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• W2138804703 abstract "HomeCirculation: Cardiovascular ImagingVol. 6, No. 3More Evidence for the Survival Benefit of Coronary Revascularization Versus Medical Therapy in Patients With Ischemic Cardiomyopathy and Hibernating Myocardium Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMore Evidence for the Survival Benefit of Coronary Revascularization Versus Medical Therapy in Patients With Ischemic Cardiomyopathy and Hibernating Myocardium George A. Beller, MD George A. BellerGeorge A. Beller From the Cardiovascular Division, University of Virginia Health System, Charlottesville, VA. Search for more papers by this author Originally published1 May 2013https://doi.org/10.1161/CIRCIMAGING.113.000466Circulation: Cardiovascular Imaging. 2013;6:355–357For many years, it has been recognized that patients with coronary artery disease (CAD) and left ventricular (LV) dysfunction who manifest substantial myocardial viability in asynergic myocardial regions have improved LV regional and global function, exhibit reverse LV remodeling, and exhibit a reduction in ischemic mitral regurgitation and a reduction in heart failure symptoms after revascularization. Observational studies using a variety of noninvasive methodologies for assessment of myocardial viability have also shown enhanced survival with revascularization versus medical therapy in such patients. A much quoted meta-analysis of observational studies in the literature that reported outcomes in patients undergoing noninvasive viability studies with Tl-201 redistribution scintigraphy, positron emission tomography (PET) with F-18-fluorodeoxyglucose (FDG), or dobutamine echocardiography showed a ≈80% reduction in mortality (3.2% versus 16.0%) during follow-up with revascularization versus medical therapy in those patients with predominantly hibernating myocardium.1 In contrast, patients with predominantly nonviable myocardium showed no benefit from revascularization versus medical therapy. In most of these prior studies, the greater the amount of hibernating myocardium, the better the outcome with revascularization. For example, the larger the amounts of mismatch between perfusion and FDG uptake by PET, combined with revascularization, the less the probability of cardiac death, myocardial infarction, and hospitalization for cardiac causes.2 Cardiac magnetic resonance accurately quantifies the amount of transmural myocardial scar using measurements of late gadolinium enhancement. With this noninvasive technique, the greater the amount of late gadolinium enhancement, the greater the chance of functional recovery after revascularization.3 Revascularization also shows a survival benefit compared with medical therapy in the presence of dysfunctional but viable myocardium by delayed-enhanced cardiac magnetic resonance.4Article see p 363All the noninvasive viability imaging techniques in clinical use can adequately identify hibernating myocardium in patients with ischemic cardiomyopathy. When the relative sensitivities and specificities of these modalities are compared, PET-FDG had the highest sensitivity and dobutamine echocardiography had the highest specificity for detection of viability.5 A meta-analysis was conducted to determine the optimal cutoff values for the assessment of viability using these various imaging techniques for which revascularization would offer a survival benefit in patients with ischemic cardiomyopathy.6 The optimal threshold for the presence of myocardial viability needed to improve survival with revascularization was estimated to be 25.8% by PET-FDG and 38.7% by single-photon emitted computed tomography (SPECT) imaging.On the basis of the data from these observational studies, which are consistent in concluding that ischemic cardiomyopathy patients with dysfunctional but viable myocardium benefit most from coronary revascularization, many cardiologists and cardiac surgeons order one of these noninvasive viability tests to assist in clinical decision making whether to recommend revascularization. Often, such viability tests are ordered after cardiac catheterization had shown that target vessels are suitable for coronary bypass surgery. If a substantial amount of hibernating myocardium is demonstrated on viability testing, then the likelihood is greater for a better short- and long-term outcome with revascularization. However, this management practice has been based on the cumulative experience reported in nonrandomized studies cited previously. In these studies, outcomes were reported in patients treated either with revascularization or solely with medical therapy, at the discretion of their physicians. Nevertheless, the cumulative evidence of benefit of viability testing from these observational studies yielded a class IIa recommendation for this practice by the American College of Cardiology and the American Heart Association.7The Surgical Treatment for Ischemic Heart Failure (STICH) trial was a randomized study designed to evaluate the role of cardiac surgery in the treatment of patients with CAD and LV dysfunction.8 In this trial of patients randomly assigned to coronary artery bypass surgery (CABG) plus medical therapy or medical therapy alone, the CABG plus medical therapy group had lower rates of death from cardiovascular causes, of death from any cause or hospitalization for cardiovascular causes. This was the composite secondary end point for the study. No difference was seen between the 2 groups with respect to the primary end point, which was death from any cause. Surprisingly, the STICH viability substudy, in which viability imaging was performed in 601 of the 1212 patients enrolled in STICH, did not show a significant interaction between viability status and treatment assignment with respect to mortality.9 In contrast to the prior published observational studies, the STICH viability substudy showed that assessment of myocardial viability did not identify patients with CAD and LV dysfunction with a differential survival benefit from CABG.The STICH viability substudy has some limitations that deserve mention. The use of viability imaging was not randomized, and the results were not blinded. The patients enrolled in the substudy already had been identified as being suitable candidates for coronary revascularization, and their coronary anatomy was known. Only 19% of the patients in the STICH viability study had nonviable myocardium. They had fewer comorbid conditions compared with patients in the prior observational studies and had less prior CABG. The viability imaging techniques were variable and not standardized. PET-FDG or delayed enhancement cardiac magnetic resonance studies were not performed. Only slightly more than one third of the patients had 3-vessel CAD. Outcomes were not analyzed with viability being considered as a continuous variable.The only randomized trial to assess the effectiveness of viability imaging, the PET and Recovery Following Revascularization (PARR 2) trial, used PET-FDG.10 The patients in PARR 2 were randomized to management assisted by PET-FDG or standard care. The primary outcome was the composite of cardiac death, myocardial infarction, or recurrent hospitalization for a cardiac cause within 1 year. The overall study did not demonstrate a significant reduction in cardiac events for PET-FDG–assisted management versus standard care. However, when only patients who adhered to PET recommendations for revascularization were considered, significant benefits were observed. The Ottawa-FIVE post hoc substudy11 of the PARR 2 trial comprised 111 patients in a center with PET experience with a history of integrating PET-FDG into clinical practice. As performed for the overall PARR 2 trial, patients in the substudy were randomized to PET-FDG strategy versus standard care. The results were quite impressive; 19% in the PET-FDG–assisted management group experienced the composite event versus 41% in the standard care group. Multivariable Cox proportional hazards regression showed a significant benefit for the PET-FDG group (hazard ratio, 0.34).In this issue of Circulation: Cardiovascular Imaging, Ling et al12 provide further evidence that hibernating myocardium identified by PET-FDG identifies those patients with ischemic cardiomyopathy who accrue a survival benefit with revascularization versus medical therapy. It is a very well-done study by a superb group of noninvasive imaging investigators at the Cleveland Clinic. The study comprised 648 consecutive patients who underwent PET-FDG with Rb-82 used as the imaging agent for evaluation of myocardial perfusion. The mean LV ejection fraction of the cohort was 31%, and the mean age was 65 years. Follow-up was started 92 days after the index PET allowing for definitive treatment assignment. Mean follow-up was 2.8 years. The end point was all-cause mortality. Because patients were not randomized to revascularization or medical therapy, adjustment was made for potential confounders using Cox proportional hazards modeling, including a propensity score to adjust for nonrandomized treatment allocation. The investigators found that revascularization in the setting of significant myocardial hibernation improved survival, especially when the extent of viability exceeded 10% of the LV myocardium. As shown previously, the study showed that with medical therapy, the risk of death increased proportionally with the amount of hibernating myocardium. Early revascularization was associated with superior survival as percent of hibernation increased. No significant interaction was observed between the use of early revascularization and either proportion of ischemic myocardium as assessed by vasodilator stress imaging, or the amount of nonviable myocardium. Interestingly, the authors found that the survival benefit associated with the use of early revascularization in the setting of extensive hibernation was limited to patients without diabetes mellitus. Of importance is that the study by Ling et al12 showed survival benefit for revascularization with ≈75% of the patients taking β-blockers as part of medical therapy for heart failure or asymptomatic LV dysfunction. A weakness of the earlier observational viability studies performed in the late 1980s and 1990s, that showed survival benefit for revascularization compared with medical therapy alone, was that most were undertaken before the widespread use of β-blocker therapy for heart failure. The current study results by Ling et al12 are also consistent with the PARR 2 trial substudy findings cited above,11 when recommendations for treatment based on the PET-FDG imaging data in patients randomized to the PET-FDG management arm were performed. Compared with patients in the STICH trial, the patients reported in the study by Ling et al12 were older, had a higher prevalence of diabetes mellitus, had more prior revascularization, included more patients with prior implantable cardioverter-defibrillator implantation, and presence of greater amount of hibernating myocardium.There are some weaknesses of the study by Ling et al12 that primarily relate to its observational nature. It was undertaken in a single center. Although propensity scoring was used to diminish selection bias, some important confounders may not have been measured. For example, no coronary angiographic data are provided. Thus, we do not know how many patients with a large area of hibernating myocardium did not undergo revascularization because of poor target vessels. Coronary anatomic findings can be a confounding variable, and they were not included in the propensity scoring scheme. Another variable that was not considered was renal function. Renal dysfunction is an independent predictor of outcome in patients with ischemic heart disease and was shown to be an independent predictor of outcome in patients with ischemic cardiomyopathy undergoing PET-FDG imaging2. One possible explanation for why patients with diabetic mellitus with significant hibernation did not benefit from revascularization versus medical therapy is because of a higher prevalence of renal failure in the subgroup with diabetes mellitus. Certainly, diabetes mellitus could have adversely affected PET methodology for measuring glucose metabolism. This may have altered the PET-FDG imaging results in patients with diabetes mellitus compared with patients without diabetes mellitus in this study.In considering the clinical value of viability imaging, it is worthwhile to examine the issue from another perspective. In the early years of clinical viability assessment, patients underwent viability imaging as part of a research protocol before coronary bypass surgery that was already scheduled on the basis of clinical indications (eg, angina, multivessel CAD, good target vessels suitable for grafting, and absence of severe comorbidities). Surgeons most often did not know or consider the results of viability imaging preoperatively. In one such study by Pagley et al13 from the University of Virginia, 70 patients with multivessel CAD, with a mean LV ejection fraction of 28%, underwent preoperative rest-redistribution quantitative Tl-201 scintigraphy before CABG. The extent of viability was significantly related to 3-year survival postoperatively. Patients with poor viability had a markedly higher rate of cardiac death/cardiac transplant during follow-up, yet they were similar to the patients with good viability with respect to age, comorbidities, preoperative LV ejection fraction, and anatomic extent of CAD. By 5 years of follow-up, ≈50% of the patients with poor viability who underwent CABG had died or undergone cardiac transplant. This higher cardiac death rate in ischemic cardiomyopathy patients with poor viability compared with good viability undergoing CABG was reported in the meta-analysis of Allman et al.1 The meta-analysis showed that the death rate in patients with viable myocardium after CABG was 3.2% versus 7.7% in those with poor or nonviable myocardium. One strength of these earlier studies is that the decision for revascularization was not based on viability imaging data, but on the standard of care at that time. Patients with angina, LV dysfunction, and multivessel CAD were considered good candidates for surgery based on prior randomized studies of CABG versus medical therapy (eg, the Coronary Artery Surgery [CASS] study).In conclusion, the excellent study by Ling et al12 published in this issue adds further evidence, supporting the concept that CAD patients with extensive myocardial hibernation (>10% of the LV) seem to have a significant survival benefit with revascularization versus medical therapy. The findings are in contrast to the observational STICH substudy, which concluded that myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. Thus, prospective randomized viability studies seem warranted to further ascertain whether viability testing is useful in identifying those patients with CAD and severe LV dysfunction who benefit more from revascularization and optimal medical therapy versus medical therapy alone. Because PET-FDG has the highest sensitivity for viability detection, this modality should be used for imaging. Ideally, multimodality imaging with cardiac magnetic resonance and PET-FDG should be considered in such a study. Presently, despite the results of the STICH viability substudy, we know, with a rather high degree of certainty, that patients with extensive areas of hibernating myocardium have a better outcome with revascularization than do patients with similar clinical characteristics and extent of anatomic CAD, who have extensive areas of nonviable myocardium. On the basis of multiple observational studies, with some using propensity analysis to adjust for nonrandomized treatment allocation, it also still seems the case that patients with ischemic cardiomyopathy and extensive hibernation have a better outcome with revascularization and optimal medical therapy compared with optimal medical therapy alone.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to George A. Beller, MD, Cardiovascular Division, University of Virginia Health System, Box 800158, Charlottesville, VA 22908. E-mail [email protected]References1. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. 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; 39:1151–1158.CrossrefMedlineGoogle Scholar2. D’Egidio G, Nichol G, Williams KA, Guo A, Garrard L, deKemp R, Ruddy TD, DaSilva J, Humen D, Gulenchyn KY, Freeman M, Racine N, Benard F, Hendry P, Beanlands RSB, for the PARR-2 Investigators. J Am Coll Img. 2009; 2:1060–68.CrossrefGoogle Scholar3. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow RO, Judd RM. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction.N Engl J Med. 2000; 343:1445–1453.CrossrefMedlineGoogle Scholar4. Gerber BL, Rousseau MF, Ahn SA, le Polain de Waroux J-B, Pouleur A-C, Phlips T, Vancraeynest D, Pasquet A, Vanoverschelde J-L J. Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction.J Am Coll Cardiol. 2012; 59:825–35.CrossrefMedlineGoogle Scholar5. Schinkel AF, Bax JJ, Poldermans D, Elhendy A, Ferrari R, Rahimtoola SH. Hibernating myocardium: diagnosis and patient outcomes.Curr Probl Cardiol. 2007; 32:375–410.CrossrefMedlineGoogle Scholar6. Inaba Y, Chen JA, Bergmann SR. Quantity of viable myocardium required to improve survival with revascularization in patients with ischemic cardiomyopathy: A meta-analysis.J Nucl Cardiol. 2010; 17:646–654.CrossrefMedlineGoogle Scholar7. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW; American College of Cardiology Foundation; American Heart Association. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2009; 53:e1–90.CrossrefMedlineGoogle Scholar8. Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, Ali IS, Pohost G, Gradinac S, Abraham WT, Yii M, Prabhakaran D, Szwed H, Ferrazzi P, Petrie MC, O’Connor CM, Panchavinnin P, She L, Bonow RO, Rankin GR, Jones RH, Rouleau JL; STICH Investigators. Coronary-artery bypass surgery in patients with left ventricular dysfunction.N Engl J Med. 2011; 364:1607–1616.CrossrefMedlineGoogle Scholar9. Bonow RO, Maurer G, Lee KL, Holly TA, Binkley PF, Desvigne-Nickens P, Drozdz J, Farsky PS, Feldman AM, Doenst T, Michler RE, Berman DS, Nicolau JC, Pellikka PA, Wrobel K, Alotti N, Asch FM, Favaloro LE, She L, Velazquez EJ, Jones RH, Panza JA; STICH Trial Investigators. Myocardial viability and survival in ischemic left ventricular dysfunction.N Engl J Med. 2011; 364:1617–1625.CrossrefMedlineGoogle Scholar10. Beanlands RS, Nichol G, Huszti E, Humen D, Racine N, Freeman M, Gulenchyn KY, Garrard L, deKemp R, Guo A, Ruddy TD, Benard F, Lamy A, Iwanochko RM; PARR-2 Investigators. F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).J Am Coll Cardiol. 2007; 50:2002–2012.CrossrefMedlineGoogle Scholar11. Abraham A, Nichol G, Williams KA, Guo A, deKemp RA, Garrard L, Davies RA, Duchesne L, Haddad H, Chow B, DaSilva J, Beanlands RS; PARR 2 Investigators. 18F-FDG PET imaging of myocardial viability in an experienced center with access to 18F-FDG and integration with clinical management teams: the Ottawa-FIVE substudy of the PARR 2 trial.J Nucl Med. 2010; 51:567–574.CrossrefMedlineGoogle Scholar12. Ling LF, Marwick TH, Flores DR, Jaber WA, Brunken RC, Cerqueira MD, Hachamovitch R. Identification of therapeutic benefit from revascularization in patients with left ventricular dysfunction: inducible ischemia versus hibernating myocardium.Circ Cardiovasc Imaging. 2013; 6:363–372.LinkGoogle Scholar13. Pagley PR, Beller GA, Watson DD, Gimple LW, Ragosta M. Improved outcome after coronary bypass surgery in patients with ischemic cardiomyopathy and residual myocardial viability.Circulation. 1997; 96:793–800.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Li D and Kronenberg M (2021) Myocardial Perfusion and Viability Imaging in Coronary Artery Disease: Clinical Value in Diagnosis, Prognosis, and Therapeutic Guidance, The American Journal of Medicine, 10.1016/j.amjmed.2021.03.011, 134:8, (968-975), Online publication date: 1-Aug-2021. Pepin M, Ha C, Crossman D, Litovsky S, Varambally S, Barchue J, Pamboukian S, Diakos N, Drakos S, Pogwizd S and Wende A (2018) Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure, Laboratory Investigation, 10.1038/s41374-018-0104-x, 99:3, (371-386), Online publication date: 1-Mar-2019. Mc Ardle B, Shukla T, Nichol G, deKemp R, Bernick J, Guo A, Lim S, Davies R, Haddad H, Duchesne L, Hendry P, Masters R, Ross H, Freeman M, Gulenchyn K, Racine N, Humen D, Benard F, Ruddy T, Chow B, Mielniczuk L, DaSilva J, Garrard L, Wells G, Beanlands R, Higginson L, Mesana T, Ukkonen H, Yoshinaga K, Renaud J, Klein R, Aung M, Kostuk W, Wisenberg G, White M, Iwanochko R, Mickleborough L, Abramson B, Latter D, Lamy A, Fallen E and Coates G (2016) Long-Term Follow-Up of Outcomes With F-18-Fluorodeoxyglucose Positron Emission Tomography Imaging–Assisted Management of Patients With Severe Left Ventricular Dysfunction Secondary to Coronary Disease, Circulation: Cardiovascular Imaging, 9:9, Online publication date: 1-Sep-2016.Beller G (2016) Clinical Value of F-18-Fluorodeoxyglucose Positron Emission Tomographic Imaging of Myocardial Viability Is Dependent on Adherence to Treatment Strategy Based on Imaging Results, Circulation: Cardiovascular Imaging, 9:9, Online publication date: 1-Sep-2016. Wang Q, Yang S, Jiang C, Li J, Wang C, Chen L, Jin Q, Song S, Feng Y, Ni Y, Zhang J and Yin Z (2016) Discovery of Radioiodinated Monomeric Anthraquinones as a Novel Class of Necrosis Avid Agents for Early Imaging of Necrotic Myocardium, Scientific Reports, 10.1038/srep21341, 6:1, Online publication date: 1-Aug-2016. Fukushima Y, Kumita S, Tokita Y and Sato N (2015) Prognostic Value of Myocardial Perfusion SPECT After Intravenous Bolus Administration of Nicorandil in Patients with Acute Ischemic Heart Failure, Journal of Nuclear Medicine, 10.2967/jnumed.115.162420, 57:3, (385-391), Online publication date: 1-Mar-2016. Kalyuzhin V, Teplyakov A, Bespalova I and Kalyuzhina Y (2014) TOWARD THE QUESTION OF ISCHEMIC MYOCARDIAL DYSFUNCTION, Bulletin of Siberian Medicine, 10.20538/1682-0363-2014-6-57-71, 13:6, (57-71) May 2013Vol 6, Issue 3 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.113.000466PMID: 23696583 Originally publishedMay 1, 2013 Keywordspositron emission tomographymedical therapyEditorialshibernating myocardiumcoronary revascularizationPDF download Advertisement SubjectsImaging" @default.
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