The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis

OBJECTIVE: While there are several trials that support the efficacy of various drugs for migraine prophylaxis against placebo, there is limited evidence addressing the comparative safety and efficacy of these drugs. We conducted a systematic review and network meta-analysis to facilitate comparison between drugs for migraine prophylaxis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to August 13, 2022, for randomized trials of pharmacological treatments for migraine prophylaxis in adults. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist random-effects network meta-analysis and rated the certainty (quality) of evidence as either high, moderate, low, or very low using the GRADE approach. RESULTS: We identified 74 eligible trials, reporting on 32,990 patients. We found high certainty evidence that monoclonal antibodies acting on the calcitonin gene related peptide or its receptor (CGRP(r)mAbs), gepants, and topiramate increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo. We found moderate certainty evidence that beta-blockers, valproate, and amitriptyline increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, and low certainty evidence that gabapentin may not be different from placebo. We found high certainty evidence that, compared to placebo, valproate and amitriptyline lead to substantial adverse events leading to discontinuation, moderate certainty evidence that topiramate, beta-blockers, and gabapentin increase adverse events leading to discontinuation, and moderate to high certainty evidence that (CGRP(r)mAbs) and gepants do not increase adverse events. CONCLUSIONS: (CGRP(r)mAbs) have the best safety and efficacy profile of all drugs for migraine prophylaxis, followed closely by gepants.info:eu-repo/semantics/publishedVersio

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure

BACKGROUND: Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. MAIN BODY: The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient's well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. CONCLUSIONS: The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.info:eu-repo/semantics/publishedVersio

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

The 5-HT_1F receptor as the target of ditans in migraine — from bench to bedside

Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans — a group of selective serotonin 5-HT1F receptor agonists — has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency.</p

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention—part 2: flunarizine

Abstract Objective Novel disease-specific and mechanism-based treatments sharing good evidence of efficacy for migraine have been recently marketed. However, reimbursement by insurers depends on treatment failure with classic anti-migraine drugs. In this systematic review and meta-analysis, we aimed to identify and rate the evidence for efficacy of flunarizine, a repurposed, first- or second-line treatment for migraine prophylaxis. Methods A systematic search in MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Eligible trials for meta-analysis were randomized, placebo–controlled studies comparing flunarizine with placebo. Outcomes of interest according to the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) were the proportion of patients reaching a 50% or more reduction in monthly migraine days, the change in monthly migraine days (MMDs), and Adverse Events (AEs) leading to discontinuation. Results Five trials were eligible for narrative description and three for data synthesis and analysis. No studies reported the predefined outcomes, but one study assessed the 50% reduction in monthly migraine attacks with flunarizine as compared to placebo showing a benefit from flunarizine with a low or probably low risk of bias. We found that flunarizine may increase the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.02; 95% CI -0.03 to 0.06). Conclusions Published flunarizine trials predate the recommended endpoints for evaluating migraine prophylaxis drugs, hence the lack of an adequate assessment for these endpoints. Further, modern-day, large‐scale studies would be valuable in re-evaluating the efficacy of flunarizine for the treatment of migraines, offering additional insights into its potential benefits

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 1: amitriptyline

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. METHODS: We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more). CONCLUSIONS: Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention

European Headache Federation (EHF) critical reappraisal and meta-analysis of oral drugs in migraine prevention – part 3: topiramate

Abstract Objective Topiramate is a repurposed first-line treatment for migraine prophylaxis. The aim of this systematic review and meta-analysis is to critically re-appraise the existing evidence supporting the efficacy and tolerability of topiramate. Methods A systematic search in MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis as of August 13, 2022, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Randomized controlled trials in adult patients that used topiramate for the prophylactic treatment of migraine, with placebo as active comparator, were included. Two reviewers independently screened the retrieved studies and extracted all data. Outcomes of interest were the 50% responder rates, the reduction in monthly migraine days, and adverse events leading to treatment discontinuation. Results were pooled and meta-analyzed, with sensitivity analysis based on the risk of bias of the studies, the monthly migraine days at baseline, and the previous use of other prophylactic treatments. Certainty evidence was judged according to the GRADE framework. Results Eight out of 10,826 studies fulfilled the inclusion/exclusion criteria, accounting for 2,610 randomized patients. Six studies included patients with episodic migraine and two with chronic migraine. Topiramate dose ranged from 50 to 200 mg/day, and all studies included a placebo arm. There was a high certainty that topiramate: 1) increased the proportion of patients who achieved a 50% responder rate in monthly migraine days, compared to placebo [relative risk: 1.61 (95% confidence interval (CI): 1.29–2.01); absolute risk difference: 168 more per 1,000 (95% CI: 80 to 278 more)]; 2) was associated with 0.99 (95% CI: 1.41–0.58) fewer migraine days than placebo; 3) and had a higher proportion of patients with adverse events leading to treatment discontinuation [absolute risk difference 80 patients more per 1,000 (95% CI: 20 to 140 more patients)]. Conclusions There is high-quality evidence of the efficacy of topiramate in the prophylaxis of migraine, albeit its use poses a risk of adverse events that may lead to treatment discontinuation, with a negative effect on patient satisfaction and adherence to care

Burden and attitude to resistant and refractory migraine:a survey from the European Headache Federation with the endorsement of the European Migraine &amp; Headache Alliance

New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities. The online version contains supplementary material available at 10.1186/s10194-021-01252-4