Revascularization in Severe LV Dysfunction: The Role of Inducible Ischemia and Viability Testing

Revascularization in Severe LV Dysfunction: The Role of Inducible Ischemia and Viability Testing Evidence and Uncertainties Robert O. Bonow, MD, MS, MACC Northwestern University Feinberg School of Medicine Northwestern Memorial Hospital

CAD and Heart Failure Indications for revascularization: Medically intractable angina Left main disease 3-vessel disease 2-vessel disease with proximal LAD stenosis ESC 2010 Guidelines on Myocardial Revascularization ACC/AHA 2011 Guidelines for Coronary Artery Bypass Graft Surgery ACC/AHA 2013 Guideline for Management of Heart Failure

10 Year Survival Rate (%) Prognosis in Chronic CAD Influence of LV Ejection Fraction 8080 74% 60 60 65% 50% 62% 56% 40 40 27% 20 20 0 0 Medical Surgical Medical Surgical Medical Surgical EF >50% EF 35-50% EF <35% from Muhlbaier et al, Circulation 1992;86:II-198

Increase in Survival (%) Prognosis in Ischemic LV Dysfunction Increase in Survival by Revascularization 60 55% 57% 50 40 37% 41% 44% 30 30% 20 10 10% 0 0

Increase in Survival (%) Prognosis in Ischemic LV Dysfunction Increase in Survival by Medical Therapy 100 9 80 8 7 77% [43,91] 90% [70,96] 60 6 5 40 4 3 20 2 38% [20,68] 1 0 0 ACEi / ARB ACEi / ARB + β blocker ACEi / ARB + β blocker + ICD / CRT from Yancy CW, J Am Heart Assoc 2012;1:16-26

Surgical Treatment for Ischemic Heart Failure

STICH Trial 1212 patients with EF <35% 99 sites in 22 countries Primary Endpoint: All-cause mortality Secondary Endpoints: CV mortality Death + CV hospitalization Death + HF hospitalization

STICH Primary Outcome All-Cause Mortality Medical therapy CABG HR 95% CI P 0.86 0.72,1.04 0.123 Velazquez et al. N Engl J Med 2011;364:1607-1616

STICH Secondary Outcome Cardiovascular Mortality Medical therapy CABG HR 95% CI P 0.81 0.66,1.00 0.050 Velazquez et al. N Engl J Med 2011;364:1607-1616

STICH Secondary Outcome Death + CV Hospitalization Medical therapy CABG HR 95% CI P 0.74 0.64,0.85 <0.001 Velazquez et al. N Engl J Med 2011;364:1607-1616

1212 Randomized medicine 602 610 Randomized CABG Velazquez et al. N Engl J Med 2011;364:1607-1616

1212 Randomized medicine 602 610 Randomized CABG 537 55 Early crossover Received medicine 592 Velazquez et al. N Engl J Med 2011;364:1607-1616

1212 Randomized medicine 602 610 Randomized CABG 537 Early crossover 55 65 555 Received medicine 592 620 Received CABG Velazquez et al. N Engl J Med 2011;364:1607-1616

STICH Secondary Outcome All Cause Mortality Treatment Received Medical therapy CABG HR 95% CI P 0.70 0.58,0.84 <0.001 Doenst et al. Circ Heart Fail 2013;6:443-450

STICH Secondary Outcome All Cause Mortality Per Protocol Medical therapy CABG HR 95% CI P 0.76 0.62,0.92 0.005 Doenst et al. Circ Heart Fail 2013;6:443-450

STICH Quality of LIfe KCCQ: Overall Summary KCCQ Overall Summary 80 75 70 80 75 70 CABG + Medical CABG Medical alone Medical 65 65 60 60 55 Baseline 4 mo 12 mo 24 mo 36 mo 0 1 2 3 Mark et al, Ann Intern Med 2014;161:392-399

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Is STICH a positive trial or a negative trial?

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG?

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Myocardial viability

Mortality Rate (%/year) Myocardial Viability and Improved Survival 20 Revascularization 16.0 Medical 15 10 7.7 6.2 24 studies n=3088 EF=32.9% 5 3.2 0 n=748 n=557 n=330 n=734 Viable Non-Viable Allman et al, J Am Coll Cardiol 2002;39:1151-1158

Mortality Rate (%/year) Myocardial Viability and Improved Survival 20 p<0.001 Revascularization 16.0 Medical 15 10 7.7 6.2 24 studies n=3088 EF=32.9% 5 3.2 0 n=748 n=557 n=330 n=734 Viable Non-Viable Allman et al, J Am Coll Cardiol 2002;39:1151-1158

Mortality Rate (%/year) Myocardial Viability and Improved Survival 20 15 10 5 3.2 16.0 7.7 p=ns Revascularization Medical 6.2 24 studies n=3088 EF=32.9% 0 n=748 n=557 n=330 n=734 Viable Non-Viable Allman et al, J Am Coll Cardiol 2002;39:1151-1158

Mortality Rate (%/year) Myocardial Viability and Improved Survival 20 Revascularization Medical 15 10 10.8 7.7 9.5 28 studies n=3531 EF=31.5% 5 0 3.5 n=955 n=854 n=778 n=944 Viable Non-Viable from Schinkel et al, Curr Prob Cardiol 2007;32:375-410

Mortality Rate (%/year) Myocardial Viability and Improved Survival 20 Revascularization Medical 15 10 10.6 8.5 11.7 13 studies n=2433 EF=29.9% 5 3.7 0 n=699 n=595 n=423 n=500 Viable Non-Viable from Camici et al, Circulation 2008;117:103-114

Limitations of Cohort Studies Retrospective Heteropgeneous methodology 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

LV Ejection Fraction (percent) 50 50 45 40 40 35 30 30 25 20 20 15 10 10 5 00 32.9% 31.5% 29.9% 26.7% n=3088 n=3531 n=2433 n=601 Allman Schinkel Camici STICH Allman et al, J Am Coll Cardiol 2002;39:1151-1158 Schinkel et al. Curr Prob Cardiol 2007;32:375-410 Camici et al. Circulation 2008;117:103-114 Bonow et al. N Engl J Med 2011;364:1617-1635

Mortality Rate (%/year) Medical Therapy in Patients with Viable Myocardium 20 20 15 15 16% 10 10 55 10.8% 10.1% 7.1% 00 n=557 n=854 n=595 n=243 Allman Schinkel Camici STICH Allman et al, J Am Coll Cardiol 2002;39:1151-1158 Schinkel et al. Curr Prob Cardiol 2007;32:375-410 Camici et al. Circulation 2008;117:103-114 Bonow et al. N Engl J Med 2011;364:1617-1635

Myocardial Viability and Mortality Bonow et al. N Engl J Med 2011;364:1617-1635

Myocardial Viability and Mortality 38% Bonow et al. N Engl J Med 2011;364:1617-1635

Event Rate Mortality + CV Hospitalization 85% 80% 72% 55% N Events HR 95% CI 114 96 0.84 0.56, 1.25 487 326 0.68 0.55, 0.84 Interaction P value 0.390 Bonow et al. N Engl J Med 2011;364:1617-1635

STICH Trial in Context Viability Testing: Alive and Well Viability testing does identify high risk patient subgroups and predicts: Response to beta blocker therapy Response to revascularization Viability testing should not be considered a prerequisite for decisions regarding medical versus surgical management in patients with ischemic LV dysfunction

3-Year Survival (%) Revascularization vs Medical Therapy in Patients with Left Ventricular Dysfunction 800 600 n=306 Medical p=ns 400 40 200 20 Revascularization 0 0 10 20 30 40 50 1 2 3 4 Amount of Compromised Viable Myocardium (%) from Tarakji et al, Circulation 2006;113:230-237

Survival (percent) 100 80 Revascularization vs Medical Therapy in Patients with Myocardial Viability n=138 p=ns 60 40 20 Revascularization (n=69) Medical therapy (n=69) 0 0 1 2 3 4 1 2 3 4 Time (years) 5 from Cleland et al, Eur J Heart Fail 2011;13:227-233

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Myocardial ischemia

Mortality Rate Myocardial Ischemia and Mortality 1.0 0.8 No Ischemia MED (31 deaths) CABG (22 deaths) Ischemia MED (56 deaths) CABG (47 deaths) 0.6 0.4 0.39 0.39 0.2 0.33 0.35 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Subgroup Without ischemia With ischemia N Deaths HR 95% CI 143 58 0.72 0.42, 1.25 256 103 0.83 0.56, 1.23 0.25 CABG better 0.50 1.00 2.00 MED better Interaction P value 0.643 Panza et al. J Am Coll Cardiol 2013;61:1860-1870

Log hazard ratio Impact of Ischemia and Scar on Therapeutic Benefit of Coronary Revascularization N=13,555 P<0.001 Total myocardium ischemic (%) Medical therapy Early revascularization Hachamovich et al, Eur Heart J 2011;32:1012-1024

Log hazard ratio Impact of Ischemia and Scar on Therapeutic Benefit of Coronary Revascularization N=13,555 P<0.001 Magnitude of ischemic myocardium associated with survival benefit with revascularization Total myocardium in ischemic (%) patients without prior MI No such benefit in patients with prior MI Role of ischemia not significant in patients with >10% myocardial scar Hachamovich et al, Eur Heart J 2011;32:1012-1024 Medical therapy Early revascularization

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Biomarkers?

Mortality Rate Brain Natriuretic Peptide Levels 0.8 0.6 0.4 P<0.001 CABG BNP tertile HR 95% CI Tertile 1 Tertile 1 Tertile 2 Tertile 2 Tertile 3 Tertile 3 0.394 P<0.001 Medicine BNP tertile HR 95% CI T2 : T1 2.02 1.23,3.34 T2 : T1 1.94 1.21,3.09 T3 : T1 3.05 1.87,4.05 T3 : T1 2.43 1.52,3.87 0.392 0.2 0.329 0.348 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Feldman et al, Circ Heart Fail 2013;6:461-472

Mortality Rate Tumor Necrosis Factor-α Receptor-1 0.8 0.6 0.4 Tertile 1 Tertile 2 Tertile 3 CABG 0.394 Medicine TNFR1 tertile HR 95% CI TNFR1 tertile HR 95% CI P<0.001 T2 : T1 1.45 0.90,2.34 T3 : T1 2.51 1.59,3.96 P<0.001 Tertile 1 Tertile 2 Tertile 3 T2 : T1 1.36 0.83,2.20 T3 : T1 2.32 1.48,3.63 0.392 0.2 0.329 0.348 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Feldman et al, Circ Heart Fail 2013;6:461-472

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Functional capacity?

Mortality Rate 6-Minute Walk and Physical Activity Score 0.8 0.6 0.4 PAS >55 + 6MW 300m MED CABG Hazard ratio 95% CI P-value 0.71 0.52,0.97 0.033 PAS 55 + 6MW <300m MED CABG Hazard ratio 95% CI P-value 0.95 0.75,1.19 0.626 0.392 0.30 0.2 0.30 0.348 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Interaction P value = 0.167 Stewart et al. JACC Heart Fail 2014;2:335-343

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Severity of CAD and LV remodeling?

Mortality Rate Extent of CAD, EF, ESV and Mortality 0.8 0.6 2 3 Factors MED (31 deaths) CABG (22 deaths) Hazard ratio 95% CI P-value 0.71 0.36,0.89 0.0004 0.51 0 1 Factor MED (56 deaths) CABG (47 deaths) Hazard ratio 95% CI P-value 1.08 0.81,1.44 0.591 0.4 0.394 0.39 0.392 0.30 0.2 0.30 0.329 0.348 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Interaction P value = 0.022 Panza et al. J Am Coll Cardiol 2014;64:553-561

Myocardial Revascularization in Patients with LV Dysfunction Factors to consider: More important Severity of LV dysfunction Severity of LV remodeling Angiographic severity of CAD Functional capacity Less important Extent of myocardial viability Severity of myocardial ischemia Biomarkers

Patients with LV dysfunction CABG CABG PCI

Patients with chronic heart failure and systolic left ventricular dysfunction (ejection fraction 35%) presenting predominantly with heart failure symptoms

Mild to moderate LV systolic dysfunction (EF 35% to 50%) class IIa CABG to improve survival is reasonable in patients with significant multivessel CAD or proximal LAD coronary artery stenosis when viable myocardium is present in the region of intended revascularization. (LOE: B) Severe LV systolic dysfunction (EF <35%) class IIa CABG or medical therapy is reasonable to improve morbidity and CV mortality in patients with significant CAD. (LOE: B)

class I 1. Hypertension and lipid disorders should be controlled in accordance with contemporary guidelines to lower the risk of HF. (LOE: A) 2. Other conditions that can lead or contribute to HF, such as obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents, should be controlled or avoided. (LOE: A) class I 1. In all patients with recent of remote history of MI or ACS and reduced EF, ACE inhibitors, evidence-based beta blockers, and statins should be used to prevent symptomatic HF and reduce mortality. (LOE: A)