BOSTON (EGMN) – The surgical treatment of ischemic heart failure trial promised to be a landmark study that would provide the evidence base for the selection of patients who would benefit from the addition of surgical ventricular restoration to coronary artery bypass grafting, yet flaws in the design and implementation of the trial have led to erroneous outcomes, Dr. Gerald D. Buckberg said at the annual meeting of the American Association for Thoracic Surgery.
In a debate arguing the merits of the U.S. National Institutes of Health–funded STICH trial outcomes presented earlier this year at the annual meeting of the American College of Cardiology in Orlando and simultaneously published in the New England Journal of Medicine (2009;360:1705-17), Dr. Buckberg contended that the conclusions presented by STICH investigator Dr. Robert H. Jones of Duke University in Durham, North Carolina, were misguided. He took specific issue with the claim that surgical ventricular restoration (SVR), when added to coronary artery bypass grafting (CABG), offered no benefit over CABG alone in patients with heart failure due to coronary artery disease. Dr. Buckberg, distinguished professor of surgery at the division of cardiothoracic surgery at the University of California, Los Angeles, cited a series of study design changes through which “the wrong operation was done on the wrong patients, employing a wrong method of measuring volume, inevitably resulting in the wrong conclusions.”
In his presentation, Dr. Jones provided a synopsis of the findings of the STICH hypothesis 2 investigation, which looked at whether SVR combined with CABG and medical therapy improves survival free of hospitalization when compared with CABG and medical therapy without SVR. (The STICH hypothesis 1 trial, which compares medical therapy plus CABG to medical therapy alone, is ongoing.) This arm of the trial randomized approximately 1,000 patients with left ventricular dysfunction to either bypass surgery alone or bypass surgery with ventricular “tailoring.” The study was predicated on earlier data that suggested that, if you do some surgical modeling, you will get a better functioning ventricle, smaller end-diastolic volume and improved overall efficiency of the heart, said Dr. Jones. “The findings validated that heart volume was lower [with SVR], but surprisingly it showed that surgical reshaping of the left ventricle to improve cardiac performance with CABG was not better than surgery alone at reducing symptoms, deaths, or cardiac hospitalizations, nor did it improve patients’ exercise tolerance,” he added, suggesting there is no role for this type of ventricular repair with CABG.
Critics of the trial strongly disagree, according to Dr. Buckberg, who noted that this conclusion contradicts the “significant body of worldwide data supporting the role of SVR in the treatment of congestive heart failure patients with ventricular dilation following regional scar after anterior myocardial infarction.” Additionally, the immediate publication of the trial findings by the New England Journal of Medicine, despite the lack of adherence to evidence-based medicine standards, has created confusion and deprives cardiologists “of understanding the potential role of volume reduction in treating ischemic congestive heart failure patients.”
Among the many problems with the trial, according to Dr. Buckberg, is that two vital entry criteria that were established for the original STICH hypothesis 2 protocol – that left ventricular end-systolic volume index must be over 60mL/m2 and that patients have evidence of more than 35% akinesia from necrosis in the anterior wall before undergoing SVR – were subsequently altered, with the new primary objective being documented left ventricular anterior wall dysfunction. With the change, “necrosis and volume measurements were absent, and 13% of the study population was without myocardial infarction.”
In other words, SVR was being used not only in patients with wall motion disorders secondary to scar but also in those with wall motion disorders occurring from ischemia without necrosis, either because of acute ischemia or hibernation, said Dr. Buckberg. “Ischemic muscle without scar may recover following CABG, but such recovery cannot occur following CABG [in patients in whom] more than 50% of muscle is scarred,” he said. “More importantly, SVR has never been reported or recommended in ventricles without scar, and the potential use of this procedure differs markedly from observations [of the RESTORE patient cohort] on which the SVR procedure is based.”
Additionally, according to the original study design, ventricular volume quantification by cardiac magnetic resonance (CMR) was required in all patients before and after SVR, yet echocardiography was used to make this measurement, despite its exclusion as an invalid tool, said Dr. Buckberg. Moreover, he noted, “trial entry required that 100% have volume measured by CMR, yet only 38% had any volume measurement; SVR is indicated only if ESVI [end-systolic volume index] is beyond 60mL/m2, yet the trial does not report a volume measurement in each SVR candidate or in CABG without SVR patients; and the Surgical Therapy Committee defined a 30% reduction of ESVI at 4 months by CMR study as a required criterion for an acceptable SVR procedure, but ESVI was lowered only 19% in the 33% of patients that had any form of study – demonstrated an inadequate end point was achieved.”
Acceptance of the reported STICH trial outcomes despite the inconsistencies between the initial trial criteria and those used to reach the reported conclusions could have a number of serious consequences, including hindering proper decisions for the treatment of heart failure patients with dilated hearts; limiting the development of surgical ventricular restoration; compromising physician and surgeon confidence in scientific integrity; and contributing to unnecessarily excessive health care costs associated with heart failure treatment, said Dr. Buckberg.
In order to achieve meaningful results from the STICH trial, the investigators have to revisit the original criteria and exclude patients with invalid volume measurements by echocardiography, include only patients with more than 35% akinesia and regional nonviability documented by nuclear medicine studies; quantify all patients with more than 30% volume reduction by CMR study; and report only patients with acceptable volume reduction by CMR at 4 months, Dr. Buckberg stated. “Without this action, the STICH trial conclusions simply show that statisticians can defy nature from a flawed database.”
In his response, Dr. Jones noted that all of the study protocol amendments, which were described in the December 2007 issue of the Journal of Thoracic and Cardiovascular Surgery, were approved by the STICH steering committee (J. Thorac. Cardiovasc. Surg. 2007;134:1540-7). The changes, which were implemented to help facilitate enrollment, “did not change the primary objective of the study,” he stated.
The STICH trial was funded by the U.S. National Heart, Lung, and Blood Institute. Dr. Jones reported he had no relevant financial conflicts of interest. Dr. Buckberg holds various cardiovascular patents, some including ventricular restoration.
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波士顿(EGMN)——Gerald D. Buckberg博士在美国胸外科协会的年会上指出，一项外科治疗缺血性心力衰竭试验所提供的证据，有助于挑选可从左心室成形术(SVR)+冠状动脉旁路移植术(CABG)中受益的患者，因此有望成为里程碑式的研究，但是该试验在设计和执行方面的缺陷却导致了错误结果。
今年早些时候，美国国立卫生研究院资助的STICH试验的结果在奥兰多市举办的美国心脏病学会年会上公布，并同时发表于《新英格兰医学杂志》上(2009;360:1705-17)。在争论该试验结果是否具有价值时，Buckberg博士指出，STICH研究者——北卡罗来纳州达勒姆市杜克大学的Robert H. Jones博士提出的结论具有误导性。Buckberg博士明确指出，与CABG单一治疗相比，SVR+CABG联合治疗冠状动脉疾病所致心力衰竭患者无任何治疗优势可言。Buckberg博士是加州大学洛杉矶分校胸心外科的知名外科教授。他指出，该试验在设计方面做了许多改变，“对错误的患者进行了错误的手术，采用错误的方法测定心脏容积，因此不可避免地产生了错误的结论。”
Jones博士在会上发言时简单介绍了STICH假说2试验的结果。该试验旨在探讨，与CABG+药物治疗相比，在此基础上额外进行SVR是否可改善无住院生存率 (STICH假说1试验旨在对药物+CABG联合治疗与药物单一治疗进行比较，目前正在进行中)。 在STICH假说2试验中，约1,000例左室功能不全患者随机接受CABG单一治疗或CABG+SVR联合治疗。Jones博士表示，既往研究表明，手术治疗可改善心室功能和心脏总体功能及减少舒张末期容积；该试验正是基于这些既往结果而开展的。他补充说道，“结果证明，SVR可进一步降低心脏容积；但令人惊奇地是，在减少症状、死亡率或心源性住院率方面，可改善心功能的SVR+CABG联合治疗并不优于单一手术治疗，而且该联合治疗也不能改善患者的运动耐量。”这表明SVR+CABG联合治疗并无治疗优势可言。
评论者表示强烈质疑，正如Buckberg博士指出，该结论与以下说法相矛盾：“广泛数据表明，SVR可有效治疗前壁心肌梗死后出现局部瘢痕的充血性心力衰竭伴心室扩张患者。” 此外，在《新英格兰医学杂志》上发表的该试验，除了未遵照循证医学标准，还存在令人困惑的地方，且未向心脏病专家说明“减少心脏容积在治疗缺血性充血性心力衰竭患者方面的潜在作用。”
Buckberg博士指出，该试验存在的诸多问题之一是：研究者随后对原始STICH假说2试验方案中确立的2项关键入组标准(左心室收缩末期容积指数必须超过60ml/m2；在进行SVR治疗前，检查提示因坏死所致运动不能的前壁心肌比例超过35%)进行修改，以及将记录到的左心室前壁功能不全作为新的主要目标。 由于做了这些改变，因此“未进行坏死和容积方面的测定；13%的研究人群无心肌梗死。”
换言之，Buckberg博士说道，SVR不仅用于治疗因瘢痕所致室壁运动障碍的患者，也用于治疗因缺血(急性缺血或冬眠)所致无坏死性室壁运动障碍的患者。他表示，“在进行CABG治疗后，无瘢痕缺血心肌的功能可恢复正常，但如果患者的瘢痕心肌比例超过50%，则在进行CABG治疗后，心肌功能不能恢复正常。” “更为重要地是，目前尚无应用SVR治疗无瘢痕心室的报告或治疗建议；SVR手术的潜在应用与(基于SVR手术的)RESTORE患者队列的观察结果也大相径庭。”
另外，Buckberg博士表示，根据原始研究设计，本应在进行SVR前后采用心脏磁共振(CMR)测定所有患者的心室容积，但却采用了被排除的无效方法——超声心动检查进行测定。他还指出，“试验入组标准要求采用CMR测定100%患者的心室容积，但仅对38%患者进行这方面的测定；SVR仅是收缩末期容积指数(ESVI)超过60ml/m2的患者的手术适应证，但是该试验并未报告任何SVR适应证患者或CABG适应证患者的容积测定情况；外科治疗委员会规定，4个月时如CMR检查提示ESVI减少40%，才能够进行SVR手术，但研究中33%患者的ESVI仅减少19%，表明未能充分达到终点。”
Buckberg博士表示，原始试验标准与产生所报告结论的标准不一致，若忽视这点而接受所报告的STICH试验结果的话，可引起一系列严重后果，包括妨碍做出针对心力衰竭伴心脏扩张患者的正确治疗决策；限制SVR的发展；影响内外科医生对科学诚实性的信心；导致心力衰竭治疗相关医疗费用不必要地增加。
Buckberg博士指出，为了使STICH试验结果具有意义，研究者必须重新采纳原始标准，并排除通过超声心动法无效测定容积的患者，以及仅纳入磁共振检查提示运动不能心肌比例超过35%且局部心肌坏死的患者；确定CMR检查提示容积减少超过30%的患者数量；仅报告4个月时经CMR检查提示容积减少在可接受范围内的患者。 “如未采取上述措施，则STICH试验结论只能表明统计人员对数据的缺陷性视而不见。”
Jones博士回应指出，该试验方案的所有修订案均已获得STICH筹划指导委员会的批准。这些修订案发表于2007年12月刊《胸心血管外科杂志》上(J. Thorac. Cardiovasc. Surg. 2007;134:1540-7)。 他表示，做这些改变是为了加快招募工作；他们“并未改变该试验的主要目标。”
STICH试验获美国国立心肺血液研究院的资助。Jones博士披露无相关经济利益冲突。Buckberg博士持有多项心血管疾病治疗专利，包括SVR。
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