Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT-BioLINCC)

<u>Data Access NOTE</u><br>Please refer to the "Authorized Access" section below for information about how access to the data from this accession. Access differs from many other dbGaP accessions. <u>Biospecimens</u><br>Access to Biospecimens is through the [NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC)](https://biolincc.nhlbi.nih.gov/home/). Biospecimens from TOPCAT include Buffy Coat, DNA, Plasma, Serum, Urine, and Whole Blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. <u>Objectives </u><br>The TOPCAT trial evaluated the effectiveness of aldosterone antagonist therapy in reducing cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization in patients who have heart failure with preserved systolic function. <u>Background </u><br>Many patients with heart failure have a normal, or near-normal, left ventricular ejection fraction (LVEF). Such patients share similar signs and symptoms as patients who have heart failure and a reduced LVEF, as well as an impaired quality of life and a poor prognosis. However, at the time of TOPCAT, the benefit of medical therapies for heart failure were limited to those with a reduced LVEF. Due to a lack of favorable evidence from clinical trials, clinical guidelines offered no specific recommendations for the management of heart failure in patients with preserved LVEF, except for attention to coexisting conditions. Among patients with heart failure and a reduced LVEF and those with myocardial infarction complicated by heart failure and left ventricular dysfunction, mineralocorticoid receptor antagonists have been shown to be effective in reducing overall mortality and hospitalizations for heart failure. In small mechanistic studies involving patients with heart failure and preserved left ventricular function, mineralocorticoid receptor antagonists improved measures of diastolic function. However, rigorous testing was needed regarding their effect on clinical outcomes in patients with preserved LVEF. Therefore, the TOPCAT trial was initiated to determine whether treatment with spironolactone, an aldosterone antagonist, would improve clinical outcomes in patients with symptomatic heart failure and a relatively preserved LVEF. <u>Participants </u><br>A total of 3445 participants were enrolled, with 1722 assigned to the spironolactone group and 1723 assigned to the placebo group. Among these, 2464 participants were enrolled via the hospitalization stratum and 981 were enrolled via the BNP stratum. <u>Design </u><br>TOPCAT was a phase 3, multicenter, international, randomized, double-blind, and placebo controlled trial. Eligible participants were randomly assigned to receive either spironolactone or placebo in a 1:1 ratio. Randomization was stratified according to whether the patient met the criterion for previous hospitalization or BNP elevation. The baseline visit included assessment of socio-demographics, physical characteristics, medical history, lifestyle factors, laboratory measures, electrocardiography variables and health-related quality of life and functional status. Study drugs were initially administered at a dose of 15 mg once daily, which was increased as tolerated to a maximum of 45 mg daily during the first four months after randomization. Subsequent dose adjustments were made as required and subjects continued to receive other treatments for heart failure and co-existing illnesses. Measurement of potassium and creatinine levels was required within 1 week after a change in the study-drug dose and at each scheduled study visit. Follow-up visits to monitor symptoms, medications, and events and to dispense study drug were scheduled every four months during the subject's first year on the study, and every six months thereafter. The mean follow-up interval was 3.3 years in each study group. Repository blood and urine samples were collected at the baseline and 1 year visits from consenting subjects. The primary endpoint was a composite of cardiovascular mortality, aborted cardiac arrest or hospitalization for the management of heart failure. Secondary endpoints included all-cause mortality, hospitalization for heart failure management, new onset of diabetes mellitus or atrial fibrillation, and quality of life. A subset of subjects also participated in the Echocardiography or Echocardiography and Vascular Stiffness ancillary studies. Echocardiography, and additionally tonometry in the Echocardiography and Vascular Stiffness study, were performed at baseline and at either 12 or 18 months following randomization. If the subject was already enrolled in the TOPCAT trial at the time the ancillary study was initiated, but had not yet reached the 18 month visit, baseline was determined via a retrospective analysis performed on any echocardiographic images completed within 60 days prior to TOPCAT enrollment and no tonometry was performed if applicable. <u>Conclusions </u><br>In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. However, the drug reduced the secondary endpoint of heart failure hospitalization incidence.<u>数据获取说明</u> 请参阅下文的"授权获取"章节，了解如何获取本次收录号对应的数据集。本次收录号的数据获取方式与多数dbGaP收录号有所不同。 <u>生物样本</u> 生物样本的获取需通过[美国国家心肺血液研究所生物样本与数据仓库信息协调中心（BioLINCC）](https://biolincc.nhlbi.nih.gov/home/)进行。TOPCAT研究的生物样本包括血沉棕黄层、DNA、血浆、血清、尿液与全血。请注意，使用生物样本开展遗传学研究需遵守分层知情同意要求。 <u>研究目标</u> TOPCAT试验评估了醛固酮拮抗剂治疗对于降低射血分数保留型心力衰竭（heart failure with preserved systolic function）患者的心血管死亡率、心搏骤停复苏成功发生率以及心力衰竭住院率的有效性。 <u>研究背景</u> 多数心力衰竭患者的左心室射血分数（LVEF）处于正常或接近正常水平。此类患者与射血分数降低型心力衰竭患者具有相似的体征与症状，同时生活质量受损且预后较差。但在TOPCAT试验开展之时，心力衰竭的药物治疗获益仅局限于射血分数降低型心力衰竭患者。由于缺乏临床试验的阳性证据，临床指南未针对射血分数保留型心力衰竭患者的管理给出具体建议，仅要求关注其合并症。 针对射血分数降低型心力衰竭患者以及合并心力衰竭与左心室功能障碍的心肌梗死患者，盐皮质激素受体拮抗剂已被证实可有效降低全因死亡率与心力衰竭住院率。在针对射血分数保留型心力衰竭患者的小型机制研究中，盐皮质激素受体拮抗剂可改善舒张功能相关指标。但仍需开展严格的临床试验，以验证其对射血分数保留型心力衰竭患者临床结局的影响。因此，TOPCAT试验旨在探究醛固酮拮抗剂螺内酯治疗能否改善有症状且左心室射血分数相对保留的心力衰竭患者的临床结局。 <u>研究对象</u> 本研究共纳入3445名受试者，其中1722名被分配至螺内酯组，1723名被分配至安慰剂组。按分层方式纳入的受试者中，2464名通过住院分层纳入，981名通过B型利钠肽（BNP）分层纳入。 <u>研究设计</u> TOPCAT试验为一项Ⅲ期多中心国际随机双盲安慰剂对照试验。符合纳入标准的受试者按1:1比例随机接受螺内酯或安慰剂治疗。随机分组根据受试者是否满足既往住院史或B型利钠肽升高的标准进行分层。基线访视需评估受试者的社会人口学特征、体格特征、病史、生活方式因素、实验室检测指标、心电图指标以及健康相关生活质量与功能状态。 研究药物初始剂量为每日1次、每次15mg，在随机分组后的前4个月内，可根据受试者耐受情况调整剂量，最大剂量增至每日45mg。后续可根据需要调整剂量，受试者同时可继续接受心力衰竭及合并症的其他治疗。在研究药物剂量调整后的1周内以及每次预定研究访视时，均需检测血钾与肌酐水平。在受试者参与研究的第一年，每4个月安排一次随访访视以监测症状、用药情况、不良事件并发放研究药物；此后每6个月安排一次随访。两组受试者的平均随访时长均为3.3年。本研究在基线访视与1年访视时，从知情同意的受试者处采集留存血液与尿液样本。 主要终点为复合终点，包括心血管死亡率、心搏骤停复苏成功发生率以及心力衰竭住院率。次要终点包括全因死亡率、心力衰竭住院率、新发糖尿病或心房颤动发生率以及生活质量。 部分受试者还参与了超声心动图附属研究，或超声心动图与血管僵硬度附属研究。超声心动图检查在基线访视以及随机分组后12或18个月时进行；在超声心动图与血管僵硬度附属研究中，还需额外完成张力测定。若受试者在附属研究启动时已参与TOPCAT试验，但尚未完成18个月访视，则通过对TOPCAT入组前60天内完成的超声心动图图像进行回顾性分析来确定基线状态；若适用，无需额外进行张力测定。 <u>研究结论</u> 针对射血分数保留型心力衰竭患者，螺内酯治疗并未显著降低主要复合终点事件的发生率，该复合终点包括心血管死亡、心搏骤停复苏成功以及心力衰竭住院。但该药物可降低心力衰竭住院这一次要终点的发生率。