Surgical Treatment for Ischemic Heart Failure (STICH-BioLINCC)

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<u>Objective</u><br>

To compare medical therapy with coronary bypass surgery and/or surgical ventricular reconstruction for patients with congestive heart failure and coronary artery disease.<br>

<u>Background</u><br>Coronary artery disease (CAD) is the most common cause of heart failure, which in turn is a major cause of death and disability globally. Evidence from previous clinical trials supports the use of coronary-artery bypass grafting (CABG) to relieve disabling symptoms of angina, particularly among high-risk subgroups with extensive CAD. However, the studies did not include patients with severe left ventricular dysfunction, and developments in medical therapy have since led to updated guidelines. In addition, the benefits of CABG in patients with ischemic cardiomyopathy had still not been clearly established at the time of this study. STICH sought to evaluate the role of CABG in the treatment of patients with CAD and left ventricular systolic dysfunction.<br>

Reduced left ventricular function may occur after myocardial infarction, often in conjunction with left ventricular remodeling, including left ventricular enlargement and changes in chamber geometry. Left ventricular remodeling is correlated with progression of heart failure and a poor prognosis. Therefore, a surgical approach to remodeling through left ventricular volume reduction could improve outcomes for patients with CAD and heart failure. Surgical ventricular reconstruction (SVR) has been shown to reduce the left ventricular volume, increase the ejection fraction, and improve ventricular function. There is also evidence that SVR performed with CABG may reduce the rate of hospitalization and improve ventricular function, as compared to CABG alone. As part of a second hypothesis, STICH additionally investigated whether SVR when added to CABG would improve outcomes in patients with heart failure and CAD.

<u>Participants</u><br>A total of 2,136 participants were enrolled in STICH. 1,212 were enrolled in the hypothesis 1 component of the trial, with 602 participants assigned to receive medical therapy alone, and 610 participants assigned to receive medical therapy plus CABG. 1,000 were enrolled in the hypothesis 2 component, with 499 participants assigned to receive medical therapy plus CABG, and 501 participants assigned to receive medical therapy plus CABG and SVR. 76 participants that were assigned to the CABG with medical therapy treatment were enrolled in both hypothesis components.<br>

<u>Design</u><br>After initial determination of overall eligibility, participants were evaluated to determine which component of the STICH program was appropriate for them on the basis of suitable therapeutic options. All participants underwent cardiac imaging for assessment of left ventricular function and wall motion. Participants in the hypothesis 1 component were randomly assigned to receive either medical therapy alone or medical therapy plus CABG. Participants in the hypothesis 2 component were randomly assigned to receive either medical therapy plus CABG or medical therapy plus CABG and SVR.<br>

At baseline, demographic factors and clinical characteristics were assessed, including current medications and prior diagnostic and other cardiovascular procedures, and a physical examination was performed. Guideline-based recommendations for drug and device use were emphasized for all participants. All participants underwent follow-up evaluations at the time of discharge or at 30 days for participants still hospitalized, every 4 months for the first year, and every 6 months thereafter. The median length of follow-up was 56 months for hypothesis 1 and 48 months for hypothesis 2.<br>

For participants receiving CABG, arterial grafting for stenosis of the left anterior descending coronary artery was required for all participants without specific contraindications. The use of additional arterial conduits supplemented by vein grafts was recommended for revascularization of all major vessels with clinically significant stenoses. Concurrent mitral-valve surgery for regurgitation was performed at the discretion of the surgeon. For participants receiving SVR, the operation was most commonly performed during a single period of cardioplegic arrest after construction of bypass grafts. However, the procedure could also be performed with the heart beating in order to facilitate identification of the noncontractile zone of scarring. After an anterior left ventriculotomy was centered in the zone of anterior asynergy, a suture was placed in the interior of the ventricle to encircle the scar at the boundary between the akinetic and viable tissue. Visual inspection and palpation facilitated the judgment of whether a patch was needed to optimize the chamber size without deforming the left ventricle during closure of the ventriculotomy.<br>

The primary outcome for hypothesis 1 was the rate of death from any cause. The primary outcome for hypothesis two was a composite of death from any cause and hospitalization for cardiac causes.<br>

<u>Conclusions</u><br>There was no significant difference between medical therapy alone and medical therapy plus CABG for death from any cause, though participants that underwent CABG had lower rates of death from cardiovascular causes, death from any cause, or hospitalization for cardiovascular causes. Adding SVR to CABG reduced the left ventricular volume, as compared with CABG alone. However, this anatomical change was not associated with a greater improvement in symptoms or exercise tolerance, or with a reduction in the rate of death or hospitalization for cardiac causes.

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<u>**研究目标**:</u>
对比药物治疗与冠状动脉旁路移植术（coronary artery bypass grafting, CABG）及/或外科心室重建术（surgical ventricular reconstruction, SVR）用于充血性心力衰竭合并冠状动脉疾病患者的临床疗效。

<u>**研究背景**:</u>
冠状动脉疾病（coronary artery disease, CAD）是心力衰竭最常见的病因，而心力衰竭又是全球范围内致死与致残的主要原因之一。既往临床试验证据支持采用冠状动脉旁路移植术缓解心绞痛的致残性症状，尤其适用于存在广泛冠状动脉疾病的高危亚组人群。然而，上述研究未纳入重度左心室功能不全患者，且此后药物治疗的进展推动了临床指南的更新。此外，在本研究开展之时，冠状动脉旁路移植术对缺血性心肌病患者的获益仍未明确。缺血性心力衰竭外科治疗研究（Surgical Treatment for Ischemic Heart Failure, 下称STICH）旨在评估冠状动脉旁路移植术在冠状动脉疾病合并左心室收缩功能不全患者治疗中的作用。

左心室功能降低常发生于心肌梗死后，多伴随左心室重构，包括左心室扩大与腔室几何形态改变。左心室重构与心力衰竭进展及不良预后相关。因此，通过外科手段实施左心室容积缩减以改善重构，或可改善冠状动脉疾病合并心力衰竭患者的预后。外科心室重建术已被证实可降低左心室容积、提升射血分数并改善心室功能。另有证据显示，与单纯冠状动脉旁路移植术相比，联合外科心室重建术可降低住院率并改善心室功能。作为第二项研究假说的组成部分，STICH同时探究了在冠状动脉旁路移植术基础上加用外科心室重建术，是否可改善心力衰竭合并冠状动脉疾病患者的临床结局。

<u>**研究对象**:</u>
本研究共纳入2136名受试者。其中1212名受试者纳入假说1亚组，602名被分配至单纯药物治疗组，610名被分配至药物治疗联合冠状动脉旁路移植术组。另有1000名受试者纳入假说2亚组，499名被分配至药物治疗联合冠状动脉旁路移植术组，501名被分配至药物治疗、冠状动脉旁路移植术联合外科心室重建术组。另有76名被分配至药物治疗联合冠状动脉旁路移植术组的受试者，同时参与了两个假说亚组的研究。

<u>**研究设计**:</u>
在初步确定整体入组资格后，研究人员对受试者进行评估，结合合适的治疗方案确定其适配的STICH研究亚组。所有受试者均接受心脏影像学检查以评估左心室功能与室壁运动情况。假说1亚组受试者被随机分配至单纯药物治疗组或药物治疗联合冠状动脉旁路移植术组。假说2亚组受试者被随机分配至药物治疗联合冠状动脉旁路移植术组，或药物治疗、冠状动脉旁路移植术联合外科心室重建术组。

基线阶段，研究人员对受试者的人口统计学特征与临床特征进行评估，包括当前用药情况、既往诊断及其他心血管操作，并完成体格检查。所有受试者均需遵循基于指南的药物与器械使用建议。所有受试者均接受随访评估：出院时或仍住院者于30天时完成首次评估，第一年每4个月随访一次，此后每6个月随访一次。假说1亚组的中位随访时长为56个月，假说2亚组为48个月。

对于接受冠状动脉旁路移植术的受试者，若无明确禁忌证，均需采用动脉移植物治疗左前降冠状动脉狭窄。推荐使用额外的动脉移植物辅以静脉移植物，以实现存在临床显著狭窄的主要血管的血运重建。根据术者判断，可同期行二尖瓣手术治疗反流。对于接受外科心室重建术的受试者，手术通常在完成旁路移植物构建后，通过单次心脏停搏灌注术实施。不过，也可在心脏跳动状态下完成该操作，以便于识别瘢痕性无收缩区域。在前壁室壁运动不能区域中心行左心室前壁切开术后，于心室腔内放置缝线，在无运动瘢痕组织与存活心肌组织的边界处环绕瘢痕。通过目视检查与触诊，判断是否需要补片以优化腔室大小，避免在闭合左心室切开术时造成左心室变形。

假说1的主要结局为全因死亡率。假说2的主要结局为全因死亡与因心脏原因住院的复合终点。

<u>**研究结论**:</u>
单纯药物治疗与药物治疗联合冠状动脉旁路移植术在全因死亡率上无显著差异，但接受冠状动脉旁路移植术的受试者，其心血管原因死亡率、全因死亡率及因心血管原因住院率均更低。与单纯冠状动脉旁路移植术相比，在冠状动脉旁路移植术基础上加用外科心室重建术可降低左心室容积，但该解剖学改变并未带来症状或运动耐量的更显著改善，也未降低心脏原因死亡或住院率。