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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