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Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. 塞马鲁肽与安慰剂在射血分数轻度降低或保留的心衰患者中的应用:SELECT、FLOW、STEP-HFpEF 和 STEP-HFpEF DM 随机试验的汇总分析。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 Epub Date: 2024-08-30 DOI: 10.1016/S0140-6736(24)01643-X
Mikhail N Kosiborod, John Deanfield, Richard Pratley, Barry A Borlaug, Javed Butler, Melanie J Davies, Scott S Emerson, Steven E Kahn, Dalane W Kitzman, Ildiko Lingvay, Kenneth W Mahaffey, Mark C Petrie, Jorge Plutzky, Søren Rasmussen, Cecilia Rönnbäck, Sanjiv J Shah, Subodh Verma, Peter E Weeke, A Michael Lincoff
<p><strong>Background: </strong>Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established.</p><p><strong>Methods: </strong>We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete.</p><p><strong>Findings: </strong>Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]).</p><p><strong>Interpretation: </strong>In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or
背景:射血分数轻度降低或保留的心力衰竭(以下简称HFpEF)是最常见的心力衰竭类型,与住院和死亡的高风险相关,尤其是在超重、肥胖或2型糖尿病患者中。在STEP-HFpEF和STEP-HFpEF DM试验中,semaglutide改善了HFpEF参与者的心衰相关症状和身体限制。塞马鲁肽是否也能减少这一群体的临床心衰事件仍有待确定:我们对四项随机安慰剂对照试验(SELECT、FLOW、STEP-HFpEF和STEP-HFpEF DM)进行了一项事后汇总的参与者水平分析,以研究每周一次皮下注射塞马鲁肽(SELECT、STEP-HFpEF和STEP-HFpEF DM中为2-4毫克;FLOW中为1-0毫克)对心衰事件的影响。STEP-HFpEF 和 STEP-HFpF DM 试验招募了肥胖相关的 HFpEF 患者,SELECT 试验招募了患有动脉粥样硬化性心血管疾病和超重或肥胖的患者,FLOW 试验招募了患有 2 型糖尿病和慢性肾病的患者。因此,在本分析中,我们纳入了 STEP-HFpEF 试验的所有参与者,以及 SELECT 和 FLOW 试验中研究者报告有 HFpEF 病史的参与者。本分析的主要结果是心血管死亡或首次心衰恶化事件(定义为因心衰住院或紧急就诊)发生时间、首次心衰恶化事件发生时间和心血管死亡时间的复合终点。疗效和安全性终点分析采用全分析集(即根据意向治疗原则随机分配接受治疗的所有参与者)。SELECT、FLOW、STEP-HFpEF和STEP-HFpEF DM试验分别在ClinicalTrials.gov上注册,注册号分别为NCT03574597、NCT03819153、NCT04788511和NCT04916470,所有试验均已完成:在这四项试验中,22282名参与者中有3743人(16%-8%)曾患有高房颤动性心力衰竭(1914人被分配接受舍马鲁肽治疗,1829人被分配接受安慰剂治疗)。在这组 HFpEF 参与者中,塞马鲁肽降低了心血管死亡或心衰事件这一综合终点的风险(塞马鲁肽组 1914 人中有 103 人 [5-4%] 发生心衰事件,安慰剂组 1829 人中有 138 人 [7-5%] 发生心衰事件;危险比 [HR] 0-69 [95% CI 0-53-0-89];P=0-0045)。塞马鲁肽还降低了心衰事件恶化的风险(54 [2-8%] vs 86 [4-7%];HR 0-59 [0-41-0-82]; p=0-0019)。仅对心血管死亡无明显影响(59 [3-1%] vs 67 [3-7%];HR 0-82 [0-57-1-16];P=0-25)。与安慰剂相比,接受塞马鲁肽治疗的患者发生严重不良事件的比例较低(572 [29-9%] vs 708 [38-7%]):在高频心衰患者中,semaglutide可降低心血管死亡或心衰恶化事件以及单纯心衰恶化事件的合并终点风险,而其对单纯心血管死亡的影响并不显著。这些数据支持使用semaglutide作为一种有效的疗法来降低HFpEF患者发生临床心力衰竭事件的风险,目前可供选择的治疗方案很少:诺和诺德公司。
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引用次数: 0
De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials. 急性冠状动脉综合征患者和非急性冠状动脉综合征患者降级至替卡格雷单药治疗与 12 个月双联抗血小板治疗的比较:随机试验的系统回顾和单个患者层面的荟萃分析。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 Epub Date: 2024-08-31 DOI: 10.1016/S0140-6736(24)01616-7
Marco Valgimigli, Sung-Jin Hong, Felice Gragnano, Konstantina Chalkou, Anna Franzone, Bruno R da Costa, Usman Baber, Byeong-Keuk Kim, Yangsoo Jang, Shao-Liang Chen, Gregg W Stone, Joo-Yong Hahn, Stephan Windecker, Michael C Gibson, Young Bin Song, Zhen Ge, Pascal Vranckx, Shamir Mehta, Hyeon-Cheol Gwon, Renato D Lopes, George D Dangas, Eùgene P McFadden, Dominick J Angiolillo, Sergio Leonardi, Dik Heg, Paolo Calabrò, Peter Jüni, Roxana Mehran, Myeong-Ki Hong
<p><strong>Background: </strong>Dual antiplatelet therapy (DAPT) for 12 months is the standard of care after coronary stenting in patients with acute coronary syndrome (ACS). The aim of this individual patient-level meta-analysis was to summarise the evidence comparing DAPT de-escalation to ticagrelor monotherapy versus continuing DAPT for 12 months after coronary drug-eluting stent implantation.</p><p><strong>Methods: </strong>A systematic review and individual patient data (IPD)-level meta-analysis of randomised trials with centrally adjudicated endpoints was performed to evaluate the comparative efficacy and safety of ticagrelor monotherapy (90 mg twice a day) after short-term DAPT (from 2 weeks to 3 months) versus 12-month DAPT in patients undergoing percutaneous coronary intervention with a coronary drug-eluting stent. Randomised trials comparing P2Y<sub>12</sub> inhibitor monotherapy with DAPT after coronary revascularisation were searched in Ovid MEDLINE, Embase, and two websites (www.tctmd.com and www.escardio.org) from database inception up to May 20, 2024. Trials that included patients with an indication for long-term oral anticoagulants were excluded. The risk of bias was assessed using the revised Cochrane risk-of-bias tool. The principal investigators of the eligible trials provided IPD by means of an anonymised electronic dataset. The three ranked coprimary endpoints were major adverse cardiovascular or cerebrovascular events (MACCE; a composite of all-cause death, myocardial infarction, or stroke) tested for non-inferiority in the per-protocol population; and Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding and all-cause death tested for superiority in the intention-to-treat population. All outcomes are reported as Kaplan-Meier estimates. The non-inferiority was tested using a one-sided α of 0·025 with the prespecified non-inferiority margin of 1·15 (hazard ratio [HR] scale), followed by the ranked superiority testing at a two-sided α of 0·05. This study is registered with PROSPERO (CRD42024506083).</p><p><strong>Findings: </strong>A total of 8361 unique citations were screened, of which 610 records were considered potentially eligible during the screening of titles and abstracts. Of these, six trials that randomly assigned patients to ticagrelor monotherapy or DAPT were identified. De-escalation took place a median of 78 days (IQR 31-92) after intervention, with a median duration of treatment of 334 days (329-365). Among 23 256 patients in the per-protocol population, MACCE occurred in 297 (Kaplan-Meier estimate 2·8%) with ticagrelor monotherapy and 332 (Kaplan-Meier estimate 3·2%) with DAPT (HR 0·91 [95% CI 0·78-1·07]; p=0·0039 for non-inferiority; τ<sup>2</sup><0·0001). Among 24 407 patients in the intention-to-treat population, the risks of BARC 3 or 5 bleeding (Kaplan-Meier estimate 0·9% vs 2·1%; HR 0·43 [95% CI 0·34-0·54]; p<0·0001 for superiority; τ<sup>2</sup>=0·079) and all-cause death (Kaplan-Meier estimate 0·
背景:急性冠状动脉综合征(ACS)患者冠状动脉支架置入术后的标准治疗是持续 12 个月的双联抗血小板疗法(DAPT)。这项患者个体层面的荟萃分析旨在总结冠状动脉药物洗脱支架植入术后DAPT降级为替卡格雷单药治疗与继续DAPT 12个月的比较证据:我们对具有集中裁定终点的随机试验进行了系统回顾和患者个体数据(IPD)级荟萃分析,以评估在使用冠状动脉药物洗脱支架接受经皮冠状动脉介入治疗的患者中,短期DAPT(2周至3个月)后使用替卡格雷单药治疗(90毫克,一天两次)与12个月DAPT的疗效和安全性比较。在 Ovid MEDLINE、Embase 和两个网站(www.tctmd.com 和 www.escardio.org)上检索了冠状动脉血运重建后 P2Y12 抑制剂单药治疗与 DAPT 比较的随机试验,检索时间从数据库建立之初至 2024 年 5 月 20 日。排除了纳入长期口服抗凝药适应症患者的试验。偏倚风险采用修订后的 Cochrane 偏倚风险工具进行评估。符合条件的试验的主要研究者通过匿名电子数据集提供了IPD。三项排名靠前的主要共同终点是:在按方案治疗人群中检测主要不良心血管或脑血管事件(MACCE;全因死亡、心肌梗死或中风的复合指标)的非劣效性;在意向治疗人群中检测出血学术研究联盟(BARC)3或5次出血和全因死亡的优效性。所有结果均以 Kaplan-Meier 估计值报告。非劣效性测试采用单侧α为0-025,预设非劣效性差值为1-15(危险比[HR]表),然后采用双侧α为0-05进行排序优效性测试。本研究已在 PROSPERO 注册(CRD42024506083):共筛选出 8361 条独特的引文,其中 610 条记录在筛选标题和摘要时被认为可能符合条件。其中,有六项试验将患者随机分配给替卡格雷单药治疗或DAPT。干预后中位数为 78 天(IQR 31-92),中位数治疗时间为 334 天(329-365)。在23 256例按方案治疗的患者中,297例(Kaplan-Meier估计为2%-8%)接受替卡格雷单药治疗的患者发生了MACCE,332例(Kaplan-Meier估计为3%-2%)接受DAPT治疗的患者发生了MACCE(HR 0-91 [95% CI 0-78-1-07];P=0-0039为非劣性;τ22=0-079)和全因死亡(Kaplan-Meier估计值0-9% vs 1-2%;0-76 [0-59-0-98];P=0-034为优越性;τ2解释:我们的研究发现了强有力的证据,与12个月的DAPT相比,降级为替卡格雷单药治疗不会增加缺血风险,并能降低大出血风险,尤其是在ACS患者中。替卡格雷单药治疗还可能降低死亡率,尤其是女性患者,这值得进一步研究:资助机构:提契诺心脏病中心、Ente Ospedaliero Cantonale。
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引用次数: 0
Polygenic risk scores for genomics and population screening. 用于基因组学和人口筛查的多基因风险评分。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 DOI: 10.1016/S0140-6736(24)01689-1
Sarah L Perrott, Siddhartha P Kar
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引用次数: 0
Strengthening community resilience: lessons from COVID-19 for mpox prevention. 加强社区复原力:从 COVID-19 中汲取预防水痘的经验教训。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 Epub Date: 2024-08-22 DOI: 10.1016/S0140-6736(24)01752-5
Francesco Branda, Giancarlo Ceccarelli, Massimo Ciccozzi, Fabio Scarpa
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引用次数: 0
The health of migrants at the intersection of mpox and HIV. 处于 mpox 和 HIV 交汇点的移民的健康。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 Epub Date: 2024-08-23 DOI: 10.1016/S0140-6736(24)01753-7
Archibong Edem Bassey
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引用次数: 0
Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study. ATSN-101 对 GUCY2D 双重突变导致的 Leber 先天性羊角疯患者的安全性和疗效:1/2 期、多中心、开放标签、单侧剂量递增研究。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 DOI: 10.1016/S0140-6736(24)01447-8
Paul Yang, Laura P Pardon, Allen C Ho, Andreas K Lauer, Dan Yoon, Shannon E Boye, Sanford L Boye, Alejandro J Roman, Vivian Wu, Alexandra V Garafalo, Alexander Sumaroka, Malgorzata Swider, Iryna Viarbitskaya, Tomas S Aleman, Mark E Pennesi, Christine N Kay, Kenji P Fujita, Artur V Cideciyan

Background: Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1.

Methods: 15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were treated with three ascending doses: 1·0 × 1010 vg/eye (low dose), 3·0 × 1010 vg/eye (middle dose), and 1·0 × 1011 vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), and secondary endpoints included full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported.

Findings: Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, mean change in dark-adapted FST was 20·3 decibels (dB; 95% CI 6·6 to 34·0) for treated eyes and 1·1 dB (-3·7 to 5·9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0·012). Modest improvements in BCVA were also observed (p=0·10). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye.

Interpretation: ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose.

Funding: Atsena Therapeutics.

背景:由 GUCY2D 基因突变引起的 Leber 先天性无视力症 1 (LCA1)是一种罕见的遗传性视网膜疾病,通常会在儿童早期导致失明。本研究旨在评估ATSN-101(一种治疗LCA1的视网膜下AAV5基因疗法)递增剂量的安全性和初步疗效。所有患者均接受了单侧视网膜下注射 ATSN-101。在剂量递增阶段,三组成人患者(每组 3 人)接受了三个递增剂量的治疗:1-0 × 1010 vg/眼(低剂量)、3-0 × 1010 vg/眼(中剂量)和 1-0 × 1011 vg/眼(高剂量)。在剂量扩展阶段,一组成人(3 人)和一组儿童(3 人)接受了高剂量治疗。主要终点是治疗突发不良事件(TEAEs)的发生率,次要终点包括全视野刺激测试(FST)和最佳矫正视力(BCVA)。此外,还进行了多亮度移动性测试(MLMT)。报告了为期12个月的主要研究期间的数据:患者于2019年9月12日至2022年5月5日期间入组。共观察到 68 例 TEAE,其中 56 例与手术过程有关。没有严重的TEAE与研究药物有关。眼部炎症轻微,经类固醇治疗后可逆转。对于接受高剂量治疗的患者,在第12个月时(白色刺激),治疗眼的暗适应FST平均变化为20-3分贝(dB;95% CI为6-6至34-0),未治疗眼为1-1分贝(-3-7至5-9);第28天时首次观察到改善,并持续12个月(P=0-012)。BCVA 也有轻微改善(p=0-10)。在接受高剂量治疗并进行MLMT的六名患者中,有三名患者的治疗眼达到了最高分:ATSN-101在治疗12个月后耐受性良好,未出现与药物相关的严重不良事件。接受高剂量治疗的患者视网膜灵敏度持续得到临床显着改善:Atsena Therapeutics。
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引用次数: 0
Perinatal risk in India's Scheduled Tribes. 印度在册部落的围产期风险。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 DOI: 10.1016/S0140-6736(24)01679-9
Taranand Singh, Dinesh Kumar
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引用次数: 0
GLP-1 receptor agonists in heart failure: how far to expand use? GLP-1 受体激动剂在心力衰竭中的应用:如何扩大使用范围?
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 Epub Date: 2024-08-30 DOI: 10.1016/S0140-6736(24)01763-X
Camilla Hage
{"title":"GLP-1 receptor agonists in heart failure: how far to expand use?","authors":"Camilla Hage","doi":"10.1016/S0140-6736(24)01763-X","DOIUrl":"10.1016/S0140-6736(24)01763-X","url":null,"abstract":"","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":" ","pages":"909-911"},"PeriodicalIF":98.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120188","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}
引用次数: 0
Is this the conclusive evidence for ticagrelor monotherapy in acute coronary syndromes? 这就是在急性冠脉综合征中使用替卡格雷单药治疗的确凿证据吗?
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 Epub Date: 2024-08-31 DOI: 10.1016/S0140-6736(24)01678-7
Giulio G Stefanini, Angelo Oliva
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引用次数: 0
Congenital syphilis in a 2-month-old infant during Japanese outbreak. 日本疫情爆发时一名 2 个月大婴儿的先天性梅毒。
IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL Pub Date : 2024-09-07 DOI: 10.1016/S0140-6736(24)01685-4
Tomoaki Hirate, Kaori Kanda, Yumi Ohshima, Kunihiro Shinoda, Nobuyuki Tetsuka
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引用次数: 0
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