Revascularization in Patients With Left Ventricular Dysfunction: Lessons From STICH Robert O. Bonow, MD, MS Northwestern University Feinberg School of Medicine Bluhm Cardiovascular Institute Northwestern Memorial Hospital Editor-in-Chief JAMA Cardiology No Relationships to Disclose

Prognosis in Chronic CAD Influence of LV Ejection Fraction 80 74% 65% 62% 60 56% 50% 10 Year Survival Rate (%) 40 27% 20 Medical Surgical Medical Surgical Medical Surgical EF >50% EF 35-50% EF <35% from Muhlbaier et al, Circulation 1992;86:II-198

Prognosis in Chronic CAD Influence of LV Ejection Fraction 100 EF >50% 80 EF 35-49% 60 Survival (percent) 40 EF <35% 20 p<0.001 2 4 6 8 10 12 14 Years Emond et al, Circulation 1994;90:2654-2657

Prognosis in Chronic CAD Effect of Revasularization 100 Patients with EF <35% 80 CABG 60 Survival (percent) 40 Medical 20 p<0.001 1 2 3 4 5 6 Years Alderman et al, Circulation 1983;68:785-795

Prognosis in Ischemic LV Dysfunction Increase in Survival by Revascularization 60 57% 55% 50 44% 41% 40 37% 30% Increase in Survival (%) 30 20 10% 10 Vliestra Alderman Manley Pigott Bounous Faulkner 1977 1983 Muhlbaier 1976 1992 1985 1988 1977

Prognosis in Ischemic LV Dysfunction Increase in Survival by Medical Therapy 100 90% [70,96] 80 77% [43,91] 60 Increase in Survival (%) 40 38% [20,68] 20 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

STICH Trial Median age 59 years Median LVEF 29% Men 88% Diabetes 40% Prior heart failure 95% Prior PCI or CABG 12%

Years After Randomization STICH Primary Outcome All-Cause Mortality 0.8 Medical therapy CABG 1212 patients EF <35% 0.6 HR 95% CI 0.86 0.72.1.04 P = 0.123 Medical therapy Mortality Rate 0.4 CABG 0.2 1 2 3 4 5 6 Years After Randomization Velazquez et al. N Engl J Med 2011;364:1607-1616

STICH Secondary Outcome Cardiovascular Mortality 0.8 Medical therapy CABG 1212 patients EF <35% 0.6 HR 95% CI 0.81 0.66.1.00 P = 0.050 CV Mortality Rate 0.4 Medical therapy CABG 0.2 1 2 3 4 5 6 Years After Randomization Velazquez et al. N Engl J Med 2011;364:1607-1616

STICH Secondary Outcome Death + CV Hospitalization 0.8 Medical therapy CABG Medical therapy 0.6 HR 95% CI 0.74 0.64.0.85 CABG P <0.001 Death or CV Hospitalization 0.4 0.2 1 2 3 4 5 6 Years After Randomization Velazquez et al. N Engl J Med 2011;364:1607-1616

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

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

1212 602 610 592 620 537 555 55 18 Randomized medicine Randomized CABG Received medicine Received CABG 592 620 Velazquez et al. N Engl J Med 2011;364:1607-1616

STICH Secondary Outcome All-Cause Mortality – Treatment Received 0.8 Medical therapy CABG 0.6 HR 95% CI 0.70 0.58,0.84 Medical therapy P <0.001 Mortality Rate 0.4 CABG 0.2 1 2 3 4 5 6 Years After Randomization Doenst et al. Circ Heart Fail 2013;6:443-450 Velazquez et al. N Engl J Med 2011;364:1607-1616

STICH Secondary Outcome All-Cause Mortality – Per Protocol 0.8 Medical therapy CABG 0.6 HR 95% CI 0.76 0.62,0.92 Medical therapy P = 0.005 Mortality Rate 0.4 CABG 0.2 1 2 3 4 5 6 Years After Randomization Doenst et al. Circ Heart Fail 2013;6:443-450 Velazquez et al. N Engl J Med 2011;364:1607-1616

Is STICH a negative trial or a positive trial? STICH Quality of LIfe KCCQ: Overall Summary KCCQ Overall Summary 80 CABG + Medical CABG 75 Medical alone Medical 70 65 Is STICH a negative trial or a positive trial? 60 Baseline 4 mo 12 mo 24 mo 36 mo Mark et al, Ann Intern Med 2014;161:392-399

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

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Myocardial viability 0.8 Without Viability With Viability MED (33 deaths) 0.56 MED (95 deaths) 0.6 CABG (25 deaths) CABG (83 deaths) 0.35 0.4 Mortality Rate 0.42 0.31 0.2 Interaction P value 0.528 1 2 3 4 5 6 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Bonow et al. N Engl J Med 2011;364:1617-1635

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Myocardial viability The Heart Trial 0.8 With Viability With Viability Medical therapy (n=69) MED (95 deaths) 0.6 Revascularization (n=69) CABG (83 deaths) 0.35 0.4 n=138 Mortality Rate p=NS 0.31 0.2 1 2 3 4 5 6 1 2 3 4 5 6 Years Following Randomization Years Following Randomization from Cleland et al, Eur J Heart Fail 2011;13:227-233 Bonow et al. N Engl J Med 2011;364:1617-1635

Patients with ESVI ≤84 ml/m2 Bonow et al, JACC Cardiovasc Imaging 2015;8:1121-1129

Patients with ESVI >84 ml/m2 Bonow et al, JACC Cardiovasc Imaging 2015;8:1121-1129

Revascularization vs Medical Therapy in Patients with Left Ventricular Dysfunction 80 n=306 p=NS 60 Medical 3-Year Mortaltiy (%) 40 Revascularization 20 10 20 30 40 50 Amount of Compromised Viable Myocardium (%) from Tarakji et al, Circulation 2006;113:230-237

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

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Myocardial ischemia No Ischemia Ischemia 0.6 MED (31 deaths) MED (56 deaths) CABG (22 deaths) CABG (47 deaths) 0.39 0.39 0.4 Mortality Rate 0.35 0.33 0.2 1 2 3 4 5 6 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Panza et al. J Am Coll Cardiol 2013;61:1860-1870

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

Myocardial Revascularization in Patients with LV Dysfunction The STICH Trial: Are there subsets who benefit from CABG? Functional capacity PAS >55 + 6MW ≥300m PAS ≤55 + 6MW <300m 0.6 MED MED CABG CABG 0.39 HR 95% CI P value HR 95% CI P value 0.4 0.71 0.52,0.97 0.033 0.95 0.75,1.19 0.626 Mortality Rate P=0.033 P=0.626 0.33 0.2 1 2 3 4 5 6 1 2 3 4 5 6 Years Following Randomization Years Following Randomization 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? CAD severity, EF, ESV 0.8 2 – 3 Factors 0 – 1 Factor MED (31 deaths) MED (56 deaths) 0.6 CABG (22 deaths) 0.51 CABG (47 deaths) 0.39 0.39 HR 95% CI P value HR 95% CI P value 0.4 0.71 0.36,0.89 0.033 1.08 0.81,1.44 0.626 Mortality Rate 0.30 P=0.0004 0.39 P=0.591 0.35 0.33 0.2 0.30 1 2 3 4 5 6 1 2 3 4 5 6 Years Following Randomization Years Following Randomization Panza et al. J Am Coll Cardiol 2014;64:553-561

Myocardial Revascularization in Patients with LV Dysfunction Factors to consider: • Severity of LV dysfunction • Severity of LV remodeling • Angiographic severity of CAD • Functional capacity • Extent of myocardial viability • Severity of myocardial ischemia • Biomarkers \ More important Less important Velazquez and Bonow. J Am Coll Cardiol 2015;65:615-624

STICHES (STICH Extention) 1212 patients with EF <35% Mean follow-up 9.8 years Final ascertainment in 98% Primary Endpoint: All-cause mortality Secondary Endpoints: CV mortality Death + CV hospitalization

Years After Randomization STICH Primary Outcome All-Cause Mortality 0.8 Medical therapy CABG 1212 patients EF <35% 0.6 Medical therapy Mortality Rate 0.4 CABG HR 95% CI 0.86 0.72 1.04 0.2 P = 0.123 2 4 6 8 10 Years After Randomization Velazquez et al. N Engl J Med 2011;364:1607-1616

STICHES Primary Outcome Years After Randomization All-Cause Mortality 0.8 Medical therapy CABG 1212 patients EF <35% 0.6 HR 95% CI 0.86 0.72.1.04 Medical therapy Mortality Rate 0.4 CABG HR 95% CI 0.84 0.73 0.97 0.2 P = 0.020 2 4 6 8 10 Years After Randomization Velazquez et al. N Engl J Med 2016;374:1511-1520

STICHES Secondary Outcome Cardiovascular Mortality 0.8 Medical therapy CABG 1212 patients EF <35% 0.6 HR 95% CI 0.86 0.72.1.04 Medical therapy Mortality Rate 0.4 CABG HR 95% CI 0.79 0.66 0.93 0.2 P = 0.006 2 4 6 8 10 Years After Randomization Velazquez et al. N Engl J Med 2016;374:1511-1520

STICHES Secondary Outcome All-Cause Mortality – Treatment Received 0.8 Medical therapy CABG 1212 patients EF <35% 0.6 HR 95% CI 0.86 0.72.1.04 Medical therapy Mortality Rate 0.4 CABG HR 95% CI 0.75 0.65 0.87 0.2 P < 0.001 2 4 6 8 10 Years After Randomization Velazquez et al. N Engl J Med 2016;374:1511-1520

STICHES Secondary Outcome Death + CV Hospitalization 1.0 Medical therapy CABG 1212 patients EF <35% 0.8 Medical therapy 0.6 CABG Mortality Rate 0.4 HR 95% CI 0.72 0.64 0.82 0.2 P < 0.001 2 4 6 8 10 Years After Randomization Velazquez et al. N Engl J Med 2016;374:1511-1520

Implications of STICH Extention Study Patients with HF and CAD remain at substantial risk despite excellent medical adherence - 68% 10-year mortality risk CABG added to medical therapy leads to a robust, durable reduction in all-cause mortality Number needed to treat: To prevent 1 death = 14 patients To prevent 1 CV death = 11 patients Among patients with HF and LVD, a diagnostic approach to evaluate the extent and severity of CAD and potential for CABG should be strongly considered