1. Viability assessment and its role in Revascularization Review of evidence Dr. Nithin P G Dr Nithin P G

2. Overview Introduction Viability assessment by various investigations Comparisons Clinical correlations Benefits of viability assessment in clinical scenario Conclusion Dr Nithin P G

3. Introduction TERMS – ‘Stunning’ – ‘C/C Stunning’ – ‘Hibernation’ – ‘Ischemic cardiomyopathy’ – Viability??? Dr Nithin P G

4. Introduction Viable vs Non- viable Heart 2004;90(Suppl V):v26–v33 Dr Nithin P G

5. Introduction Contractile reserve vs. Metabolic parameters 52% 59% 33% Heart 2004;90(Suppl V):v26–v33 Dr Nithin P G

6. Introduction What to look for in viable tissues? [endpoints used in viability studies] – Improvement in regional LV function (segments) – Improvement in global LV function (LVEF) – Improvement in symptoms (NYHA functional class) – Improvement in exercise capacity (metabolic equivalents) – Reverse LV remodeling (LV volumes) – Prevention of sudden death (ventricular arrhythmias) – Long-term prognosis (survival) Dr Nithin P G

7. Introduction – Segmental LV function – LVEF – LV volumes – Long-term prognosis (survival) Pooled data-105 studies (n= 3,003) [Nucl. Im., DSE] 15,045 dysfunctional segments analyzed; 7,941 (53%) showed improvement in function after revasc. [84% detected prior as viable] Pooled data-105 studies (n= 3,003) [Nucl. Im., DSE] 15,045 dysfunctional segments analyzed; 7,941 (53%) showed improvement in function after revasc. [84% detected prior as viable] Curr Probl Cardiol. 2001;26:142–186 20%–30% of LV viable to allow improvement in the LVEF Trials use criteria of >5% increase in EF 20%–30% of LV viable to allow improvement in the LVEF Trials use criteria of >5% increase in EF J Nucl Med 2007; 48:1135–1146 ESV ≥140 mL low improvement in LVEF post-revascularization [sens 68%; spec 65% to predict absence of global recovery] EDV  70% of patients with EDV 140-180 ml & 35% with EDV>180 ml improved LVEF by 5% J Thorac Cardiovasc Surg 2004;127:385-390 Eur Heart J 2000;21:125-136 Dr Nithin P G

8. Viability assessment by different investigations Dr Nithin P G

9. Viability assessment Nuclear imaging with PET 18 F-FDG tracer with oral glucose loading protocol most commonly used. European Heart Journal (2010) 31, 2984–2995 Dr Nithin P G

10. Viability assessment % sensitivity% specificity% NPV%PPV 20 studies [N= 598] 93588577 [without flow tracer] 8874 J Nucl Med 2007; 48:1135–1146 Curr Probl Cardiol. 2001;26:142–186 Ability to predict improvement in LVEF Viability presentViability absent % LVEF pre% LVEF post% LVEF pre% LVEF post 12 studies [N=33] 37473940 J Nucl Med 2007; 48:1135–1146 J Nucl Med. 1994;35:707–715 Dr Nithin P G

11. Viability assessment % event rates Viability presentViability absent RevascularizationMedical trt.RevascularizationMedical trt. 7 studies (N= 619) 72912 Viability, Trt. type & Event Rates in Pts with LVD and c/c CAD J Nucl Med 2007; 48:1135–1146 Dr Nithin P G

12. Viability assessment Nuclear imaging with SPECT Tracers- 201 Tl-Chloride & 99m Tc-Labeled Agents [sestamibi] Viability assessment Stress -Normal perfusion Stress- defects with redistribution on delayed images Delayed rest images or reinjection- fixed defect showing redistribution Delayed rest images or reinjection- more than 50% tracer uptake Dr Nithin P G

13. Viability assessment % sensitivity% specificity% NPV%PPV 201 Tl-Chloride 33 trials[N=858] 87558164 99m Tc-Labeled Agents 20 trials[N=488] 81667771 J Nucl Med 2007; 48:1135–1146 Curr Probl Cardiol. 2001;26:142–186 Ability to predict improvement in LVEF Viability presentViability absent % LVEF pre% LVEF post% LVEF pre% LVEF post 201 Tl 5 trials [N=96] 30382931 99m Tc 4 trials [N=75] 47534039 J Nucl Med 2007; 48:1135–1146 J Nucl Med. 1994;35:707–715 Dr Nithin P G

14. Viability assessment DSE Low dose- High dose dobutamine infusion best Viability assessment Biphasic response- viability with superimposed ischemia Worsening-severe ischemia with critical stenosis Sustained improvement- subendocardial necrosis No change- transmural scar Dr Nithin P G

15. Viability assessment % sensitivity% specificity% NPV%PPV 32 studies [N= 1090] 81808577 J Nucl Med 2007; 48:1135–1146 Curr Probl Cardiol. 2001;26:142–186 Ability to predict improvement in LVEF Viability presentViability absent % LVEF pre% LVEF post% LVEF pre% LVEF post 8 studies [N=254] 35433536 J Nucl Med 2007; 48:1135–1146 J Nucl Med. 1994;35:707–715 Dr Nithin P G

16. Viability assessment % event rates Viability presentViability absent RevascularizationMedical trt.RevascularizationMedical trt. 6 studies (N= 686) 6221628 Viability, Trt. type & Event Rates in Pts with LVD and c/c CAD J Nucl Med 2007; 48:1135–1146 Dr Nithin P G

17. Viability Assessment Contrast echocardiography – Myocardial perfusion correlate positively with microvascular density and capillary area and inversely with the extent of fibrosis – DSE, 201 Tl imaging, and contrast echo [N=18], pts undergoing revascularization[contrast echo  89% sens., 51% spec.] TDI- strain rate imaging – Augmentation of strain and strain rate with dobutamine is a marker of myocardial viability – PET detected viable segments compared with strain rate imaging during low-dose dobutamine stress test [N=37]. An increase in the longitudinal strain rate of more than -0.23 S -1 identified viable tissue [83% sens., 84% spec.] J Am Coll Cardiol. 1997;29:985–993 J Am Coll Cardiol 2002;39:443-449 Dr Nithin P G

18. Viability Assessment CMR Viability criteria – End-diastolic wall thickening > 5.5 mm – Contrast enhanced CMR- delayed hyperenhancement For predicting functional recovery % sensitivity% specificity 3 studies [N= 100] 9541 For predicting functional recovery % sensitivity% specificity 4 studies [N= 132] 9545 Heart 2005;91:1359–1365 Addl. information on LVEF, LV volumes, ischaemic MR & LV shape Dr Nithin P G

19. Viability Assessment DE CMR Viability criteria – Increase in End-diastolic wall thickening > 2 mm For predicting functional recovery % sensitivity% specificity 9 studies [N= 252] 73(50-89)83(70-95) Heart 2005;91:1359–1365 Dr Nithin P G

20. Viability Assessment Contrast CT Studies Compared with Results Hyperenhancement [subendocardial if 50%] J Am Coll Cardiol. 2007;49:1178-1185. DSE Agreement in 560 of 576 (97%) segments. 2 weeks of STEMI [N=28] J Am Coll Cardiol. 2005;45:2042-2047 CE-CMR Agreement in 415 of 448 (93%) segments A/c or c/c MI [first-pass MDCT, first-pass CMR, DE- MDCT, and DE-CMR] Circulation. 2006;113:823-833 b/w DE- MDCT & DE- CMR Good agreement (82%) in delayed hyperenhanced regions on a segmental basis Slightly better concordance for a/c than c/c pts. Dr Nithin P G

21. Comparison b/w different investigations Dr Nithin P G

22. Comparison Ability to predict improvement in LVEF DSE vs. SPECT Agreement b/w 60.8% - 72% Segments with viability but no contractile reserve [rarely < 50% uptake but with contractile reserve] 72% agreement [N=114]- 92% of segments without perfusion no contractile reserve, but 47% with perfusion also without contractile reserve DSE vs. SPECT Agreement b/w 60.8% - 72% Segments with viability but no contractile reserve [rarely < 50% uptake but with contractile reserve] 72% agreement [N=114]- 92% of segments without perfusion no contractile reserve, but 47% with perfusion also without contractile reserve J Nucl Med 2007; 48:1135–1146 JACC 1996;28:530-535 Circulation. 2002;106(suppl 1):14–18 DSE vs. MRI Agreement around 79% More severe LV dysfunction [mean EF ~25%] and NYHA class > III have higher false negative rates with DSE DSE vs. MRI Agreement around 79% More severe LV dysfunction [mean EF ~25%] and NYHA class > III have higher false negative rates with DSE Heart 1999;82;684-688 J Am Coll Cardiol 1990;15:1021-1031 Curr Probl Cardiol. 2001;26:142–186 Dr Nithin P G

23. Comparison DE-CMR vs 201 Tl redistribution vs DSE Ischemic cardiomyopathy 3 days before transplantation Number of viable segments detected similar in DSE & DE CMR, but less than 201 Tl, confirmed by HPE Am J Cardiol 2002;90:455-459 % necrosis+LR-LR DSE315.57.7 DE-CMR335.25.5 201 Tl402.23.6 Dr Nithin P G

24. Comparison European Heart Journal (2010) 31, 2984–2995 Dr Nithin P G

25. Clinical correlation Dr Nithin P G

26. How much viable tissue? J Teh Univ Heart Ctr 1 (2009) 5-15 Dr Nithin P G

27. How much viable tissue? EF- 27%  33% NYHA-3.2  1.6 EF- 27%  33% NYHA-3.2  1.6 Non viable revasc- 17% Non viable revasc- 50% J Teh Univ Heart Ctr 1 (2009) 5-15 Dr Nithin P G

28. Timing of revascularization Circulation. 2003;108(suppl 1):II39–II42 N=40 20+12 days N=40 20+12 days 2 yr mort. 5% N=45 87+47 days N=45 87+47 days 2 yr mort. 20% Dr Nithin P G

29. Viability and coronary circulation StudyImagingFindings [N=41] previous Q wave infarction and SV-CAD [compared viability with angiographic variables, including the degree of patency & collateralization]. Rev Port Cardiol 1996;15:313-320 201 Tl SPECT No association b/w TIMI grade and reversibility Collateral circulation associated with viability, but absence did not exclude viability. [N=64]CAD & LV dysfunction [whether coronary patency could help in assessing viability] Clin Cardiol 2003;26:60-66 PET Patent arteries  more likely to be viable Akinetic segments  by occluded arteries (56 vs. 23, 72%) Dyskinetic segments  non-viable (86%) and supplied by occluded arteries (77%). [N=47] total occlusion. good coronary collaterals had a high sensitivity (75%) and specificity (65.7%) as well as high positive predictive (75%) and negative predictive values (79%) Angiology 2007;58:550-555 DSE 18 (38.3%)  viable 29 (61.7%)  non-viable significant coronary collateral circulation in viable [66.7% (12 patients)] and non viable [20.7% (6 patients]. Good coronary collaterals sens. (75%) & spec. (65.7%) Dr Nithin P G

30. Benefits of Viability Assessment Dr Nithin P G

31. Meta-analysis J Am Coll Cardiol 2002;39:1151– 8 Late survival with revasc. vs. medical therapy after myocardial viability testing in pts with severe CAD & LV dysfunction 24 studies Thallium, PET & DSE N= 3,088 (2,228 men), EF 32+8%, followed for 25+10 months Late survival with revasc. vs. medical therapy after myocardial viability testing in pts with severe CAD & LV dysfunction 24 studies Thallium, PET & DSE N= 3,088 (2,228 men), EF 32+8%, followed for 25+10 months Dr Nithin P G

32. Meta-analysis Dr Nithin P G

33. Meta-analysis Dr Nithin P G

34. Meta-analysis Drawbacks Most studies very small (n < 100) Not randomized and highly selected Most patients had angina; few had overt symptoms of heart failure Most had only mild LV dysfunction Most reported from imaging labs and surgical services Drawbacks Most studies very small (n < 100) Not randomized and highly selected Most patients had angina; few had overt symptoms of heart failure Most had only mild LV dysfunction Most reported from imaging labs and surgical services Decision for CABG may have been influenced by viability status No (or inadequate) adjustment for key baseline variables (age, comorbidities) Cohort studies carried out before modern aggressive medical therapy Decision for CABG may have been influenced by viability status No (or inadequate) adjustment for key baseline variables (age, comorbidities) Cohort studies carried out before modern aggressive medical therapy Dr Nithin P G

35. PARR2 [N=430]; EF ≤ 35% considered for revascularization, transplant, or HF work ‐ up with high suspicion of CAD. Randomized patients to a PET ‐ guided therapy or “standard care” (no PET). Imaging physicians issued a therapy recommendation based on PET findings and treating physicians then made a decision regarding revascularization. Patients in the standard care arm had no PET, but could have another viability test, which was performed in 138 of 209 (66%) patients. Primary outcome: composite of cardiac death, myocardial infarction, or recurrent cardiac hospitalization within 1 year. [N=430]; EF ≤ 35% considered for revascularization, transplant, or HF work ‐ up with high suspicion of CAD. Randomized patients to a PET ‐ guided therapy or “standard care” (no PET). Imaging physicians issued a therapy recommendation based on PET findings and treating physicians then made a decision regarding revascularization. Patients in the standard care arm had no PET, but could have another viability test, which was performed in 138 of 209 (66%) patients. Primary outcome: composite of cardiac death, myocardial infarction, or recurrent cardiac hospitalization within 1 year. J Am Coll Cardiol 2007;50:2002-2012 Dr Nithin P G

36. PARR2 Hazard ratio 0.78 [95% CI –(0.58 to1.1)] [p= 0.15] Dr Nithin P G

37. PARR2 Hazard ratio 0.62 [95% CI- (0.42 to 0.93)][p=0.019] Dr Nithin P G

38. HEART Trial RCT [N=800] symptomatic HF, EF ≤ 35%, and evidence of substantial myocardial viability to conservative vs. CAG with the intention of revascularization. Stopped early -138 pts enrolled, 69 randomized to revascularization, but only 45 underwent a procedure. RCT [N=800] symptomatic HF, EF ≤ 35%, and evidence of substantial myocardial viability to conservative vs. CAG with the intention of revascularization. Stopped early -138 pts enrolled, 69 randomized to revascularization, but only 45 underwent a procedure. Eur J Heart Fail 2011;13:227-33 Dr Nithin P G

39. HEART Trial A conservative management strategy may not be inferior to one of coronary arteriography with the intent to revascularize in patients with HF, LV systolic dysfunction, and extensive myocardial viability Dr Nithin P G

40. The first prospective randomized trial testing the hypothesis that CABG improves survival in patients with ischemic LV dysfunction [EF- 26.7%±8.6] compared to outcome with aggressive medical therapy Myocardial viability identifies patients with CAD and LV dysfunction who have the greatest survival benefit with CABG compared to aggressive medical therapy The first prospective randomized trial testing the hypothesis that CABG improves survival in patients with ischemic LV dysfunction [EF- 26.7%±8.6] compared to outcome with aggressive medical therapy Myocardial viability identifies patients with CAD and LV dysfunction who have the greatest survival benefit with CABG compared to aggressive medical therapy N Engl J Med 2011;364:1617-25 Dr Nithin P G

41. STICH Trial- substudy All pts eligible for viability testing with SPECT [Tl or Tc] or DSE – Viability testing optional – Criteria for myocardial viability were prospective and pre- specified [SPECT (11/17); DSE (5/16)] Primary endpoint: – All cause mortality Secondary endpoints: – Mortality plus cardiovascular hospitalization – Cardiovascular mortality All pts eligible for viability testing with SPECT [Tl or Tc] or DSE – Viability testing optional – Criteria for myocardial viability were prospective and pre- specified [SPECT (11/17); DSE (5/16)] Primary endpoint: – All cause mortality Secondary endpoints: – Mortality plus cardiovascular hospitalization – Cardiovascular mortality Dr Nithin P G

42. 321 150 130 SPECT 471 DSE 471 1212 618 594 17 611 601 Patients with viability test Patients with usable viability test Pateints with no usable viability test Patients with no viability test Unusable test 487 114 243 244 6054 MED 49.9% MED 49.9% MED 52.6% MED 52.6% CABG 50.1% CABG 47.4% ViableNon-Viable Dr Nithin P G

43. STICH Trial- substudy After multivariate analysis p=0.21 Dr Nithin P G

44. STICH Trial- substudy Dr Nithin P G

45. STICH Trial- substudy Substudy of a major trial Viability study according to the judgement of physician Small number of non viable group for comparison Sx influenced by timing and results of viability test Two types of viability tests-SPECT & DSE Better medical therapy available Combined procedure [CABG + SVR] done probably not optimum In patients with CAD and LV dysfunction, assessment of myocardial viability does not identify patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy Substudy of a major trial Viability study according to the judgement of physician Small number of non viable group for comparison Sx influenced by timing and results of viability test Two types of viability tests-SPECT & DSE Better medical therapy available Combined procedure [CABG + SVR] done probably not optimum In patients with CAD and LV dysfunction, assessment of myocardial viability does not identify patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy Dr Nithin P G

46. Conclusions Dr Nithin P G

47. Conclusions Limitations in study design and test inaccuracies -prevented the detection of a true interaction b/w viability & benefit of revascularization Advances in medical therapy markedly reduced the added benefit of revascularization The critical information may not lie in the presence but rather in the absence of viability. The benefit of CABG may only be related to revascularization of potentially ischemic segments. The greatest benefit of CABG may be limited to those patients with more advanced forms of the disease[those with relatively small amount of viable myocardium] Limitations in study design and test inaccuracies -prevented the detection of a true interaction b/w viability & benefit of revascularization Advances in medical therapy markedly reduced the added benefit of revascularization The critical information may not lie in the presence but rather in the absence of viability. The benefit of CABG may only be related to revascularization of potentially ischemic segments. The greatest benefit of CABG may be limited to those patients with more advanced forms of the disease[those with relatively small amount of viable myocardium] Dr Nithin P G

48. Conclusions Currently available evidence does not support the use of viability testing as the arbitrator in the decision making process regarding revascularization in ischemic cardiomyopathy Ischemic cardiomyopathy [heterogeneous population]  multiple factors play important prognostic role. Viability alone cannot provide an unequivocal answer Prospective trials demystify the emphasis previously placed – without appropriate evidence‐‐ in the significance of myocardial viability These observations urge physicians to consider the multiplicity of factors involved in the decision making process in this complex population of patients. Currently available evidence does not support the use of viability testing as the arbitrator in the decision making process regarding revascularization in ischemic cardiomyopathy Ischemic cardiomyopathy [heterogeneous population]  multiple factors play important prognostic role. Viability alone cannot provide an unequivocal answer Prospective trials demystify the emphasis previously placed – without appropriate evidence‐‐ in the significance of myocardial viability These observations urge physicians to consider the multiplicity of factors involved in the decision making process in this complex population of patients. Dr Nithin P G

49. Thank you Dr Nithin P G