2024年10月24日 |《新英格兰医学杂志》英文音频和中英文摘要

英文音频来自NEJM官网nejm.org

非奈利酮治疗射血分数轻度降低型或保留型心力衰竭

Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

背景

甾体类盐皮质激素受体拮抗剂可降低射血分数降低型心力衰竭患者的致病率和死亡率，但此类药物对射血分数轻度降低型或保留型心力衰竭患者的疗效尚未确定。有关非甾体类盐皮质激素受体拮抗剂非奈利酮对射血分数轻度降低型或保留型心力衰竭患者的疗效和安全性还需要数据支持。

Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed.

方法

在此项国际性、双盲试验中，我们以1:1比例将左心室射血分数≥40%的心力衰竭患者随机分组，两组分别在常规治疗基础上接受非奈利酮（最大剂量为20 mg或40 mg，每日一次）或相应安慰剂治疗。主要结局是由总计心力衰竭恶化事件（事件定义为因心力衰竭首次或反复计划外住院或紧急就诊）和心血管原因死亡构成的复合结局。本试验还评估了主要结局的各构成部分和安全性。

In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed.

结果

在中位32个月随访期间，非奈利酮组3003例患者中的624例发生了1083起主要结局事件，安慰剂组2998例患者中的719例发生了1283起主要结局事件（率比，0.84；95%置信区间[CI]，0.74~0.95；P=0.007）。非奈利酮组的心力衰竭恶化事件总数为842起，安慰剂组为1024起（率比，0.82；95% CI，0.71~0.94；P=0.006）。两组中，心血管原因死亡的患者百分比分别为8.1%和8.7%（风险比，0.93；95% CI，0.78~1.11）。非奈利酮与高钾血症风险增加和低钾血症风险降低相关。

Result

Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P=0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P=0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia.

结论

对于射血分数轻度降低型或保留型心力衰竭患者，与安慰剂相比，非奈利酮显著降低了由总计心力衰竭恶化事件和心血管原因死亡构成的复合结局发生率。（由拜耳公司资助；FINEARTS-HF在ClinicalTrials.gov注册号为NCT04435626）。

Conclusions

In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.)

amivantamab联合lazertinib用于既往未经治疗的EGFR突变晚期NSCLC

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC

背景

amivantamab联合lazertinib（amivantamab-lazertinib）已在既往未接受过治疗或接受过奥希替尼治疗的EGFR（表皮生长因子受体）突变晚期非小细胞肺癌（NSCLC）患者中显示出具有临床意义的持久抗肿瘤活性。

在一项3期、国际性、随机试验中，我们以2:2:1比例将既往未经治疗的EGFR突变（第19号外显子缺失或L858R）局部晚期或转移性NSCLC患者分成三组，分别接受amivantamab-lazertinib（开放标签）、奥希替尼（盲法）或lazertinib（盲法，旨在评估治疗方案中各种药物的效应）治疗。主要终点是通过盲法独立集中审核方式评估的amivantamab-lazertinib组与奥希替尼组无进展生存期比较。

Methods

In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab–lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab–lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review.

共计1074例患者接受随机分组（amivantamab-lazertinib组429例，奥希替尼组429例，lazertinib组216例）。amivantamab-lazertinib组的中位无进展生存期显著超过奥希替尼组（23.7个月 vs. 16.6个月；疾病进展或死亡风险比，0.70；95%置信区间[CI]，0.58~0.85；P<0.001）。amivantamab-lazertinib组的客观缓解率为86%（95% CI，83~89），奥希替尼组为85%（95% CI，81~88）；在确认达到缓解的患者中（amivantamab-lazertinib组336例，奥希替尼组314例），两组的中位缓解持续时间分别为25.8个月（95% CI，20.1至无法估计）和16.8个月（95% CI，14.8~18.5）。在计划的期中总生存期分析中，amivantamab-lazertinib组与奥希替尼组相比，死亡风险比为0.80（95% CI，0.61~1.05）。主要不良事件是EGFR相关毒性效应。amivantamab-lazertinib和奥希替尼因治疗相关不良事件导致的所有药物停药率分别为10%和3%。

Result

Overall, 1074 patients underwent randomization (429 to amivantamab–lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab–lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab–lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab–lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab–lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab–lazertinib and 3% with osimertinib.

结论

在EGFR突变晚期NSCLC一线治疗中，amivantamab-lazertinib疗效优于奥希替尼。（由Janssen Research and Development资助；MARIPOSA在ClinicalTrials.gov注册号为NCT04487080）

注射胶原酶与部分筋膜切除术治疗掌腱膜挛缩症的比较

Collagenase Injection versus Limited Fasciectomy for Dupuytren’s Contracture

背景

掌腱膜挛缩症的治疗方法包括部分筋膜切除术和注射胶原酶。对两种疗法进行的比较非常有限。

我们对中度掌腱膜挛缩症患者进行了一项非盲法、多中心、实效性、两组随机对照非劣效性试验，比较注射胶原酶与部分筋膜切除术。主要结局是治疗后1年时的患者评估指标-手部健康状况（PEM，Patient Evaluation Measure–Hand Health Profile）评分，这是一份由患者报告的手部健康评估问卷。PEM评分范围为0~100分，评分较高表示结局较差。预设的非劣效性界值为6分。

Methods

We performed an unblinded, multicenter, pragmatic, two-group, randomized, controlled noninferiority trial comparing collagenase injection with limited fasciectomy in persons with moderate Dupuytren’s contracture. The primary outcome was the score on the Patient Evaluation Measure–Hand Health Profile (PEM), a questionnaire for assessing hand health as reported by the patient, at 1 year after treatment. Scores on the PEM range from 0 to 100, with higher scores indicating worse outcomes. The prespecified noninferiority margin was 6 points.

共计672人（每组336人）被分配接受胶原酶注射或部分筋膜切除术。主要分析包括599人：胶原酶组314人，部分筋膜切除术组285人。胶原酶组284例有数据患者在1年时的PEM平均评分为17.8分，部分筋膜切除术组250例有数据患者的PEM平均评分为11.9分（估计差异，5.9分；95%置信区间[CI]，3.1~8.8；非劣效性单侧P=0.49）。在有数据的患者中（胶原酶组229例，部分筋膜切除术组197例），2年时PEM平均评分的估计差异为7.2分（95% CI，4.2~10.9）。胶原酶组和部分筋膜切除术组分别有1.8%和5.1%的患者出现了中度或严重治疗并发症；两组分别有14.6%和3.4%的患者出现了需要再次接受治疗的挛缩复发。

Result

A total of 672 persons (336 per group) were assigned to receive collagenase injection or to undergo limited fasciectomy. The primary analysis included 599 persons: 314 in the collagenase group and 285 in the limited-fasciectomy group. The mean score on the PEM at 1 year was 17.8 among the 284 patients with available data in the collagenase group and 11.9 among the 250 patients with available data in the limited-fasciectomy group (estimated difference, 5.9 points; 95% confidence interval [CI], 3.1 to 8.8; one-sided P=0.49 for noninferiority). Among the patients with available data (229 patients in the collagenase group and 197 patients in the limited-fasciectomy group), the estimated difference in the mean score on the PEM at 2 years was 7.2 points (95% CI, 4.2 to 10.9). Moderate or severe complications of treatment occurred in 1.8% of the patients in the collagenase group and in 5.1% of those in the limited-fasciectomy group; recurrent contracture resulted in reintervention in 14.6% and 3.4%, respectively.

结论

在治疗后1年时的PEM评分方面，注射胶原酶不劣于部分筋膜切除术。（由英国国家卫生和医疗研究所[National Institute for Health and Care Research]医疗技术评估计划[Health Technology Assessment Programme]资助；DISC在ISRCTN注册号为ISRCTN18254597）。

lncRNA基因CHASERR缺失导致的神经发育障碍

Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene

摘要

CHASERR编码与CHD2相邻的人类长链非编码RNA（lncRNA），CHD2是一个编码基因，其从头失活变异可导致发育性和癫痫性脑病。本文报告了我们在三名无亲缘关系的综合征性、早发性神经发育障碍患儿身上观察到的结果，三名患儿均携带CHASERR基因座从头缺失。这些患儿患重度脑病、而且均有面部畸形、皮质萎缩和大脑髓鞘形成减少，这种表型与CHD2单倍不足患者的表型截然不同。我们发现，CHASERR缺失会导致患者来源细胞系中CHD2蛋白丰度增加，同一染色体上CHD2转录本表达增加。这些研究结果表明，CHD2在人类疾病中具有双向剂量敏感性，我们建议对其他lncRNA编码基因进行评估，尤其是位于孟德尔疾病相关基因上游的基因。（由美国国立人类基因组研究所[National Human Genome Research Institute]等资助）。