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血管紧张素脑啡肽酶抑制疗法治疗射血分数保留的心力衰竭
Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction
摘 要
背景
在射血分数降低的心力衰竭患者中，血管紧张素受体脑啡肽酶抑制剂沙库巴曲-缬沙坦降低了心力衰竭住院或心血管原因死亡的风险。在射血分数保留的心力衰竭患者中，血管紧张素受体脑啡肽酶抑制疗法的疗效尚未明确。
方法
我们将患纽约心脏学会（NYHA）心功能分级II至IV级心力衰竭，射血分数≥45%，钠尿肽水平升高且有结构性心脏病的4822例患者随机分组，分别接受沙库巴曲-缬沙坦（目标剂量，每日2次，每次97 mg沙库巴曲和103 mg缬沙坦）或缬沙坦（目标剂量，每日2次，每次160 mg）治疗。主要结局是由心力衰竭住院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、次要结局（包括NYHA心功能分级变化、肾功能恶化和堪萨斯城心肌病问卷[Kansas City Cardiomyopathy Questionnaire，KCCQ]临床总分[量表，0~100，评分较高表示症状和躯体活动受限较少]的变化）和安全性。
结果
沙库巴曲-缬沙坦组526例患者发生了894起主要事件，缬沙坦组557例患者发生了1009起主要事件（率比，0.87；95%置信区间[CI]，0.75~1.01；P=0.06）。沙库比里-缬沙坦组和缬沙坦组的心血管原因死亡率分别为8.5%和8.9%（风险比，0.95；95% CI，0.79~1.16）；心力衰竭住院的总数分别为690和797（率比，0.85；95% CI，0.72~1.00）。沙库巴曲-缬沙坦组和缬沙坦组分别有15.0%和12.6%患者的NYHA心功能分级改善（比值比，1.45；95% CI，1.13~1.86）；分别有1.4%和2.7%患者的肾功能恶化（风险比，0.50；95% CI，0.33~0.77）。8个月时，沙库巴曲-缬沙坦组KCCQ临床总分的平均变化比缬沙坦组大1.0分（95% CI，0.0~2.1）。沙库巴曲-缬沙坦组患者的低血压和血管性水肿发生率较高，高钾血症发生率较低。12个预设的亚组分析结果提示沙库巴曲-缬沙坦治疗获益存在异质性，其中射血分数较低的患者和女性患者可能获益。
结论
在射血分数≥45%的心力衰竭患者中，沙库巴曲-缬沙坦未显著降低心力衰竭住院率和心血管原因死亡率。（由诺华资助；PARAGON-HF在ClinicalTrials.gov注册号为NCT01920711。）
Scott D. Solomon, John J.V. McMurray, Inder S. Anand, et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. DOI: 10.1056/NEJMoa1908655
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直接PCI中基因型指导的口服P2Y12抑制剂选择策略
A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI
摘 要
背景
目前尚不了解接受直接经皮冠状动脉介入治疗（PCI）的患者可否从基因型指导的口服P2Y12抑制剂选择策略中获益。
方法
我们开展了一项随机、开放标签、评估人设盲的试验。试验将通过支架置入术接受直接PCI的患者以1:1的比例分组，分别根据早期CYP2C19基因检测接受一种P2Y12抑制剂治疗（基因型指导组），或接受替格瑞洛或普拉格雷标准治疗（标准治疗组），为期12个月。在基因型指导组中，CYP2C19*2或CYP2C19*3功能丧失型等位基因携带者接受了替格瑞洛或普拉格雷治疗，非携带者接受了氯吡格雷治疗。两项主要结局是12个月时的净临床不良事件（定义为全因死亡、心肌梗死、明确支架内血栓形成、卒中或根据血小板抑制和患者结局[Platelet Inhibition and Patient Outcomes，PLATO]试验标准定义的大出血）（主要复合结局；进行非劣效性检验，非劣效性界值是绝对差异2个百分点）和12个月时的PLATO大出血或小出血（主要出血结局）。
结果
主要分析纳入了2488例患者：基因型指导组1242例，标准治疗组1246例。基因型指导组63例患者（5.1%）和标准治疗组73例患者（5.9%）发生了主要复合结局（绝对差异，-0.7个百分点；95%置信区间[CI]，-2.0~0.7；非劣效性P<0.001）。基因型指导组122例患者（9.8%）和标准治疗组156例患者（12.5%）发生了主要出血结局（风险比，0.78；95% CI，0.61~0.98；P=0.04）。
结论
在接受直接PCI的患者中，在血栓形成事件方面，CYP2C19基因型指导的口服P2Y12抑制剂选择策略在12个月时不劣于替格瑞洛或普拉格雷标准治疗，且出血发生率较低。（由荷兰卫生研究与发展组织[Netherlands Organization for Health Research and Development]资助；POPular Genetics在ClinicalTrials.gov注册号为NCT01761786；在Netherlands Trial Register注册号为NL2872。）
Daniel M.F. Claassens, Gerrit J.A. Vos, Thomas O. Bergmeijer, et al. A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI. DOI: 10.1056/NEJMoa1907096
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BRAFV600E突变结直肠癌的encorafenib、binimetinib和西妥昔单抗三联治疗
Encorafenib, Binimetinib, and Cetuximab in BRAFV600E–Mutated Colorectal Cancer
摘 要
背景
BRAFV600E突变转移性结直肠癌患者预后不良，初始治疗失败后的中位总生存期为4~6个月。由于通过表皮生长因子受体信号传导发生通路再激活，因此仅抑制BRAF的活性有限。
方法
在这项开放标签的3期试验中，我们纳入了经过一种或两种方案治疗后发生疾病进展的665例BRAFV600E突变转移性结直肠癌患者。我们以1:1:1的比例将患者随机分组，分别接受encorafenib、binimetinib和西妥昔单抗（三联治疗组）；encorafenib和西妥昔单抗（二联治疗组）；或者研究者选择的西妥昔单抗和伊立替康或西妥昔单抗和FOLFIRI（亚叶酸、氟尿嘧啶和伊立替康）（对照组）。主要终点是与对照组相比，三联治疗组的总生存期和客观缓解率。次要终点是与对照组相比，二联治疗组的总生存期。我们在本文中报告了预设的期中分析的结果。
结果
三联治疗组的中位总生存期为9.0个月，对照组为5.4个月（死亡的风险比，0.52；95%置信区间[CI]，0.39~0.70；P<0.001）。三联治疗组经证实的缓解率为26%（95% CI，18~35），对照组为2%（95% CI，0~7）（P<0.001）。二联治疗组的中位总生存期为8.4个月（与对照组相比，死亡的风险比，0.60；95% CI，0.45~0.79；P<0.001）。三联治疗组的3级或更高级别不良事件发生率为58%，二联治疗组为50%，对照组为61%。
结论
在BRAFV600E突变转移性结直肠癌患者中，与标准治疗相比，encorafenib、西妥昔单抗和binimetinib三联治疗使患者达到了显著较长的总生存期和显著较高的缓解率。（由Array BioPharma等资助；BEACON CRC在ClinicalTrials.gov注册号为NCT02928224；在EudraCT注册号为2015-005805-35。）
Scott Kopetz, Axel Grothey, Rona Yaeger, Eric Van Cutsem, et al. Encorafenib, Binimetinib, and Cetuximab in BRAFV600E–Mutated Colorectal Cancer. DOI: 10.1056/NEJMoa1908075
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一种罕见遗传病的患者定制寡核苷酸疗法
Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease
摘 要
基因组测序通常是诊断罕见病的关键，但许多罕见病缺乏特异性治疗方法。我们在本文中介绍了对一种罕见致死性神经退行性疾病的分子诊断是如何促使我们合理设计、检测和制造出milasen，即为1例患者定制的，用于调节剪接的反义寡核苷酸药物。在该患者细胞系中进行的概念验证实验成为了首次接触患者后1年内启动milasen“单一患者”（N-of-1）研究的基础。本试验未发生严重不良事件，且治疗与癫痫发作的客观减少相关（通过脑电图和家长报告确定）。本研究为针对患者快速开发出定制治疗提供了一个可能的模板。（由Mila的奇迹基金会[Mila's Miracle]等资助。）
Jinkuk Kim, Chunguang Hu, Christelle Moufawad El Achkar, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. DOI: 10.1056/NEJMoa1813279本周五 中午十二点 app和官网发布全文中译
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Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction
血管紧张素脑啡肽酶抑制疗法治疗射血分数保留的心力衰竭
Abstract
Background
The angiotensin receptor–neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor–neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear.
Methods
We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed.
Results
There were 894 primary events in 526 patients in the sacubitril–valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril–valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril–valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril–valsartan group. Patients in the sacubitril–valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril–valsartan in patients with lower ejection fraction and in women.
Conclusion
Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.)
Scott D. Solomon, John J.V. McMurray, Inder S. Anand, et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. DOI: 10.1056/NEJMoa1908655
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A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI
直接PCI中基因型指导的口服P2Y12抑制剂选择策略
Abstract
Background
It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors.
Methods
We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events — defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria — at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome).
Results
For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, ?0.7 percentage points; 95% confidence interval [CI], ?2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P=0.04).
Conclusion
In patients undergoing primary PCI, a CYP2C19 genotype–guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.)
Daniel M.F. Claassens, Gerrit J.A. Vos, Thomas O. Bergmeijer, et al. A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI. DOI: 10.1056/NEJMoa1907096
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Encorafenib, Binimetinib, and Cetuximab in BRAFV600E–Mutated Colorectal Cancer
BRAFV600E突变结直肠癌的encorafenib、binimetinib和西妥昔单抗三联治疗
Abstract
Background
Patients with metastatic colorectal cancer with the BRAFV600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.
Methods
In this open-label, phase 3 trial, we enrolled 665 patients with BRAFV600E–mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.
Results
The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.
Conclusion
A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAFV600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.)
Scott Kopetz, Axel Grothey, Rona Yaeger, Eric Van Cutsem, et al. Encorafenib, Binimetinib, and Cetuximab in BRAFV600E–Mutated Colorectal Cancer. DOI: 10.1056/NEJMoa1908075
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Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease
一种罕见遗传病的患者定制寡核苷酸疗法
Abstract
Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an “N-of-1” study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila’s Miracle Foundation and others.)
Jinkuk Kim, Chunguang Hu, Christelle Moufawad El Achkar, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. DOI: 10.1056/NEJMoa1813279
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