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Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity肥胖会增加射血分数保留型心力衰竭患病风险。替尔泊肽是葡萄糖依赖性促胰岛素多肽和胰高血糖素样肽-1受体的长效激动剂，可显著减轻体重，但目前缺乏有关其对心血管结局所产生影响的数据。Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes.在这项国际性、双盲、随机、安慰剂对照试验中，我们以1:1比例随机分配731例射血分数至少为50%、体质指数（体重[kg]除以身高[m]的平方）至少为30的心力衰竭患者接受替尔泊肽（每周皮下注射一次，每次最多15 mg）或安慰剂治疗，疗程至少52周。两项主要终点是由经过裁定的心血管原因死亡或心力衰竭恶化事件构成的复合终点（在至首次事件发生时间分析中评估），以及堪萨斯城心肌病问卷临床总分（KCCQ-CSS，Kansas City Cardiomyopathy Questionnaire clinical summary score；评分范围为0~100分，评分较高表示生活质量较好）从基线到52周的变化。In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).共计364例患者被分配到替尔泊肽组，367例患者被分配到安慰剂组；中位随访时间为104周。替尔泊肽组36例患者（9.9%）和安慰剂组56例患者（15.3%）发生了经过裁定的心血管原因死亡或心力衰竭恶化事件（风险比，0.62；95%置信区间[CI]，0.41~0.95；P=0.026）。替尔泊肽组29例患者（8.0%）和安慰剂组52例患者（14.2%）发生了心力衰竭恶化事件（风险比，0.54；95% CI，0.34~0.85），两组分别有8例患者（2.2%）和5例患者（1.4%）发生了经过裁定的心血管原因死亡（风险比，1.58；95% CI，0.52~4.83）。52周时，替尔泊肽组的KCCQ-CSS平均（±SD）变化为19.5±1.2，而安慰剂组为12.7±1.3（组间差异，6.9；95% CI，3.3~10.6；P<0.001）。替尔泊肽组23例患者（6.3%）和安慰剂组5例患者（1.4%）发生了导致停用试验药物的不良事件（主要是胃肠道事件）。A total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P=0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group.对于射血分数保留型心力衰竭合并肥胖患者与安慰剂相比，替尔泊肽治疗可降低由心血管原因死亡或心力衰竭恶化构成的复合终点风险，并改善健康状况。（由礼来公司资助；SUMMIT在ClinicalTrials.gov注册号为NCT04847557）。Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.)Milton Packer, Michael R. Zile, Christopher M. Kramer, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. DOI: 10.1056/NEJMoa2410027
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TAVI期间持续与中断口服抗凝治疗的比较
Continuation versus Interruption of Oral Anticoagulation during TAVI
在接受经导管主动脉瓣植入术（TAVI）的患者中，有三分之一的患者因合并症而有接受口服抗凝治疗的适应证。在TAVI期间中断口服抗凝治疗可降低出血风险，而继续口服抗凝治疗可降低血栓栓塞风险。One third of patients undergoing transcatheter aortic-valve implantation (TAVI) have an indication for oral anticoagulation owing to concomitant diseases. Interruption of oral anticoagulation during TAVI may decrease the risk of bleeding, whereas continuation may decrease the risk of thromboembolism.我们开展了一项国际性、开放标签、随机、非劣效性试验，该试验纳入正在接受口服抗凝剂治疗并计划接受TAVI的患者。试验以1:1比例将患者随机分成两组，分别在围术期继续或中断口服抗凝治疗。主要结局是由TAVI后30天内心血管原因死亡、全因卒中、心肌梗死、主要血管并发症或大出血构成的复合结局。We conducted an international, open-label, randomized, noninferiority trial involving patients who were receiving oral anticoagulants and were planning to undergo TAVI. Patients were randomly assigned in a 1:1 ratio to periprocedural continuation or interruption of oral anticoagulation. The primary outcome was a composite of death from cardiovascular causes, stroke from any cause, myocardial infarction, major vascular complications, or major bleeding within 30 days after TAVI.共计858例患者被纳入改良意向性治疗人群：其中431人被分配继续口服抗凝治疗，427人被分配中断口服抗凝治疗。继续治疗组71例患者（16.5%）和中断治疗组63例患者（14.8%）发生了主要结局事件（风险差异，1.7个百分点；95%置信区间[CI]，－3.1~6.6；非劣效性P=0.18）。继续治疗组38例患者（8.8%）和中断治疗组35例患者（8.2%）发生了血栓栓塞事件（风险差异，0.6个百分点；95% CI，－3.1~4.4）。继续治疗组134例患者（31.1%）和中断治疗组91例患者（21.3%）发生了出血（风险差异，9.8个百分点；95% CI，3.9~15.6）。A total of 858 patients were included in the modified intention-to-treat population: 431 were assigned to continuation and 427 to interruption of oral anticoagulation. A primary-outcome event occurred in 71 patients (16.5%) in the continuation group and in 63 (14.8%) in the interruption group (risk difference, 1.7 percentage points; 95% confidence interval [CI], −3.1 to 6.6; P=0.18 for noninferiority). Thromboembolic events occurred in 38 patients (8.8%) in the continuation group and in 35 (8.2%) in the interruption group (risk difference, 0.6 percentage points; 95% CI, −3.1 to 4.4). Bleeding occurred in 134 patients (31.1%) in the continuation group and in 91 (21.3%) in the interruption group (risk difference, 9.8 percentage points; 95% CI, 3.9 to 15.6).对于接受TAVI且有口服抗凝治疗适应证的患者，在由30天内心血管原因死亡、卒中、心肌梗死、主要血管并发症或大出血构成的复合结局发生率方面，TAVI围手术期继续口服抗凝治疗不劣于中断口服抗凝治疗。（由荷兰卫生研究与发展组织[Netherlands Organization for Health Research and Development]和圣安东尼斯研究基金[St. Antonius Research Fund]资助；POPular PAUSE TAVI在ClinicalTrials.gov注册号为NCT04437303）。In patients undergoing TAVI with a concomitant indication for oral anticoagulation, periprocedural continuation was not noninferior to interruption of oral anticoagulation during TAVI with respect to the incidence of a composite of death from cardiovascular causes, stroke, myocardial infarction, major vascular complications, or major bleeding at 30 days. (Funded by the Netherlands Organization for Health Research and Development and the St. Antonius Research Fund; POPular PAUSE TAVI ClinicalTrials.gov number, NCT04437303.)Dirk Jan van Ginkel, Willem L. Bor, Hugo M. Aarts, et al.A Continuation versus Interruption of Oral Anticoagulation during TAVI. DOI:10.1056/NEJMoa2407794
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Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A重度血友病A需要使用因子VIII替代制品或止血制品，用于止血或预防出血。目前仍缺乏基于造血干细胞（HSC）表达因子VIII的基因疗法治疗重度血友病A的数据。Severe hemophilia A is managed with factor VIII replacement or hemostatic products that stop or prevent bleeding. Data on gene therapy with hematopoietic stem-cell (HSC)–based expression of factor VIII for the treatment of severe hemophilia A are lacking.
我们开展了一项单中心研究，本研究纳入5名年龄22~41岁，且无因子VIII抑制剂抑制物的重度血友病A患者。使用CD68-LV-ET3（一种慢病毒载体，包含带有髓系导向CD68启动子的新F8转基因[ET3]）转导自体HSC，转导时应用转导增强剂（第1组）或不应用转导增强剂（第2组）。转导后的HSC被移植到经过清髓预处理的受者体内。本研究评估上述治疗的安全性（植入情况和与治疗方案相关的毒性效应）和疗效（因子VIII活性和年出血率）。We conducted a single-center study involving five participants 22 to 41 years of age with severe hemophilia A without factor VIII inhibitors. Autologous HSCs were transduced with CD68-LV-ET3 — a lentiviral vector including a new F8 transgene (ET3) with a myeloid-directed CD68 promoter — either without transduction enhancer (group 1) or with transduction enhancer (group 2). Transduced HSCs were transplanted into recipients after myeloablative conditioning. The treatment was assessed for safety (engraftment and regimen-related toxic effects) and efficacy (factor VIII activity and annualized bleeding rate).参与者接受了每千克体重5.0×106~6.1×106剂量的CD68-ET3-LV转导自体CD34+ HSC。第1组两名参与最终药物制品中的载体拷贝数分别为每个细胞1.0和0.6拷贝，第2组三名参与者分别为每个细胞1.5、0.6和2.2拷贝。重度中性粒细胞减少症的持续时间为7~11天，重度血小板减少症的持续时间为1~7天。从第28天后至最后一次随访前，对于第1组两名参与者，使用一步法测得的中位因子VIII活性水平分别为5.2 IU/dL（范围，3.0~8.7）和1.7 IU/dL（范围，1.0~4.0），外周血载体拷贝数分别为每个细胞0.2和0.1拷贝，对于第2组三名参与者，中位因子VIII活性水平分别为37.1 IU/dL（范围，18.3~73.6）、19.3 IU/dL（范围，6.6~34.5）和39.9 IU/dL（范围，20.6~55.1），外周血载体拷贝数分别为每个细胞4.4、3.2和4.8拷贝。在累计81个月随访期间（中位随访期，14个月；范围，9~27个月），所有五名参与者的年出血率均为零。Participants received CD68-ET3-LV–transduced autologous CD34+ HSCs at doses of 5.0×106 to 6.1×106 per kilogram of body weight. The vector copy numbers in the final drug product were 1.0 and 0.6 copies per cell for the two participants in group 1 and 1.5, 0.6, and 2.2 copies per cell for the three participants in group 2. The duration of severe neutropenia was 7 to 11 days and of severe thrombocytopenia was 1 to 7 days. The median factor VIII activity level, measured with the use of a one-stage assay, after day 28 until the last follow-up visit was 5.2 IU per deciliter (range, 3.0 to 8.7) and 1.7 IU per deciliter (range, 1.0 to 4.0) with a peripheral-blood vector copy number of 0.2 and 0.1 copies per cell, respectively, in the two group 1 participants, and 37.1 IU per deciliter (range, 18.3 to 73.6), 19.3 IU per deciliter (range, 6.6 to 34.5), and 39.9 IU per deciliter (range, 20.6 to 55.1) with a peripheral-blood vector copy number of 4.4, 3.2, and 4.8 copies per cell, respectively, in the three group 2 participants. The annualized bleeding rate was zero for all five participants over a cumulative follow-up of 81 months (median follow-up, 14 months; range, 9 to 27).使用慢病毒载体转导自体HSC对血友病A实施基因疗法，可实现稳定的因子VIII表达，并且因子VIII活性与外周血中的载体拷贝数相关。（由印度政府科技部[Ministry of Science and Technology, Government of India]等资助；在ClinicalTrials.gov注册号为NCT05265767；在印度临床试验注册系统注册号为[Clinical Trials Registry–India]CTRI/2022/03/041304）。Gene therapy for hemophilia A with the use of lentiviral vector–transduced autologous HSCs resulted in stable factor VIII expression, with factor VIII activity correlating to vector copy number in the peripheral blood. (Funded by the Ministry of Science and Technology, Government of India, and others; ClinicalTrials.gov number, NCT05265767; Clinical Trials Registry–India number, CTRI/2022/03/041304.)Alok Srivastava, Aby Abraham, Fouzia Aboobacker, et al. Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A. DOI: 10.1056/NEJMoa2410597
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CRISPR-Based Therapy for Hereditary Angioedema遗传性血管性水肿是一种罕见遗传病，其特征是重度且不可预测的肿胀发作。NTLA-2002是一种体内基因编辑疗法，它是基于规律成簇的间隔短回文重复序列（CRISPR）-CRISPR相关蛋白9。NTLA-2002以激肽释放酶B1编码基因（KLKB1）作为靶点。单剂NTLA-2002可终生控制患者的血管性水肿发作。Hereditary angioedema is a rare genetic disease characterized by severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy that is based on clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1). A single dose of NTLA-2002 may provide lifelong control of angioedema attacks.在此项1~2期试验的2期部分，我们以2:2:1比例随机分配遗传性血管性水肿成人患者接受单剂25 mg或50 mg NTLA-2002或安慰剂治疗。主要终点是从第1周至第16周，每月的血管性水肿发作次数（每月发作率）。次要终点包括安全性、药代动力学和药效学（即血浆总激肽释放酶水平与基线相比的变化）；探索性终点包括患者报告的结局。In this phase 2 portion of a phase 1–2 trial, we randomly assigned adults with hereditary angioedema in a 2:2:1 ratio to receive NTLA-2002 in a single dose of 25 mg or 50 mg or placebo. The primary end point was the number of angioedema attacks per month (the monthly attack rate) from week 1 through week 16. Secondary end points included safety, pharmacokinetics, and pharmacodynamics (i.e., the change from baseline in total plasma kallikrein protein level); exploratory end points included patient-reported outcomes.在接受随机分组的27例患者中，10人接受了25 mg NTLA-2002，11人接受了50 mg NTLA-2002，6人接受了安慰剂。从第1周至第16周，25 mg NTLA-2002组的估计平均每月发作率为0.70（95%置信区间[CI]，0.25~1.98），50 mg NTLA-2002组为0.65（95% CI，0.24~1.76），安慰剂组为2.82（95% CI，0.80~9.89）；NTLA-2002与安慰剂相比的估计平均发作率差异为25 mg组－75%，50 mg组－77%。在接受NTLA-2002治疗的患者中，25 mg组10例患者中的4例（40%）和50 mg组11例患者中的8例（73%）在第1周至第16周期间未出现发作，且未接受其他治疗。在接受NTLA-2002治疗的患者中，最常见的不良事件是头痛、疲劳和鼻咽炎。从基线至第16周，血浆总激肽释放酶水平的平均变化百分比为25 mg组－55%，50 mg组－86%，安慰剂组保持不变。Of the 27 patients who underwent randomization, 10 received 25 mg of NTLA-2002, 11 received 50 mg, and 6 received placebo. From week 1 through week 16, the estimated mean monthly attack rate was 0.70 (95% confidence interval [CI], 0.25 to 1.98) with 25 mg of NTLA-2002, 0.65 (95% CI, 0.24 to 1.76) with 50 mg, and 2.82 (95% CI, 0.80 to 9.89) with placebo; the difference in the estimated mean attack rate with NTLA-2002 as compared with placebo was −75% with 25 mg and −77% with 50 mg. Among patients who received NTLA-2002, 4 of the 10 patients who received 25 mg (40%) and 8 of the 11 who received 50 mg (73%) were attack-free with no additional treatment during the period from week 1 through week 16. The most common adverse events among patients who received NTLA-2002 were headache, fatigue, and nasopharyngitis. The mean percent change in total plasma kallikrein protein levels from baseline to week 16 was −55% with 25 mg and −86% with 50 mg; levels remained unchanged with placebo.单剂25 mg或50 mg NTLA-2002可减少遗传性血管性水肿患者的血管性水肿发作，并稳健、持续降低血浆总激肽释放酶水平。这些结果支持在更大规模3期试验中继续开展研究。（由Intellia Therapeutics资助；在ClinicalTrials.gov注册号为NCT05120830；在EudraCT编号为2021-001693-33）。NTLA-2002 administered in a single dose of 25 mg or 50 mg reduced angioedema attacks and led to robust and sustained reduction in total plasma kallikrein levels in patients with hereditary angioedema. These results support continued investigation in a larger phase 3 trial. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830; EudraCT number, 2021-001693-33.)Danny M. Cohn, Padmalal Gurugama, Markus Magerl, et al. CRISPR-Based Therapy for Hereditary Angioedema. DOI:10.1056/NEJMoa2405734![]()
Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis几十年来，治疗方案不完善和低质量证据一直困扰着利福平耐药结核病患者的治疗。随着结核病新药的发明和资金的增加，现在可以对利福平耐药结核病的短疗程、全口服治疗开展随机对照试验。For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis.我们开展了一项3期、多国、开放标签、随机、对照、非劣效性试验，目的是将氟喹诺酮类敏感、利福平耐药结核病的标准疗法与5种为期9个月的口服治疗方案进行比较，这5种方案包括贝达喹啉（B）、delamanid（D）、利奈唑胺（L）、左氧氟沙星（Lfx）或莫西沙星（M）、氯法齐明（C）和吡嗪酰胺（Z）的不同组合。参与者被随机分配（采用贝叶斯应答-自适应随机化方法）接受五种联合治疗方案之一或标准疗法。主要终点是第73周时达到良好结局，其定义是两次痰培养结果均为阴性，或者细菌学、临床和放射学变化情况良好。非劣效性界值为－12个百分点。We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was −12 percentage points.在接受随机分组的754名参与者中，699人被纳入改良意向性治疗分析，562人被纳入符合方案分析。在改良意向性治疗分析中，标准疗法组80.7%的患者达到了良好结局。在改良意向性治疗人群中，标准疗法与四种证明非劣效性的新疗法之间的风险差异如下：BCLLfxZ为9.8个百分点（95%置信区间[CI]，0.9~18.7）；BLMZ为8.3个百分点（95% CI，－0.8~17.4）；BDLLfxZ为4.6个百分点（95% CI，－4.9~14.1）；DCMZ为2.5个百分点（95% CI，－7.5~12.5）。符合方案人群中的差异相似，只有DCMZ是例外，它在该人群中不具有非劣效性。不同治疗方案中出现3级或更高级别不良事件的参与者比例相似。总体参与者中11.7%的人和接受标准疗法的参与者中7.1%的人出现了3级或更高级别肝毒性事件。Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, −0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, −4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, −7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy.所有分析的一致结果表明，三种全口服短疗程方案治疗利福平耐药结核病具有非劣效性。（由Unitaid等资助；endTB在ClinicalTrials.gov注册号为NCT02754765）。Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.)Lorenzo Guglielmetti, Uzma Khan, Gustavo E. Velásquez, et al. Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis. DOI: 10.1056/NEJMoa2400327![]()
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