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An indictment of the STICH trial: “True, true, and unrelated”
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PERSPECTIVE
An indictment of the STICH trial: “True, true, and unrelated” The Surgical Treatment for Ischemic Heart Failure (STICH) trial was a National Institutes of Health (NIH)-sponsored trial investigating the relative efficacy of medical vs surgical therapy for patients with ischemic cardiomyopathy. The trial consisted of one medical and two surgical arms. The two surgical therapy arms consisted of a time-tested, wellstudied and generally recognized procedure, coronary artery bypass grafting (CABG), and CABG plus surgical ventricular restoration (SVR), a time-tested but less well-studied and generally not well-recognized procedure. The STICH trial was designed, in part, to contribute a prospective, randomized trial to a body of literature composed largely of retrospective analyses. Hypothesis II studied the efficacy of the two surgical therapies and was reported in The New England Journal of Medicine.1 Surgical trials are difficult to conduct and the outcomes are sometimes hard to interpret because of difficulties assessing the appropriateness of patient selection and the quality of surgery performed at the different sites. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) was a multi-institutional trial comparing medical vs surgical therapy for the treatment of symptomatic carotid stenosis. This trial is looked upon as one of the more successful surgical trials ever conducted and, as a result, the treatment paradigm for obstructive carotid artery disease was forever changed.2 There were strict criteria established for becoming a recognized site for inclusion in NASCET. Investigators were required to demonstrate a multidisciplinary team with successful outcomes in 50 patients. There were rigid study-patient criteria, which included mandatory pre-operative testing reviewed by a core lab to ensure appropriate patient selection. The exact surgical technique was not proscribed, but the definition of a successful operation was agreed upon. Mandatory postoperative testing to assess the adequacy of the surgery was performed and the outcomes for each surgeon were monitored by the lead investigator. Surgeons whose results were sub-standard and the patients whose operations did not meet the defined post-operative criteria were eligible for censure Reprint requests: John Conte, MD, Division of Cardiac Surgery, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 212874618. Telephone: 410-955-1753. Fax: 410-955-3809. E-mail address: [email protected]
and exclusion. The investigators recognized that in order to adequately assess the effectiveness of any surgical procedure it was important to make sure that the procedure was done properly in the correct patients. A comparison of the NASCET and STICH studies sheds light on why the latter is not as highly regarded and can explain why knowledgeable individuals believe that the published results were “true, true, and unrelated” to how experts currently continue to use SVR to treat patients with ischemic cardiomyopathy. To understand this, some background information is necessary. Surgical Ventricular Restoration After myocardial infarction, the ventricle undergoes a process of pathologic and physiologic adaptation that has come to be known as ventricular remodeling. If unchecked, the process can result in a ventricle that is enlarged and spherical, and may exhibit diminished ventricular function in the area of the infarction as well as in viable areas remote from the infarct. As the ventricle enlarges it often develops varying degrees of mitral regurgitation due to leaflet restriction.3,4 Electrical and mechanical dyssynchrony often develops after infarction due to ventricular remodeling and further impacts the post-infarction ventricular dysfunction.5 Electrical dyssynchrony is the result of post-infarction abnormalities in the conduction system, resulting in differential timing of left and right ventricular contraction. This dyssynchronous contraction diminishes overall ventricular function. Mechanical dyssynchrony is a phenomenon of impaired left ventricular function caused by nonuniform contraction, relaxation, and filling of the left ventricle due to the juxtaposition of areas of akinesis, dyskinesis and hypokinesis alongside normal areas.6 The ultimate clinical impact of post-infarction remodeling is heart failure (HF) and death. Ischemic cardiomyopathy is the leading cause of heart failure in the USA and in the Western world.7 Mortality in congestive heart failure (CHF) patients has long ago been shown to be related to ventricular size and residual left ventricular function.3,8 –10 Survival in patients with HF due to ischemic cardiomopathy is, in addition, impacted by revascularization of viable, even if non-functional, myocardium,11 and preservation of left ventricular geometry.12 Revascularization alone, however, has not been as effective in the face of extensive left ventricular (LV) remodeling and it may be a case of “too little too late.”13
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Table 1
Indications for Surgical Ventricular Restoration
● ● ● ●
Anteroseptal myocardial infarction Congestive heart failure Depressed ejection fraction (%) Large area of akinesis/dyskinesis Asynergy of ⬎30% of LV surface ● Enlarged ventricle End-diastolic volume index ⬎120 cm/m2 End-systolic volume index ⬎60 cm/m2 ● Retained basilar heart function ● Candidate for revascularization ● Candidate for valve repair/replacement ● Good right ventricular function Relative contraindications ● Multiple areas of infarction ● Loss of basilar myocardial function ● Pulmonary hypertension and right ventricular dysfunction ● Unreconstructable coronary artery disease Absolute contraindications ● Viable myocardium anterior wall ● Active ischemia with unreconstructable coronary artery disease
What Hypothesis II of STICH was supposed to help us understand is the role of SVR in addition to CABG alone to treat appropriate patients with ischemic cardiomyopathy. Surgical ventricular restoration is a term that has come to be applied to a group of surgical procedures designed to counteract the effects of post-infarction ventricular remodeling. SVR as a surgical procedure arose out of surgical techniques to repair ventricular aneurysms.14 –16 It is also referred to as surgical ventricular remodeling or reconstruction, SAVER (surgical anterior ventricular endocardial reconstruction), and the Dor procedure, after the individual credited with developing this field of study, Dr Vincent Dor. The technique, as described by Dor and colleagues, was introduced to improve geometric reconstruction as compared with standard linear repair in LV aneurysm surgery.17 Subsequently, Dor and colleagues began to use the technique, which he called endoventricular circular patch plasty, to treat large akinetic ventricles in CHF patients in addition to patients with classic aneurysms.
Figure 1
Although there are several accepted surgical techniques for performing SVR that have evolved since the Dor et al study, the goals of each technique are the same.17–21 Specifically, SVR is intended to reduce the size and sphericity of the left ventricle by excluding akinetic and dyskinetic areas, in conjunction with complete revascularization and repair of any valvular defects. The goal is to revascularize ischemic myocardium; reduce end-diastolic pressure; reduce ventricular dyssynchrony; improve ventricular function, including that of viable but poorly functioning remote areas; and have a positive impact on measurable parameters of HF and survival. Most commonly, patients are considered candidates for SVR if they have had a remote anterior or anteroseptal myocardial infarction, significant ventricular enlargement with a large area of akinesis or dyskinesis of non-viable myocardium, and a clinical picture consistent with HF. They should have retained function of the basilar and lateral portions of the heart, and have good right ventricular function. They should also be candidates for revascularization and valve repair if indicated. The indications and contraindications to SVR that I consider are shown in Table 1. The only truly absolute contraindications to SVR are a viable anterior wall and documented ischemia due to coronary artery disease not amenable to revascularization. It is therefore imperative to document the infarction, ventricular enlargement and, most importantly, non-viability of the anterior wall. I do so most commonly with magnetic resonance imaging (MRI) using gadolinium enhancement. Figure 1 is an image from a patient with the appropriate anatomy for SVR, as demonstrated by gadolinium enhancement. Although we do use MRI in many patients with defibrillators and biventricular pacers, we have also used positron emission tomography (PET) and nuclear scanning to document non-viability of the anterior wall.22 Results with SVR have been reported in several large retrospective series. Dr Dor’s personal experiences, as well as those of Dr Lorenzo Menicanti of Milan, Italy, and a large multicenter database of 1,200 patients, known as the RESTORE group, represent over 3,000 patients alone.23–25 The consistent findings in all of the major retrospective studies include an improvement in ejection fraction (EF) of
MRI with gadolinium enhancement demonstrating post-infarction thinning and scar formation of the left ventricle.
Conte Table 2 ● ● ● ● ● ● ● ●
True, True, and Unrelated Post-SVR Improvements22,23
Reduced ventricular size Improved ventricular function Neurohormone normalization Reduced mechanical dyssynchrony Reduced ventricular arrhythmias Improved ventricular efficiency and energetics Improved NYHA functional class Improved heart failure scores Functional and psychologic
about 10% to 20%; a reduction of end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) of 40%; and better clinical outcomes, such as improved New York Heart Association (NYHA) functional class, freedom from CHF rehospitalization, and survival rates superior to those of medically treated patients.23–25 Many smaller series have looked at different measurable morphologic, physiologic and clinical outcomes after SVR. In these studies, morphologic improvements and increases in EF have consistently been reported as they have in the larger series. In addition, there have been reported real-time improvements in LV energetics with the use of high-fidelity conductance catheters, normalization of heart failure neurohormone levels, reductions in electrical and mechanical dyssynchrony, improvements in physiologic parameters such as 6-minute walk tests, improvements in HF questionnaire scores, equivalent outcomes to transplantation up to 5 years, as well as survival outcomes of up to 20 years (Table 2).23–34 Despite these findings, and many other supporting studies, many investigators believed that revascularization alone was sufficient.35 The stage was set for a prospective, multicenter trial to study the impact of revascularization vs revascularization plus SVR. The STICH trial randomized 490 patients to CABG vs CABG plus SVR. It was concluded that “adding SVR to CABG was not associated with a greater improvement in symptoms, exercise tolerance or reduced immediate mortality.”1 This was a shock and an eyeopener to the many who believed the worldwide published data
493 on ⬎5,000 patients. It was particularly surprising to those who witnessed stunning clinical successes in patients who underwent SVR without revascularization but did remarkably well after SVR alone (Figure 2). Was SVR another Batista operation or is there something wrong with the study? Close scrutiny of the published work proves quite revealing. The Patients The STICH trial was supposed to have rigid entry criteria, but in fact did not, and many patients did not even meet the entry criteria that were set for the trial. The original grant funded by NIH required that “all patients be evaluated for appropriateness of surgical ventricular reconstruction indicated by evidence of absent viability in the anterior ventricle by nuclear scan determination, an end systolic volume index of ⬎60 ml/m2 and akinesis of ⬎30% of the anterior LV wall.”36 The demonstration of non-viability is what was recommended by the surgical therapy committee (STC). This is what surgeons with expertise in performing SVR for heart failure do routinely. A demonstration of non-viability is part of the standard work-up. The published paper does not make any mention of viability testing. Table 1 tells us that 50% of the anterior wall demonstrates akinesis or dyskinesis, but we are not told about the viability. This means that 50% of the anterior wall is viable and the other 50% we don’t know about because viable myocardium can demonstrate wall motion abnormalities. Another 13% were reported to have not experienced a myocardial infarction. An operation designed to treat non viable scar following myocardial infarction may have been done in patients with viable myocardiu. STICH investigators themselves acknowledged the importance of establishing non-viability before proceeding with SVR. In an article published in The Journal of Thoracic and Cardiovascular Surgery, the STICH investigators provided an example of a patient who was considered a candidate for SVR. That patient had a PET scan demonstrating non-viability.37 Why was that standard not maintained throughout the study? More importantly, in the funded grant itself, Section 4.8.8 states unequivocally, “A
Figure 2 MRI of LV before and after the SVR procedure and mitral valve annuloplasty demonstrating a reduction of LV volume and restoration of a more elliptical LV shape.
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measure of myocardial viability must be obtained.”36 If it was, why was this important information not reported? This operation was intended for the scarred, thinned-out fibrotic walls of enlarged post-infarction ventricles, even those that may have had a thin rim of viable cells after reperfusion. This is not the population presented in the published trial. In my personal series of SVR patients, for every 3 patients I evaluate, I exclude 1 because they do not meet this simple criterion. Viability was supposed to be assessed in a standard fashion, and it was not. Why? The Operation To participate in the STICH trial, there was no specific requirement that centers demonstrate a multidisciplinary CHF team or have any expertise in heart failure surgery. It was simply required that each surgeon have an operative mortality of ⱕ5% in 25 patients who have undergone CABG in patients with an EF ⬍40%. They also had to report an operative mortality of ⬍10% and an average ESVI decrease of 30% in 5 SVR cases.36 Certainly, this represents a lower bar than for the NASCET investigation, which scrutinized the program and the surgeons’ results to a far greater degree before accepting them into the trial and, importantly, scrutinized their surgical results during the trial to determine if the operation was performed successfully. Assuring that a technically successful SVR procedure was performed was of great concern to the STC of the STICH trial. Because there are several methods to achieve the same morphologic results with the SVR procedure the STC did not want to mandate a specific surgical technique, but rather they defined an “acceptable STICH procedure.” It was further stated that, “The two criteria used by the Surgical Therapy Committee to define the acceptable range of specific operative maneuvers essential to be considered an acceptable technical SVR operation for the STICH trial will be any ventricular reconstruction method
Table 3
that consistently results in (1) a low operative mortality and (2) an average EF increase of 10% and average LVESVI decrease of 30% as assessed on the 4-month post-operative CMR measurement.”36 What was reported in the original article is an average ESVI reduction of 19% and an ESVI of 67 ml/m2. This is far below what the SCT deemed an acceptable SVR procedure. Why were these inferior surgical results accepted when they did not even meet their own definition of a successful operation? Furthermore, they are far below the standard in the published literature. Table 3 demonstrates the average volume reduction after SVR according to published studies from a variety of centers with experience in performing SVR. These findings were compiled by Dr Hisayoshi Suma from Tokyo. The data demonstrate an average ESVI reduction of 40%, with a range of 30% to 58%. Why is this important? It is important because it is clear that a large percentage of the patients did not have an adequate “STICH” procedure. It is also important because a LVESVI of 67ml/kg is larger than the volumes reported to represent an optimal volume index post SVR and the patients still have an ESVI large enough to qualify for the trial!38 Yet these patients were still used to assess the outcome of the operation. Would a patient whose biventricular pacer was unable to pace both ventricles be included in a study assessing the efficacy of biventricular pacing? How can any one rationalize using these patients to assess SVR? Furthermore, presumably to overcome poor enrollment, STICH expanded to 127 sites from the intended 50 sites, assessing 10 cases per site.36 Based on 490 patients this means there was an average of only 4 procedures done per site.1 How can the outcome of a technically challenging surgical procedure be evaluated if the procedure is not done properly by surgeons whose experience is limited. Even more amazing is that no one seemed to question this. Why? Because SVR is performed relatively infrequently, many
LV Volume Change After SVR ESVI (ml/m2)
Investigators (year) 42
Data from Di Donato et al
Data Data Data Data Data Data Data Data Data Data Data
from from from from from from from from from from from
(2009)
Suma et al43 (2009) Dor et al44 (2008) Menicanti et al24 (2007) O’Neil et al45 (2006) Adams et al46 (2006) Schreuder et al47 (2005) Tulner et al48 (2006) Yamaguchi et al49 (2005) Mickleborough et al50 (2004) RESTORE trial25 (2004) STICH trial1 (2009)
Data compiled by Dr Hisayoshi Suma, Tokyo, Japan. a ESV (in milliliters), not indexed.
No. of patients
Pre-op
Post-op
Reduction (%)
56 (Type 1) 55 (Type 2) 67 (Type 3) 76 104 301 135 8 9 21 20 41 671 161
83 87 96 123 93 173a 120 92 92 186a 137 97 80.4 83
35 39 57 74 51 100a 77 59 45 101a 65 65 56.6 67
48 48 39 49 42 73a 43 33 47 85a 72 32 24 16
(58) (55) (41) (40) (45) (42) (36) (36) (51) (46) (53) (33) (30) (19)
Conte
True, True, and Unrelated
surgeons and cardiologists have little insight into what it is, how it is performed, or even what constitutes an acceptable outcome. Most physicians know that a patient can survive a mitral valve repair but still have a poor outcome because of the degree of mitral regurgitation remaining when there is a technically sub-standard procedure. However, many competent surgeons and cardiologists do not realize that one can have a “bad SVR” due to a technically inferior operation (i.e., inadequate volume reduction) without obvious morbidity or mortality. Many believe that if the patient does not die outright, then the operation was done correctly. Unfortunately, this appears to be true of many of the investigators in the STICH study, who should have known better, as well as many who chose to comment and write about the outcomes of this trial. This lack of insight was clearly demonstrated by the many pundits who analyzed the results and in the editorial that accompanied the publication of the study.38 – 41 No one demonstrated insight in knowing whether the operation was done properly on the correct group of patients or to even ask the question. It appears that man y of the operations were not done properly or, at the very minimum, did not meet the standards set forth by the STICH investigators themselves or in the published literature. How then can we accept the results of any technical procedure when they do not meet the standards established by the trial? Although all investigators share culpability in this area, where were the surgical investigators? They hold even greater responsibility for the lack of oversight on the surgical outcomes. Why was there no concurrent assessment of the outcomes as there was in the NASCET study to ensure that the operations were being done correctly? How could they not identify these obvious oversights and address them before publication of such clearly flawed data?
495 of non-viability, no impartial observer can look at this study and say that the patients represent the same group of patients that SVR experts and the STC of the STICH would recommend for SVR surgery. Second, no impartial observer can look at this study and say there are not very significant reservations about the quality of the SVR procedures performed based on the numbers performed per center and the volume reduction achieved as compared with the published literature and the STICH STC recommendation. What we can say is that patients with potentially viable anterior walls and inadequate volume reductions do no better than patients receiving CABG alone. This is not a surprise. The only way that the data from the cohort of Hypothesis II patients can have any significant meaning would be to exclude all patients without documentation of non-viable anterior walls, those who do not have adequate volume reductions as defined by the STC, and those who do not have the appropriate follow-up with complete data sets including MRI analysis as the funded grant set forth. Until this reassessment is made, the results of Hypothesis II of the STICH trial will remain “true, true, and unrelated” to the state of the art in SVR and will go down as an expensive but clinically meaningless exercise in surgical research.
Disclosure statement The author has no conflicts of interest to disclose. The views expressed those of the author and not those of the Journal, its Editors or the ISHLT. John Conte, MD From the Division of Cardiac Surgery, The Johns Hopkins Hospital, Baltimore, Maryland
Other Issues There were several other issues with this study. The trial had a relatively healthy group of patients for an SVR investigation. Fewer than 50% of the STICH patients were NYHA Class 3 and 4 compared with 67% in the RESTORE group and ⬎90% in my own series of patients. Several changes were made in the protocol during the study. Why was that done? Why was the study expanded to over twice as many centers as originally planned and why were there so many in Eastern Europe with dramatically different health-care systems? The site expansion dramatically reduced the number of patients per center and significantly calls into question the level of experience of the surgical investigators. What about the incomplete data, particularly the volume measurements? How is it that volume measurements were obtained for only 212 of the 490 CABG patients and 161 of the 490 patients in the SVR group when this was such an important outcome measure and a determinant of a successful operation? Furthermore, many measurements were not obtained by nuclear or MRI scans as originally planned by the STC to define a successful operation. Why? The conclusions that can be made from the published cohort of patients are limited. First, without documentation
References 1. Jones RH, Velazquez EJ, Michler RE, et al. Coronary bypass surgery with or without surgical ventricular reconstruction. N Engl J Med 2009;360:1705-17. 2. The North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-53. 3. Gaudron P, Eilles C, Kugler I, et al. Progressive left ventricular dysfunction and remodeling after myocardial infarction: potential mechanisms and early predictors Circulation 1993;87:755-63. 4. Di Donato M, Sabatier M, Toso A, et al. Regional myocardial performance of non-ischemic zones remote from anterior wall left ventricular aneurysm. Eur Heart J 1995;16:1285-92. 5. Fauchier L, Marie O, Cassett D, et al. Intraventriacular and interventriculaar dyssynchrony in idiopathic dilated cardiomyopathy: a prognostic study with Fournier phase analysis of radionucleotide angioscintigraphy. Am Coll Cardiol 2002;40:2022-30. 6. Di Donato M, Toso A, Dor V, et al. Surgical ventricular restoration improves mechanical intraventricular dyssynchrony in ischemic cardiomyopathy. Circulation 2004;109:2536-43. 7. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease Circulation 1998;97:282-9. 8. White HD, Norris RM, Brown PW, et al. Left ventricular end systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44-51.
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9. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347: 1397-402. 10. Migrin RQ, Young, JB, Ellis SG, et al. End-systolic volume index at 90 to 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality: the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I Angiographic Investigators. Circulation 1997;96:116-21. 11. Allman KC, Shaw LJ, Hachamovitch R, et al. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39:1151-8. 12. Senior R, Lahiri A, Kaul S. Effect of revascularization on left ventricular remodeling in patients with heart failure from severe chronic ischemic left ventricular dysfunction. Am J Cardiol 2001;88:624-9. 13. Bax JJ, Schinkel AF, Boersma E, et al. Extensive left ventricular remodeling does not allow viable myocardium to improve in left ventricular ejection fraction after revascularization and is associated with worse long term prognosis. Circulation 2004;110:II-18-22. 14. Cooley DA, Collins HA, Hall GA, et al. Ventricular aneurysm after myocardial infarction: surgical excision with use of temporary cardiopulmonary bypass. JAMA 1958;167:557. 15. Jatene AD. Left ventricular aneurysmectomy: resection or reconstruction? J Thorac Cardiovasc Surg 1985;89:321-31. 16. Fontan F. Transplantation of knowledge. J Thorac Cardiovasc Surg 1990;99:387-95. 17. Dor V, Kreitmann P, Jourdan J. Interest of “physiological” closure of left ventricle after resection and endocardiectomy for aneurysm or akinetic zone comparison with classical technique about a series of 209 left ventricular resections [abstract]. J Cardiovascular Surg 1985;26:73. 18. Cox JL. Surgical management of left ventricular aneurysms: a clarification of the similarities and differences between the Jatene and Dor techniques. Semin Thorac Cardiovasc Surg 1997;9:131-8. 19. Caldiera C, McCarthy PM. A simple method of left ventricular reconstruction without patch for ischemic cardiomyopathy. Ann Thorac Surg 2001;72:2148-9. 20. Mickleborough LL. Tech Card Thorac Surg 1997;2:118-131. 21. Conte JV. Surgical ventricular restoration: technique and outcomes. Congest Heart Fail 2004;10:248-51. 22. Natori S, Conte JV, Lima JAC, et al. Magnetic resonance imaging evaluation of surgical ventricular restoration. Ann Thorac Surg 2005;80:743. 23. Dor V. Left ventricular reconstruction: the aim and the reality after twenty years. J Thorac Cardiovasc Surg 2004;128:17-20. 24. Menicanti L, Castelvecchio S, Ranucci M, et al. Surgical therapy for ischemic heart failure: single center experience with surgical anterior ventricular restoration. J Thorac Cardiovasc Surg 2007;134:433-41. 25. Athanasuleas CL, Buckberg GD, Stanley AH, et al. RESTORE group surgical ventricular restoration in the treatment of congestive heart failure due to post-infarction ventricular dilation. J Am Coll Cardiol 2004;44:1439-42. 26. Schreuder JJ, Castiglioni A, Maisano F, et al. Acute decrease of left ventricular mechanical dyssynchrony and improvement of contractile state and energy efficiency after left ventricular restoration. J Thorac Cardiovasc Surg 2005;129:138-45. 27. Castelvecchio S, Menicanti L, Ranucci M, et al. Impact of surgical ventricular restoration on diastolic function: implications of shape and residual ventricular size. Ann Thorac Surg 2008;86:1849-54. 28. Di Donato M, Toso A, Dor V, et al. Surgical ventricular restoration improves mechanical ventricular dyssynchrony in ischemic cardiomyopathy. Circulation 2004;109:2536-43. 29. Setser RM, Smedira NG, Lieber ML, et al. Left ventricular torsional mechanics after left ventricular reconstruction surgery for ischemic cardiomyopathy. J Thorac Cardiovasc Surg 2007;134:888-96.
30. Schenk S, McCarthy PM, Starling RC, et al. Neurohormonal response to left ventricular reduction surgery in ischemic cardiomyopathy. J Thorac Cardiovasc Surg 2003;128:38-43. 31. Tulner SA, Steendijk P, Klautz RJ, et al. Clinical efficacy of surgical heart failure therapy by ventricular restoration and restrictive mitral annuloplasty. J Card Fail 2007;13:178-83. 32. Di Donato M, Sabatier M, Dor V, et al. Surgical ventricular restoration in patients with post-infarction coronary artery disease: effectiveness on spontaneous and inducible ventricular tachycardia. Semin Thorac Cardiovasc Surg 2001;13:480-5. 33. Di Donato M, Sabatier V, Dor G, et al. Ventricular arrhythmias after LV remodelling: surgical ventricular restoration or ICD? Heart Fail Rev 2004;9:299-306. 34. William JA, Weiss ES, Patel ND, et al. Surgical ventricular restoration versus cardiac transplantation: a comparison of cost, outcomes and survival. J Card Fail 2008;7:547-54. 35. Elefteriades JA, Edwards R. Coronary bypass in left heart failure. Semin Thorac Cardiovasc Surg 2002;14:125-32. 36. STICH trial protocol: http://clinicaltrials.gov/archive/NCT00023595/ 2005_06_23 37. Doenst T, Velazquez EJ, Beyersdorf F, et al. To STICH or not to STICH: we know the answer, but do we understand the question? J Thorac Cardiovasc Surg 2005;129:246-9 (see also http://clinicaltrials. gov/show/NCT00023595). 38. Menicanti L, Di Donato M. Surgical ventricular reconstruction and mitral regurgitation: what have we learned from 10 years of experience? Semin Thorac Cardiovasc Surg 2001;13:496-503. 39. theheart.org http://www.theheart.org/editorial-program/956041.do (accessed May 12, 2009). 40. American College of Cardiology. http://www.acc.org/media/acc_scientific_ session_09/press/sunday/ACC09Mark_930.pdf (accessed March 29, 2009). 41. Eisen HJ. Surgical ventricular reconstruction for heart failure. N Engl J Med 2009;360:1781-4. 42. Di Donato M, Castelvecchio S, Kukulski T, et al. Surgical ventricular restoration: left ventricular shape influence on cardiac function, clinical status, and survival. Ann Thorac Surg 2009;87:455-61. 43. Suma H, Tanabe H, Uejima T, et al. Surgical ventricular restoration combined with mitral valve procedure for endstage ischemic cardiomyopathy. Eur J Cardiothorac Surg 2009;36:280-4. 44. Dor V, Civaia F, Alexandrescu C, et al. The post-myocardial infarction scarred ventricle and congestive heart failure: the preeminence of magnetic resonance imaging for preoperative, intraoperative, and postoperative assessment. J Thorac Cardiovasc Surg 2008;136:1405-12. 45. O’Neill JO, Starling RC, McCarthy PM, et al. The impact of left ventricular reconstruction on survival in patients with ischemic cardiomyopathy. Eur J Cardiothorac Surg 2006;30:753-9. 46. Adams JD, Fedoruk LM, Tache-Leon CA, et al. Does preoperative ejection fraction predict operative mortality with left ventricular restoration? Ann Thorac Surg 2006;82:1715-9. 47. Schreuder JJ, Castiglioni A, Maisano F, et al. Acute decrease of left ventricular mechanical dyssynchrony and improvement of contractile state and energy efficiency after left ventricular restoration. J Thorac Cardiovasc Surg 2005;129:138-45. 48. Tulner SA, Steendijk P, Klautz RJ, et al. Surgical ventricular restoration in patients with ischemic dilated cardiomyopathy: evaluation of systolic and diastolic ventricular function, wall stress, dyssynchrony, and mechanical efficiency by pressure–volume loops. J Thorac Cardiovasc Surg 2006;132:610-20. 49. Yamaguchi A, Adachi H, Kawahito K, et al. Left ventricular reconstruction benefits patients with dilated ischemic cardiomyopathy. Ann Thorac Surg 2005;79:456-61. 50. Mickleborough LL, Merchant N, Ivanov J, et al. Left ventricular reconstruction: early and late results. J Thorac Cardiovasc Surg 2004;128:27-37.
PERSPECTIVE
An indictment of the STICH trial: “True, true, and unrelated” The Surgical Treatment for Ischemic Heart Failure (STICH) trial was a National Institutes of Health (NIH)-sponsored trial investigating the relative efficacy of medical vs surgical therapy for patients with ischemic cardiomyopathy. The trial consisted of one medical and two surgical arms. The two surgical therapy arms consisted of a time-tested, wellstudied and generally recognized procedure, coronary artery bypass grafting (CABG), and CABG plus surgical ventricular restoration (SVR), a time-tested but less well-studied and generally not well-recognized procedure. The STICH trial was designed, in part, to contribute a prospective, randomized trial to a body of literature composed largely of retrospective analyses. Hypothesis II studied the efficacy of the two surgical therapies and was reported in The New England Journal of Medicine.1 Surgical trials are difficult to conduct and the outcomes are sometimes hard to interpret because of difficulties assessing the appropriateness of patient selection and the quality of surgery performed at the different sites. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) was a multi-institutional trial comparing medical vs surgical therapy for the treatment of symptomatic carotid stenosis. This trial is looked upon as one of the more successful surgical trials ever conducted and, as a result, the treatment paradigm for obstructive carotid artery disease was forever changed.2 There were strict criteria established for becoming a recognized site for inclusion in NASCET. Investigators were required to demonstrate a multidisciplinary team with successful outcomes in 50 patients. There were rigid study-patient criteria, which included mandatory pre-operative testing reviewed by a core lab to ensure appropriate patient selection. The exact surgical technique was not proscribed, but the definition of a successful operation was agreed upon. Mandatory postoperative testing to assess the adequacy of the surgery was performed and the outcomes for each surgeon were monitored by the lead investigator. Surgeons whose results were sub-standard and the patients whose operations did not meet the defined post-operative criteria were eligible for censure Reprint requests: John Conte, MD, Division of Cardiac Surgery, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 212874618. Telephone: 410-955-1753. Fax: 410-955-3809. E-mail address: [email protected]
and exclusion. The investigators recognized that in order to adequately assess the effectiveness of any surgical procedure it was important to make sure that the procedure was done properly in the correct patients. A comparison of the NASCET and STICH studies sheds light on why the latter is not as highly regarded and can explain why knowledgeable individuals believe that the published results were “true, true, and unrelated” to how experts currently continue to use SVR to treat patients with ischemic cardiomyopathy. To understand this, some background information is necessary. Surgical Ventricular Restoration After myocardial infarction, the ventricle undergoes a process of pathologic and physiologic adaptation that has come to be known as ventricular remodeling. If unchecked, the process can result in a ventricle that is enlarged and spherical, and may exhibit diminished ventricular function in the area of the infarction as well as in viable areas remote from the infarct. As the ventricle enlarges it often develops varying degrees of mitral regurgitation due to leaflet restriction.3,4 Electrical and mechanical dyssynchrony often develops after infarction due to ventricular remodeling and further impacts the post-infarction ventricular dysfunction.5 Electrical dyssynchrony is the result of post-infarction abnormalities in the conduction system, resulting in differential timing of left and right ventricular contraction. This dyssynchronous contraction diminishes overall ventricular function. Mechanical dyssynchrony is a phenomenon of impaired left ventricular function caused by nonuniform contraction, relaxation, and filling of the left ventricle due to the juxtaposition of areas of akinesis, dyskinesis and hypokinesis alongside normal areas.6 The ultimate clinical impact of post-infarction remodeling is heart failure (HF) and death. Ischemic cardiomyopathy is the leading cause of heart failure in the USA and in the Western world.7 Mortality in congestive heart failure (CHF) patients has long ago been shown to be related to ventricular size and residual left ventricular function.3,8 –10 Survival in patients with HF due to ischemic cardiomopathy is, in addition, impacted by revascularization of viable, even if non-functional, myocardium,11 and preservation of left ventricular geometry.12 Revascularization alone, however, has not been as effective in the face of extensive left ventricular (LV) remodeling and it may be a case of “too little too late.”13
1053-2498/10/$ -see front matter © 2010 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2009.12.010
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Table 1
Indications for Surgical Ventricular Restoration
● ● ● ●
Anteroseptal myocardial infarction Congestive heart failure Depressed ejection fraction (%) Large area of akinesis/dyskinesis Asynergy of ⬎30% of LV surface ● Enlarged ventricle End-diastolic volume index ⬎120 cm/m2 End-systolic volume index ⬎60 cm/m2 ● Retained basilar heart function ● Candidate for revascularization ● Candidate for valve repair/replacement ● Good right ventricular function Relative contraindications ● Multiple areas of infarction ● Loss of basilar myocardial function ● Pulmonary hypertension and right ventricular dysfunction ● Unreconstructable coronary artery disease Absolute contraindications ● Viable myocardium anterior wall ● Active ischemia with unreconstructable coronary artery disease
What Hypothesis II of STICH was supposed to help us understand is the role of SVR in addition to CABG alone to treat appropriate patients with ischemic cardiomyopathy. Surgical ventricular restoration is a term that has come to be applied to a group of surgical procedures designed to counteract the effects of post-infarction ventricular remodeling. SVR as a surgical procedure arose out of surgical techniques to repair ventricular aneurysms.14 –16 It is also referred to as surgical ventricular remodeling or reconstruction, SAVER (surgical anterior ventricular endocardial reconstruction), and the Dor procedure, after the individual credited with developing this field of study, Dr Vincent Dor. The technique, as described by Dor and colleagues, was introduced to improve geometric reconstruction as compared with standard linear repair in LV aneurysm surgery.17 Subsequently, Dor and colleagues began to use the technique, which he called endoventricular circular patch plasty, to treat large akinetic ventricles in CHF patients in addition to patients with classic aneurysms.
Figure 1
Although there are several accepted surgical techniques for performing SVR that have evolved since the Dor et al study, the goals of each technique are the same.17–21 Specifically, SVR is intended to reduce the size and sphericity of the left ventricle by excluding akinetic and dyskinetic areas, in conjunction with complete revascularization and repair of any valvular defects. The goal is to revascularize ischemic myocardium; reduce end-diastolic pressure; reduce ventricular dyssynchrony; improve ventricular function, including that of viable but poorly functioning remote areas; and have a positive impact on measurable parameters of HF and survival. Most commonly, patients are considered candidates for SVR if they have had a remote anterior or anteroseptal myocardial infarction, significant ventricular enlargement with a large area of akinesis or dyskinesis of non-viable myocardium, and a clinical picture consistent with HF. They should have retained function of the basilar and lateral portions of the heart, and have good right ventricular function. They should also be candidates for revascularization and valve repair if indicated. The indications and contraindications to SVR that I consider are shown in Table 1. The only truly absolute contraindications to SVR are a viable anterior wall and documented ischemia due to coronary artery disease not amenable to revascularization. It is therefore imperative to document the infarction, ventricular enlargement and, most importantly, non-viability of the anterior wall. I do so most commonly with magnetic resonance imaging (MRI) using gadolinium enhancement. Figure 1 is an image from a patient with the appropriate anatomy for SVR, as demonstrated by gadolinium enhancement. Although we do use MRI in many patients with defibrillators and biventricular pacers, we have also used positron emission tomography (PET) and nuclear scanning to document non-viability of the anterior wall.22 Results with SVR have been reported in several large retrospective series. Dr Dor’s personal experiences, as well as those of Dr Lorenzo Menicanti of Milan, Italy, and a large multicenter database of 1,200 patients, known as the RESTORE group, represent over 3,000 patients alone.23–25 The consistent findings in all of the major retrospective studies include an improvement in ejection fraction (EF) of
MRI with gadolinium enhancement demonstrating post-infarction thinning and scar formation of the left ventricle.
Conte Table 2 ● ● ● ● ● ● ● ●
True, True, and Unrelated Post-SVR Improvements22,23
Reduced ventricular size Improved ventricular function Neurohormone normalization Reduced mechanical dyssynchrony Reduced ventricular arrhythmias Improved ventricular efficiency and energetics Improved NYHA functional class Improved heart failure scores Functional and psychologic
about 10% to 20%; a reduction of end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) of 40%; and better clinical outcomes, such as improved New York Heart Association (NYHA) functional class, freedom from CHF rehospitalization, and survival rates superior to those of medically treated patients.23–25 Many smaller series have looked at different measurable morphologic, physiologic and clinical outcomes after SVR. In these studies, morphologic improvements and increases in EF have consistently been reported as they have in the larger series. In addition, there have been reported real-time improvements in LV energetics with the use of high-fidelity conductance catheters, normalization of heart failure neurohormone levels, reductions in electrical and mechanical dyssynchrony, improvements in physiologic parameters such as 6-minute walk tests, improvements in HF questionnaire scores, equivalent outcomes to transplantation up to 5 years, as well as survival outcomes of up to 20 years (Table 2).23–34 Despite these findings, and many other supporting studies, many investigators believed that revascularization alone was sufficient.35 The stage was set for a prospective, multicenter trial to study the impact of revascularization vs revascularization plus SVR. The STICH trial randomized 490 patients to CABG vs CABG plus SVR. It was concluded that “adding SVR to CABG was not associated with a greater improvement in symptoms, exercise tolerance or reduced immediate mortality.”1 This was a shock and an eyeopener to the many who believed the worldwide published data
493 on ⬎5,000 patients. It was particularly surprising to those who witnessed stunning clinical successes in patients who underwent SVR without revascularization but did remarkably well after SVR alone (Figure 2). Was SVR another Batista operation or is there something wrong with the study? Close scrutiny of the published work proves quite revealing. The Patients The STICH trial was supposed to have rigid entry criteria, but in fact did not, and many patients did not even meet the entry criteria that were set for the trial. The original grant funded by NIH required that “all patients be evaluated for appropriateness of surgical ventricular reconstruction indicated by evidence of absent viability in the anterior ventricle by nuclear scan determination, an end systolic volume index of ⬎60 ml/m2 and akinesis of ⬎30% of the anterior LV wall.”36 The demonstration of non-viability is what was recommended by the surgical therapy committee (STC). This is what surgeons with expertise in performing SVR for heart failure do routinely. A demonstration of non-viability is part of the standard work-up. The published paper does not make any mention of viability testing. Table 1 tells us that 50% of the anterior wall demonstrates akinesis or dyskinesis, but we are not told about the viability. This means that 50% of the anterior wall is viable and the other 50% we don’t know about because viable myocardium can demonstrate wall motion abnormalities. Another 13% were reported to have not experienced a myocardial infarction. An operation designed to treat non viable scar following myocardial infarction may have been done in patients with viable myocardiu. STICH investigators themselves acknowledged the importance of establishing non-viability before proceeding with SVR. In an article published in The Journal of Thoracic and Cardiovascular Surgery, the STICH investigators provided an example of a patient who was considered a candidate for SVR. That patient had a PET scan demonstrating non-viability.37 Why was that standard not maintained throughout the study? More importantly, in the funded grant itself, Section 4.8.8 states unequivocally, “A
Figure 2 MRI of LV before and after the SVR procedure and mitral valve annuloplasty demonstrating a reduction of LV volume and restoration of a more elliptical LV shape.
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measure of myocardial viability must be obtained.”36 If it was, why was this important information not reported? This operation was intended for the scarred, thinned-out fibrotic walls of enlarged post-infarction ventricles, even those that may have had a thin rim of viable cells after reperfusion. This is not the population presented in the published trial. In my personal series of SVR patients, for every 3 patients I evaluate, I exclude 1 because they do not meet this simple criterion. Viability was supposed to be assessed in a standard fashion, and it was not. Why? The Operation To participate in the STICH trial, there was no specific requirement that centers demonstrate a multidisciplinary CHF team or have any expertise in heart failure surgery. It was simply required that each surgeon have an operative mortality of ⱕ5% in 25 patients who have undergone CABG in patients with an EF ⬍40%. They also had to report an operative mortality of ⬍10% and an average ESVI decrease of 30% in 5 SVR cases.36 Certainly, this represents a lower bar than for the NASCET investigation, which scrutinized the program and the surgeons’ results to a far greater degree before accepting them into the trial and, importantly, scrutinized their surgical results during the trial to determine if the operation was performed successfully. Assuring that a technically successful SVR procedure was performed was of great concern to the STC of the STICH trial. Because there are several methods to achieve the same morphologic results with the SVR procedure the STC did not want to mandate a specific surgical technique, but rather they defined an “acceptable STICH procedure.” It was further stated that, “The two criteria used by the Surgical Therapy Committee to define the acceptable range of specific operative maneuvers essential to be considered an acceptable technical SVR operation for the STICH trial will be any ventricular reconstruction method
Table 3
that consistently results in (1) a low operative mortality and (2) an average EF increase of 10% and average LVESVI decrease of 30% as assessed on the 4-month post-operative CMR measurement.”36 What was reported in the original article is an average ESVI reduction of 19% and an ESVI of 67 ml/m2. This is far below what the SCT deemed an acceptable SVR procedure. Why were these inferior surgical results accepted when they did not even meet their own definition of a successful operation? Furthermore, they are far below the standard in the published literature. Table 3 demonstrates the average volume reduction after SVR according to published studies from a variety of centers with experience in performing SVR. These findings were compiled by Dr Hisayoshi Suma from Tokyo. The data demonstrate an average ESVI reduction of 40%, with a range of 30% to 58%. Why is this important? It is important because it is clear that a large percentage of the patients did not have an adequate “STICH” procedure. It is also important because a LVESVI of 67ml/kg is larger than the volumes reported to represent an optimal volume index post SVR and the patients still have an ESVI large enough to qualify for the trial!38 Yet these patients were still used to assess the outcome of the operation. Would a patient whose biventricular pacer was unable to pace both ventricles be included in a study assessing the efficacy of biventricular pacing? How can any one rationalize using these patients to assess SVR? Furthermore, presumably to overcome poor enrollment, STICH expanded to 127 sites from the intended 50 sites, assessing 10 cases per site.36 Based on 490 patients this means there was an average of only 4 procedures done per site.1 How can the outcome of a technically challenging surgical procedure be evaluated if the procedure is not done properly by surgeons whose experience is limited. Even more amazing is that no one seemed to question this. Why? Because SVR is performed relatively infrequently, many
LV Volume Change After SVR ESVI (ml/m2)
Investigators (year) 42
Data from Di Donato et al
Data Data Data Data Data Data Data Data Data Data Data
from from from from from from from from from from from
(2009)
Suma et al43 (2009) Dor et al44 (2008) Menicanti et al24 (2007) O’Neil et al45 (2006) Adams et al46 (2006) Schreuder et al47 (2005) Tulner et al48 (2006) Yamaguchi et al49 (2005) Mickleborough et al50 (2004) RESTORE trial25 (2004) STICH trial1 (2009)
Data compiled by Dr Hisayoshi Suma, Tokyo, Japan. a ESV (in milliliters), not indexed.
No. of patients
Pre-op
Post-op
Reduction (%)
56 (Type 1) 55 (Type 2) 67 (Type 3) 76 104 301 135 8 9 21 20 41 671 161
83 87 96 123 93 173a 120 92 92 186a 137 97 80.4 83
35 39 57 74 51 100a 77 59 45 101a 65 65 56.6 67
48 48 39 49 42 73a 43 33 47 85a 72 32 24 16
(58) (55) (41) (40) (45) (42) (36) (36) (51) (46) (53) (33) (30) (19)
Conte
True, True, and Unrelated
surgeons and cardiologists have little insight into what it is, how it is performed, or even what constitutes an acceptable outcome. Most physicians know that a patient can survive a mitral valve repair but still have a poor outcome because of the degree of mitral regurgitation remaining when there is a technically sub-standard procedure. However, many competent surgeons and cardiologists do not realize that one can have a “bad SVR” due to a technically inferior operation (i.e., inadequate volume reduction) without obvious morbidity or mortality. Many believe that if the patient does not die outright, then the operation was done correctly. Unfortunately, this appears to be true of many of the investigators in the STICH study, who should have known better, as well as many who chose to comment and write about the outcomes of this trial. This lack of insight was clearly demonstrated by the many pundits who analyzed the results and in the editorial that accompanied the publication of the study.38 – 41 No one demonstrated insight in knowing whether the operation was done properly on the correct group of patients or to even ask the question. It appears that man y of the operations were not done properly or, at the very minimum, did not meet the standards set forth by the STICH investigators themselves or in the published literature. How then can we accept the results of any technical procedure when they do not meet the standards established by the trial? Although all investigators share culpability in this area, where were the surgical investigators? They hold even greater responsibility for the lack of oversight on the surgical outcomes. Why was there no concurrent assessment of the outcomes as there was in the NASCET study to ensure that the operations were being done correctly? How could they not identify these obvious oversights and address them before publication of such clearly flawed data?
495 of non-viability, no impartial observer can look at this study and say that the patients represent the same group of patients that SVR experts and the STC of the STICH would recommend for SVR surgery. Second, no impartial observer can look at this study and say there are not very significant reservations about the quality of the SVR procedures performed based on the numbers performed per center and the volume reduction achieved as compared with the published literature and the STICH STC recommendation. What we can say is that patients with potentially viable anterior walls and inadequate volume reductions do no better than patients receiving CABG alone. This is not a surprise. The only way that the data from the cohort of Hypothesis II patients can have any significant meaning would be to exclude all patients without documentation of non-viable anterior walls, those who do not have adequate volume reductions as defined by the STC, and those who do not have the appropriate follow-up with complete data sets including MRI analysis as the funded grant set forth. Until this reassessment is made, the results of Hypothesis II of the STICH trial will remain “true, true, and unrelated” to the state of the art in SVR and will go down as an expensive but clinically meaningless exercise in surgical research.
Disclosure statement The author has no conflicts of interest to disclose. The views expressed those of the author and not those of the Journal, its Editors or the ISHLT. John Conte, MD From the Division of Cardiac Surgery, The Johns Hopkins Hospital, Baltimore, Maryland
Other Issues There were several other issues with this study. The trial had a relatively healthy group of patients for an SVR investigation. Fewer than 50% of the STICH patients were NYHA Class 3 and 4 compared with 67% in the RESTORE group and ⬎90% in my own series of patients. Several changes were made in the protocol during the study. Why was that done? Why was the study expanded to over twice as many centers as originally planned and why were there so many in Eastern Europe with dramatically different health-care systems? The site expansion dramatically reduced the number of patients per center and significantly calls into question the level of experience of the surgical investigators. What about the incomplete data, particularly the volume measurements? How is it that volume measurements were obtained for only 212 of the 490 CABG patients and 161 of the 490 patients in the SVR group when this was such an important outcome measure and a determinant of a successful operation? Furthermore, many measurements were not obtained by nuclear or MRI scans as originally planned by the STC to define a successful operation. Why? The conclusions that can be made from the published cohort of patients are limited. First, without documentation
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30. Schenk S, McCarthy PM, Starling RC, et al. Neurohormonal response to left ventricular reduction surgery in ischemic cardiomyopathy. J Thorac Cardiovasc Surg 2003;128:38-43. 31. Tulner SA, Steendijk P, Klautz RJ, et al. Clinical efficacy of surgical heart failure therapy by ventricular restoration and restrictive mitral annuloplasty. J Card Fail 2007;13:178-83. 32. Di Donato M, Sabatier M, Dor V, et al. Surgical ventricular restoration in patients with post-infarction coronary artery disease: effectiveness on spontaneous and inducible ventricular tachycardia. Semin Thorac Cardiovasc Surg 2001;13:480-5. 33. Di Donato M, Sabatier V, Dor G, et al. Ventricular arrhythmias after LV remodelling: surgical ventricular restoration or ICD? Heart Fail Rev 2004;9:299-306. 34. William JA, Weiss ES, Patel ND, et al. Surgical ventricular restoration versus cardiac transplantation: a comparison of cost, outcomes and survival. J Card Fail 2008;7:547-54. 35. Elefteriades JA, Edwards R. Coronary bypass in left heart failure. Semin Thorac Cardiovasc Surg 2002;14:125-32. 36. STICH trial protocol: http://clinicaltrials.gov/archive/NCT00023595/ 2005_06_23 37. Doenst T, Velazquez EJ, Beyersdorf F, et al. To STICH or not to STICH: we know the answer, but do we understand the question? J Thorac Cardiovasc Surg 2005;129:246-9 (see also http://clinicaltrials. gov/show/NCT00023595). 38. Menicanti L, Di Donato M. Surgical ventricular reconstruction and mitral regurgitation: what have we learned from 10 years of experience? Semin Thorac Cardiovasc Surg 2001;13:496-503. 39. theheart.org http://www.theheart.org/editorial-program/956041.do (accessed May 12, 2009). 40. American College of Cardiology. http://www.acc.org/media/acc_scientific_ session_09/press/sunday/ACC09Mark_930.pdf (accessed March 29, 2009). 41. Eisen HJ. Surgical ventricular reconstruction for heart failure. N Engl J Med 2009;360:1781-4. 42. Di Donato M, Castelvecchio S, Kukulski T, et al. Surgical ventricular restoration: left ventricular shape influence on cardiac function, clinical status, and survival. Ann Thorac Surg 2009;87:455-61. 43. Suma H, Tanabe H, Uejima T, et al. Surgical ventricular restoration combined with mitral valve procedure for endstage ischemic cardiomyopathy. Eur J Cardiothorac Surg 2009;36:280-4. 44. Dor V, Civaia F, Alexandrescu C, et al. The post-myocardial infarction scarred ventricle and congestive heart failure: the preeminence of magnetic resonance imaging for preoperative, intraoperative, and postoperative assessment. J Thorac Cardiovasc Surg 2008;136:1405-12. 45. O’Neill JO, Starling RC, McCarthy PM, et al. The impact of left ventricular reconstruction on survival in patients with ischemic cardiomyopathy. Eur J Cardiothorac Surg 2006;30:753-9. 46. Adams JD, Fedoruk LM, Tache-Leon CA, et al. Does preoperative ejection fraction predict operative mortality with left ventricular restoration? Ann Thorac Surg 2006;82:1715-9. 47. Schreuder JJ, Castiglioni A, Maisano F, et al. Acute decrease of left ventricular mechanical dyssynchrony and improvement of contractile state and energy efficiency after left ventricular restoration. J Thorac Cardiovasc Surg 2005;129:138-45. 48. Tulner SA, Steendijk P, Klautz RJ, et al. Surgical ventricular restoration in patients with ischemic dilated cardiomyopathy: evaluation of systolic and diastolic ventricular function, wall stress, dyssynchrony, and mechanical efficiency by pressure–volume loops. J Thorac Cardiovasc Surg 2006;132:610-20. 49. Yamaguchi A, Adachi H, Kawahito K, et al. Left ventricular reconstruction benefits patients with dilated ischemic cardiomyopathy. Ann Thorac Surg 2005;79:456-61. 50. Mickleborough LL, Merchant N, Ivanov J, et al. Left ventricular reconstruction: early and late results. J Thorac Cardiovasc Surg 2004;128:27-37.