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Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis对于患无症状重度主动脉瓣狭窄且左室射血分数保留的患者，现行指南建议每6~12个月进行一次常规临床监测。目前缺乏评估经导管主动脉瓣置换术（TAVR）早期干预可否改善这些患者结局的随机试验数据。For patients with asymptomatic severe aortic stenosis and preserved left ventricular ejection fraction, current guidelines recommend routine clinical surveillance every 6 to 12 months. Data from randomized trials examining whether early intervention with transcatheter aortic-valve replacement (TAVR) will improve outcomes in these patients are lacking.在美国和加拿大的75家中心，我们以1:1比例随机分配无症状重度主动脉瓣狭窄患者接受经胸置入球扩式瓣膜的早期TAVR或临床监测。主要终点是由死亡、卒中或因心血管原因意外住院构成的复合终点。优效性检验在意向性治疗人群中进行。At 75 centers in the United States and Canada, we randomly assigned, in a 1:1 ratio, patients with asymptomatic severe aortic stenosis to undergo early TAVR with transfemoral placement of a balloon-expandable valve or clinical surveillance. The primary end point was a composite of death, stroke, or unplanned hospitalization for cardiovascular causes. Superiority testing was performed in the intention-to-treat population.共计901例患者接受了随机分组，其中455例患者被分配接受TAVR，446例患者被分配接受临床监测。患者的平均年龄为75.8岁，胸外科医师学会预测死亡风险（Society of Thoracic Surgeons Predicted Risk of Mortality）平均评分为1.8%（评分范围为0~100%，评分较高表示术后30天内死亡风险较大），83.6%的患者手术风险较低。TAVR组122例患者（26.8%）和临床监测组202例患者（45.3%）发生了主要终点事件（风险比，0.50；95%置信区间，0.40~0.63；P<0.001）。TAVR组8.4%的患者和临床监测组9.2%的患者死亡；两组分别有4.2%和6.7%的患者发生卒中；分别有20.9%和41.7%的患者因心血管原因意外住院。在中位3.8年随访期间，临床监测组87.0%的患者接受了主动脉瓣置换术。在TAVR组患者与接受主动脉瓣置换术的临床监测组患者之间，手术相关不良事件没有明显差异。A total of 901 patients underwent randomization; 455 patients were assigned to TAVR and 446 to clinical surveillance. The mean age of the patients was 75.8 years, the mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 1.8% (on a scale from 0 to 100%, with higher scores indicating a greater risk of death within 30 days after surgery), and 83.6% of patients were at low surgical risk. A primary end-point event occurred in 122 patients (26.8%) in the TAVR group and in 202 patients (45.3%) in the clinical surveillance group (hazard ratio, 0.50; 95% confidence interval, 0.40 to 0.63; P<0.001). Death occurred in 8.4% of the patients assigned to TAVR and in 9.2% of the patients assigned to clinical surveillance, stroke occurred in 4.2% and 6.7%, respectively, and unplanned hospitalization for cardiovascular causes occurred in 20.9% and 41.7%. During a median follow-up of 3.8 years, 87.0% of patients in the clinical surveillance group underwent aortic-valve replacement. There were no apparent differences in procedure-related adverse events between patients in the TAVR group and those in the clinical surveillance group who underwent aortic-valve replacement.在无症状重度主动脉瓣狭窄患者中，在降低死亡、卒中或因心血管原因意外住院的发生率方面，早期TAVR策略优于临床监测策略。（由Edwards Lifesciences资助；EARLY TAVR在ClinicalTrials.gov注册号为NCT03042104）。Among patients with asymptomatic severe aortic stenosis, a strategy of early TAVR was superior to clinical surveillance in reducing the incidence of death, stroke, or unplanned hospitalization for cardiovascular causes. (Funded by Edwards Lifesciences; EARLY TAVR ClinicalTrials.gov number, NCT03042104.)Philippe Généreux, Allan Schwartz, J. Bradley Oldemeyer, et al. Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis. DOI: 10.1056/NEJMoa2405880
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西非人的APOL1双等位基因和单等位基因变异与慢性肾病
APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans
载脂蛋白L1基因（APOL1）变异是非洲裔美国人患慢性肾病（CKD）的危险因素。西非人是黑种人人群中的一个主要群体，关于西非人CKD遗传流行病学以及APOL1变异与CKD之间临床关联的数据非常少。Apolipoprotein L1 gene (APOL1) variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of APOL1 variants with CKD in West Africans, a major group in the Black population.我们进行了一项病例对照研究，参与者来自加纳和尼日利亚，他们患2至5期CKD、活检证实的肾小球疾病或无肾疾病。我们通过拟合逻辑斯谛回归模型并控制临床试验中心、年龄和性别等协变量，分析了高危基因型（两个APOL1风险等位基因）和低危基因型（少于两个APOL1风险等位基因）参与者的CKD与APOL1变异的关系。We conducted a case–control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease. We analyzed the association of CKD with APOL1 variants among participants with high-risk genotypes (two APOL1 risk alleles) and those with low-risk genotypes (fewer than two APOL1 risk alleles) by fitting logistic-regression models that controlled for covariates, including clinical site, age, and sex.在8355名参与者中（4712人患2至5期CKD，866人患肾小球疾病，2777人无肾疾病），单等位基因APOL1变异的发生率为43.0%，双等位基因APOL1变异的发生率为29.7%。有两个APOL1风险等位基因的参与者患CKD的几率高于只有一个风险等位基因或没有风险等位基因的参与者（校正后的比值比，1.25；95%置信区间[CI]，1.11~1.40），前者患局灶节段性肾小球硬化症的几率也较高（校正后的比值比，1.84；95% CI，1.30~2.61）。有一个APOL1风险等位基因的参与者患CKD的几率高于没有风险等位基因的参与者（校正后的比值比，1.18；95% CI，1.04~1.33），前者患局灶节段性肾小球硬化症的几率也较高（校正后的比值比，1.61；95% CI，1.04~2.48）。加入协变量并不会改变单等位基因和双等位基因APOL1变异与CKD或局灶节段性肾小球硬化症的关系。Among 8355 participants (4712 with CKD stages 2 through 5, 866 with glomerular diseases, and 2777 with no kidney disease), the prevalence of monoallelic APOL1 variants was 43.0% and that of biallelic APOL1 variants was 29.7%. Participants with two APOL1 risk alleles had higher odds of having CKD than those with one risk allele or no risk alleles (adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.11 to 1.40), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.84; 95% CI, 1.30 to 2.61). Participants with one APOL1 risk allele had higher odds of having CKD than those with no risk alleles (adjusted odds ratio, 1.18; 95% CI, 1.04 to 1.33), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.61; 95% CI, 1.04 to 2.48). The inclusion of covariates did not modify the association of monoallelic and biallelic APOL1 variants with CKD or focal segmental glomerulosclerosis.在此项研究中，单等位基因APOL1变异与患CKD几率增加18%，患局灶节段性肾小球硬化症几率增加61%相关；双等位基因APOL1变异与患CKD几率增加25%，患局灶节段性肾小球硬化症几率增加84%相关。（由美国国立人类基因组研究所[National Human Genome Research Institute]等资助）。In this study, monoallelic APOL1 variants were associated with 18% higher odds of CKD and 61% higher odds of focal segmental glomerulosclerosis; biallelic APOL1 variants were associated with 25% higher odds of CKD and 84% higher odds of focal segmental glomerulosclerosis. (Funded by the National Human Genome Research Institute and others.)Rasheed A. Gbadegesin, Ifeoma Ulasi, Samuel Ajayi, et al.APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans. DOI:10.1056/NEJMoa2404211
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Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age每12~18个月用药一次的唑来膦酸可预防老年女性骨折，但其对骨密度和骨转换的影响会持续5年以上。唑来膦酸长间隔期用药能否预防绝经后早期女性的脊椎骨折尚不清楚。Zoledronate prevents fractures in older women when administered every 12 to 18 months, but its effects on bone density and bone turnover persist beyond 5 years. Whether infrequent zoledronate administration would prevent vertebral fractures in early postmenopausal women is unknown.
我们开展了一项为期10年的前瞻性、双盲、随机、安慰剂对照试验，参与者为绝经后早期女性（50~60岁），其腰椎、股骨颈或髋部的骨矿物质密度T值低于0且高于－2.5（T值≥－1通常表示骨矿物质密度正常）。参与者被随机分成三组，第一组在基线和5年时接受5 mg唑来膦酸输注（唑来膦酸-唑来膦酸组），第二组在基线时接受5 mg唑来膦酸，5年时接受安慰剂输注（唑来膦酸-安慰剂组），第三组在基线和5年时接受安慰剂输注（安慰剂-安慰剂组）。患者分别在基线、5年和10年时拍摄脊柱X线照片。主要终点是形态测量学脊椎骨折，采用半定量方法评估，定义为脊椎高度与基线X线照片相比至少发生20%变化。次要终点是脆性骨折、任何骨折和主要骨质疏松性骨折。We conducted a 10-year, prospective, double-blind, randomized, placebo-controlled trial involving early postmenopausal women (50 to 60 years of age) with bone mineral density T scores lower than 0 and higher than −2.5 (scores of −1 or higher typically indicate normal bone mineral density) at the lumbar spine, femoral neck, or hip. Participants were randomly assigned to receive an infusion of zoledronate at a dose of 5 mg at baseline and at 5 years (zoledronate–zoledronate group), zoledronate at a dose of 5 mg at baseline and placebo at 5 years (zoledronate–placebo group), or placebo at both baseline and 5 years (placebo–placebo group). Spinal radiographs were obtained at baseline, 5 years, and 10 years. The primary end point was morphometric vertebral fracture, which was assessed semiquantitatively and defined as at least a 20% change in vertebral height from that seen on the baseline radiograph. Secondary end points were fragility fracture, any fracture, and major osteoporotic fracture.在基线平均年龄为56.0岁的1054名女性中，有1003人（95.2%）完成了10年随访。唑来膦酸-唑来膦酸组22名女性（6.3%）、唑来膦酸-安慰剂组23名女性（6.6%）和安慰剂-安慰剂组39名女性（11.1%）发生了新发形态测量学骨折（相对危险度，唑来膦酸-唑来膦酸组 vs. 安慰剂-安慰剂组，0.56[95%置信区间{CI}，0.34~0.92；P=0.04]；唑来膦酸-安慰剂组 vs. 安慰剂-安慰剂组，0.59[95% CI，0.36~0.97；P=0.08]）。唑来膦酸-唑来膦酸组与安慰剂-安慰剂组相比，脆性骨折、任何骨折和主要骨质疏松性骨折的相对危险度分别为0.72（95% CI，0.55~0.93）、0.70（95% CI，0.56~0.88）和0.60（95% CI，0.42~0.86），唑来膦酸-安慰剂组与安慰剂-安慰剂组相比，相对危险度分别为0.79（95% CI，0.61~1.02）、0.77（95% CI，0.62~0.97）和0.71（95% CI，0.51~0.99）。Of 1054 women with a mean age of 56.0 years at baseline, 1003 (95.2%) completed 10 years of follow-up. A new morphometric fracture occurred in 22 women (6.3%) in the zoledronate–zoledronate group, in 23 women (6.6%) in the zoledronate–placebo group, and in 39 women (11.1%) in the placebo–placebo group (relative risk, zoledronate–zoledronate vs. placebo–placebo, 0.56 [95% confidence interval {CI}, 0.34 to 0.92; P=0.04]; and zoledronate–placebo vs. placebo–placebo, 0.59 [95% CI, 0.36 to 0.97; P=0.08]). The relative risk of fragility fracture, any fracture, and major osteoporotic fracture was 0.72 (95% CI, 0.55 to 0.93), 0.70 (95% CI, 0.56 to 0.88), and 0.60 (95% CI, 0.42 to 0.86), respectively, when zoledronate–zoledronate was compared with placebo–placebo and 0.79 (95% CI, 0.61 to 1.02), 0.77 (95% CI, 0.62 to 0.97), and 0.71 (95% CI, 0.51 to 0.99), respectively, when zoledronate–placebo was compared with placebo–placebo.试验启动十年后，在基线和5年时用药的唑来膦酸可有效预防绝经后早期女性的形态测量学脊椎骨折。（由新西兰健康研究委员会[Health Research Council of New Zealand]资助；在澳大利亚和新西兰临床试验注册系统[Australian New Zealand Clinical Trials Registry]注册号为ACTRN12612000270819）。Ten years after trial initiation, zoledronate administered at baseline and 5 years was effective in preventing morphometric vertebral fracture in early postmenopausal women. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12612000270819.)Mark J. Bolland, Zaynah Nisa, Anna Mellar, et al. Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age. DOI: 10.1056/NEJMoa2407031
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残留HER2阳性乳腺癌患者接受恩美曲妥珠单抗治疗的生存期Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer人表皮生长因子受体2（HER2）阳性早期乳腺癌患者接受新辅助全身性治疗后，如果有残留浸润性疾病，则复发和死亡风险较高。KATHERINE是一项3期开放标签试验，其主要分析结果表明，与单纯曲妥珠单抗辅助治疗相比，恩美曲妥珠单抗（T-DM1）辅助治疗可使浸润性乳腺癌或死亡风险降低50%。Patients with human epidermal growth factor receptor 2 (HER2)–positive early breast cancer with residual invasive disease after neoadjuvant systemic therapy have a high risk of recurrence and death. The primary analysis of KATHERINE, a phase 3, open-label trial, showed that the risk of invasive breast cancer or death was 50% lower with adjuvant trastuzumab emtansine (T-DM1) than with trastuzumab alone.我们将患HER2阳性早期乳腺癌，并且接受以紫杉类药物为基础的化疗和曲妥珠单抗新辅助全身性治疗后乳房或腋下有残留浸润性疾病的患者随机分组，分别接受T-DM1或曲妥珠单抗治疗14个周期。本文报告对无浸润性疾病生存期的预设最终分析和对总生存期的第二次期中分析。We randomly assigned patients with HER2-positive early breast cancer with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment with taxane-based chemotherapy and trastuzumab to receive T-DM1 or trastuzumab for 14 cycles. Here, we report the prespecified final analysis of invasive disease–free survival and the second interim analysis of overall survival.中位随访8.4年时，T-DM1与曲妥珠单抗相比，持续改善无浸润性疾病生存期（未分层的浸润性疾病或死亡风险比，0.54；95%置信区间[CI]，0.44~0.66）。T-DM1组的7年无浸润性疾病生存率为80.8%，曲妥珠单抗组为67.1%（差异，13.7个百分点）。T-DM1与曲妥珠单抗相比还显著降低了死亡风险（未分层风险比，0.66；95% CI，0.51~0.87；P=0.003）。T-DM1组的7年总生存率为89.1%，曲妥珠单抗组为84.4%（差异，4.7个百分点）。在T-DM1组和曲妥珠单抗组中，分别有26.1%和15.7%的患者出现了3级或更高级别不良事件。With a median follow-up of 8.4 years, T-DM1 sustained the improvement in invasive disease–free survival over trastuzumab (unstratified hazard ratio for invasive disease or death, 0.54; 95% confidence interval [CI], 0.44 to 0.66). Seven-year invasive disease–free survival was 80.8% with T-DM1 and 67.1% with trastuzumab (difference, 13.7 percentage points). T-DM1 also led to a significantly lower risk of death than trastuzumab (unstratified hazard ratio, 0.66; 95% CI, 0.51 to 0.87; P=0.003). Seven-year overall survival was 89.1% with T-DM1 and 84.4% with trastuzumab (difference, 4.7 percentage points). Adverse events of grade 3 or higher were noted in 26.1% of the patients in the T-DM1 group and 15.7% of those in the trastuzumab group.对于接受新辅助治疗后有残留浸润性疾病的HER2阳性早期乳腺癌患者，与曲妥珠单抗相比，T-DM1可改善总生存期，并可持续改善无浸润性疾病生存期。（由罗氏/基因泰克资助；KATHERINE在ClinicalTrials.gov注册号为NCT01772472）。As compared with trastuzumab, T-DM1 improved overall survival with sustained improvement in invasive disease–free survival among patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. (Funded by F. Hoffmann–La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472.)Charles E. Geyer, Jr., Michael Untch, Chiun-Sheng Huang, et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. DOI: 10.1056/NEJMoa2406070![]()
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