![]()
Transcatheter Valve Replacement in Severe Tricuspid Regurgitation重度三尖瓣反流与导致失能的症状和死亡风险增加相关。经皮经导管三尖瓣置换术后的结局仍需数据支持。Severe tricuspid regurgitation is associated with disabling symptoms and an increased risk of death. Data regarding outcomes after percutaneous transcatheter tricuspid-valve replacement are needed.在此项国际性、多中心试验中，我们以2:1比例随机分配400例重度有症状三尖瓣反流患者接受经导管三尖瓣置换术和药物治疗（瓣膜置换组）或单纯药物治疗（对照组）。分级复合主要结局为全因死亡、植入右心室辅助装置或心脏移植、首次干预后的三尖瓣干预、心力衰竭住院、堪萨斯城心肌病问卷总分（KCCQ-OS，Kansas City Cardiomyopathy Questionnaire overall summary）至少改善10分、纽约心脏学会（NYHA，New York Heart Association）心功能分级至少改善一级、6分钟步行距离至少改善30 m。从分级中的第一种事件开始，通过对所有可能的患者配对进行比较，计算出主要结局方面的胜率。In this international, multicenter trial, we randomly assigned 400 patients with severe symptomatic tricuspid regurgitation in a 2:1 ratio to undergo either transcatheter tricuspid-valve replacement and medical therapy (valve-replacement group) or medical therapy alone (control group). The hierarchical composite primary outcome was death from any cause, implantation of a right ventricular assist device or heart transplantation, postindex tricuspid-valve intervention, hospitalization for heart failure, an improvement of at least 10 points in the score on the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS), an improvement of at least one New York Heart Association (NYHA) functional class, and an improvement of at least 30 m on the 6-minute walk distance. A win ratio was calculated for the primary outcome by comparing all possible patient pairs, starting with the first event in the hierarchy.共计267例患者被分配到瓣膜置换组，133例患者被分配到对照组。1年时，偏向瓣膜置换术的胜率为2.02（95%置信区间[CI]，1.56~2.62；P<0.001）。在患者配对比较中，瓣膜置换组在以下方面的胜率高于对照组：全因死亡（14.8% vs. 12.5%）、首次干预后的三尖瓣干预（3.2% vs. 0.6%）、KCCQ-OS评分改善（23.1% vs. 6.0%）、NYHA心功能分级（10.2% vs. 0.8%）和6分钟步行距离（1.1% vs. 0.9%）。在每年的心力衰竭住院率方面，瓣膜置换组的胜率低于对照组（9.7% vs. 10.0%）。瓣膜置换组和对照组分别有15.4%和5.3%的患者出现重度出血（P=0.003）；两组分别有17.4%和2.3%的患者植入了新的永久起搏器（P<0.001）。A total of 267 patients were assigned to the valve-replacement group and 133 to the control group. At 1 year, the win ratio favoring valve replacement was 2.02 (95% confidence interval [CI], 1.56 to 2.62; P<0.001). In comparisons of patient pairs, those in the valve-replacement group had more wins than the control group with respect to death from any cause (14.8% vs. 12.5%), postindex tricuspid-valve intervention (3.2% vs. 0.6%), and improvement in the KCCQ-OS score (23.1% vs. 6.0%), NYHA class (10.2% vs. 0.8%), and 6-minute walk distance (1.1% vs. 0.9%). The valve-replacement group had fewer wins than the control group with respect to the annualized rate of hospitalization for heart failure (9.7% vs. 10.0%). Severe bleeding occurred in 15.4% of the valve-replacement group and in 5.3% of the control group (P=0.003); new permanent pacemakers were implanted in 17.4% and 2.3%, respectively (P<0.001).对于重度三尖瓣反流患者，在主要复合结局方面，经导管三尖瓣置换术优于单纯药物治疗，这主要是由于症状和生活质量改善。（由Edwards Lifesciences资助；TRISCEND II在ClinicalTrials.gov注册号为NCT04482062）。For patients with severe tricuspid regurgitation, transcatheter tricuspid-valve replacement was superior to medical therapy alone for the primary composite outcome, driven primarily by improvements in symptoms and quality of life. (Funded by Edwards Lifesciences; TRISCEND II ClinicalTrials.gov number, NCT04482062.)Rebecca T. Hahn, Raj Makkar, Vinod H. Thourani, et al. Transcatheter Valve Replacement in Severe Tricuspid Regurgitation. DOI: 10.1056/NEJMoa2401918
![]()
应用plozasiran控制持续性乳糜微粒血症和胰腺炎风险
Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk
持续性乳糜微粒血症是一种隐性遗传病，通常是由家族性乳糜微粒血症综合征（FCS）引起，但也有多因素病因。该疾病与急性胰腺炎复发风险相关。plozasiran是一种小干扰RNA，可减少肝脏生成的载脂蛋白C-III和循环甘油三酯。Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides..在一项3期试验中，我们随机分配75例持续性乳糜微粒血症患者（有或没有基因诊断）接受皮下注射plozasiran（25 mg或50 mg）或安慰剂，每3个月一次，持续12个月。主要终点是10个月时空腹甘油三酯水平与基线相比的中位变化百分比。关键次要终点是空腹甘油三酯水平从基线到10个月和12个月平均值的变化百分比、空腹载脂蛋白C-III水平从基线到10个月和12个月的变化，以及急性胰腺炎发生率。In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis.基线时，中位甘油三酯水平为2044 mg/dL。10个月时，25 mg plozasiran组空腹甘油三酯水平与基线相比的中位变化（主要终点）为－80%，50 mg plozasiran组为－78%，安慰剂组为－17%（P<0.001）。关键次要终点显示，plozasiran组的结果优于安慰剂组，其中包括急性胰腺炎发生率（比值比，0.17；95%置信区间，0.03~0.94；P=0.03）。各组发生不良事件的风险相似；最常见的不良事件是腹痛、鼻咽炎、头痛和恶心。plozasiran组的重度和严重不良事件发生率低于安慰剂组。一些基线时患前驱糖尿病或糖尿病的患者使用plozasiran后出现了高血糖。At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was −80% in the 25-mg plozasiran group, −78% in the 50-mg plozasiran group, and −17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P=0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline.持续性乳糜微粒血症患者接受plozasiran治疗后的甘油三酯水平和胰腺炎发生率显著低于接受安慰剂治疗后。（由Arrowhead制药公司资助；PALISADE在ClinicalTrials.gov注册号为NCT05089084）。Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.)Gerald F. Watts, Robert S. Rosenson, Robert A. Hegele, et al.Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. DOI:10.1056/NEJMoa2409368
![]()
talquetamab联合特立妥单抗治疗复发或难治性多发性骨髓瘤Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myelomatalquetamab（抗G蛋白偶联受体C家族5组D成员）和特立妥单抗（抗B细胞成熟抗原）是通过靶向CD3激活T细胞的双特异性抗体，已被批准用于接受过三类药物治疗的复发或难治性多发性骨髓瘤。Talquetamab (anti–G protein–coupled receptor family C group 5 member D) and teclistamab (anti–B-cell maturation antigen) are bispecific antibodies that activate T cells by targeting CD3 and that have been approved for the treatment of triple-class–exposed relapsed or refractory multiple myeloma.
我们对复发或难治性多发性骨髓瘤患者开展了talquetamab联合特立妥单抗治疗的1b-2期研究。在1期研究中，我们在剂量递增研究中评估了五个剂量水平。推荐的2期剂量方案为0.8 mg/kg体重talquetamab联合3.0 mg/kg体重特立妥单抗，每隔一周给药一次。主要目的是评估不良事件和剂量限制性毒性效应。We conducted a phase 1b–2 study of talquetamab plus teclistamab in patients with relapsed or refractory multiple myeloma. In phase 1, we investigated five dose levels in a dose-escalation study. Talquetamab at a dose of 0.8 mg per kilogram of body weight plus teclistamab at a dose of 3.0 mg per kilogram every other week was selected as the recommended phase 2 regimen. The primary objective was to evaluate adverse events and dose-limiting toxic effects.共计94例患者接受了治疗，其中44人接受了推荐的2期剂量方案。中位随访期为20.3个月。3例患者出现了剂量限制性毒性效应（其中1例接受推荐的2期剂量方案的患者出现了4级血小板减少症）。在所有剂量水平中，最常见的不良事件是细胞因子释放综合征、中性粒细胞减少症、味觉改变和非皮疹性皮肤事件。96%的患者出现了3级或4级不良事件，其中最常见的是血液学事件。64%的患者出现了3级或4级感染。接受推荐的2期剂量方案后，80%的患者（包括61%髓外疾病患者）达到缓解；在所有剂量水平，78%的患者达到缓解。接受推荐的2期剂量方案后，患者在18个月时保持缓解的可能性为86%（髓外疾病患者为82%），在所有剂量水平，保持缓解的可能性为77%。A total of 94 patients received treatment, with the recommended phase 2 regimen used in 44. The median follow-up was 20.3 months. Three patients had dose-limiting toxic effects (including grade 4 thrombocytopenia in 1 patient with the recommended phase 2 regimen). Across all dose levels, the most common adverse events were cytokine release syndrome, neutropenia, taste changes, and nonrash skin events. Grade 3 or 4 adverse events, most commonly hematologic events, occurred in 96% of the patients. Grade 3 or 4 infections occurred in 64% of the patients. With the recommended phase 2 regimen, a response occurred in 80% of the patients (including in 61% of those with extramedullary disease); across all dose levels, a response occurred in 78%. The likelihood of patients continuing in response at 18 months was 86% with the recommended phase 2 regimen (82% among those with extramedullary disease) and 77% across all dose levels.患者接受talquetamab联合特立妥单抗治疗后，3级或4级感染发生率高于单独使用其中任一药物的发生率。在所有剂量水平观察到较高比例患者达到缓解，接受推荐的2期剂量方案可达到持久缓解。（由Janssen Research and Development资助；RedirecTT-1在ClinicalTrials.gov注册号为NCT04586426）。The incidence of grade 3 or 4 infections with talquetamab plus teclistamab was higher than has been observed with either therapy alone. A response was observed in a high percentage of patients across all dose levels, with durable responses with the recommended phase 2 regimen. (Funded by Janssen Research and Development; RedirecTT-1 ClinicalTrials.gov number, NCT04586426.)Yael C. Cohen, Hila Magen, Moshe Gatt, et al. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. DOI: 10.1056/NEJMoa2406536
![]()
Clearance of Driver Mutations after Transplantation for Myelofibrosis异基因造血干细胞移植是骨髓纤维化的唯一治愈方法。驱动突变是该病的病理生理标志，但移植后突变清除所发挥的作用尚不清楚。Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for myelofibrosis. Driver mutations are the pathophysiological hallmark of the disease, but the role of mutation clearance after transplantation is unclear.我们使用高灵敏度聚合酶链反应技术分析了在降低强度预处理后接受移植的324例骨髓纤维化患者（73%有JAK2突变，23%有CALR突变，4%有MPL突变）外周血样中的驱动突变动力学。在移植前以及移植后30天、100天和180天检测突变，以评估突变清除情况及其对复发和治愈的影响。两项主要终点是复发和无病生存期。We used highly sensitive polymerase-chain-reaction technology to analyze the dynamics of driver mutations in peripheral-blood samples from 324 patients with myelofibrosis (73% with JAK2 mutations, 23% with CALR mutations, and 4% with MPL mutations) who were undergoing transplantation after reduced-intensity conditioning. Mutations were detected before transplantation and at 30, 100, and 180 days after transplantation to measure clearance and its effect on relapse and cure. The two primary end points were relapse and disease-free survival.移植后第30天，42%的JAK2突变患者、73%的CALR突变患者和54%的MPL突变患者被检测出突变清除；第100天的相应百分比分别为63%、82%和100%。移植后第30天时突变清除患者在1年时的累积复发率为6%（95%置信区间[CI]，2~10），而30天时突变未清除患者的累积复发率为21%（95% CI，15~27）。在移植后第30天时突变清除的患者中，6年无病生存率和总生存率分别为61%和74%，而在移植后第30天时突变未清除的患者中，无病生存率和总生存率分别为41%和60%。作为应答指标，第30天时的突变清除情况似乎优于传统的供者细胞嵌合情况；突变清除与复发或进展风险降低独立相关（风险比，0.36；95% CI，0.21~0.61），并且似乎克服了基于驱动突变类型（JAK2 vs. MPL或CALR）的预后差异。At day 30 after transplantation, mutation clearance was found in 42% of the patients who had JAK2 mutations, 73% of those who had CALR mutations, and 54% of those who had MPL mutations; the corresponding percentages at day 100 were 63%, 82%, and 100%. The cumulative incidence of relapse at 1 year was 6% (95% confidence interval [CI], 2 to 10) among patients with mutation clearance at day 30 after transplantation and 21% (95% CI, 15 to 27) among those without mutation clearance at day 30. Disease-free and overall survival at 6 years were 61% and 74%, respectively, among patients with mutation clearance at day 30 after transplantation and 41% and 60%, respectively, among those without mutation clearance at day 30. Mutation clearance at day 30 appeared to outperform traditional donor chimerism as a measure of response; it was independently associated with a reduced risk of relapse or progression (hazard ratio, 0.36; 95% CI, 0.21 to 0.61) and appeared to overcome differences in prognosis based on the type of driver mutation (JAK2 vs. MPL or CALR).在骨髓纤维化患者中，移植后第30天时驱动突变清除似乎会影响复发和患者生存，并且与基础驱动突变无关。In patients with myelofibrosis, clearance of driver mutations at day 30 after transplantation appeared to influence relapse and survival, irrespective of the underlying driver mutation.Nico Gagelmann, Marie Quarder, Anita Badbaran, et al. Clearance of Driver Mutations after Transplantation for Myelofibrosis. DOI: 10.1056/NEJMoa2408941![]()
A Comparison of Peripherally Inserted Central Catheter Materials用于经外周静脉穿刺中心静脉导管（PICC）的新型导管材料可降低因感染、血栓和导管闭塞事件而导致器械故障的风险。但是，目前缺乏比较这些导管的随机试验数据。New catheter materials for peripherally inserted central catheters (PICCs) may reduce the risk of device failure due to infectious, thrombotic, and catheter occlusion events. However, data from randomized trials comparing these catheters are lacking.我们在澳大利亚三家三级医院开展了一项随机对照优效性试验。我们以1:1:1比例将转诊接受PICC置管术的成人和儿童患者分组，三组分别接受疏水性或氯己定PICC或者标准聚氨酯PICC，并接受8周随访。主要结局是器械故障，它是由感染性（血流或局部）或非感染性（血栓、断裂或闭塞）并发症构成的复合结局。We conducted a randomized, controlled, superiority trial in three Australian tertiary hospitals. Adults and children who were referred for PICC placement were assigned in a 1:1:1 ratio to receive a hydrophobic or chlorhexidine PICC or a standard polyurethane PICC and were followed for 8 weeks. The primary outcome was device failure, which was a composite of infectious (bloodstream or local) or noninfectious (thrombosis, breakage, or occlusion) complications.共计1098名参与者接受了随机分组，其中365人被分配到疏水性PICC组，365人被分配到氯己定PICC组，368人被分配到标准聚氨酯PICC组。疏水性PICC组358名参与者中的21人（5.9%）、氯己定PICC组363人中的36人（9.9%）和标准聚氨酯PICC组359人中的22人（6.1%）出现器械故障（风险差异，疏水性PICC vs. 标准聚氨酯PICC，－0.2个百分点[95置信区间{CI}，－3.7~3.2；P=0.89]；氯己定PICC vs. 标准聚氨酯PICC，3.8个百分点[95% CI，－0.1~7.8；P=0.06]）。疏水性PICC组与标准聚氨酯PICC组相比，器械故障的比值比为0.96（95% CI，0.51~1.78），而氯己定PICC组与标准聚氨酯PICC组相比，比值比为1.71（95% CI，0.98~2.99）。在PICC置管术期间，疏水性PICC组77人（21.5%）、氯己定PICC组140人（38.6%）和标准聚氨酯PICC组78人（21.7%）出现了并发症（任何原因）（比值比，疏水性PICC vs. 标准聚氨酯PICC，0.99[95% CI，0.69~1.42]；氯己定PICC vs. 标准聚氨酯PICC，2.35[95% CI，1.68~3.29]）。干预措施未导致任何不良事件。A total of 1098 participants underwent randomization; 365 were assigned to the hydrophobic group, 365 to the chlorhexidine group, and 368 to the standard-polyurethane group. Device failure occurred in 21 of 358 participants (5.9%) in the hydrophobic group, in 36 of 363 (9.9%) in the chlorhexidine group, and in 22 of 359 (6.1%) in the standard-polyurethane group (risk difference, hydrophobic vs. standard polyurethane, −0.2 percentage points [95% confidence interval {CI}, −3.7 to 3.2; P=0.89]; and chlorhexidine vs. standard polyurethane, 3.8 percentage points [95% CI, −0.1 to 7.8; P=0.06]). In the hydrophobic group as compared with the standard-polyurethane group, the odds ratio for device failure was 0.96 (95% CI, 0.51 to 1.78), and in the chlorhexidine group as compared with the standard-polyurethane group, the odds ratio was 1.71 (95% CI, 0.98 to 2.99). Complications from any cause during the period of PICC placement occurred in 77 participants (21.5%) in the hydrophobic group, in 140 (38.6%) in the chlorhexidine group, and in 78 (21.7%) in the standard-polyurethane group (odds ratio, hydrophobic vs. standard polyurethane, 0.99 [95% CI, 0.69 to 1.42]; and chlorhexidine vs. standard polyurethane, 2.35 [95% CI, 1.68 to 3.29]). No adverse events were attributable to the interventions.在被转诊接受PICC置管术的成人和儿童中，疏水性或氯己定PICC组中因非感染性或感染性并发症导致的器械故障风险并未低于标准聚氨酯PICC组。（由澳大利亚国家健康和医学研究委员会［National Health and Medical Research Council of Australia］资助；PICNIC在澳大利亚和新西兰临床试验注册系统[Australian New Zealand Clinical Trials Registry]的注册号为ACTRN12619000022167。）Among adults and children who were referred for PICC placement, the risk of device failure due to noninfectious or infectious complications was not lower with hydrophobic or chlorhexidine PICCs than with standard polyurethane PICCs. (Funded by the National Health and Medical Research Council of Australia; PICNIC Australian New Zealand Clinical Trials Registry number, ACTRN12619000022167.)Amanda J. Ullman, Deanne August, Tricia M. Kleidon, et al. A Comparison of Peripherally Inserted Central Catheter Materials. DOI: 10.1056/NEJMoa2406815![]()
关注《NEJM医学前沿》
版权信息
本文由《NEJM医学前沿》编辑部负责翻译、编写或约稿。对于源自NEJM集团旗下英文产品的翻译和编写文章，内容请以英文原版为准。中译全文以及所含图表等，由马萨诸塞州医学会NEJM集团独家授权。如需转载，请联系nejmqianyan@nejmqianyan.cn。未经授权的翻译是侵权行为，版权方保留追究法律责任的权利。
