Pub Date : 2024-04-01DOI: 10.1016/S1474-4422(24)00037-1
David J Seiffge, Virginia Cancelloni, Lorenz Räber, Maurizio Paciaroni, Andreas Metzner, Paulus Kirchhof, Urs Fischer, David J Werring, Ashkan Shoamanesh, Valeria Caso
Atrial fibrillation is one of the most common cardiac arrhythmias and is a major cause of ischaemic stroke. Recent findings indicate the importance of atrial fibrillation burden (device-detected, subclinical, or paroxysmal and persistent or permanent) and whether atrial fibrillation was known before stroke onset or diagnosed after stroke for the risk of recurrence. Secondary prevention in patients with atrial fibrillation and stroke aims to reduce the risk of recurrent ischaemic stroke. Findings from randomised controlled trials assessing the optimal timing to introduce direct oral anticoagulant therapy after a stroke show that early start (ie, within 48 h for minor to moderate strokes and within 4-5 days for large strokes) seems safe and could reduce the risk of early recurrence. Other promising developments regarding early rhythm control, left atrial appendage occlusion, and novel factor XI inhibitor oral anticoagulants suggest that these therapies have the potential to further reduce the risk of stroke. Secondary prevention strategies in patients with atrial fibrillation who have a stroke despite oral anticoagulation therapy is an unmet medical need. Research advances suggest a heterogeneous spectrum of causes, and ongoing trials are investigating new approaches for secondary prevention in this vulnerable patient group. In patients with atrial fibrillation and a history of intracerebral haemorrhage, the latest data from randomised controlled trials on stroke prevention shows that oral anticoagulation reduces the risk of ischaemic stroke but more data are needed to define the safety profile.
心房颤动是最常见的心律失常之一，也是缺血性中风的主要原因。最近的研究结果表明，心房颤动负荷（设备检测到的、亚临床的或阵发性的、持续性的或永久性的）以及中风发病前是否知道心房颤动或中风后是否诊断出心房颤动对复发风险都很重要。心房颤动合并中风患者的二级预防旨在降低缺血性中风的复发风险。随机对照试验评估了卒中后采用直接口服抗凝疗法的最佳时机，结果表明尽早开始（即轻度至中度卒中在 48 小时内，大面积卒中在 4-5 天内）似乎是安全的，而且可以降低早期复发的风险。有关早期节律控制、左心房阑尾闭塞和新型 XI 因子抑制剂口服抗凝药的其他有希望的进展表明，这些疗法有可能进一步降低卒中风险。心房颤动患者在接受口服抗凝治疗后仍发生中风的二级预防策略是一项尚未满足的医疗需求。研究进展表明，导致中风的原因多种多样，目前正在进行的试验正在研究针对这一易受影响患者群体的二级预防新方法。对于有脑出血病史的心房颤动患者，预防中风随机对照试验的最新数据显示，口服抗凝药可降低缺血性中风的风险，但还需要更多数据来确定其安全性。
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Pub Date : 2024-04-01DOI: 10.1016/S1474-4422(24)00036-X
Eugenio Mercuri, Juan J Vilchez, Odile Boespflug-Tanguy, Craig M Zaidman, Jean K Mah, Nathalie Goemans, Wolfgang Müller-Felber, Erik H Niks, Ulrike Schara-Schmidt, Enrico Bertini, Giacomo P Comi, Katherine D Mathews, Laurent Servais, Krista Vandenborne, Jessika Johannsen, Sonia Messina, Stefan Spinty, Laura McAdam, Kathryn Selby, Barry Byrne, Chamindra G Laverty, Kevin Carroll, Giulia Zardi, Sara Cazzaniga, Nicoletta Coceani, Paolo Bettica, Craig M McDonald
<p><strong>Background: </strong>Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy.</p><p><strong>Methods: </strong>This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete.</p><p><strong>Findings: </strong>Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those rec
背景：杜兴氏肌营养不良症是最常见的儿童肌营养不良症，由肌营养不良蛋白缺乏症引起。临床前和二期研究数据表明，组蛋白去乙酰化酶抑制剂吉维诺司他可能有助于抵消这种缺乏症的影响。我们旨在评估吉维诺司他治疗杜氏肌营养不良症的安全性和有效性：这项多中心、随机、双盲、安慰剂对照的 3 期试验在 11 个国家的 41 个三级医疗机构进行。符合条件的参与者均为行动自如的男性，年龄至少6岁，经基因确诊患有杜氏肌营养不良症，完成两次四级爬楼评估的平均时间为8秒或更短（方差≤1秒），爬楼时间至少3秒但少于10秒，接受过至少6个月的系统性皮质类固醇治疗。参与研究的男孩被随机分配（2:1，根据交互式响应技术提供商生成的名单分配）到吉维诺司他口服液或匹配的安慰剂中，每天两次，持续 72 周，根据同时使用类固醇的情况进行分层。男孩、研究人员、研究机构和赞助商的工作人员均被蒙蔽，不知道治疗分配情况。治疗剂量根据体重灵活掌握，如果不能耐受，则减少剂量。根据男孩的基线侧阔肌脂肪率（VLFF，通过磁共振波谱测量）将其分为两组：A 组包括 VLFF 超过 5%、但不超过 30% 的男孩，而 B 组包括 VLFF 在 5%或以下、或超过 30% 的男孩。主要终点是比较吉维司他和安慰剂对意向治疗 A 组人群在基线和 72 周之间四楼攀爬评估结果变化的影响。对所有接受过至少一剂研究药物的随机分配男孩进行了安全性评估。当 A 组的前 50 名男孩完成 12 个月的治疗后，进行了中期无效性评估，之后利用四层爬楼梯评估的蒙蔽数据调整了样本量。此外，在修订方案后，吉维诺司他的起始剂量也有所减少。该试验已在ClinicalTrials.gov（NCT02851797）上注册，并已完成：2017年6月6日至2022年2月22日期间，359名男孩接受了资格评估。其中179名男孩（中位年龄9-8岁[IQR 8-1-11-0]）被纳入研究，所有男孩均被随机分配（118名男孩接受吉维司他治疗，61名男孩接受安慰剂治疗）；170名男孩（95%）完成了研究。在注册的 179 名男孩中，120 人（67%）被分到 A 组（81 人接受吉维司他治疗，39 人接受安慰剂治疗）；其中 114 人（95%）完成了研究。就A组参与者而言，比较72周时和基线时的四楼攀爬评估结果，接受吉维司他治疗的男孩的几何最小二乘法平均比值为1-27（95% CI 1-17-1-37），接受安慰剂治疗的男孩的几何最小二乘法平均比值为1-48（1-32-1-66）（比值比为0-86，95% CI 0-745-0-989；P=0-035）。吉维司他组最常见的不良反应是腹泻（118名男孩中有43名[36%]，61名接受安慰剂的男孩中有11名[18%]）和呕吐（34名[29%]，8名[13%]）；没有发生与治疗相关的死亡事件：在患有杜兴氏肌肉营养不良症的步行男孩中，两组的四楼攀爬评估结果在研究期间都有所恶化；但吉维诺司他的下降幅度明显小于安慰剂。经过中期安全性分析后，吉维诺他的剂量有所降低，但没有报告新的安全性信号。目前正在进行一项扩展研究，评估吉维诺他在杜氏肌营养不良症患者中的长期安全性和有效性：资金来源：Italfarmaco。
{"title":"Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.","authors":"Eugenio Mercuri, Juan J Vilchez, Odile Boespflug-Tanguy, Craig M Zaidman, Jean K Mah, Nathalie Goemans, Wolfgang Müller-Felber, Erik H Niks, Ulrike Schara-Schmidt, Enrico Bertini, Giacomo P Comi, Katherine D Mathews, Laurent Servais, Krista Vandenborne, Jessika Johannsen, Sonia Messina, Stefan Spinty, Laura McAdam, Kathryn Selby, Barry Byrne, Chamindra G Laverty, Kevin Carroll, Giulia Zardi, Sara Cazzaniga, Nicoletta Coceani, Paolo Bettica, Craig M McDonald","doi":"10.1016/S1474-4422(24)00036-X","DOIUrl":"10.1016/S1474-4422(24)00036-X","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy.</p><p><strong>Methods: </strong>This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete.</p><p><strong>Findings: </strong>Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those rec","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 4","pages":"393-403"},"PeriodicalIF":46.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/S1474-4422(24)00090-5
Udani Samarasekera
{"title":"Cristina Tassorelli: making a difference in headache research.","authors":"Udani Samarasekera","doi":"10.1016/S1474-4422(24)00090-5","DOIUrl":"10.1016/S1474-4422(24)00090-5","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 4","pages":"339"},"PeriodicalIF":48.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01DOI: 10.1016/S1474-4422(23)00504-5
Stefania Galimberti, Matteo Petrosino, Paola Rebora, Mauro Oddo, Fabio S Taccone, Giuseppe Citerio
{"title":"The predictive value and clinical use of the neurological pupillary index - Authors' reply.","authors":"Stefania Galimberti, Matteo Petrosino, Paola Rebora, Mauro Oddo, Fabio S Taccone, Giuseppe Citerio","doi":"10.1016/S1474-4422(23)00504-5","DOIUrl":"10.1016/S1474-4422(23)00504-5","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 3","pages":"229-230"},"PeriodicalIF":48.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139746873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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