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心房颤动合并稳定型冠心病的艾多沙班抗血栓治疗
Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease
背景
尽管不同临床指南已提出一致建议，但目前仍缺乏关于心房颤动合并稳定型冠心病患者长期抗血栓治疗策略的随机试验数据。
Despite consistent recommendations from clinical guidelines, data from randomized trials on a long-term antithrombotic treatment strategy for patients with atrial fibrillation and stable coronary artery disease are still lacking.
方法
我们开展了一项多中心、开放标签、裁定者设盲的随机试验，目的是在心房颤动合并稳定型冠心病（定义为既往接受过血运重建或药物治疗的冠心病）患者中比较艾多沙班单药治疗与双药抗血栓治疗（艾多沙班联合一种抗血小板药）。卒中风险根据CHA2DS2-VASc评分进行评估（评分范围为0~9，评分较高表示卒中风险较大）。主要结局是由12个月内全因死亡、心肌梗死、卒中、体循环栓塞、计划外紧急血运重建、大出血或临床相关非大出血构成的复合结局。次要结局包括由主要缺血事件构成的复合结局，以及由大出血或临床相关非大出血构成的安全性结局。
We conducted a multicenter, open-label, adjudicator-masked, randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease (defined as coronary artery disease previously treated with revascularization or managed medically). The risk of stroke was assessed on the basis of the CHA2DS2-VASc score (scores range from 0 to 9, with higher scores indicating a greater risk of stroke). The primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major bleeding or clinically relevant nonmajor bleeding at 12 months. Secondary outcomes included a composite of major ischemic events and the safety outcome of major bleeding or clinically relevant nonmajor bleeding.
结果
我们在韩国18个研究中心将524例患者分配到艾多沙班单药治疗组，将516例患者分配到双药抗血栓治疗组。患者平均年龄为72.1岁，22.9%为女性，平均CHA2DS2-VASc评分为4.3分。12个月时，艾多沙班单药治疗组34例患者（Kaplan–Meier估计值，6.8%）和双药抗血栓治疗组79例患者（16.2%）发生了主要结局事件（风险比，0.44；95%置信区间[CI]，0.30~0.65；P<0.001）。两组12个月内的主要缺血事件累积发生率似乎相似。艾多沙班单药治疗组23例患者（Kaplan-Meier估计值，4.7%）和双药抗血栓治疗组70例患者（14.2%）发生大出血或临床相关非大出血（风险比，0.34；95% CI，0.22~0.53）。
Result
We assigned 524 patients to the edoxaban monotherapy group and 516 patients to the dual antithrombotic therapy group at 18 sites in South Korea. The mean age of the patients was 72.1 years, 22.9% were women, and the mean CHA2DS2-VASc score was 4.3. At 12 months, a primary-outcome event had occurred in 34 patients (Kaplan–Meier estimate, 6.8%) assigned to edoxaban monotherapy and in 79 patients (16.2%) assigned to dual antithrombotic therapy (hazard ratio, 0.44; 95% confidence interval [CI], 0.30 to 0.65; P<0.001). The cumulative incidence of major ischemic events at 12 months appeared to be similar in the trial groups. Major bleeding or clinically relevant nonmajor bleeding occurred in 23 patients (Kaplan–Meier estimate, 4.7%) in the edoxaban monotherapy group and in 70 patients (14.2%) in the dual antithrombotic therapy group (hazard ratio, 0.34; 95% CI, 0.22 to 0.53).
结论
对于心房颤动合并稳定型冠心病患者，艾多沙班单药治疗与双药抗血栓治疗相比，降低了复合结局发生风险（12个月内全因死亡、心肌梗死、卒中、体循环栓塞、计划外紧急血运重建、大出血或临床相关非大出血）。（由心血管研究基金会[CardioVascular Research Foundation]等资助；EPIC-CAD在ClinicalTrials.gov注册号为NCT03718559）。
Conclusions
In patients with atrial fibrillation and stable coronary artery disease, edoxaban monotherapy led to a lower risk of a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, or major bleeding or clinically relevant nonmajor bleeding at 12 months than dual antithrombotic therapy. (Funded by the CardioVascular Research Foundation and others; EPIC-CAD ClinicalTrials.gov number, NCT03718559.)
女性的炎症、胆固醇、脂蛋白(a)和30年心血管结局
Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women
背景
高敏C反应蛋白（CRP）、低密度脂蛋白（LDL）胆固醇和脂蛋白(a)水平有助于预测5年和10年心血管风险，并且是采取药物干预的独特途径。由于早年干预是降低风险的重要方法，因此需要收集更多信息，以了解这些生物标志物在预测女性远期心血管风险方面的实用性。
我们测定了27,939名最初健康的美国女性在基线时的高敏CRP、LDL胆固醇和脂蛋白(a)水平，随后对这些女性进行长达30年随访。主要终点是首次主要不良心血管事件，即由心肌梗死、冠状动脉血运重建、卒中或心血管原因死亡构成的复合终点。我们计算了每项生物标志物各五分位数的校正后风险比和95%置信区间，以及根据年龄和竞争风险校正后的30年累积发生率曲线。
Methods
We measured high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels at baseline in 27,939 initially healthy U.S. women who were subsequently followed for 30 years. The primary end point was a first major adverse cardiovascular event, which was a composite of myocardial infarction, coronary revascularization, stroke, or death from cardiovascular causes. We calculated the adjusted hazard ratios and 95% confidence intervals across quintiles of each biomarker, along with 30-year cumulative incidence curves adjusted for age and competing risks.
参与者的基线平均年龄为54.7岁。30年随访期间共发生3662起首次主要心血管事件。高敏CRP、LDL胆固醇和脂蛋白(a)基线水平升高幅度的五分位数可预测30年风险。对于主要终点，在最高五分位数和最低五分位数的比较中，根据协变量校正后的风险比如下：高敏CRP为1.70（95%置信区间[CI]，1.52~1.90），LDL胆固醇为1.36（95 CI，1.23~1.52），脂蛋白(a)为1.33（95 CI，1.21~1.47）。冠心病和卒中的分析结果似乎与主要终点的结果一致。每种生物标志物对总体风险产生独立影响。在包含全部三种生物标志物的模型中，风险散布最大。
Result
The mean age of the participants at baseline was 54.7 years. During the 30-year follow-up, 3662 first major cardiovascular events occurred. Quintiles of increasing baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) all predicted 30-year risks. Covariable-adjusted hazard ratios for the primary end point in a comparison of the top with the bottom quintile were 1.70 (95% confidence interval [CI], 1.52 to 1.90) for high-sensitivity CRP, 1.36 (95% CI, 1.23 to 1.52) for LDL cholesterol, and 1.33 (95% CI, 1.21 to 1.47) for lipoprotein(a). Findings for coronary heart disease and stroke appeared to be consistent with those for the primary end point. Each biomarker showed independent contributions to overall risk. The greatest spread for risk was obtained in models that incorporated all three biomarkers.
结论
在最初健康的美国女性中，包含高敏CRP、LDL胆固醇和脂蛋白(a)水平的单一综合指标可预测30年内的新发心血管事件。这些数据支持将动脉粥样硬化事件一级预防策略扩展到传统的10年风险估计值之外。（由美国国立卫生研究院[National Institutes of Health]资助；Women’s Health Study在ClinicalTrials.gov注册号为NCT00000479）。
xalnesiran联合或不联合免疫调节剂治疗慢性乙型肝炎
Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B
背景
xalnesiran是一种靶向乙型肝炎病毒（HBV）基因组保守区并可静默多个HBV转录本的小干扰RNA分子。xalnesiran联合或不联合免疫调节剂可能对慢性HBV感染患者有效。
我们开展了一项2期、多中心、随机、对照、适应性、开放标签平台试验。该试验在接受核苷或核苷酸类似物（NA）治疗后达到病毒学抑制的慢性HBV感染者中评估了应用以下五种方案治疗48周：100 mg xalnesiran（第1组）、200 mg xalnesiran（第2组）、200 mg xalnesiran联合150 mg ruzotolimod（第3组）、200 mg xalnesiran联合180 μg聚乙二醇化干扰素α-2a（第4组）或NA单药治疗（第5组）。主要疗效终点是治疗结束后24周，乙型肝炎表面抗原（HBsAg）转阴（HBsAg水平，<0.05 IU/mL）。本试验还评估了安全性。
Methods
We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed.
在159名参与者（第1~5组分别为30、30、34、30和35人）中，主要终点事件发生率分别为第1组7%（95%置信区间[CI]，1~22），第2组3%（95 CI，0~17），第3组12%（95 CI，3~28），第4组23%（95 CI，10~42），第5组无（95 CI，0~10）。治疗结束后24周，第1~5组的HBsAg血清学转换率分别为3%、0、3%、20%和0。HBsAg转阴（伴随或不伴随血清学转换）只发生于筛选时HBsAg水平<1000 IU/mL的参与者。第1~5组的3级或4级不良事件发生率分别为17%、10%、18%、50%和6%，其中最常见的事件是丙氨酸氨基转移酶水平升高。
Result
Among 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level.
结论
在接受NA治疗后达到病毒学抑制的慢性HBV感染者中，xalnesiran联合免疫调节剂治疗使相当一部分参与者在治疗结束后24周时HBsAg转阴。3级或4级不良事件并不少见。（由罗氏资助；Piranga在ClinicalTrials.gov注册号为NCT04225715）。
接受过内分泌治疗的转移性乳腺癌患者应用德曲妥珠单抗治疗试验
Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer
背景
经过一线或多线内分泌治疗后，激素受体阳性转移性乳腺癌患者的结局开始恶化。德曲妥珠单抗对既往接受过化疗，并且人表皮生长因子受体2（HER2）低表达的转移性乳腺癌患者有效。
我们开展了一项3期、多中心、开放标签试验，该试验纳入患HER2低表达（免疫组化[IHC]分析评分为1+或2+，原位杂交结果为阴性）或HER2超低表达（IHC 0且伴膜染色）的激素受体阳性转移性乳腺癌，并且既往因转移性乳腺癌接受过一线或多线内分泌治疗，且未接受过化疗的患者。以1:1比例随机分配患者接受德曲妥珠单抗治疗或医师选择的化疗。主要终点是HER2低表达疾病患者的无进展生存期（根据盲法独立集中审核结果）。次要终点包括所有随机分组患者的无进展生存期、总生存期和安全性。
Methods
We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor–positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety.
在接受随机分组的866例患者中，713人患HER2低表达疾病，153人患HER2超低表达疾病。在HER2低表达疾病患者中，德曲妥珠单抗组的中位无进展生存期为13.2个月（95%置信区间[CI]，11.4~15.2），化疗组为8.1个月（95% CI，7.0~9.0）（疾病进展或死亡的风险比，0.62；95% CI，0.51~0.74；P<0.001）；探索性HER2超低表达人群的结果与此一致。总生存期数据尚不成熟。德曲妥珠单抗组52.8%的患者和化疗组44.4%的患者发生了3级或更高级别不良事件。两组分别有49例患者（11.3%；3起事件严重程度为5级）和1例患者（0.2%；2级）发生了经过裁定的间质性肺病或肺炎。
Result
Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively.
结论
在接受过一线或多线内分泌治疗的激素受体阳性、HER2低表达或HER2超低表达转移性乳腺癌患者中，与化疗相比，德曲妥珠单抗治疗延长了无进展生存期。未发现新的安全性信号。（由阿斯利康和第一三共资助；DESTINY-Breast06在ClinicalTrials.gov注册号为NCT04494425）。
产前cfDNA测序与偶然检出孕产妇癌症
Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer
背景
为筛查胎儿非整倍体而进行的游离DNA（cfDNA）序列分析可偶然检出孕产妇癌症。我们需要收集更多数据，以确定有助于识别最有可能患癌症孕妇的DNA测序模式和其他生物标志物，并确定最佳随访方法。
在此项正在进行的研究中，我们对并无癌症症状或体征，但北美12个商业实验室之一的临床cfDNA测序结果显示异常或无法报告（即无法评估胎儿非整倍体状态）的孕妇或产后女性进行了癌症筛查。我们采用了统一的癌症筛查方案，包括快速全身磁共振成像（MRI）、实验室检测，以及用于研究目的，通过全基因组平台进行的标准化cfDNA测序。主要结局是参与者在初始癌症筛查评估后患癌症。二次分析包括检测性能。
Methods
In this ongoing study we performed cancer screening in pregnant or postpartum persons who did not perceive signs or symptoms of cancer but received unusual clinical cfDNA-sequencing results or results that were nonreportable (i.e., the fetal aneuploidy status could not be assessed) from one of 12 different commercial laboratories in North America. We used a uniform cancer-screening protocol including rapid whole-body magnetic resonance imaging (MRI), laboratory tests, and standardized cfDNA sequencing for research purposes with the use of a genomewide platform. The primary outcome was the presence of cancer in participants after the initial cancer-screening evaluation. Secondary analyses included test performance.
在初始队列的107名参与者中，52人（48.6%）患癌症。全身MRI检测隐匿性癌症的灵敏度和特异性分别为98.0%和88.5%。查体和实验室检测在确定患癌症参与者方面作用有限。研究性测序显示，49名参与者同时存在多条（≥3条）染色体拷贝数增加和减少；在显示这一测序模式的参与者中，有47人（95.9%）患癌症。在患子宫肌瘤等非恶性疾病的参与者中，发现了只有染色体增加（多对染色体为三体）或只有染色体减少（一对或多对染色体为单体）的cfDNA测序模式。
Result
Cancer was present in 52 of the 107 participants in the initial cohort (48.6%). The sensitivity and specificity of whole-body MRI in detecting occult cancer were 98.0% and 88.5%, respectively. Physical examination and laboratory tests were of limited use in identifying participants with cancer. Research sequencing showed that 49 participants had a combination of copy-number gains and losses across multiple (≥3) chromosomes; cancer was present in 47 of the participants (95.9%) with this sequencing pattern. Sequencing patterns of cfDNA in which there were only chromosomal gains (multiple trisomies) or only chromosomal losses (one or more monosomies) were found in participants with nonmalignant conditions, such as fibroids.
结论
此项研究显示，在临床cfDNA测序结果异常或无法报告的参与者中，有48.6%患隐匿性癌症。有必要进一步研究在产前筛查中提示隐匿性癌症的DNA测序模式。（由NIH内部研究计划[Intramural Research Program]资助；在ClinicalTrials.gov注册号为NCT04049604）。
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