Heart Fail Rev DOI 10.1007/s10741-014-9433-z

Surgical ventricular restoration: Where do we go from here? Constantine L. Athanasuleas MD • Gerald Buckberg MD

Ó Springer Science+Business Media New York 2014

Abstract The surgical treatment for ischemic heart failure (STICH) trial concluded that the addition of surgical ventricular restoration (SVR) to coronary bypass grafting did not lead to improved survival in patients with dilated ischemic cardiomyopathy. Observational studies at multiple centers over the last 15 years have shown consistent improvement in global ventricular function and approximately 70 % long-term survival. The causes of this discrepancy are reviewed here and likely relate to how the STICH trial was conducted. Recent subset analyses from the STICH investigators have provided some additional data relating ventricular volumes to outcomes. However, including patients with unsuitable entry criteria and operations confounds the data. We recommend an analysis of the STICH data based on the trial’s initial design in order to determine if there are patients who may benefit by SVR. Keywords Ischemic cardiomyopathy  Post-infarction ventricular dilation  Surgical ventricular restoration  Cardiomyopathy Surgical ventricular restoration (SVR) is an operation applied to patients with congestive heart failure and ventricular dilation following infarction. Ventricular scar tissue replaces normal muscle and the remote muscle remodels becoming more spherical. Myocardial fibers become reoriented in a more horizontal rather than C. L. Athanasuleas MD (&) Department of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL, USA e-mail: [email protected] G. Buckberg MD Department of Cardiothoracic Surgery, UCLA Medical Center, Los Angeles, CA, USA

elliptical formation [1]. Left ventricular (LV) volume can increase substantially from the normal 25 ml/m2. The SVR operation reduces ventricular size by excluding the scarred segment, rebuilds a more normal elliptical architecture and improves LV function [2]. SVR has been done for over 25 years, and thousands of patients have undergone the operation [3–5]. Observational data of SVR from 64 published articles reported operative mortality and summarized 34 series with long-term survival [6]. Operative mortality varied by center from 3 to 15 %, and five-year survival was approximately 70 %, irrespective of when the operations were reported. This has led the European Task Force on Myocardial Revascularization to recommend SVR as a surgical option combined with coronary bypass grafting (CABG) in selected patients with advanced heart failure due to ischemic cardiomyopathy who have documented scar, and a LV end-systolic volume index (LVESVI) C60 ml/m2 if done in centers with a high level of surgical competence [7]. The surgical treatment for ischemic heart failure trial (STICH) is the first and only randomized trial comparing this treatment to CABG alone [8]. The results showed that the addition of SVR did not improve survival when compared to CABG alone. Many experts in the heart failure community accept this conclusion because it is the only randomized trial of this therapy. Clinical guidelines depend on expert opinion derived from randomized trials and observational data. How does the clinician determine good from bad evidence-based medicine? What should we do when observational and registry data differ from randomized trial data? The case of SVR illustrates this dilemma. The purpose of this review was to examine the design and implementation of the STICH trial since this is the framework for subsequent reported analyses. We propose a further simple inquiry that may help clinicians decide if

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there are some patients who may benefit by the addition of SVR to CABG alone. STICH was originally conceived and built on observational studies from multiple centers that defined appropriate candidates for operation and the key components of a successful SVR operation. These inclusion criteria consisted of congestive heart failure following a prior anterior myocardial infarction that causes LV necrosis involving [35 % of the muscle mass, a proven scar by radionuclide (RN) or cardiac magnetic resonance imaging (CMR), LV akinesia or dyskinesia, an ejection fraction \35 %, and LV end-systolic volume index (LVESVI) C60 ml/m2.. CMR and RN were the only methods felt by experts to accurately measure LV volume [9]. In fact, the initially selected 50 centers were chosen because they had these modalities. Equally important was the definition of what constituted an effective SVR procedure, determined in consultation with experts who had extensive prior experience and publications. An effective SVR was defined as a LV reduction of 30 % or more that was measured by CMR 4 months postoperatively. How this was to be achieved surgically was not described because of the variability of techniques; however, centers were to be included if their surgeons could demonstrate low mortality in CABG operations on patients with low ejection fractions and experience with at least five SVR operations where LV volume was reduced by at least 30 %. Here is what actually happened in the STICH trial. The study randomized 1,000 patients to SVR plus CABG or CABG alone [8]. Perhaps due to the challenges of enrollment, the original 50 centers were expanded to include 127 centers in 26 countries. Many centers did very few operations without prior experience. Decision to perform SVR was left to the surgeon’s visual assessment of the ventricular surface at the time of surgery. In many cases, this could have represented hibernating ventricle in the absence of viability data. Exactly what operation was done in such patients? Was it exploratory myotomy and some form of closure or LV volume reduction? Demonstrable scar by viability testing was an essential determinant of eligibility and was violated in the actual trial. As a result, STICH reported no history of infarction in 13 % of patients and only 58 % had akinesia or dyskinesia in the report by Zembala [10]. Volume was measured mostly by echocardiography (ECHO), a method that was rejected in the original study design due to its inaccuracy. LV baseline volume was obtained in 710 patients by ECHO, in 352 patients by CMR, and in 344 patients using RM [11]. Bonow reported RN to detect scar in 50 % of patients in hypothesis I comparing medical treatment against CABG, but his analysis has not yet reported outcomes in patients with documented necrosis in the SVR cohort [12].

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Furthermore, SVR in STICH reduced LV volume only 19 %, significantly lower than what is reported in multiple observational data registries [13]. This inclusion is deliberately different from the original grant submission (LV reduction C30 %). The details of the changes in the STICH protocol are available on the National Institutes of Health website http://clinicaltrials.gov/archive/NCT00023595. Despite these deficiencies, subset analyses have recently been reported by the STICH investigators based on flawed data [14–16]. Michler published a post hoc STICH subset analysis of preoperative LVESVI on outcome from 195 patients with paired CMR studies, 276 with paired ECHO studies, and 84 with paired RN [17]. Among patients with a preoperative baseline LVESVI B60 ml/m2, SVR decreased volume 30 % or more in only 26 % of patients and in 41 % of patients there was no decrease at all! Most likely, a hibernating LV was opened and simply closed. There was a trend toward improved survival in this group with small preoperative volumes (\60 ml/m2) compared with CABG alone, yet this cohort was not considered eligible for the trial in the initial design. Their data suggest a cutoff of preoperative volume where operation may be warranted. Operating on larger ventricles had worse outcomes, but only 36 and 42 % of patients with LVESVI 60–90 and [90 ml/m2 had [30 % volume reduction. This conclusion is in sharp contrast to the vast experience of SVR operations reported in many centers over many years, where more than 1,500 patients had [40 % volume reduction [13]. Moreover, since a small number of patients received a volume reduction in the smaller ventricles in STICH, questions arise regarding what specific operation was done and what this conclusion means. Does it extend the criteria to perform SVR in smaller hearts, as the normal LVESVI is \25 ml/m2? Certainly, the LVESVI \60 ml/m2 would have otherwise been excluded, so that the procedure may be useful in this subset. The same STICH study analyzed outcomes based on postoperative LVESVI and revealed interesting findings. First, a postoperative LVESVI B70 ml/m2 after CABG plus SVR resulted in improved survival compared with CABG alone, and the contrary was true with a postoperative LVESVI C70 ml/m2 compared with CABG alone. Furthermore, among SVR plus CABG patients, a postoperative LVESVI \60 ml/m2 showed significant survival advantage compared with SVR plus CABG patients with LVESVI[60 ml/m2. What about extent of volume reduction? Michler’s analysis showed that survival comparing SVR plus CABG with CABG alone was not influenced by large (C25 ml/m2) or small volume (B25 ml/m2) reductions. This becomes apparent in the larger hearts where LVESVI is [90 ml/m2 (average 153 ml/m2), so that a 25 ml/m2 reduction is a minor one. Among these SVR patients whose LVESVI was reduced

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30 % or more, there was no significant survival advantage over CABG alone. So apparently the finally achieved volume may be very important. This is consistent with findings of Di Donato who observed improved short- and long-term results if postoperative LVESVI is\60 ml/m2 [18]. There is controversy regarding operating on larger ventricles. STICH investigators caution against operating on larger ventricles based on the trial data. However, operation on the very large ventricle has excellent longterm survival as illustrated in an observational study in patients with preoperative LVESVI [80 ml/m2. Skelley reported on SVR where volume reduction of 31 % was achieved as measured by CMR. Three-year survival of 73.4 % was reported in the preoperative LVESVI 80–120 ml/m2 group, and the authors concluded that this may be the group of patients most helped by operation [19]. The RESTORE group reported 70 % five-year survival in patients with SVR among patients with LVESVI 80–120 ml/m2 [5]. Oh and STICH colleagues recently reported that 18.5 % of patients in the trial had ejection fraction[35 %, a cohort that should have clearly been excluded from the SVR [11]. The analysis was aimed at identifying any subgroups that may benefit from SVR based only on preoperative baseline LV function. The authors concluded that patients with smaller ventricles (LVESVI\60 ml/m2) and LVEF C33 % may have benefited by SVR and CABG compared with CABG alone. This is a curious finding, given that these patients were not originally even considered for operation [13]. Oh’s conclusions further depend on how volume was measured in the STICH trial. Baseline core laboratory data were assigned as adequate quality, obtained in 710 patients by ECHO, in 352 patients by CMR, and in 344 patients using RN. Outcomes are based on 13 algorithms using a different hierarchy of imaging modalities and their quality. Depending on which algorithm is chosen, the results differ. One algorithm (preferential hierarchy ECHO, CMR, RN) shows significance (p = .037) favoring CABG over SVR plus CABG for death/hospitalization. However, if a different algorithm was chosen for analysis where the hierarchy of analysis was CMR, ECHO then RN, the findings comparing CABG plus SVR versus CABG only show different results. CABG plus SVR is favored for LVESVI \ 60 ml/m2.; CABG fared better for LVESVI 60–90 ml/m2 and CABG also fared better for LVESVI [90 ml/m2 but not significantly (p = 0.19). However, this analysis does not consider the extent LV volume reduction, an essential factor for long-term survival [18]. Observational studies from registry data may influence our clinical decisions. For example, Di Donato examined residual volume after the SVR operation in a study of 216 patients from an experienced single center that underwent

SVR and grouped them according to postoperative LVESVI at discharge [18]. LVESVI decreased by 41 % in the overall population reflecting a substantial volume reduction compared with the STICH data. Postoperative LVESVI C60 ml/m2 was an independent predictor of mortality at 5 years. Furthermore, a preoperative LVESVI of 94 ml/m2 was the cutoff for an optimal postoperative volume \60 ml/m2. There seems to be an end-stage LV dilation that defines patients who may not benefit from the SVR procedure, but the highest preoperative LVESVI that precludes surgery has yet to be defined. The RESTORE data showed a decreased five-year survival of 64 % in preoperative hearts with LVESVI [120 ml/m2 compared with 80 % when preoperative LVESVI is \80 ml/m2 [5]. The magnitude of LV reduction is emphasized by Isomura [20]. LVESVI was measured by ECHO, LV angiography, and RN. ECHO underestimated LVESVI by approximately 30 %, most likely due to postischemic ventricular asynergy. Long-term (8 years) prognosis depended on the extent of SVR reduction. Survival of [80 % was achieved if there was a [33 % reduction of LVESVI and the residual volume was \90 ml/m2. His finding in large hearts (LVESVI [ 120 ml/m2) implies that [30 % volume reduction is indicated following SVR for very large ventricles. Conversely, inadequate volume reduction of approximately 15 % resulted in 100 % eightyear mortality if the postoperative LVESVI was [90 ml/ m2. Isomura’s further analysis of his data showed the advantage of reconstruction of LV size and shape, as seven-year survival improved from 61 to 72 % when SVR fashioned a more elliptical ventricle. Creating an elliptical ventricle is a variant of the classical SVR operation where the intraventricular patch is oriented obliquely in the ventricle, extending from the non-scarred ventricular outflow tract beneath the aortic valve to the scarred apex. This procedure also results in a greater ventricular volume reduction than that achieved by the standard elliptical apical patch placement. The concept of SVR has evolved from observations about size and shape in diseased ventricle. Douglas reviewed LV shape, afterload and survival in idiopathic dilated cardiomyopathy. Size (LV end-diastolic dimension) and specifically shape (sphericity index) provided the best correlation with survival [21]. Bolognese examined the prognostic impact of LV remodeling after acute myocardial infarction successfully treated by primary percutaneous coronary angioplasty (PTCA). LV dilation ([20 %) occurs in about 15 % and persists at 6 months despite patency of the infarct-related artery. Patients with LV dilation had the worse long term (80 months) [22]. These findings are consistent with the concept of early mitral valve repair in degenerative disease to prevent ventricular dilation. Suri reports that mitral valve repair functional improvement is

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reduced when LVESVI exceeds 36 ml/m2 [23]. Guidelines suggest early surgical correction before the ventricle enlarges. Perhaps in the near future, this concept will be applied in the treatment of postinfarction ventricles before massive dilation occurs. A refinement of operative risk for SVR was reported by Wasaka who elucidated factors of mortality after SVR by creating a risk scoring system. All of their patients had either dyskinesia (31 %) or akinesia (69 %). This differs from the STICH trial where 58 % had these wall motion abnormalities. Four independent predictors of mortality were identified: Interagency Registry for Mechanically Assisted Circulatory Support profile (INTERMACS), LV ejection fraction, severity of mitral regurgitation, and age Three risk scores were developed from high to low, and three-year survivals were significantly different among these groups [24]. In their series, the goal of LVESVI reduction of 30 % with surgery was achieved in only 44, 55, and 69 % of patients with preoperative volumes of \60, 60–90, and [90 ml/m2. The severity of mitral regurgitation was addressed in Isomura’s study that showed that mitral procedures did not affect prognosis in SVR patients if the postoperative LVESVI was \90 ml/m2 [20]. A comparable finding was observed in the RESTORE registry when mitral procedures with SVR were compared with SVR alone [5, 25]. Despite its implementation flaws, the STICH trial has raised some new areas of interest and future research. Specifically, should patients with the non-massively dilated hearts (LVESVI \ 60 ml/m2) undergo SVR? Such volumes have traditionally not been considered for SVR by most surgeons. Dor, however, has always advocated operation in these patients because of the known natural history of postinfarction ventricular dilation treated by CABG alone [3]. What is the greatest ventricular volume beyond which no improvement is expected by SVR? This is a new and inviting question since novel procedures to rebuild shape as well as size have been reported with excellent results even in large ventricles [20]. There will likely be more subset analyses of the STICH data. The original study design was simple and was intended to address significant issues that were based on extensive observational data. So where do we go from here? We urge the STICH investigators to analyze a subset of patients in whom accurate and complete data were recovered. STICH data should be probed to include a comparison of treatments based on the following original inclusions: (1) advanced congestive heart failure (NYHA class III and IV) after documented myocardial infarction, EF \35 %, a [35 % LV necrosis with a regional anterior akinetic or dyskinetic scarred segment (2) LVESVI measured preoperatively and postoperatively by CMR, and (3) postoperative LVESVI volume reduction by SVR [30 %.

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Such a breakdown would be provide clinicians valuable guidance in their management of a difficult group of patients. This analysis would also alleviate concerns and misgivings about the STICH trial that is perceived by many to have deviated significantly from its original design. Conflict of interest

None.

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Heart Fail Rev 15. Conte J (2010) An indictment of the STICH trial: ‘‘True, true, and unrelated’’. J Heart Lung Transplant 29:491–496 16. Balsam LB, Grossi EA (2013) Surgical ventricular reconstruction has a role in surgical remodeling in patients with LV systolic dysfunction even post-STICH? Prog Cardiovasc Dis 55:481–486 17. Michler RE, Rouleau JL, Al-Khalidi HR, Bonow RO, Pellikka PA, Pohost GM, et al. (2012) Insights from the STICH trial: change in left ventricular size after coronary artery bypass grafting with and without surgical ventricular reconstruction. J Thorac Cardiovasc Surg 146:1139–1145 18. Di Donato M, Castelvecchio S, Menicanti L (2010) End-systolic volume following surgical ventricular reconstruction impacts survival in patients with ischaemic dilated cardiomyopathy. Eur J Heart Fail 12:375–381 19. Skelley NW, Allen JG, Arnaoutakis GJ, Weiss ES, Patel ND, Conte JV (2011). The impact of volume reduction on early and long-term outcomes in surgical ventricular restoration for severe heart failure. Ann Thorac Surg 91:104–11; discussion 11–2 20. Isomura T, Hoshino J, Fukada Y, Kitamura A, Katahira S, Kondo T et al (2011) Volume reduction rate by surgical ventricular restoration determines late outcome in ischaemic cardiomyopathy. Eur J Heart Fail 13:423–431

21. Douglas PS, Morrow R, Ioli A, Reichek N (1989) Left ventricular shape, afterload and survival in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 13:311–315 22. Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM et al (2002) Left Ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 106:2351– 2357 23. Suri RM, Schaff HV, Dearani JA, Sundt TM, Daly RC, Mullany CJ et al (2009) Recovery of left ventricular function after surgical correction of mitral regurgitation caused by leaflet prolapse. J Thorac Cardiovasc Surg 137:1071–1076 24. Wakasa S, Matsui Y, Isomura T, Takanashi S, Yamaguchi A, Komiya T et al (2013) Impact of left ventricular remodelling on outcomes after left ventriculoplasty for ischaemic cardiomyopathy: Japanese surgical ventricular reconstruction group experience. Interact CardioVasc Thorac Surg 16:785–791 25. Buckberg GD (2006) Form versus disease: optimizing geometry during ventricular restoration. Eur J Cardiothorac Surg 29 Suppl 1:S238-44

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Surgical ventricular restoration: where do we go from here?

The surgical treatment for ischemic heart failure (STICH) trial concluded that the addition of surgical ventricular restoration (SVR) to coronary bypa...
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