 (HALO CM, https://clinicaltrials.gov/ct2/show/NCT02621931), NCT03308968 (FOCUS, https://clinicaltrials.gov/ct2/ show/NCT03308968) [ABSTRACT FROM AUTHOR]

Background: The effect of different anticoagulants on recanalization after cerebral venous thrombosis has not been studied in a randomized controlled trial. Methods: RE-SPECT CVT (ClinicalTrials.gov number: NCT02913326) was a Phase III, prospective, randomized, parallel-group, open-label, multicenter, exploratory trial with blinded endpoint adjudication. Acute cerebral venous thrombosis patients were allocated to dabigatran 150 mg twice daily, or dose-adjusted warfarin, for 24 weeks, after 5–15 days' treatment with unfractionated or low-molecular-weight heparin. A standardized magnetic resonance protocol including arterial spin labeling, three-dimensional time-of-flight venography, and three-dimensional contrast-enhanced magnetic resonance angiography was obtained at the end of the treatment period. Cerebral venous recanalization at six months was assessed by two blinded adjudicators, using the difference in a score of occluded sinuses and veins (predefined secondary efficacy endpoint) and in the modified Qureshi scale (additional endpoint), between baseline and the end of the treatment. Results: Of 120 cerebral venous thrombosis patients randomized, venous recanalization could be evaluated in 108 (55 allocated to dabigatran and 53 to warfarin, 1 patient had a missing occlusion score at baseline). No patient worsened in the score of occluded cerebral veins and sinuses, while 33 (60%) on dabigatran and 35 (67%) on warfarin improved. The mean score change from baseline in the occlusion score was similar in the two treatment groups (dabigatran −0.8, SD 0.78; warfarin −1.0, SD 0.92). In the modified Qureshi score, full recanalization was adjudicated in 24 (44%) and 19 (36%), and partial recanalization in 23 (42%) and 26 (49%) patients in the dabigatran and warfarin arms, respectively. No statistically significant treatment difference in the modified Qureshi score could be detected (p = 0.44). Conclusion: The majority of patients with cerebral venous thrombosis, anticoagulated with either dabigatran or warfarin for six months, showed partial or complete recanalization of occluded sinuses and veins at the end of the treatment. Clinical trial registration: Trial registry name: ClinicalTrials.gov URL: https://clinicaltrials.gov Registration number: NCT02913326 [ABSTRACT FROM AUTHOR]

Background: This post-hoc analysis was conducted to evaluate the effect of erenumab on monthly migraine days, monthly migraine attacks, and attack duration in patients with episodic migraine to investigate whether erenumab actually prevents the occurrence of migraine attacks and/or shortens them. Methods: We conducted a post-hoc analysis of the data from the STRIVE study, in 955 patients with episodic migraine. Relative changes from baseline to mean over months 4, 5 and 6 of the double-blind treatment phase in monthly migraine days, monthly migraine attacks and mean migraine attack duration were assessed. Results: Erenumab reduced monthly migraine days and monthly migraine attacks compared with placebo in a similar way. Erenumab had only a minor impact on shortening the duration of migraine attacks. Conclusion: These post-hoc analyses demonstrate that the decrease in monthly migraine days by erenumab is mainly driven by a reduction in the frequency of monthly migraine attacks and to a much lesser extent by shortening the duration of migraine attacks. Trial registration: This study is registered at ClinicalTrials.gov (NCT02456740) [ABSTRACT FROM AUTHOR]

Background: Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine.Methods: An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine.Results: Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created.Conclusions: Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment. [ABSTRACT FROM AUTHOR]

This document published by the International Headache Society provides practical recommendations for the preventive pharmacological treatment of migraines. The recommendations are categorized into two levels: Optimal and Essential, based on medication availability in different regions. The document includes a table listing drugs with evidence of efficacy for migraine prevention and their availability in the World Health Organization Model List of Essential Medicines. The recommendations aim to establish essential standards of migraine management worldwide and provide guidance on evaluating treatment effectiveness, switching medications, combination therapy, and duration of treatment. The document also discusses comorbidities, specific medications for chronic migraine, preventive treatment in different populations, and managing medication overuse headache. [Extracted from the article]

Background: In an effort to improve migraine management around the world, the International Headache Society (IHS) has here developed a list of practical recommendations for the acute pharmacological treatment of migraine. The recommendations are categorized into optimal and essential, in order to provide treatment options for all possible settings, including those with limited access to migraine medications. Methods: An IHS steering committee developed a list of clinical questions based on practical issues in the management of migraine. A selected group of international senior and junior headache experts developed the recommendations, following expert consensus and the review of available national and international headache guidelines and guidance documents. Following the initial search, a bibliography of twenty-one national and international guidelines was created and reviewed by the working group. Results: A total of seventeen questions addressing different aspects of acute migraine treatment have been outlined. For each of them we provide an optimal recommendation, to be used whenever possible, and an essential recommendation to be used when the optimal level cannot be attained. Conclusion: Adoption of these international recommendations will improve the quality of acute migraine treatment around the world, even where pharmacological options remain limited. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health technology assessments are systematic evaluations of the properties, effects, and consequences of healthcare technologies; this position statement is designed to inform decision makers about access to and reimbursement for medications and devices for the acute and preventive treatment of migraine. This position statement extends beyond the already available guidelines on randomized controlled trials for migraine to incorporate real-world evidence and a synthetic approach for considering multiple data sources and modelling methods when assessing the value of migraine treatments. [ABSTRACT FROM AUTHOR]

Background: Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, "speed of onset of effect" is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials. This difference, however, can be clinically irrelevant. Methods: Placebo-controlled randomised, controlled trials with pain freedom results from 30 min to 2–4 hours were retrieved from the literature. For each time-point, the therapeutic gain (drug minus placebo) (TG) was calculated. Therapeutic gain for being pain free of 5% was chosen for the definition of "onset of action", since this is approximately 1/3 of the 16% TG and 1/4 of 21% of TG for sumatriptan 50 mg and 100 mg, respectively. Results: A total of 22 time-effect curves based on randomised, controlled trials were analysed. Based on the "onset of action" of 5% pain freedom, the evaluated drugs and administration forms can be classified as follows: i) Early time to onset, ≤30 min (three randomised, controlled trials); ii) medium time to onset, 60 min (nine randomised, controlled trials); iii) delayed time to onset, 90–120 min (10 randomised, controlled trials). Conclusion: Only three non-oral administration forms with a triptan (subcutaneous sumatriptan and nasal zolmitriptan) resulted in an "onset of action" at ≥30 min; in the future, early onset of action should be a priority in the development of new drugs or new administration-forms for the treatment of acute migraine attacks. [ABSTRACT FROM AUTHOR]

Recently published long-term data from randomized controlled trials have provided evidence for the prevention of recurrent embolic stroke of undetermined source by percutaneous closure of the patent foramen ovale. However, most data were obtained from Caucasian populations and evidence on patent foramen ovale closure in Asian-Pacific patients is limited. The relative paucity in clinical data from this population, as well as the fact that Asian-Pacific patients may have higher bleeding risks than Caucasians, complicates clinical decision-making. This document, resulting from a consensus meeting of Asian-Pacific clinical experts, states the consensus among these experts about how to treat Asian-Pacific patients who had an embolic stroke of undetermined source and have a patent foramen ovale, based on currently available evidence and expert opinions. In addition, uncertainties and the need for clinical data regarding patent foramen ovale closure for prevention of recurrent embolic stroke of undetermined source in general, and specifically for Asian-Pacific patients, are identified. [ABSTRACT FROM AUTHOR]

Background: Pain freedom after 2 hours is the recommended primary endpoint by the International Headache Society in randomized trials investigating drug treatment of acute migraine attacks. In order to demonstrate an early effect of a drug, some drug companies, however, have promoted headache relief (improvement from severe or moderate pain to mild or no pain) at earlier time points than 2 hours as outcome parameter.Methods and Results: We analyzed the relationship between pain freedom and headache relief in acute migraine trials and observed that persistent mild headache constituted 90% of headache relief after 0.5 hour and 40% of headache relief after 2 hours.Conclusion: Headache relief at 2 hours should in our view only be used as an outcome measure for comparison with historic data. Prior to 2 hours, headache relief varies with time from intake and the therapeutic gain is very small. Therefore, pain freedom should be used at these early time points. [ABSTRACT FROM AUTHOR]

Clinical trials are a key component of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. Advances in drugs, devices, and biologicals, as well as novel trial designs, have prompted several updates over the nearly 30 years since, including most recently the Guidelines for controlled trials of preventive treatment of chronic migraine (2018), the Guidelines for controlled trials of acute treatment of migraine attacks in adults (2019), and Guidelines for controlled trials of preventive treatment of migraine in children and adolescents (2019). The present update incorporates findings from new research and is intended to optimize the design of controlled trials of preventive pharmacological treatment of episodic migraine in adults. A guideline for clinical trials with devices will be published separately. [ABSTRACT FROM AUTHOR]

Background: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. Aims: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. Methods: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. Results: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0–3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. Conclusion: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415).Methods: Patients (n = 667) received (3:2:2) placebo or erenumab 70/140 mg once-monthly. The proportion of patients achieving a given response threshold was assessed. A post-hoc analysis was conducted to contextualize the actual treatment benefit in subgroups of patients achieving (or not) specified response thresholds. Outcome measures included MMD, acute migraine-specific medication treatment days (MSMD) and disability.Results: The proportion of patients responding to erenumab exceeded that of placebo at the ≥50% and ≥75% response thresholds. At month 3, 39.9% and 41.2% of patients on erenumab 70 and 140 mg, respectively, achieved ≥50% response versus placebo (23.5%). Similarly, at month 3, 17.0% and 20.9% of patients on erenumab 70 and 140 mg, respectively, achieved ≥75% response versus placebo (7.8%). Compared with the overall erenumab-treated population (change in MMD: -6.6 [both 70 and 140 mg]), ≥50% responders showed MMD reductions of -12.2/-12.5 for 70 mg/140 mg versus -2.6/-2.2 for those not achieving ≥50% response. ≥75% responders showed MMD reductions of -13.9/-14.8 for 70 mg/140 mg versus -5.0/-4.3 for those not achieving ≥75% response. Relative improvements in MSMD and disability were observed in responders versus overall erenumab-treated population.Conclusion: For erenumab-treated patients achieving ≥50% response, the actual reduction in MMD was almost twice that of the overall population. These findings provide context for setting realistic expectations regarding actual treatment benefit experienced by patients responding to treatment. [ABSTRACT FROM AUTHOR]

Background: In trials of monoclonal antibodies against calcitonin gene-related peptide or its receptor for prevention of episodic migraine, we observed two problematic aspects: a) The graphic presentations; b) the methods of calculating "response rates" (≥50% decrease of monthly migraine days from baseline).Observations: Decrease in monthly migraine days is presented, over time, in figures on a downward (negative) scale from zero at baseline, with the ordinate stopped just beyond the maximum effect of the active drugs. In one trial, decreases in monthly migraine days were -1.8 after placebo, -3.2 after erenumab 70 mg and -3.7 after erenumab 140 mg, with the ordinate stopped at -4.5. The reader can perceive only a relative 2-fold benefit of erenumab versus placebo. If, however, treatment periods are compared with baseline in bar charts, MMDs persisting after treatment in the same trial can be illustrated as follows, creating a different perception: 78% for placebo, 61% for erenumab 70 mg, and 55% for erenumab 140 mg. In the nine trials, "response rates" defined as above were calculated in five different ways, taking different numbers of treatment months into account in comparisons with the one-month baseline. This makes comparisons impossible.Suggestions For Improvements: Mean monthly migraine days before and after treatment should be presented in a bar chart. Such figures, presenting persisting MMDs, are more clinically relevant and less misleading than decreases from baseline. The definition and methods of calculating and presenting "50% response rates" should be standardized by the Drug Trial Committee of the International Headache Society. [ABSTRACT FROM AUTHOR]

Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data.Methods: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6-8 hours apart).Results: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) (p = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common.Conclusions: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The "sham" device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. Study identification and registration: PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844. [ABSTRACT FROM AUTHOR]

The quality of clinical trials is an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for controlled trials of drugs in migraine. Scientific and clinical developments in headache medicine led to second and third editions in 2000 and 2012, respectively. The current, fourth edition of the Guidelines retains the structure and much content from previous editions. However, it also incorporates evidence from clinical trials published after the third edition as well as feedback from meetings with regulators, pharmaceutical and device manufacturers, and patient associations. Its final form reflects the collective expertise and judgement of the Committee. These updated recommendations and commentary are intended to meet the Society's continuing objective of providing a contemporary, standardized, and evidence-based approach to the conduct and reporting of randomised controlled trials for the acute treatment of migraine attacks. [ABSTRACT FROM AUTHOR]

Rationale To prevent recurrent venous thrombotic events after acute cerebral venous or dural sinus thrombosis, guidelines recommend long-term oral anticoagulation with vitamin K antagonists. Non-vitamin K oral anticoagulant experience in cerebral venous or dural sinus thrombosis is limited to case reports and series. Aim To compare dabigatran with dose-adjusted warfarin in patients with cerebral venous or dural sinus thrombosis for the prevention of recurrent venous thrombotic event. Sample size One hundred and twenty patients. Methods and design This study is a phase III, prospective, randomized, parallel-group, open-label, multicenter, exploratory trial with blinded endpoint adjudication. Patients with acute cerebral venous or dural sinus thrombosis after 5–15 days of treatment with parenteral heparin are randomized to either dabigatran etexilate 150 mg twice daily or dose-adjusted (international normalized ratio 2–3) warfarin (≤24 weeks). Study outcome The primary endpoint is a composite of patients with new venous thrombotic event (recurring cerebral venous or dural sinus thrombosis, deep venous thrombosis of any limb, pulmonary embolism, and major bleeding (International Society on Thrombosis and Hemostasis definition)) during the treatment period. Statistics will be descriptive (number and frequencies). Study timelines Inclusion started in December 2016. Final results are expected by the end of 2018.Discussion This exploratory trial is the first to compare vitamin K with non-vitamin K antagonists in cerebral venous or dural sinus thrombosis. It will provide evidence to guide physicians and patients in choosing oral anticoagulants to prevent venous thrombotic event after acute cerebral venous or dural sinus thrombosis. ClinicalTrials.gov number: NCT02913326. [ABSTRACT FROM AUTHOR]

Background Quality clinical trials form an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. In 2008, the Committee published the first specific guidelines on chronic migraine. Subsequent advances in drug, device, and biologicals development, as well as novel trial designs, have created a need for a revision of the chronic migraine guidelines. Objective The present update is intended to optimize the design of controlled trials of preventive treatment of chronic migraine in adults, and its recommendations do not apply to trials in children or adolescents. [ABSTRACT FROM AUTHOR]

Background: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results: Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0-3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion: Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage. [ABSTRACT FROM AUTHOR]

Background: Chronic cluster headache (CH) is a debilitating disorder for which few well-controlled studies demon.strate effectiveness of available therapies. Non-invasive vagus nerve stimulation (nVNS) was examined as adjunctive prophylactic treatment of chronic CH.Methods: PREVA was a prospective, open-label, randomised study that compared adjunctive prophylactic nVNS (n = 48) with standard of care (SoC) alone (control (n = 49)). A two-week baseline phase was followed by a four-week randomised phase (SoC plus nVNS vs control) and a four-week extension phase (SoC plus nVNS). The primary end point was the reduction in the mean number of CH attacks per week. Response rate, abortive medication use and safety/tolerability were also assessed.Results: During the randomised phase, individuals in the intent-to-treat population treated with SoC plus nVNS (n = 45) had a significantly greater reduction in the number of attacks per week vs controls (n = 48) (-5.9 vs -2.1, respectively) for a mean therapeutic gain of 3.9 fewer attacks per week (95% CI: 0.5, 7.2; p = 0.02). Higher ≥50% response rates were also observed with SoC plus nVNS (40% (18/45)) vs controls (8.3% (4/48); p < 0.001). No serious treatment-related adverse events occurred.Conclusion: Adjunctive prophylactic nVNS is a well-tolerated novel treatment for chronic CH, offering clinical benefits beyond those with SoC. [ABSTRACT FROM AUTHOR]

Background and aims: Documentation of atrial fibrillation is required to initiate oral anticoagulation therapy for recurrent stroke prevention. Atrial fibrillation often goes undetected with traditional electrocardiogram monitoring techniques. We evaluated whether atrial fibrillation detection using continuous long-term monitoring with an insertable cardiac monitor is cost-effective for preventing recurrent stroke in patients with cryptogenic stroke, in comparison to the standard of care. Methods: A lifetime Markov model was developed to estimate the cost-effectiveness of insertable cardiac monitors from a UK National Health Service perspective using data from the randomized CRYSTAL-AF trial and other published literature. We also conducted scenario analyses (CHADS2 score) and probabilistic sensitivity analyses. All costs and benefits were discounted at 3.5%. Results: Monitoring cryptogenic stroke patients with an insertable cardiac monitor was associated with fewer recurrent strokes and increased quality-adjusted life years compared to the standard of care (7.37 vs 7.22). Stroke-related costs were reduced in insertable cardiac monitor patients, but overall costs remained higher than the standard of care (£19,631 vs £17,045). The incremental cost-effectiveness ratio was £17,175 per quality-adjusted life years gained, compared to standard of care in the base-case scenario, which is below established quality-adjusted life years willingness- to-pay thresholds. When warfarin replaced non-vitamin-K oral anticoagulants as the main anticoagulation therapy, the incremental cost-effectiveness ratio was £13,296 per quality-adjusted life years gained. Conclusion: Insertable cardiac monitors are a cost-effective diagnostic tool for the prevention of recurrent stroke in patients with cryptogenic stroke. The cost-effectiveness results have relevance for the UK and across value-based healthcare systems that assess costs relative to outcomes. [ABSTRACT FROM AUTHOR]

Rationale Cryptogenic ischemic strokes constitute 20-30% of ischemic strokes, the majority of which are embolic strokes of undetermined source. The standard preventive treatment in these patients is usually acetylsalicylic acid. Aim The Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS) is designed to determine whether the oral thrombin inhibitor dabigatran, taken within three-months after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of recurrent stroke and to characterize the safety of dabigatran in this setting. Design Prospective, randomized, double-blind, multicenter trial in approximately 6000 patients and 550 centers with embolic stroke of undetermined source. Subjects are randomized to dabigatran or acetylsalicylic acid and treated for an expected minimum of six-months and up to approximately three-years. It is an event-driven trial aiming for 353 adjudicated primary outcome events. Study outcomes The primary efficacy outcome is time to first recurrent stroke (ischemic, hemorrhagic, or unspecified). Key secondary outcomes are time to first ischemic stroke and time to first occurrence in the composite outcome of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death. The primary safety outcome is major hemorrhage, including symptomatic intracranial hemorrhage. Discussion Acetylsalicylic acid is the most common antithrombotic given to patients with embolic strokes of undetermined source to reduce recurrence risk. This trial will determine whether anticoagulation with dabigatran is more effective than acetylsalicylic acid, and acceptably safe. [ABSTRACT FROM AUTHOR]

Background The Cerebrovascular Antiplatelet Trialists' Collaborative Group was formed to obtain and analyze individual patient data from the major randomized trials of common antiplatelet regimens after cerebral ischemia. Although the risk of stroke can be reduced by antiplatelet drugs, there continues to be uncertainty about the balance of risk and benefits of different antiplatelet regimens for an individual patient. Aims Our aim is to provide clinicians with a thorough evidence-based answer on these therapeutic alternatives. Methods We have identified six large randomized trials and plan to meta-analyze the data on an individual patient level. In total, these trials have enrolled 46 948 patients with cerebral ischemia. Uniquely, the Cerebrovascular Antiplatelet Trialists' Collaborative Group has secured access to the individual data of all of these trials, with the participation of key investigators and pharmaceutical companies. Our principal objective includes deriving a reliable estimate of the efficacy of different antiplatelet regimens on key outcomes including serious vascular events, major ischemic events, major bleeding, and intracranial hemorrhage. Results We propose to redefine composite outcome events, if necessary, to achieve comparability. Further, we aim to build and validate prognostic models for the risk of major bleeding and intracranial hemorrhage and to build a decision model that may support evidence-based decision making about which antiplatelet regimen would be most effective in different risk groups of patients. Conclusions This paper outlines inclusion criteria, outcome measures, baseline characteristics, and planned statistical analysis. [ABSTRACT FROM AUTHOR]

Rationale Endovascular treatment has been shown to restore blood flow effectively. Second-generation medical devices such as stent retrievers are now showing overwhelming efficacy in clinical trials, particularly in conjunction with intravenous recombinant tissue plasminogen activator. Aims and Design This statistical analysis plan utilizing a novel, sequential approach describes a prospective, individual patient data analysis of endovascular therapy in conjunction with intravenous recombinant tissue plasminogen activator agreed upon by the Thrombectomy and Tissue Plasminogen Activator Collaborative Group. Study Outcomes This protocol will specify the primary outcome for efficacy, as 'favorable' outcome defined by the ordinal distribution of the modified Rankin Scale measured at three-months poststroke, but with modified Rankin Scales 5 and 6 collapsed into a single category. The primary analysis will aim to answer the questions: 'what is the treatment effect of endovascular therapy with intravenous recombinant tissue plasminogen activator compared to intravenous tissue plasminogen activator alone on full scale modified Rankin Scale at 3 months?' and 'to what extent do key patient characteristics influence the treatment effect of endovascular therapy?'. Key secondary outcomes include effect of endovascular therapy on death within 90 days; analyses of modified Rankin Scale using dichotomized methods; and effects of endovascular therapy on symptomatic intracranial hemorrhage. Several secondary analyses will be considered as well as expanding patient cohorts to intravenous recombinant tissue plasminogen activator-ineligible patients, should data allow. Discussion This collaborative meta-analysis of individual participant data from randomized trials of endovascular therapy vs. control in conjunction with intravenous thrombolysis will demonstrate the efficacy and generalizability of endovascular therapy with intravenous thrombolysis as a concomitant medication. [ABSTRACT FROM AUTHOR]

In 2008, the recently founded European Stroke Organisation published its guidelines for the management of ischemic stroke and transient ischemic attack. This highly cited document was translated in several languages and was updated in 2009. Since then, the European Stroke Organisation has published guidelines for the management of intracranial aneurysms and subarachnoidal hemorrhage, for the establishment of stroke units and stroke centers, and recently for the management of intracerebral hemorrhage. In recent years, the methodology for the development of guidelines has evolved significantly. To keep pace with this progress and driven by the strong determination of the European Stroke Organisation to further promote stroke management, education, and research, the European Stroke Organisation decided to delineate a detailed standard operating procedure for its guidelines. There are two important cornerstones in this standard operating procedure: The first is the implementation of the Grading of Recommendations Assessment, Development, and Evaluation methodology for the development of its Guideline Documents. The second one is the decision of the European Stroke Organisation to move from the classical model of a single Guideline Document about a major topic (e.g. management of ischemic stroke) to focused modules (i.e. subdivisions of a major topic). This will enable the European Stroke Organisation to react faster when new developments in a specific stroke field occur and update its recommendations on the related module rather swiftly; with the previous approach of a single large Guideline Document, its entire revision had to be completed before an updated publication, delaying the production of up-to-date guidelines. After discussion within the European Stroke Organisation Guidelines Committee and significant input from European Stroke Organisation members as well as methodologists and analysts, this document presents the official standard operating procedure for the development of the Guideline Documents of the European Stroke Organisation. [ABSTRACT FROM AUTHOR]

Rationale Early reperfusion in patients experiencing acute ischemic stroke is critical, especially for patients with large vessel occlusion who have poor prognosis without revascularization. Solitaire™ stent retriever devices have been shown to immediately restore vascular perfusion safely, rapidly, and effectively in acute ischemic stroke patients with large vessel occlusions. Aim The aim of the study was to demonstrate that, among patients with large vessel, anterior circulation occlusion who have received intravenous tissue plasminogen activator, treatment with Solitaire revascularization devices reduces degree of disability 3 months post stroke. Design The study is a global multicenter, two-arm, prospective, randomized, open, blinded end-point trial comparing functional outcomes in acute ischemic stroke patients who are treated with either intravenous tissue plasminogen activator alone or intravenous tissue plasminogen activator in combination with the Solitaire device. Up to 833 patients will be enrolled. Procedures Patients who have received intravenous tissue plasminogen activator are randomized to either continue with intravenous tissue plasminogen activator alone or additionally proceed to neurothrombectomy using the Solitaire device within six-hours of symptom onset. Study Outcomes The primary end-point is 90-day global disability, assessed with the modified Rankin Scale (mRS). Secondary outcomes include mortality at 90 days, functional independence (mRS ≤ 2) at 90 days, change in National Institutes of Health Stroke Scale at 27 h, reperfusion at 27 h, and thrombolysis in cerebral infarction 2b/3 flow at the end of the procedure. Analysis Statistical analysis will be conducted using simultaneous success criteria on the overall distribution of modified Rankin Scale ( Rankin shift) and proportions of subjects achieving functional independence (mRS 0-2). [ABSTRACT FROM AUTHOR]

Background: Numerous studies have described a relationship between migraine and stroke, and there is emerging evidence that migraine is also associated with cardiovascular disease. The combination of migraine and both cerebrovascular and cardiovascular disease has implications for therapy. Methods: We conducted a review of the modifications in medical therapy in patients with comorbid migraine and cardioand cerebrovascular disorders based on publications from the last 15 years. Results: Some drugs are contraindicated to treat migraine attacks (ergots, triptans) or for migraine prevention in patients after transient ischemic attack (TIA)/ischemic stroke. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in patients with cerebral bleeding. Some drugs for the treatment of acute migraine attacks are contraindicated in patients with symptomatic coronary heart disease. Conclusions: Given the large number of patients with comorbid migraine and cardiovascular as well as cerebrovascular disease, there is an unmet need to treat these patients. [ABSTRACT FROM AUTHOR]

Background: Recent experience in designing and running clinical trials on new medications for the prevention of migraine in children and adolescents highlighted the need for revision of the 1st edition of the International Headache Society Guidelines for clinical trials of preventive treatment of migraine in children and adolescents which were published in 2019. Methods: The authors of the 1st edition of the guidelines formed an informal focus group with aims of appraising the performance of the guidelines, clarifying any ambiguity and providing improvements, where needed, based on personal experience and expert analysis. Results: This review and the following update were able to address issues related to the classification of migraine, the duration of migraine attacks, the age groups of children and adolescents, the use of electronic diaries, the assessment of outcome measures, the need for an interim analysis and the issues related to placebo response. Conclusions: This update provides necessary clarifications of the guidelines in order to enable better design and running of future clinical trials for the preventive treatment of migraine in children and adolescents. [ABSTRACT FROM AUTHOR]

Introduction: The trigeminal autonomic cephalalgias (TACs) subsume four primary headache disorders. Hemicrania continuais increasingly regarded as an additional TAC. In rare cases patients may present with two different TACs or a TACand hemicrania continua.Cases: We report four patients with two different TACs or one TAC and hemicrania continua. Two patients presentedwith cluster headache and paroxysmal hemicrania, one patient with cluster headache and hemicrania continua, and onepatient suffered from cluster headache and SUNCT.Discussion: While the International Classification of Headache Disorders (ICHD-II) proposes specific diagnostic criteria,the variability of clinical presentation may make clear diagnosis difficult. All patients fulfilled the ICHD-II criteria.The manifestation of two different TACs or hemicrania continua in one patient is uncommon but possible and shouldbe taken into account especially when chronic headache patients present with changing headache symptoms. [ABSTRACT FROM AUTHOR]

Background: Occipital nerve stimulation (ONS) has been shown to be effective for selected patients with intractable headache disorders. We performed a prospective critical evaluation of complications and direct treatment costs. Methods: Twenty-seven patients with chronic cluster headache (CCH, n¼24) or chronic migraine (CM, n¼3) underwent a trial phase with bilateral ONS and subsequent implantation of a permanent generator (IPG), if responsive to treatment according to predefined criteria. Procedural and long-term complications as well as direct treatment costs of neuromodulation therapy of ONS were recorded over a mean follow-up period of 20 months (range 5–47 months). Results: Twenty-five of 27 patients (93%) responded to treatment. Twenty-one complications in 14 patients were identified, necessitating reoperation in 13 cases. Overall treatment costs were E761,043, including hardware-related costs of E506,019, costs for primary hospital care of E210,496, and complications related to hospitalization costs of E44,528. This results in a per case-based cost of E9445 for hospitalization and E18,741 for hardware costs, totaling E28,186. Conclusion: ONS for treatment of refractory CCH and CM is a cost-intensive treatment option with a significant complication rate. Nevertheless, patients with refractory primary headache disorders may experience substantial relief of pain attacks, and headache days, respectively. [ABSTRACT FROM AUTHOR]

Background Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke ( Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. Methods We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran- Mantel- Haenszel test. Results Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients ( odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups ( OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. Conclusion Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment. [ABSTRACT FROM AUTHOR]

Background: Current textbook knowledge states that patients with chronic migraine and medication overuse should be withdrawn from acute medication before initiating preventive drug therapy.Overview: This recommendation is based on the clinical impression that patients with chronic migraine and medication overuse are refractory to preventive therapy. Recently, however, four randomised trials, two with topiramate and two with onabotulinum toxin A, showed that about half of patients with chronic migraine and medication overuse will respond to these treatments and show both a reduction in migraine days and intake of acute medication.Conclusions: Therefore, we propose to educate patients on the mechanisms of medication overuse and motivate them to reduce intake frequency. Patients who fail should be offered either topiramate or onabotulinum toxin A in combination with behavioural therapy and regular exercise. If this approach fails, patients should be offered withdrawal therapy. [ABSTRACT FROM PUBLISHER]

Introduction Analysis of reliable registry data can direct future research to influence clinical care. Data from the Virtual International Stroke Trials Archive have been used to test hypotheses and inform trial design. We sought to expand Virtual International Stroke Trials Archive into a broader stroke resource with new opportunities for research and international collaboration. Methods Using procedures initially developed for an acute stroke trial archive, we invited trialists to lodge data on rehabilitation, secondary prevention, intracerebral haemorrhage, imaging, and observational stroke studies. Results We have extended Virtual International Stroke Trials Archive into six subsections: Virtual International Stroke Trials Archive- Acute ( n = 28 190 patients' data), Virtual International Stroke Trials Archive- Rehab ( n = 10 194), Virtual International Stroke Trials Archive-intracerebral haemorrhage ( n = 1829), Virtual International Stroke Trials Archive- Prevention, Virtual International Stroke Trials Archive- Imaging ( n = 1300), and Virtual International Stroke Trials Archive- Plus ( n = 6573). Enrollment continues, with commitments for the contribution of six further trials to Virtual International Stroke Trials Archive- Prevention, 13 trials to Virtual International Stroke Trials Archive- Rehab, and one registry to Virtual International Stroke Trials Archive- Plus. Data on age, type of stroke, medical history, outcomes by modified Rankin scale and Barthel Index (BI), mortality, and adverse events are available for analyses. The Virtual International Stroke Trials Archive network encourages the development of young investigators and provides opportunities for international peer review and collaboration. Conclusions Application of the original Virtual International Stroke Trials Archive concepts beyond acute stroke trials can extend the value of clinical research at low cost, without threatening commercial or intellectual property interests. This delivers valuable research output to inform the efficiency of future stroke research. We invite stroke researchers to participate actively in Virtual International Stroke Trials Archive and encourage the extension of Virtual International Stroke Trials Archive principles to other disease areas. [ABSTRACT FROM AUTHOR]

Rationale Zinc is both a direct neurotoxin and a signaling mediator in multiple early and late detrimental processes following ischemia. DP-b99, a lipophilic moderate-affinity chelator of zinc, is a first-in-class multitargeted neuroprotective agent for ischemic stroke. DP-b99 has completed several Phase I studies and two double-blind placebo-controlled Phase II trials, which supported the safety of DP-b99 and were consistent with a beneficial effect on poststroke recuperation. Aim: Membrane-Activated Chelator Stroke Intervention is a Phase III study. The primary objective is to evaluate the safety and therapeutic effects of intravenous 1.0mg/kg/day DP-b99, initiated within nine-hours of stroke onset in patients with moderately severe hemispheric acute ischemic stroke, through the analysis across the whole distribution of scores of the primary efficacy endpoint of the modified Rankin Scale, 90 days after the stroke. Methods The Membrane-Activated Chelator Stroke Intervention study is a randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-arm trial comparing a placebo group to a group treated with intravenous DP-b99 for four consecutive days. Non-rtPA-treated acute ischemic stroke patients - with a baseline NIHSS score of 10-16 and a clinical syndrome that includes language dysfunction, visual field defect and/or neglect -will be stratified on a 1 : 1 basis to one of the two treatments. Half will be randomized within 0- 4.5 h of stroke onset. Follow-up after the four treatment days will occur on days 12, 30 and 90. An interim futility analysis will be performed after primary endpoint data have been collected for 50% of 770 subjects planned to be enrolled. A data and safety monitoring board will assess safety data and will oversee the interim analysis. Conclusion This Phase III Membrane-Activated Chelator Stroke Intervention trial is based on promising data derived from previous Phase I and II DP-b99 trials and capitalizes on lessons learned from failures of past stroke studies in relation to neuroprotection, patient selection and data analysis. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the current evidence on the association between migraine, including aura status, and cervical artery dissection.Methods: We performed a systematic review and meta-analysis of studies investigating the association between migraine or migraine subtypes (e.g. migraine with aura) and cervical artery dissection published through October 2010.Results: We identified five case-control studies investigating the association between migraine and cervical artery dissection. In pooled analysis, migraine doubled the risk of cervical artery dissection (pooled odds ratio [OR] = 2.06, 95% confidence interval [CI] 1.33–3.19). All studies allowed evaluation of migraine aura status. While the effect estimate for migraine without aura (pooled OR = 1.94, 95% CI 1.21–3.10) was similar to overall migraine, the association was weaker for migraine with aura (pooled OR = 1.50, 95% CI 0.76–2.96). However, there is no evidence that aura status significantly modifies the association between migraine and cervical artery dissection (meta-regression on aura status p = .58). The risk does not appear to differ between women and men; however, only few studies presented gender-specific data. Heterogeneity among studies was low to moderate.Conclusion: In this meta-analysis migraine is associated with a two-fold increased risk of cervical artery dissection. This risk does not appear to significantly differ by migraine aura status or gender. [ABSTRACT FROM PUBLISHER]

Methods: Four hundred and sixty-one adult subjects with migraine were randomised to one of five treatments, the oral antagonist at the calcitonin gene-related peptide (CGRP) receptor BI 44370 TA (50 mg, 200 mg, 400 mg), active comparator eletriptan 40 mg or placebo. The analysis included 341 subjects who took study medication.Results: The primary endpoint, pain-free after two hours, was reached by significantly more subjects in the BI 44370 TA 400 mg (20/73 = 27.4%) and eletriptan 40 mg (24/69 = 34.8%) groups compared to placebo (6/70 = 8.6%, p = .0016), but not by subjects in the BI 44370 TA 200 mg group (14/65 = 21.5%). The effect of 50 mg BI 44370 TA (5/64 = 7.8%) was similar to that of placebo. Analysis of secondary endpoints supported the conclusion from the primary analysis. The frequency of adverse events was low in all groups.Conclusion: Efficacy of BI 44370 TA was shown in a dose-dependent manner in the treatment of acute migraine attacks. [ABSTRACT FROM PUBLISHER]

Patients with transient ischemic attack (TIA) or ischemic stroke carry a risk of recurrent stroke of between 5% and 20% per year. In patients with TIA or ischemic stroke of non-cardiac origin, antiplatelet drugs are able to decrease the relative risk of stroke by 11–15% and the risk of stroke, myocardial infarction, and vascular death by 15–22%. Aspirin is the most widely used drug. It is affordable and effective. Low doses of 50–325 mg aspirin are as effective as high doses and cause less gastrointestinal side-effects. The combination of aspirin with slow-release dipyridamole is superior to aspirin alone for stroke prevention but not for the prevention of cardiac events. The risk of major bleeding complications is not increased with the combination, which suggests that dipyridamole might act in another way than as antiplatelet drug. Clopidogrel is not superior to aspirin in unselected stroke patients but is superior in patients at high risk of recurrence. The combination of aspirin plus clopidogrel is not more effective than clopidogrel alone, but carries a higher bleeding risk. The most effective antiplatelet drugs, the GP IIb/IIIa antagonists, are not superior to aspirin and carry a higher risk of bleeding. These results indicate that any antiplatelet therapy with a more potent drug than aspirin will only have a marginally higher efficacy, which might be offset by a higher bleeding rate. Therefore, selection of patients who might benefit from antiplatelet therapy other than aspirin is important. [ABSTRACT FROM AUTHOR]

Background: The International Headache Society has been offering multiple award opportunities for young researchers and clinicians for many years, with the aim of supporting the development of careers in headache science and medicine. Methods: In order to assess the outcomes of the International Headache Society award grants, a questionnaire was sent to all previous recipients, investigating a series of aspects related to their work, both during and after award completion. Results: Of 44 total questionnaires sent, 36 were returned. Eighty-one percent of the recipients reported to have remained in the headache field since the award, half of them held a current academic position and over three-quarters had stayed in contact with the host institution. The totality of questionnaire responders stated that the grant had had a significantly positive impact on their careers. Conclusions: The International Headache Society grants have assisted many young researchers in building an academic and clinical career in the field of headache, throughout the years. [ABSTRACT FROM AUTHOR]

Atrial fibrillation is an important risk factor for stroke. New drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists like warfarin are under investigation. These include direct factor Xa inhibitors and direct thrombin-inhibitors. Recent studies provide promising results for apixaban, dabigatran, and rivaroxaban, including higher efficacy and significantly lower incidences of intracranial bleeds compared with warfarin. The new oral anticoagulants substances show similar results in secondary as in primary stroke prevention in patients with AF and will on the long run replace warfarin. [ABSTRACT FROM AUTHOR]

Purpose: In four large controlled trials with lasmiditan and ubrogepant placebo was administered in the first step to demonstrate an effect on migraine attack. In the same trials the investigators also asked the question: is a second dose of the drug effective in non-responders to the first dose? In this phase patients who received placebo in the first phase of the trial again after 2 hours received another dose of placebo. Conclusion: To be ethical, clinical research requires balancing rigorous science with the protection of human subjects; and it is, in our view, questionable whether placebo was used with "scientific rigor" in the second step of these trials, and this design is not recommended. [ABSTRACT FROM AUTHOR]