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Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease
依格列净对 2 型糖尿病合并已确诊动脉粥样硬化性心血管疾病患者发生心力衰竭相关事件的疗效

Results of the VERTIS CV Trial

Editorial, see p 2216
## 编者按，见第 2216 页

BACKGROUND: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes.
背景：在 2 型糖尿病患者中，钠-葡萄糖协同转运蛋白 2 抑制剂可降低心力衰竭住院 (HHF) 的风险。我们评估了 ertugliflozin 对 HHF 及相关结局的影响。

Abstract 摘要

METHODS: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin , or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events.
## 方法：VERTIS CV VERTIS CV（评估格列净功效和安全性的心血管结局试验）是一项双盲、安慰剂对照试验，随机将患有 2 型糖尿病和动脉粥样硬化性心血管（CV）疾病的患者分配接受每日一次的格列净（ ）或安慰剂。 预先指定的次要分析比较了格列净（合并剂量）与安慰剂在达到首次 HF 时间和包括死亡事件、总事件和根据预先指定特征分层的复合事件的时间方面的影响。使用 Cox 比例风险模型和 Fine and Gray 方法来考虑竞争性死亡风险，并使用 Andersen-Gill 模型来分析总（首次+复发）HF 事件和总 HF/CV 死亡事件。

RESULTS: A total of 8246 patients were randomly assigned to ertugliflozin ( ) or placebo ( ); had a history of heart failure (HF) and had pretrial ejection fraction (EF) available, including n=959 with EF . Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75-1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54-0.90]; ). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44-0.90]; no HF: HR, 0.79 [95% CI, ]; interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced versus preserved or unknown. However, in the overall population, the risk reduction tended to be greater for those with (HR, 0.48 [ ) versus (HR, ). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate , albuminuria, and diuretic use (each interaction ). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, ).
结果：共 8246 例患者随机分配至 ertugliflozin（ n=4123）或安慰剂（ n=4123），959 例患者既往有心力衰竭 (HF) 史，959 例患者有可获得的试验前射血分数 (EF)，包括 n=308 例患者的 EF < 40%。Ertugliflozin 未显著降低首次 HHF/CV 死亡（HR，0.88 [95% CI，0.75-1.03]）。总的来说，ertugliflozin 降低了首次 HHF 的风险（HR，0.70 [95% CI，0.54-0.90]）。先前 HF 对这一影响无调节作用（HF：HR，0.63 [95% CI，0.44-0.90]；无 HF：HR，0.79 [95% CI，0.59-1.04]； p 交互作用=0.40）。在 HF 患者中，EF 降低 (< 40%) 与保留 (≥40%) 或未知患者的首次 HHF 风险降低相似。然而，在总体人群中，EF 降低 (< 40%) 患者的风险降低趋势大于 EF 保留 (≥40%) 患者（HR，0.48 [95% CI，0.36-0.65]）与 HR，0.80 [95% CI，0.63-1.01]）。 依达格列净对首次发生 HH 的风险影响在大多数亚组中一致，但在 3 个人群中观察到依达格列净的更大益处：基线估计肾小球滤过率 ，存在白蛋白尿，和利尿剂使用（每个 交互作用 ）。依达格列净减少了 HH 的总事件（发生率比，0.70 [95% CI，0.56-0.87]）和 HH/CV 死亡的总事件（发生率比， ）。
CONCLUSIONS: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF.
## 结论： 对于 2 型糖尿病患者，ertugliflozin 降低了首次和全部心力衰竭以及全部心力衰竭/心血管死亡的风险，这为了在心力衰竭的一级和二级预防中使用钠-葡萄糖共转运蛋白 2 抑制剂提供了进一步支持。 ##
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCTO1986881.
登记：网址：https://www.clinicaltrials.gov；唯一标识符：NCTO1986881。
Francesco Cosentino( MD, PhD
弗朗切斯科·科森蒂诺（医学博士，哲学博士）
Christopher P. Cannon, MD
克里斯托弗·P·卡农，医学博士
David Z.I. Cherney(®, MD, PhD
大卫·兹·艾·切尼（®, 医学博士）
Urszula Masiukiewicz, MD
乌尔祖拉·马修基维奇，医学博士
Richard Pratley( MD 理查德·普拉特利（医学博士）
Sam Dagogo-Jack, MD, DSc
萨姆·达戈戈-杰克，医学博士，理学博士
Robert Frederich, MD, PhD
罗伯特·弗雷德里奇，医学博士，哲学博士
Bernard Charbonnel, MD 贝尔纳·沙博内尔，医学博士
James Mancuso, PhD 詹姆斯·曼库索，博士
Weichung J. Shih, PhD
魏荣金 博士
Steven G. Terra, PharmD
史蒂文·G·泰拉，药学博士
Nilo B. Cater, MD
尼洛·B. 卡特，医学博士
Ira Gantz®, MD 伊拉·甘茨®，医学博士
Darren K. McGuire , MD, MHSc
达伦·K·麦圭尔 ，医学博士，健康科学硕士
On behalf of the VERTIS CV Investigators
代表 VERTIS CV 调查员

Clinical Perspective 臨床觀點

What Is New? ## 最新进展

  • VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a study in patients with type 2 diabetes mellitus and cardiovascular disease, enrolled a large proportion of participants with history of heart failure (HF) and known pretrial ejection fraction.
    ## 翻译结果 万古肾静脉导管置入术（简称 VERTIS CV），是一项针对 II 型糖尿病合并心血管疾病患者的临床研究，该研究入组了大量既往有心衰史且在试验前已知射血分数的患者。
  • Ertugliflozin treatment reduced first and total hospitalization for HF events with relative risk for first hospitalization for HF events being similarly beneficial (1) in those with and without a history of HF, and (2) in those with a history of , with reduced ejection fraction or preserved ejection fraction .
    厄鲁格列净治疗减少了首次和全部 HF 事件的住院治疗，首次 HF 事件住院治疗的相对风险对有无 HF 史的患者同样有益，(1) 在有 史的患者中，无论射血分数下降 或射血分数保留 都有效。
  • The effect of ertugliflozin on risk for first hospitalization for HF was consistent across most baseline subgroups, but a greater benefit of ertugliflozin was observed in 3 populations: estimated glomerular filtration rate , albuminuria, and diuretic use.
    厄 tu 格列净对首次住院治疗 HF 风险的影响在大多数基线亚组中是一致的，但在 3 个人群中观察到厄 tu 格列净更大的益处：估计肾小球滤过率 <code0></code0>>、白蛋白尿和利尿剂使用。

What Are the Clinical Implications?
临床意义是什么？

  • The present results support current guidance recommending the use of sodium-glucose cotransporter 2 inhibitors to reduce risk of HF events.
    本研究结果支持目前关于使用钠-葡萄糖协同转运蛋白 2 抑制剂来降低 HF 事件风险的指南。
  • The results also complement emerging evidence suggesting greater benefit on HF events in those with impaired kidney function, and those taking diuretics.
    结果也支持新证据，这些证据表明，对于肾功能受损和服用利尿剂的患者，心脏衰竭事件的获益更大。
Patients with type 2 diabetes mellitus (T2DM) are at high risk for heart failure (HF). The lifetime adjusted cumulative hazard for incident HF in patients with T2DM, hypertension, and obesity with an index age of 55 years reaches Moreover, patients with T2DM represent a substantial proportion of patients hospitalized for HF. In a large global registry, patients with history of atherothrombosis and T2DM had a 30% greater risk of hospitalization for ) than patients with atherothrombosis but without T2DM. In a large European registry, T2DM was prevalent in approximately one-half of all patients admitted for HF in 1 year at 211 cardiology centers. In comparison with those patients without diabetes, patients with diabetes had higher cumulative rates of in-hospital and 1-year mortality, and 1-year HF rehospitalization, even when adjusting for multiple clinical risk factors.
2 型糖尿病 (T2DM) 患者发生心力衰竭 (HF) 的风险很高。 对于 55 岁的 T2DM、高血压和肥胖患者，发生 HF 的终身调整累积风险达到 此外，T2DM 患者在 HF 住院患者中所占比例很大。在一个大型全球登记研究中，有动脉血栓形成和 T2DM 既往史的患者比没有 T2DM 的动脉血栓形成患者住院治疗 ) 的风险高 30%。 在一个大型欧洲登记研究中，在 211 个心脏病学中心的一年中，所有 HF 住院患者中约有一半患有 T2DM。 与无糖尿病的患者相比，即使在调整了多个临床风险因素后，糖尿病患者的院内死亡率和 1 年死亡率以及 1 年 HF 再住院率也更高。
Results from clinical outcome trials with glucoselowering therapies have yielded mixed results with regard to effects on HF risk, with some increasing, many neutral, and some decreasing risk. Six clinical outcome trials with 4 different sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with T2DM, including
临床结果试验中葡萄糖降低疗法对 HF 风险的影响结果喜忧参半，一些增加风险，许多没有影响，一些降低风险。 在 T2DM 患者中使用 4 种不同的钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂进行的 6 项临床结果试验，包括
VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) with ertugliflozin, have demonstrated consistent reduction in risk for first HHF (with hazard ratios [HRs] ranging from 0.61 to 0.73 in the overall population) across a range of patients with and without atherosclerotic cardiovascular disease (ASCVD), and in populations with reduced estimated glomerular filtration rate (eGFR), as well, and in populations with or without T2DM with HF and reduced ejection fraction (EF) at baseline. Accordingly, the American Diabetes Association consensus report, the European Society of Cardiology with the European Association for the Study of Diabetes practice guidelines, and a statement from the American Heart Association and the Heart Failure Society of America have recommended the use of SGLT2 inhibitors in patients with T2DM to reduce the risk of HHF events.
VERTIS CV (评估格列净类药物的疗效和安全性的心血管结局试验) 使用格列净，已经证实可降低首次发生 HH 发生风险（在整体人群中，风险比[HRs] 从 0.61 到 0.73），在有或无动脉粥样硬化性心血管疾病 (ASCVD) 的患者人群中，以及在慢性肾病患者人群中，以及 在基线时有或无 T2DM 伴 HF 和射血分数 (EF) 降低的患者人群中。 因此，美国糖尿病协会共识报告， 欧洲心脏病学会与欧洲糖尿病研究协会实践指南， 以及美国心脏协会和美国心力衰竭协会的声明 都推荐在 T2DM 患者中使用 SGLT2 抑制剂来降低 HH 事件的风险。
The primary results of the VERTIS CV trial have been published recently. This cardiovascular (CV) safety trial, performed to satisfy the 2008 guidance from regulatory agencies for new antihyperglycemic agents,18,19 found that patients with T2DM with ASCVD randomly assigned to ertugliflozin 5 mg or 15 mg achieved the primary objective of noninferiority to placebo in time to first major adverse CV event, a composite end point of CV death, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio [HR], 0.97 [95.6% CI, 0.85-1.11]; for noninferiority). The first secondary outcome in the hierarchical testing sequence was superiority for the time to composite of CV death or HHF, which was not met (HR, 0.88 [95.8% Cl, 0.75-1.03]; for superiority); therefore, formal hypothesis testing ended with this end point. In this report, we present results from prespecified analyses of the effect of ertugliflozin versus placebo on a series of HF-related outcomes from the VERTIS CV randomized clinical trial.
维替格列净心血管 (CV) 结局试验（VERTIS CV）的主要结果已于近日发表。 此项 CV 安全性试验旨在满足监管机构对新抗高血糖药物的 2008 年指导意见，18、19 发现随机分配接受 5 mg 或 15 mg 维替格列净治疗的伴有 ASCVD 的 T2DM 患者，在达到首例重大不良 CV 事件（CV 死亡、非致命性心肌梗死或非致命性卒中的复合终点）的时间方面达到对安慰剂的非劣效主要目标（风险比 [HR]，0.97 [95.6% CI，0.85-1.11]； 对于非劣效）。分层检验顺序中的第一个次要结局是评估 CV 死亡或 HHF 复合终点的优效性，未达到 (HR，0.88 [95.8% Cl，0.75-1.03]； 对于优效性）；因此，正式的假设检验以该终点结束。 在本报告中，我们展示了来自 VERTIS CV 随机临床试验的预先指定分析的结果，分析了维替格列净与安慰剂对一系列 HF 相关结局的影响。

METHODS 方法

On request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual anonymized participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-andresults for more information.
根据要求，并经审查，辉瑞将提供支持本研究结果的数据。根据某些标准、条件和例外情况，辉瑞也可能提供访问相关个人匿名参与者数据。有关更多信息，请访问 https://www.pfizer.com/science/clinical-trials/trial-data-andresults。

Trial Design, Patient Population, and Treatment
### 试验设计、患者人群和治疗

The trial design, baseline characteristics, and main results of VERTIS CV have been published previously. 9 VERTIS CV was a randomized, double-blind, multicenter trial in patients with T2DM (glycohemoglobin 7.0%-10.5%) and established ASCVD, including coronary, cerebrovascular, and peripheral vascular disease, comparing the effects of ertugliflozin with placebo on CV, renal, and metabolic outcomes. Patients were randomly assigned in a 1:1:1 ratio to ertugliflozin 5 mg , ertugliflozin 15 mg , or matching placebo
VERTIS CV 试验设计、基线特征和主要结果已在先前发表。9 VERTIS CV 是一项针对 T2DM 患者（糖化血红蛋白 7.0%-10.5%）和已确诊 ASCVD（包括冠状动脉、脑血管和外周血管疾病）的随机、双盲、多中心试验，比较了 ertugliflozin 与安慰剂对 CV、肾脏和代谢结局的影响。患者以 1:1:1 的比例随机分配接受 ertugliflozin 5 mg、ertugliflozin 15 mg 或匹配的安慰剂。
once daily added to background standard-of-care diabetes therapy. VERTIS CV was initiated in 2013. Based on evolving knowledge of the potential role of SGLT2 inhibitors in reducing the risk of CV events, the study was amended in 2016 to increase patient sample size so that these potential benefits could be assessed with adequate statistical power. Therefore, patients were recruited in 2 cohorts of patients each. General inclusion/exclusion criteria were the same for the 2 cohorts with the exception of excluding patients with HF and New York Heart Association class III and IV for cohort 1 and class IV only for cohort 2. To better characterize the VERTIS CV population, medical history of HF was collected at study entry. In addition, pretrial EF was captured from medical records when available in the overall population, retrospectively for cohort 1 and prospectively for cohort 2. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each study center. All patients provided written informed consent.
每日一次添加到背景标准糖尿病治疗中。 VERTIS CV 项目于 2013 年启动。基于对 SGLT2 抑制剂在降低心血管事件风险方面潜在作用的不断了解，该研究于 2016 年进行了修订，以增加患者样本量，以便能够以充分的统计能力评估这些潜在益处。因此，患者以 名患者为一组的方式进行招募。两组患者的一般入选/排除标准相同，但第一组不包括患有心力衰竭且纽约心脏协会 III 级和 IV 级患者，第二组仅不包括 IV 级患者。为了更好地描述 VERTIS CV 的研究人群，在研究开始时收集了心力衰竭的病史。此外，在总体人群中，当可从医疗记录中获得时，回顾性地记录了第一组的试验前 EF，并前瞻性地记录了第二组的试验前 EF。该试验的实施符合赫尔辛基宣言和国际协调会议药品管理规范指南，并获得当地主管部门的批准。 在每个研究中心，独立伦理委员会或机构审查委员会批准了临床方案。所有患者均提供了书面知情同意。

Outcomes ## 翻译： 结果

The primary trial outcome was the time to first major adverse cardiovascular event. The key secondary outcomes included in the hierarchical statistical testing sequence were the time to first occurrence of the composite of CV death or HHF; time to CV death; and time to the first occurrence of a renal composite of renal death, renal replacement therapy, or doubling of serum creatinine. In addition, several prespecified secondary objectives included time to first HHF and total HHF/CV death (not censored at the time of the first event), which are the focus of this report.
主要试验结果是首次发生重大心血管不良事件的时间。分层统计检验序列中包含的主要次要结果为首次发生心血管死亡或心力衰竭的时间；心血管死亡时间；首次发生肾脏死亡、肾脏替代治疗或血清肌酐倍增的肾脏复合时间。此外，该报告重点关注的几个预先指定的次要目标包括首次发生心力衰竭的时间和总心力衰竭/心血管死亡（在首次事件发生时未审查）。
Prespecified analysis of total (first+recurrent) HHF and subgroup analyses were also performed. Subgroup analyses included the following baseline characteristics: sex, race, ethnicity, region, body mass index, diabetes duration, glycohemoglobin, albuminuria, eGFR, EF, previous HF, baseline CV conditions, and baseline medications including diuretics, mineralocorticoid receptor antagonists, -blockers, angiotensinconverting enzyme inhibitors/angiotensin receptor blockers, insulin, and metformin.
经预先指定的总 (首次+复发) 心力衰竭 (HHF) 分析以及亚组分析。亚组分析包括以下基线特征：性别、种族、民族、地区、体重指数、糖尿病持续时间、糖化血红蛋白、白蛋白尿、肾小球滤过率 (eGFR)、射血分数 (EF)、既往心衰史、基线心血管疾病和基线用药，包括利尿剂、醛固酮受体拮抗剂、 -受体阻滞剂、血管紧张素转化酶抑制剂/血管紧张素受体阻滞剂、胰岛素和二甲双胍。
The narrow HF standardized MedDRA query was used to determine if a patient had a history of HF at baseline. Prespecified analyses of outcomes were conducted based on pretrial , , and unknown, both in the subset with previous HF and in the overall study population.
使用窄化的高频标准化 MedDRA 查询来确定患者在基线时是否有 HF 史。根据预先指定的试验前 、 和未知情况，对 HF 史亚组和总体研究人群进行了预先指定的结局分析。
All CV outcomes were centrally adjudicated in a blinded manner by the independent Cardiovascular Endpoint Adjudication Committee based on previously published standardized definitions. In brief, HHF was defined as an event meeting the following criteria: (1) admission to the hospital with a primary diagnosis of HF; (2) a length-of-stay of at least 24 hours; (3) documented evidence of new or worsening symptoms of HF; (4) physical, laboratory, or diagnostic criteria for new or worsening HF; and (5) initiation or intensification of treatment specifically for HF.
所有 CV 结局均由独立的心血管终点事件判定委员会根据先前发表的标准化定义以盲法集中判定。 简而言之，HHF 定义为符合以下标准的事件：（1）因 HF 主要诊断入院；（2）住院时间至少 24 小时；（3）有记录的新发或加重的心衰症状的证据；（4）新发或加重的心衰的体格检查、实验室或诊断标准；（5）启动或强化专用于心衰的治疗。

Statistical Methods 统计方法

Analyses were prespecified in a separate statistical analysis plan that was finalized before unblinding of the trial. Analyses were performed on an intention-to-treat basis using all randomly assigned patients and all time on-study for each patient comparing the effects of pooled ertugliflozin versus placebo.
在解除试验盲法之前，预先在单独的统计分析计划中预先规定了分析。分析是在所有随机分配的患者和每个患者的所有研究时间的基础上进行意向性治疗分析的，比较了合并的 ertugliflozin 与安慰剂的效果。
Baseline characteristics are summarized with frequencies and percentages for categorical variables and with means and standard deviations for continuous variables. Baseline characteristics are summarized in subgroups based on history of HF at baseline (present, absent) and EF (reduced, preserved, or unknown). Reduced EF was defined as an available pretrial
## 翻译： 基本特征使用频率和百分比（对于分类变量）以及均值和标准差（对于连续变量）进行汇总。基本特征根据基线时的心衰史（存在、不存在）和 EF（降低、保留或未知）进行分组汇总。降低的 EF 定义为可用的审前
The main outcomes analyzed were HHF and the composite of HHF with CV death. Time to first event was analyzed using stratified Cox proportional hazards models including cohort as the stratification factor and treatment as an explanatory factor to estimate HRs and . The method of Fine and Gray was used to account for competing risk of non-CV mortality in analyses of first HHF/CV death (composite) and of all-cause mortality in analyses of first HHF. Recurrent events were analyzed using the Andersen-Gill model to estimate rate ratios and 95% Cls. Recurrent events were also summarized by the number of patients with 1,2, and events. The method of mean cumulative count was used to graphically summarize total HHF events as a cumulative number of events per 100 patients over time. Multivariable analyses included region as the stratification factor and indicators of baseline CV disease status as additional explanatory factors. Baseline CV disease status comprised separate model terms for the presence or absence of coronary artery disease, cerebrovascular disease, peripheral vascular disease, previous myocardial infarction, and previous stroke.
主要分析的结局指标包括心力衰竭（HHF）以及 HHF 或心血管死亡（CV 死亡）的综合指标。使用分层 Cox 比例风险模型，包括队列作为分层因素以及治疗作为解释性因素来估计风险比 (HRs) 和 。Fine-Gray 方法用于考虑首次 HHF 或 CV 死亡（复合）分析中的非 CV 死亡事件的竞争风险，并在首次 HHF 分析中的全因死亡率分析中进行考虑。 使用 Andersen-Gill 模型估计事件发生速率和 95% CI 来分析复发性事件。还根据患者发生的事件数量（1,2, 和）总结复发性事件。平均累积计数的方法用于以每 100 位患者为标准的事件累积数随时间的推移来图形化地总结总的 HHF 事件 。多变量分析将地区作为分层因素并包含基线 CV 疾病状况的指标作为附加解释性因素。 ## 简体中文翻译： 基线心血管疾病状况包括以下几个模型项：冠状动脉疾病有/无、脑血管疾病有/无、周围血管疾病有/无、既往心肌梗死有/无、既往卒中有/无。
Subgroup analyses based on history of HF, pretrial EF, and other factors were also conducted including assessment of treatment by subgroup interactions. Forest plots were used to summarize the results of subgroup analyses.
基于 HF 史、试验前 EF 和其他因素进行的亚组分析也进行了，包括对亚组交互作用进行治疗评估。森林图用于总结亚组分析的结果。
Analyses were performed with SAS software version 9.3 (SAS Institute Inc). Results were considered statistically significant with a 2 -sided or excluding 1.0, with no adjustment for multiple comparisons.
分析使用 SAS 软件 9.3 版（SAS Institute 公司）进行。结果以双侧 或 （不包括 1.0）且不进行多重比较调整作为统计学显著性。

RESULTS ## 结果 ##

A total of 8246 patients were randomly assigned to ertugliflozin ( ) or placebo ( ); (23.7%) had previous HF and (60.7%) had pretrial EF available, including with . Among the 1958 patients with history of HF at baseline, EF data were available in 1485 (76%) patients, among whom 1007 (68%) had EF >45% and 478 ( ) had EF . Patients were followed for a mean of 3.5 years (median 3.0 years). The Table summarizes the baseline characteristics of the study population categorized according to the presence or absence of history of HF. The baseline characteristics, in general, were well balanced between placebo and ertugliflozin. Patients with a history of HF tended
将 8246 名患者随机分配至恩格列净（ )组或安慰剂（ ）组； （23.7%）有先前 HF， （60.7%）有可获得的试验前 EF，包括 伴随 。在 1958 名基线有 HF 史的患者中，1485 名（76%）患者的 EF 数据可用，其中 1007 名（68%）的 EF>45%，478 名（ ）的 EF 。对患者进行了平均 3.5 年（中位数 3.0 年）的随访。该表总结了按有无 HF 史对研究人群基线特征的分类。一般来说，安慰剂组和恩格列净组的基线特征匹配良好。有 HF 史的患者倾向于
Table. Baseline Demographics and Clinical Characteristics in Patients With or Without History of Heart Failure and by Pretrial Ejection Fraction
表格。有或无心力衰竭史患者的基线人口统计学和临床特征，按预试验射血分数分组
{
Demographics and
characteristics
}
{ 人口统计和特征 }		 ( )
（ ）		 HF, HF, EF unknown ( )
HF、EF 未知 ( )		 Total HF ( )
总 HF ( )		 Total no HF ( )
总共 HF 为 ( )
Placebo

厄鲁格列净
Ertugliflozin
Placebo

厄 tu 格列净
Ertugliflozin
Placebo

厄图格列净
Ertugliflozin
Placebo

厄 tu 格列净
Ertugliflozin
Placebo

埃格列净
Ertugliflozin
Age, y 年龄，岁 64.7 (8.2) 63.8 (8.3) 64.4 (8.2)
Male, % 男性，% 83.0 83.1 63.3 65.6 55.9 62.7 65.9 69.3 70.4 70.6
Region, % 地区, %
North America 北美 18.2 18.2 9.8 9.4 9.7 8.7 11.8 11.4 25.3 25.2
South America 南美洲 6.3 3.8 1.8 0.9 2.7 2.1 3.1 1.9 10.5 10.9
Europe 66.0 67.4 84.7 86.8 83.3 83.3 79.9 81.2 48.6 48.6
Asia 4.4 6.3 2.8 1.5 2.2 2.4 3.0 2.9 7.4 7.4
South Africa 南非 1.3 2.5 0.3 0.6 0.5 2.4 0.6 1.5 5.9 5.5
Australia/New Zealand 澳大利亚/新西兰 3.8 1.9 0.6 0.9 1.6 1.0 1.6 1.2 2.3 2.4
Body mass index, kg/m²
身体质量指数，公斤/米²
Glycohemoglobin, % 糖化血红蛋白，%

2 型糖尿病的病程， y 年
Duration of type 2
diabetes, y
13.4 (8.9) 11.4 (8.0)
History of dyslipidemia, %
# 历史血脂异常史，%		 66.7 68.7 56.0 51.8 54.8 48.8 58.2 55.3 81.2 80.5
Current tobacco use, %
当前烟草使用率，%		 16.4 13.2 7.0 8.4 10.2 9.8 10.1 9.9 15.1 14.6
History of hypertension, %
高血压病史，%		 90.6 92.5 96.3 94.0 92.5 92.0 93.9 93.2 90.6 90.5

降糖藥物
Antihyperglycemic
agents,
59.1 47.3 53.8 50.3 51.6 50.5 54.5 49.6 50.7 49.9

降糖药
Antihyperglycemic
agents,
10.1 14.7 9.5 10.7 14.5 9.1 11.0 11.4 18.3 17.3
Estimated glomerular filtration rate,
估计肾小球滤过率，
1.3 1.6 0.6 0.4 0.0 0.7 0.6 0.8 0.3 0.3
30 to <60 30 至 <60 32.1 26.6 24.8 20.3 23.1 23.0 26.0 22.5 20.4 21.1
60 to <90 60 至 <90 47.8 50.8 50.2 55.4 57.5 54.4 51.6 54.0 53.7 53.0
18.9 21.0 24.5 23.8 19.4 22.0 21.7 22.7 25.6 25.6
Albuminuria, % 尿白蛋白， %
Normal 49.1 52.4 59.0 58.7 50.5 56.8 54.3 56.7 59.4 58.3
Micro 38.4 34.8 27.8 28.2 31.2 31.7 31.3 30.6 30.6 29.7
Macro 10.7 11.3 9.8 10.1 16.7 9.8 11.9 10.3 7.8 9.0
Type of atherosclerotic cardiovascular disease, %
动脉粥样硬化性心血管疾病的类型，%
 冠状动脉疾病
Coronary artery
disease
96.9 94.4 90.2 87.2 62.4 63.4 84.1 83.7 74.6 72.8

周围动脉疾病
Peripheral artery
disease
15.1 16.6 10.4 12.1 20.4 20.9 14.3 15.2 20.0 19.8
Cerebrovascular disease 脑血管疾病 11.3 16.0 22.6 23.4 43.0 41.5 25.6 25.6 21.3 22.5
New York Heart Association functional classification, %
纽约心脏协会功能分类，%
Class I I 类 20.8 17.6 25.7 22.5 27.4 30.0 25.0 22.9 - -
Class II II 类 67.3 64.3 67.6 67.1 66.1 62.0 67.1 65.2 - -
Class III III 级 8.8 13.5 4.6 7.1 4.3 3.8 5.5 7.9 - -
Class IV 四级 0 0 0 0.1 0 0 0 0.1 - -
Baseline medications, % ## 基线用药，％
Antiplatelets 抗血小板药 85.5 85.6 90.5 84.7 77.4 82.9 85.7 84.5 84.6 84.5
Antihypertensives 降压药

血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂
Angiotensin-
converting
enzyme inhibitors
or angiotensin
receptor blockers
90.6 84.3 86.5 84.3 78.5 82.2 85.3 83.8 80.3 80.0
-Blocking agents
- 阻断剂		 90.6 88.7 79.8 77.6 71.0 70.0 79.9 78.7 65.8 65.9
Table. Continued 表。续表
{
Demographics and
characteristics
}
{ 人口统计和特征 }		 HF, EF HF, EF > HF, EF unknown (
HF, EF 未知 ( 		Total HF ( )
总 HF ( )		 Total no HF (
总 HF 数目 ( )
Placebo

厄 tu 格列净
Ertugliflozin
Placebo

厄 tu 格列净
Ertugliflozin
Placebo

厄 tu 格列净
Ertugliflozin
Placebo

厄 tu 格列净
Ertugliflozin
Placebo

厄 tu 格列净
Ertugliflozin

钙通道阻滞剂
Calcium channel
blockers
21.4 24.5 34.6 36.3 39.2 33.8 32.7 32.8 35.2 33.8
Nonloop diuretic 非袢利尿剂 18.2 18.8 32.1 29.3 31.7 28.6 28.7 26.5 27.9 27.7
Loop diuretic 袢利尿剂 56.6 49.8 22.9 23.4 22.6 18.8 30.8 28.9 10.6 10.8

## 肾上腺皮质激素受体拮抗剂
Mineralocorticoid
receptor antagonists
40.9 41.7 9.5 12.6 9.1 11.8 16.8 19.7 5.3 4.7
Lipid-lowering drugs 降脂药物
Statins 84.9 89.0 83.8 83.1 69.9 72.8 80.2 82.3 82.1 81.8
Ezetimibe 6.3 3.1 1.2 1.2 2.2 1.4 2.7 1.7 4.7 3.7
Data are mean (standard deviation) unless otherwise stated. EF indicates ejection fraction; and HF , heart failure.
数据以均值（标准差）表示，除非另有说明。EF 表示射血分数；HF 表示心力衰竭。
to have higher prevalence of macroalbuminuria and coronary artery disease. Of the patients with HF with , a greater proportion was male and more were classified with New York Heart Association class III functional status. Patients with no history of HF tended to have a higher prevalence of dyslipidemia and were taking antihyperglycemic agents.
持有较高的大量白蛋白尿和冠状动脉疾病的患病率。在伴隨 的 HF 患者中，男性患者比例更高，更多患者被归为纽约心脏协会 III 级功能状态。无 HF 史的患者往往患有高脂血症，并正在服用 降糖药。

First Event Analyses 首次事件分析

The outcome of risk for first HHF was lower in patients on ertugliflozin (pooled doses) versus placebo (139/5499 [2.5%] versus 99/2747 [3.6%]; HR, 0.70 [95% Cl, ]; ). For ertugliflozin 5 mg versus placebo ( [2.6%] versus 99/2747 [3.6%]), the HR was 0.71 ( Cl, 0.52-0.97) and for ertugliflozin 15 mg versus placebo (68/2747 [2.5%] versus 99/2747 [3.6%]), the HR was 0.68 ( ). Figure 1 depicts the HRs for time to first HHF for the pooled dose comparison of ertugliflozin versus placebo and by individual dose (Figure 1A). The event rates per 100 patient-years were similar in the 2 ertugliflozin treatment groups ( 0.75 per 100 patient-years in ertugliflozin 5 mg and 0.72 per 100 patient-years in ertugliflozin 15 mg ) contrasted with the placebo group ( 1.05 per 100 patient-years).
第一个 HHF 风险的结果在接受 ertugliflozin 治疗的患者中低于安慰剂组（合并剂量）（139/5499 [2.5%] 对 99/2747 [3.6%]；HR，0.70 [95% Cl, ]; ）。对于 ertugliflozin 5 mg 对安慰剂（ [2.6%] 对 99/2747 [3.6%]），HR 为 0.71（ Cl, 0.52-0.97） 对于 ertugliflozin 15 mg 对安慰剂（68/2747 [2.5%] 对 99/2747 [3.6%]），HR 为 0.68（ ）。图 1 显示了 ertugliflozin 和安慰剂合并剂量比较以及按单个剂量分组的首次 HHF 时间的 HR（图 1A）。两组 ertugliflozin 治疗组的事件发生率每 100 例患者年相似（ertugliflozin 5 mg 组为每 100 例患者年 0.75 例，ertugliflozin 15 mg 组为每 100 例患者年 0.72 例），而安慰剂组为每 100 例患者年 1.05 例）。
Figure 1 also depicts the HRs for time to first composite of HHF/CV death for the pooled dose comparison of ertugliflozin versus placebo and by individual dose (Figure 1B). Pooled ertugliflozin did not significantly reduce first HHF/CV death (HR, ). The event rates per 100 patient-years in the ertugliflozin arms were similar ( 2.36 and 2.33 for 5 mg and 15 mg , respectively), with similar HRs in comparison with placebo ( 5 mg : 224/2752 [8.1%] versus placebo 250/2747 [9.1%]; HR, 0.89 [95% Cl, 0.74-1.06]; and 15 mg 220/2747 [8.0%] versus placebo 250/2747 [9.1%]; HR, .
图 1 还描述了 Ertugliflozin 与安慰剂的合并剂量比较以及按个别剂量对 HHF/CV 死亡时间（首次复合）的风险比（图 1B）。合并 Ertugliflozin 在统计意义上并未降低首次 HHF/CV 死亡风险（风险比， ）。Ertugliflozin 组每 100 例患者-年事件发生率相似（5 mg 组和 15 mg 组分别为 2.36 和 2.33），与安慰剂组相比的风险比也相似（5 mg 组：224/2752 [8.1%] vs 安慰剂组 250/2747 [9.1%]；风险比，0.89 [95% Cl, 0.74-1.06]；15 mg 组 220/2747 [8.0%] vs 安慰剂组 250/2747 [9.1%]；风险比，

Total Events Analyses 总事件分析

The total number of events for HHF and the composite of total CV death or HHF normalized for number of patients are presented in Figure 2. In these analyses of total events by the Andersen-Gill model, adjusting for history of HF and CV disease at baseline (presence of coronary artery disease, cerebrovascular disease, peripheral vascular disease, previous myocardial infarction, and previous stroke), ertugliflozin reduced total HHF (rate ratio, , ). Consistent with the reduction in risk for first HHF and lower rate of recurrent HHF events, the analysis of total CV death or HHF using the AndersenGill model showed a reduction in total events (rate ratio, 0.83 [95% Cl, 0.72-0.96]; ). The effect on the composite of total HHF or CV death events appears to be largely attributable to the reduction in HHF-related events. Recurrent hospital admission for HHF and subsequent mortality in patients with first HHF event were lower in patients treated with ertugliflozin in comparison with placebo (Table I in the Data Supplement).
HFH 和心血管死亡或 HHF 合并事件总数按患者人数进行标准化，结果如图 2 所示。在使用 Andersen-Gill 模型分析总事件时，调整基线 HF 和 CV 疾病史（冠状动脉疾病、脑血管疾病、周围血管疾病、既往心肌梗死和既往卒中），依格列净降低了总 HHF（风险比， ， ）。与首次 HHF 风险降低和复发性 HHF 事件发生率降低一致，使用 AndersenGill 模型分析总 CV 死亡或 HHF 显示总事件减少（风险比，0.83 [95% Cl, 0.72-0.96]; ）。总 HHF 或 CV 死亡事件的综合效应似乎主要归因于 HHF 相关事件的减少。与安慰剂相比，依格列净治疗的患者中首次 HHF 事件的反复住院和随后的死亡率较低（数据补充中的表 I）。

Time to Onset of Effect (First Event and Cumulative Incidence of Total HHF Events) and Subgroup Analyses for Time to First Event
## 获效时间（首个事件和总 HHF 事件的累积发生率）和首次事件时间的亚组分析

The cumulative incidences of first and total (first+recurrent) HHF events are presented in Figure 3. Ertugliflozin treatment demonstrated an early separation from placebo for both the first event and total HHF events, indicating an early effect on reduction of HHF.
### 首次和总共（首次+复发）HHF 事件的累积发生率见图 3。Ertugliflozin 治疗组与安慰剂组在首次事件和总共 HHF 事件方面均显示出早期分离，表明其对 HHF 发生率的降低具有早期效果。
Figure 4 provides results of subgroup analyses of risk for first HHF by history of HF or by pretrial EF in those randomly assigned to ertugliflozin (pooled doses) versus placebo. In these prespecified analyses, previous HF status did not modify the effect of ertugliflozin on risk for first HHF: previous HF (ertugliflozin 69/1286 [5.4%]; placebo 55/672 [8.2%]) HR, 0.63 ( Cl, 0.44-0.90) versus no previous HF (ertugliflozin 70/4213 [1.7%]; placebo
图 4 显示了根据既往 HF 史或随机接受恩格列净（合并剂量）或安慰剂治疗的人群的依从 EF 分层的第一 HHF 风险亚组分析结果。在这些预先设定的分析中，既往 HF 状态并未改变恩格列净对首个 HHF 风险的影响: 既往 HF (恩格列净 69/1286 [5.4%]；安慰剂 55/672 [8.2%]) HR，0.63 ( 95% 置信区间， 0.44-0.90) 与无既往 HF (恩格列净 70/4213 [1.7%]；安慰剂
Figure 1. Time to first event analyses.
图 1. 至首次事件时间分析。
Time to first hospitalization for heart failure (A) and composite of hospitalization for heart failure/cardiovascular death (B), overall and by the dose of ertugliflozin using the Fine and Gray method. Cl indicates confidence interval.
时间到首次住院治疗心衰 (A) 和住院治疗心衰/心血管死亡的组合 (B) 的时间，总体和使用 Fine 和 Gray 方法的厄鲁格列净剂量。Cl 表示置信区间。
44/2075 [2.1%]) HR, CI, 0.54-1.15; Pinteraction ). Because a substantial proportion of patients had pretrial EF without the presence of HF at baseline, ertugliflozin effects on risk for first HHF by pretrial EF, independent of previous HF status, was also examined and showed HR for first HHF of 0.48 ( ) for (ertugliflozin 37/638 [5.8%] versus placebo 37/321 [11.5%]); HR, 0.86 ( CI, 0.58-1.29) for EF (ertugliflozin 66/2724 [2.4%] versus placebo 37/1323 [2.8%]); and HR, 0.75 ( CI, 0.45-1.25) for EF unknown (ertugliflozin 36/2137 [1.7%] versus placebo 25/1103 [2.3%]; interaction=0.15; Figure 4). In a similar analysis comparing patients with versus combined with EF unknown, the interaction was 0.06 (Figure I in the Data Supplement).
44/2075 [2.1%]) HR， CI，0.54-1.15；Pinteraction ）。由于相当一部分患者在基线时有无心衰的前期 EF，厄 tugliflozin 对前期 EF 患者首次发生 HHF 风险的影响（与先前的心衰状态无关）也进行了研究，结果显示首次发生 HHF 的 HR 为 0.48（ ）EF 组（厄 tugliflozin 37/638 [5.8%] 对照组 37/321 [11.5%]）；HR，0.86（ CI，0.58-1.29）EF 组（厄 tugliflozin 66/2724 [2.4%] 对照组 37/1323 [2.8%]）；HR，0.75（ CI，0.45-1.25）EF 未知组（厄 tugliflozin 36/2137 [1.7%] 对照组 25/1103 [2.3%]； interaction=0.15；图 4）。在比较 EF 与 EF 联合 EF 未知组的类似分析中， interaction 为 0.06（数据补充中的图 I）。
Figure 5 shows results of risk for first HHF by baseline HF status and pretrial EF, listing results by HF or no HF and with , or unknown. The value for interaction was not significant, suggesting that effects on risk for first HHF were similar in patients with HF and , or unknown. Figure II in the Data Supplement shows the results of analyses on risk for first composite of death, CV death, or all-cause death based on the presence or absence of HF at baseline and pretrial EF, and similarly shows no significant interactions.
图 5 显示了按基线 HF 状态和试验前 EF 划分的首次 HHF 风险结果，结果按有或无 HF，以及 EF 或未知列出。交互的 值不显着，这表明对有 HF 和 或未知 EF 患者首次 HHF 风险的影响相似。数据补充中的图 II 显示了基于基线时是否存在 HF 和试验前 EF 进行的首次复合终点（ 死亡、CV 死亡或全因死亡）风险分析结果，同样显示无显着交互作用。
Ertugliflozin effects on total events of HHF or CV death by pretrial EF, independent of previous HF status, were HR, 0.60 ( ) for EF (ertugliflozin 117/638 [18.3%] versus placebo 88/321 [27.4%]); HR, 0.86 ( ) for (ertugliflozin 236/2724 [8.7%] versus placebo 131/1323 [9.9%]); and HR, 0.94 ( CI, 0.74-1.20) for EF unknown (ertugliflozin 186/2137 [8.7%] versus placebo 108/1103 [9.8%]; P interaction=0.11; Table II in the Data Supplement).
依前次 HF 状态的独立性，Ertugliflozin 对总事件（HHF 或 CV 死亡）的影响受试验前 EF 影响，HR 为 0.60 (
Subgroup analyses of risk for first HHF based on baseline demographics and clinical characteristics and baseline use of background medications showed consistent results across different subgroups (Figures III-V in the Data Supplement). As presented in Figure 6, the risk reduction of ertugliflozin on first HHF was greater in those with
基于基线人口统计学和临床特征以及基线背景药物使用的风险首先发生 HHF 的亚组分析显示，不同亚组的结果一致（数据补充中的图 III-V）。如图 6 所示，在
Figure 2. Percentage of patients with first and subsequent events by treatment.
图 2. 按治疗方法进行的首次和后续事件患者的百分比。
Analyses were conducted using the Andersen-Gill model. The prespecified analysis of total HHF was not adjusted for the competing risk of all-cause death because there was no difference between treatment groups in the competing risk event (death) and analyses of first HHF using the Fine and Gray method to adjust for competing risk of death produced similar results to the unadjusted analyses of first HHF. CVD indicates cardiovascular death; HHF, hospitalization for heart failure; and RR, rate ratio.
使用安德森-吉尔模型进行分析。由于治疗组在竞争性风险事件（死亡）方面没有差异，因此未对全部 HHF 的预先指定分析进行全因死亡竞争性风险调整，并且使用 Fine 和 Gray 方法对死亡竞争性风险进行调整的首次 HHF 分析结果与未调整的首次 HHF 分析结果相似。CVD 表示心血管死亡；HHF 表示心力衰竭住院；RR 表示风险比。
baseline eGFR , albuminuria, and those taking diuretics and the subgroup on loop diuretics ( interaction , respectively).
基线 eGFR ，白蛋白尿，以及服用利尿剂和袢利尿剂亚组（分别为 相互作用 ）。

DISCUSSION ## 讨论 ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ## ##

The overall results of VERTIS CV together with the recently published meta-analysis indicate that the effect of ertugliflozin on HHF in patients with T2DM with ASCVD is consistent with that found across the class of SGLT2 inhibitors. In the current prespecified analyses, we report more detailed data with ertugliflozin on HF-related outcomes. In comparison with other recent SGLT2 inhibitor CV outcome trials in patients with T2DM, the VERTIS CV population included the largest proportion of patients with a history of HF, of the overall trial population, similar to the proportion found in a typical diabetes clinical practice (20%-30%). VERTIS CV also had the largest set of data on pretrial EF available, for of patients in the trial, facilitating additional analyses of outcomes based on the presence or absence of HF history, and EF values, as well.
维格列汀心血管安全性研究和最近发表的荟萃分析的结果表明，在伴有 ASCVD 的 2 型糖尿病(T2DM)患者中，艾格列净对 HHF 的作用与 SGLT2 抑制剂类药物一致。在当前预先设定的分析中，我们报告了艾格列净对 HF 相关结局的更详细数据。与最近其他 SGLT2 抑制剂心血管结局试验相比，维格列汀 CV 研究人群中既往有 HF 病史的患者比例最高，占试验总人群的 %，这与典型糖尿病临床实践中的人口比例(20%-30%)相似。维格列汀 CV 还提供了最大的试验前 EF 数据，适用于 %的患者，从而方便根据 HF 病史和 EF 值分析 结局。 ## ##
Overall, patients included in VERTIS CV were well treated with guideline-directed medical therapy for use in patients with T2DM and established ASCVD, including -blockers, angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers, antiplatelets, and statins. Use of diuretics, specifically loop diuretics, and mineralocorticoid receptor antagonists were higher in patients with HF history as expected for this population. Although CV disease treatments were balanced in general, the proportion of patients reported as taking statins and mineralocorticoid receptor antagonists at baseline was slightly higher in VERTIS CV than the proportion in the other SGLT2 inhibitor CV outcome trials. In those with a history of HF in comparison with those without a history of HF , and those with HF and in comparison with those with HF and or EF unknown, the baseline use of diuretics, especially loop diuretics, was
总体而言，VERTIS CV 研究中纳入的患者均接受了指南指导的药物治疗，用于治疗伴有 T2DM 和已确诊 ASCVD 的患者，包括 - 阻滞剂、血管紧张素转换酶抑制剂/血管紧张素受体拮抗剂、抗血小板药物他和汀类药物。在有 HF 史的患者中，利尿剂（特别是袢利尿剂）和盐皮质激素受体拮抗剂的使用率高于预期。尽管总的来说，CV 疾病治疗方案是平衡的，但 VERTIS CV 研究中基线报告使用他汀类药物和盐皮质激素受体拮抗剂的患者比例略高于其他 SGLT2 抑制剂 CV 结局试验中的比例。与无 HF 史的患者相比，以及有 HF 和 的患者与有 HF 和 或 EF 未知的患者相比，基线使用利尿剂，尤其是袢利尿剂，是
Figure 3. Cumulative incidence of first and total (first+recurrent) HHF events.
图 3. 首次和总计（首次+复发）HHF 事件的累积发生率。
Ertugliflozin includes 5 mg and 15 mg doses. Cl indicates confidence interval; HHF, hospitalization for heart failure; and HR, hazard ratio.
厄鲁格列净包括 5 毫克和 15 毫克剂量。Cl 表示置信区间；HHF，因心力衰竭住院；HR，风险比。
Figure 4. Time to first hospitalization for heart failure overall and by history of heart failure at baseline or by pretrial ejection fraction.
图 4. 首次因心力衰竭住院：总体数据，按基线心力衰竭史或按预审射血分数分组。
Cl indicates confidence interval.
置信区间。
notably higher. The group of patients with HF and reduced ) had, as expected, a higher proportion of males and a higher proportion of patients with New York Heart Association class III functional status.
显著较高。如预期，心衰合并射血分数降低（ ）的患者组中男性比例和纽约心脏协会 III 级功能状态的患者比例更高。
To date, although CV outcome trials with SGLT2 inhibitors in patients with T2DM have shown heterogeneous results with regard to the effects on CV death (HRs ranging from 0.62 to 0.98 ), there has been remarkable consistency in the observed reduction in risk for first event of HHF across these trials, with HRs ranging from 0.61 to In VERTIS CV, the magnitude and timing of the reduction in risk of HHF, with consistent demonstration of an early benefit after study drug initiation, and the consistency of effect between doses correspond to what has been reported for other members of the
迄今为止，尽管 SGLT2 抑制剂对 T2DM 患者的心血管结局试验在心血管死亡方面的影响存在异质性结果（HR 范围从 0.62 到 0.98），但在这些试验中观察到的首次发生 HHF 风险降低方面一直存在着显著的一致性，HR 范围从 0.61 到 在 VERTIS CV 中，HHF 风险降低的幅度和时间，证明了在开始使用研究药物后会早期获益，并且不同剂量之间效果的一致性与其他 SGLT2 抑制剂报道的结果一致。
SGLT2 inhibitor class in patients with T2DM and different levels of CV risk (with and without ASCVD). Similar findings have been reported in trial populations with albuminuric diabetic kidney disease, and with HF and reduced EF with or without T2DM.
SGLT2 抑制剂类在患有 T2DM 和不同水平 CV 风险的患者（伴或不伴有 ASCVD）中的应用。 在伴有白蛋白尿的糖尿病肾病患者的试验人群中， 以及在伴或不伴有 T2DM 的 HF 和降低的 EF 患者中，也报告了类似的发现。
This report further characterizes the effects of ertugliflozin on HHF events by baseline subgroups. Most clinical, demographic, and background treatment characteristics in VERTIS CV had no apparent modifying effect on risk for first HHF with ertugliflozin treatment. Specifically, a history of HF, although representing a subgroup of higher absolute risk for , had no apparent influence on the relative risk reduction of ertugliflozin treatment. With regard to background treatment, findings with diuretics overall and specifically loop diuretics
本研究报告进一步根据基线亚组特征分析了恩格列净对 HH 事件的影响。在 VERTIS CV 研究中，大多数临床、人口统计学和背景治疗特征均未对恩格列净治疗首次 HHF 的风险表现出明显的改变效应。具体而言，尽管既往 HF 史代表了发生 的较高绝对风险亚组，但这对其恩格列净治疗的相对风险降低并无明显影响。关于背景治疗，利尿剂总体而言，特别是袢利尿剂，与恩格列净治疗的 HR 显著降低之间存在关联。
Figure 5. Time to first hospitalization for HF by history of HF at baseline and pretrial ejection fraction.
图 5. 基于基线 HF 病史和试验前射血分数的首次 HF 住院时间。
Cl indicates confidence interval; EF , ejection fraction; and HF , heart failure.
Cl 表示置信区间；EF，射血分数；HF，心力衰竭。
 埃尔图 N/N
Ertug
n/N

利福昔明 速率/100 人-年
liflozin
Rate/100
patient-
years
Place

bo 发生率/100 例患者年
bo
Rate/100
patient-
years

危险比（95% Cl）
Hazard ratio
(95% Cl)

与互动相关的数值
value
for
interaction
All patients 所有患者 139/5499 0.73 99/2747 1.05 ?
eGFR
94/4299
1.14
0.63
45/608
2.27
0.73
0.04
Albuminuria 白蛋白尿
Normal 51/3186 0.46 23/1597 0.41 - 0.04
Micro 0.83 46/845 1.62
Macro 2.26 28/242 3.87 —
Diuretic* 利尿剂*
Yes 94/2346 1.19 80/1196 2.05 ■  ■ ## 翻译结果： ■ 0.02
No 0.41 19/1551 0.35
Loop diuretic 袢利尿剂
Yes 57/826 2.14 57/426 4.37 0.01
No 82/4673 0.50 42/2321 0.52 —
0.25 0.5 1 4
Favors Ertugliflozin 恩格列净 acebo
Figure 6. Time to first hospitalization for heart failure overall and by EGFR, albuminuria, and use of diuretic and loop diuretic at baseline.
图 6. 整体心力衰竭首次住院时间以及基线 EGFR、白蛋白尿和使用利尿剂和袢利尿剂情况的对比。
*Includes loop and nonloop diuretics and mineralocorticoid antagonists. CI indicates confidence interval; eGFR, estimated glomerular filtration rate.
*包括袢利尿剂和非袢利尿剂以及醛固酮受体拮抗剂。CI 表示置信区间；eGFR，估计肾小球滤过率。
suggest that the treatment effect of ertugliflozin on the time to first HHF outcome appears favorable. Effect modification by diuretic use was also previously suggested for the composite of HHF/CV death. Favorable interactions with diuretics on HHF and other CV outcomes have also been noted for other members of the SGLT2 inhibitor class. In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), which had a very high proportion ( ) of patients taking diuretics at baseline, a favorable impact of dapagliflozin on time to HHF was demonstrated. SGLT2 inhibitors are functional in the proximal tubule, proximal to the site of frequently used diuretic agents, and impacting sodium, chloride, and water handling in the renal tubule; hence, functional interaction with diuretics has mechanistic plausibility.
建议 Ertugliflozin 对首次发生心衰住院时间的影响较好。之前也曾发现利尿剂的使用对心衰住院/心血管死亡的组合效应有影响。 其他 SGLT2 抑制剂在与利尿剂联合使用时，对心衰住院和其他心血管结局也显示出良好的相互作用。 在 DAPA-HF 试验（达帕格列净预防心力衰竭不良结局）中，基线使用利尿剂的患者比例很高（ ），结果显示达帕格列净对首次发生心衰住院时间有积极影响。 SGLT2 抑制剂在近曲小管发挥作用，该部位高于常用利尿剂的作用部位，并影响肾小管中的钠、氯和水处理；因此，SGLT2 抑制剂与利尿剂的相互作用在机制上是合理的。
The mechanistic plausibility of potential effect modification by ertugliflozin on risk for first HHF in patients with reduced eGFR and those with albuminuria also has supporting evidence from other members of the SGLT2 inhibitor class. Consistent with the results from VERTIS CV, in a meta-analysis of CV outcome studies of SGLT2 inhibitors that included canagliflozin, dapagliflozin, and empagliflozin, the reduction in HHF was suggested to be greater in patients with an eGFR and in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) that specifically studied patients with reduced eGFR and albuminuria, there was clear benefit with regard to HHF.
机制可信度方面，ertugliflozin 对 eGFR 降低患者和白蛋白尿患者首次发生 HHF 风险的潜在效应修饰也得到了 SGLT2 抑制剂类其他成员的支持证据。 与 VERTIS CV 的结果一致，一项包括卡格列净、达格列净和恩格列净的 SGLT2 抑制剂心血管结局研究的荟萃分析显示，eGFR 患者的 HHF 风险降低更明显；在专门研究 eGFR 降低和白蛋白尿患者的 CREDENCE 试验（卡格列净和已确诊肾病糖尿病患者肾脏事件临床评估）中，在 HHF 方面也观察到明确的获益。
Because the time to first event outcome does not account for recurrent events of HHF or subsequent mortality, the VERTIS CV protocol prespecified analyses of total HHF and the composite total HHF/CV death to better assess effects on net morbidity burden. Although the effect on risk for first event of the composite of HHF/CV death did not achieve statistical significance in the primary VERTIS CV analysis, the present prespecified secondary analysis indicates that ertugliflozin reduced total events of HHF/CV death by 17% and total HHF events by .
因为无症状心力衰竭（HF）患者的首个事件时间的结局未考虑 HF 的复发事件或随后的死亡率，VERTIS CV 协议预先规定了对总 HF 和总 HF/心血管（CV）死亡的复合终点进行分析，以便更好地评估对净发病负担的影响。虽然在 VERTIS CV 的主要分析中，复合终点 HF/CV 死亡的首次事件风险影响未达到统计学意义，但本预先规定的次要分析表明，ertugliflozin 使 HF/CV 死亡的总事件减少了 %， HF 总事件减少了 。
Subgroup analyses of the overall study population based on EF regardless of the presence or absence of HF suggested that the HR estimated for was lower with ertugliflozin treatment than that for EF or unknown EF, although the interaction test was not statistically significant. When the EF categories were split into those with and without a history of HF , the results were consistent with the overall results. Data from DAPA-HF in patients with reduced EF, together with ongoing trials in populations with HF with preserved or reduced EF, will provide additional insights into patient populations that may benefit the most from SGLT2 inhibition with regard to CV-related outcomes
基于 EF 对总体研究人群进行亚组分析，无论是否存在 HF，均提示 组接受依格列净治疗的 HR 估计值低于 EF 组或 EF 未知组，尽管交互检验无统计学意义。当将 EF 类别细分为是否有 HF 史时，结果与总体结果一致。DAPA-HF 研究中 EF 降低患者的数据，以及正在进行的 HF 伴保留或降低 EF 人群的试验，将为可能从 SGLT2 抑制剂获益最多的 CV 相关结局患者人群提供更多见解。

Limitations ## 限制

Results of EF analyses, although suggestive of potentially greater benefit in patients with reduced , has potential limitations because EF was obtained from medical records abstraction instead of by measurement at trial entry, which might not reflect EF at the time of randomization, and data were not available on of the trial cohort. The grouping of patients with with those with unknown EF also has potential limitations. In addition, because of the limited number of patients in each subgroup, the analyses are not powered to detect statistically significant differences. Finally, these analyses are not corrected for multiplicity.
EF 分析的结果提示，在 降低的患者中可能获益更大，但这存在潜在的局限性，因为 EF 是从医疗记录中提取的，而不是在试验入组时进行测量，这可能无法反映随机化时的 EF。此外，关于试验队列的 数据不可用。将 患者与 EF 未知患者分组也存在潜在的局限性。另外，由于每个亚组的患者数量有限，分析无力检测到统计学意义的差异。最后，这些分析未进行多重性校正。

Conclusions 结论

Ertugliflozin reduced risk for first HHF, for total HHF, and for total HHF/CV death events in patients with T2DM in the VERTIS CV trial, findings consistent with those reported for other members of the SGLT2 inhibitor class, and provide additional supportive evidence for the use of SGLT2 inhibition in patients with T2DM to prevent HF-related outcomes.
厄 tu 格列净降低了 T2DM 患者首次发生 HHF、总 HHF 和总 HHF/CV 死亡事件的风险，这与 VERTIS CV 试验中其他 SGLT2 抑制剂组别报告的结果一致， 并为 SGLT2 抑制剂用于 T2DM 患者预防与 HF 相关的结局提供了额外的支持证据。

ARTICLE INFORMATION 文章資訊

Received July 17, 2020; accepted September 24, 2020
收到日期：2020 年 7 月 17 日；接受日期：2020 年 9 月 24 日
This manuscript was sent to Frans Van de Werf, MD, PhD, Guest Editor, for review by expert referees, editorial decision, and final disposition.
本手稿已送交客座编辑 Frans Van de Werf 博士进行专家评审、编辑决定和最终处理。
The Data Supplement is available with this article at https://www.ahajournals. org/doi/suppl/10.1161/CIRCULATIONAHA. 120.050255
数据补充可在本文附带的以下位置获得：https://www.ahajournals. org/doi/suppl/10.1161/CIRCULATIONAHA. 120.050255
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
本篇文章可获得继续医学教育 (CME) 学分。请访问 http://cme.ahajournals.org 参加测验。

Data Accessibility 数据可访问性

On request, and subject to certain criteria, conditions and exceptions (see https:// www.pfizer.com/science/clinical-trials/trial-data-and-results for more information) Pfizer will provide access to individual deidentified participant data from Pfizer sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data wil be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
根据请求，并且符合某些标准、条件和例外情况（更多信息请参见 https:// www.pfizer.com/science/clinical-trials/trial-data-and-results），辉瑞将提供对辉瑞赞助的针对药物、疫苗和医疗器械开展的全球性干预性临床研究的个体去识别受试者数据进行访问，这些研究针对的适应症是 (1) 已在美国和/或欧盟获批的适应症，或 (2) 已终止的项目（即，已停止所有适应症的开发）。辉瑞还将考虑对方案、数据字典和统计分析计划的请求。数据请求可以在辉瑞试验完成 24 个月后提出。去识别的受试者数据将通过安全门户网站提供给符合研究标准和其他条件且不适用任何例外的研究人员。为了获得访问权限，数据请求者必须与辉瑞签署数据访问协议。

Correspondence 往來信件

Francesco Cosentino, MD, PhD, Cardiology Unit, Department of Medicine Solna, Karolinska Institute & Karolinska University Hospital, 17176 Stockholm Sweden. Email francesco.cosentino@ki.se
弗朗西斯科·科森蒂诺，医学博士，哲学博士，心脏病科，索尔纳医学系，卡罗林斯卡学院和卡罗林斯卡大学医院，17176 斯德哥尔摩，瑞典。 电子邮件：francesco.cosentino@ki.se

Affiliations 附属机构

Unit of Cardiology, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden (F.C.). Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.). University of Toronto, Ontario, Canada (D.Z.I.C.). Pfizer Inc, Groton, CT (U.M., J.M.). AdventHealth Translationa Research Institute, Orlando, FL (R.P.). University of Tennessee Health Science Center, Memphis (S.D.-J.). Pfizer Inc, Collegeville, PA (R.F.). University of Nantes, France (B.C.). Rutgers School of Public Health and Rutgers Cancer Institute of New Jer sey, New Brunswick (W.J.S.). Pfizer Inc, Andover, MA (S.G.T). Pfizer Inc, New York
卡罗林斯卡学院和卡罗林斯卡大学医院索尔纳院区心脏病科，瑞典斯德哥尔摩（F.C.）。布莱根和妇女医院，哈佛医学院，波士顿，马萨诸塞州（C.P.C.）。多伦多大学，安大略省，加拿大（D.Z.I.C.）。辉瑞公司，格罗顿，康涅狄格州（U.M.，J.M.）。安德文特健康翻译研究所，奥兰多，佛罗里达州（R.P.）。田纳西州大学健康科学中心，孟菲斯（S.D.-J.）。辉瑞公司，Collegeville，宾夕法尼亚州（R.F.）。法国南特大学（B.C.）。罗格斯公共卫生学院和罗格斯癌症研究所，新泽西州新不伦瑞克（W.J.S.）。辉瑞公司，安多弗，马萨诸塞州（S.G.T）。辉瑞公司，纽约
(N.B.C.). Merck & Co Inc, Kenilworth, NJ (I.G.). University of Texas Southwestern Medical Center, and Parkland Health and Hospital System, Dallas (D.K.M.)
(N.B.C.) 默克公司，新泽西州肯尼尔沃思市 (I.G.)。德克萨斯大学西南医学中心，以及达拉斯帕克兰健康和医院系统 (D.K.M.)

Acknowledgments 确认 ## 确认 以下是您的译文： # 致谢 ## Acknowledgements ## 确认

Editorial support was provided by D. Hoffman, PhD, CMPP, of Engage Scientific Solutions and was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, in collaboration with Pfizer Inc, New York, NY.
编辑支持由 Engage Scientific Solutions 的 D. Hoffman 博士（CMPP）提供，该项目由默沙东公司（总部位于美国新泽西州肯尼沃斯）的全资子公司默克雪兰诺公司与辉瑞制药公司（总部位于美国纽约州纽约）合作出资。

Sources of Funding 资金来源

This study was sponsored by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, in collaboration with Pfizer Inc, New York, NY.
本研究由默克公司子公司默克雪兰诺公司（新泽西州肯尼尔沃思）资助，并与辉瑞公司（纽约州纽约）合作进行。

Disclosures ## Disclosure 披露

Dr Cosentino has received research grants from Swedish Research Council, Swedish Heart & Lung Foundation, and King Gustav V and Queen Victoria Foundation, and fees from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme Corp, Mundipharma, Novo Nordisk, and Pfizer, as well. Dr Cannon has received research grants from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck & Co, Inc, Pfizer, and fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol-Myers Squibb, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck & Co, Inc, Pfizer, Rhoshan, and Sanofi, as well. Dr Cherney has received consulting fees or speaking honoraria or both from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co, Inc, Mitsubishi-Tanabe, Novo Nordisk, Prometic, and Sanofi, and has received operating funds from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co, Inc, and Sanofi. Dr Pratley has received fees (directed to his institution) from AstraZeneca, Glytec, LLC, Hanmi Pharmaceutical Co Ltd, Janssen, Lexicon Pharmaceuticals, Inc, Merck & Co, Inc, Mundipharma, Novo Nordisk, Pfizer, Poxel SA, Sanofi, Sanofi US Services, Inc, Scohia Pharma Inc, and Sun Pharmaceutical Industries. Dr Dagogo-Jack has led clinical trials for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk, Inc; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co, Inc, and Sanofi; and has equity interests in Jana Care, Inc and Aerami Therapeutics. Dr Charbonnel has received fees from AstraZeneca, Boehringer Ingelheim, Lilly, Merck Sharpe & Dohme, Mundipharma, Novo Nordisk, Sanofi, and Takeda. Dr McGuire has received honoraria or consultancy fees from Afimmune, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen Research and Development LLC, Lexicon, Lilly USA, Merck & Co, Inc, Metavant, Novo Nordisk, Pfizer, and Sanofi US. Dr Gantz is an employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, who owns stock in the company. Drs Frederich, Mancuso, Terra, Cater, and Masiukiewicz are employees and shareholders of Pfizer Inc. Dr Shih reports no conflicts.
## 翻译结果： Dr Cosentino 博士已获得瑞典研究委员会、瑞典心脏和肺基金会以及古斯塔夫五世和维多利亚女王基金会的研究资助，并获得了雅培、阿斯利康、拜耳、百时美施贵宝、默沙东、孟德菲玛、诺和诺德和辉瑞公司的费用。 Dr Cannon 博士已获得了安进、波音格殷海姆、百时美施贵宝、第一三共、杨森、默克公司、辉瑞公司的研究资助，并获得了 Aegerion、Alnylam、Amarin、Amgen、Applied Therapeutics、Ascendia、波音格殷海姆、百时美施贵宝、Corvidia、礼来、HLS Therapeutics、Innovent、杨森、久光、默克公司、辉瑞、Rhoshan 和赛诺菲的费用。 Dr Cherney 博士已从阿斯利康、拜耳、波音格殷海姆、礼来、杨森、默克公司、三菱田边、诺和诺德、Prometic 和赛诺菲获得了咨询费或演讲费或两者兼有，并从阿斯利康、波音格殷海姆、礼来、杨森、默克公司和赛诺菲获得了运营资金。 普拉特利博士已收到来自以下机构的费用（以其所在机构的的名义）：阿斯利康、Glytec，LLC、韩美制药有限公司、杨森、Lexicon Pharmaceuticals，Inc、默沙东公司、孟迪制药、诺和诺德、辉瑞、Poxel SA、赛诺菲、赛诺菲美国服务公司、Scohia 制药公司和 Sun Pharmaceutical Industries。达戈戈-杰克博士领导了阿斯利康、勃林格殷格翰和诺和诺德的临床试验；已从阿斯利康、勃林格殷格翰、杨森、默克公司和赛诺菲收取咨询费；并在 Jana Care, Inc 和 Aerami Therapeutics 持有股权。沙博内尔博士已从以下机构获得费用：阿斯利康、勃林格殷格翰、礼来、默沙东，孟迪制药、诺和诺德赛诺菲和武田。麦奎尔博士 已从阿菲姆美、应用治疗、阿斯利康、勃林格殷格翰、卫材、艾思普林、葛兰素史克、杨森研发有限责任公司、列克星敦、礼来美国、默克公司、美达万特、诺和诺德、辉瑞和赛诺菲美国收取演讲费或咨询费。甘茨博士是默克雪兰和杜美公司（默克公司在肯尼沃思的新泽西州的子公司）的雇员，该公司拥有该公司的股票。 Pfizer 公司的员工兼股东包括 Frederich 医生、Mancuso 医生、Terra 医生、Cater 医生和 Masiukiewicz 医生。Shih 医生报告没有任何利益冲突。

Supplemental Materials 补充材料

Data Supplement Tables I-II
数据补充表 I-II
Data Supplement Figures I-V
数据补充图 I-V

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  1. Key Words: cardiovascular diseases - diabetes mellitus, type 2 - heart failure - sodium-glucose cotransporter 2 inhibitors
    关键词：心血管疾病 - 2 型糖尿病 - 心力衰竭 - 钠-葡萄糖协同转运蛋白 2 抑制剂
    Sources of Funding, see page 2214
    资金来源，见第 2214 页
    (c) 2020 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made
    （c）2020 年作者。由 Wolters Kluwer Health, Inc. 代表美国心脏协会出版的《循环》。这是一篇根据知识共享署名非商业性-禁止演绎 许可协议的开放获取文章，该协议允许以任何媒介进行使用、分发和复制，前提是正确引用原始作品、使用是非商业性的并且不进行任何修改或改编。