TO REVASCULARIZE OR NOT TO REVASCULARIZE: IMAGING FOR DECISION-MAKING IN ISCHEMIC CARDIOMYOPATHYLisa M Mielniczuk MD FRCPCAssociate Professor of Medicine, University of Ottawa Heart InstituteUniversity of Ottawa Chair in Heart Function ResearchVice Chair, Patient Quality, Safety and Innovation, Department of Medicine, Ottawa HospitalDirector, Advanced Heart Disease Program

TO REVASCULARIZE OR NOT TO REVASCULARIZE: IMAGING FOR DECISION-MAKING IN ISCHEMIC CARDIOMYOPATHYLisa M Mielniczuk MD FRCPCAssociate Professor of Medicine, University of Ottawa Heart InstituteUniversity of Ottawa Chair in Heart Function ResearchVice Chair, Patient Quality, Safety and Innovation, Department of Medicine, Ottawa HospitalDirector, Advanced Heart Disease Program Disclosures•Novartis (consultant fees, speakers fees, research funding)•Servier (consultant fees, speakers fees, research funding)•Amgen (consultant fees, research funding) A Clinical Case: Mr. GS•56 year old male•Known CAD•Felt inoperable from previous angiogram 5 years previously•HTN•Dyslipidemia•PVD•Smoker/significant EtOH•ICD for primary prevention with recent appropriate shock for VT §Referred for progressive HF symptoms§FC III§No chest pain, no recent ACS§On Exam:§BP 95/60§HF 70§No evidence of significant volume overload§Medications§Bisoprolol10 mg daily§Ramipril10 mg daily§Sprionolactone25 mg daily§Lasix40 mg daily§ASA§Crestor40 mg daily ECG Echocardiogram Coronary Angiogram•99% proximal LAD with diffuse disease distally•RCA 90%•OM1 (large) occluded•LCxdiffuse moderate-severe disease PET Viability Results One Year Later: §Returned to work as a part-time machinist§FC II§No further HF symptoms Refining Risk and Maximizing BenefitMedical therapy better equipoise Surgical therapy better highabnormallownormalIntensityNormalcy CADangina agescarLVEF / HF symptoms Adapted from Rouleau: Can J Cardiol2014; 281-287 Clinical Judgment and Experience HEARTPARR-2STICH Where is the Evidence that a Viability Based Strategy Improves Long-Term Outcomes? Stunning, Hibernation and Viability Viability Hibernation revascularization Flow limiting stenosis no irreversible damage Reduced MBF and MFR Triad of Hibernation Spectrum of Myocardial Dysfunction in Ischemic Cardiomyopathy Repetitive ischemiaPersistent Repetitive ischemiaCell death Normal myocardiumStunnedmyocardiumHibernatingmyocardiumMyocardial ScarSevere CADCFRCRPERFMETSCARXCFRCRPERFMETSCARê XCFRCRPERFMETSCARêê↔↔XCFRCRPERFMETSCARêêêXXXAdapted from:ShahEurHeart J; 2013:34:1323 Multiple Modalities Available to Assess for “Viability” Schinkel; CurrProbCardiol2007;32:375 Imaging Modalities to Assess Myocardial ViabilityModalityMechanismFindings to Suggest ViabilityAdvantages/DisadvantagesCMRLGE Wall thicknessLGE<50% wall thicknessSystolic thickening of a dyskineticsegmentA: highly sensitive, no radiation,assess valvesD: limited availability, cost, devices, renal failureDobutamineecho (CMR)Contractile reserveImprovementby visual or strain rate imagingA: highlyspecific, widely available, no radiation, assess ischemiaD: interobservervariability, dobuatminerisksSPECT Thallium-201Perfusion: sarcolemmamembraneintegrity (K analogue)Tracer uptake:>50%of maxA: available, moderate costD: radiationdose, moderate sensitivity with low specificityTechnietium-99mlabeled tracersMitochondrialmembrane integrity>50-65%maximumA: available, costD: moderate accuracyPETPerfusion: 13NH3, 82Rb, 150-waterGlucose utilization: FDGFlow-metabolism mismatch = hibernationMatch=nonviableA: highlysensitiveD: limited availability, high cost, complex in diabetics How Do I Pick a Test?•Moderate LV dysfunction –any modality with local expertise•Severe LV dysfunction –nuclear methods (SPECT, PET) or CMR LGE –more sensitive than contractile reserve•Renal failure (GFR<30) or CMR incompatible devices –avoid CMR•Critical left main or proximal 3VD –avoid dobutamine•Equivocal or negative results on another viability test –consider PET or CMR as highly sensitive methods Effect of Revascularization on Mortality Allman, JACC 2002 Effect of Revascularization on Mortality in Patients with Viability Inaba, et al. J NucCardol2010;17(4) 646 Effect of Revascularization on Mortality in Patients with NO Viability Inaba, et al. J NucCardol2010;17(4) 646 GroupWeightedAverage Annual Mortality (95%CI)Medicaltherapy –viability present10.64(8.17 -13.12)Medical therapy –viability absent11.69(8.87 –14.51)Revascularization–viability present3.71 (2.31, 5.12)Revascularization–viability absent8.45 (5.80, 11.10) Limitations of the literature on viability testingÒNonrandomized studies with small sample sizesÒReferral and selection biasÒLack of uniformity of medical therapyÒLack of head-to-head comparisons between techniquesÒNo evaluation of graft/vessel patency at time of post revascularization functional assessmentÒUnknown duration and severity of LV dysfunction prior to revascularizationÒFrequent exclusion of patients who did not get revascularizedor died during revascularization Viability Testing and Prognosis: The PARR 2 Trial Time to Cardiac Death Time to Composite Endpoint(CV death, MI, cardiac admission) Beanlands; JACC 2007;50:2002 Adherence to Recommendations HR 0.6295% CI 0.42 to 0.93P=0.019 Beanlands; JACC 2007;50:2002 Time to Composite Endpoint Long Term Follow-Up of PARR-2 Whole CohortPatients who Adhered to Imaging Recommendations P=0.15P=0.04 McCardleat al. Circ CV Imag2016 Increasing Benefit with Increasing Hibernation D’EgidioJACC 2009;2:1060 Increasing Benefit with Increasing Hibernation D’EgidioJACC 2009;2:1060 Velazquez, et al N EnglJ Med 2011, April STICH Results CV Death: 28% CABG vs. 33% medical CV Death/admission: 58% CABG vs. 68% medical STICHES Long Term Extension Study Velazquez, et al N EnglJ Med 2016; 374:1511-20 STICH Viability Bonowet al. N EnglJ Med 2011; April Mortality 56% medical vs. 41% CABGMortality 35% medical vs. 31% CABG Comparing STICH to PARR2VariableSTICH Sub-studyPARR2Patient populationRandomized?No YesMeanage(years)60.7 63MaleSex(%) 85 84PreviousCABG(%) 3 19Multi-vesseldisease(%) 75 90DM(%) 39 39GFR<60(%) 7.5 34Meanserumcreatinine 108MeanLVEF 27 26Viability testingSPECT or dobutamineecho81% viablePET22% viableReport No report of ischemia or hibernationIschemia/hibernation reported What Other Clinical Factors Can Help Guide Us in Decision Making? Extent of Disease May Predict Benefit CENTRAL ILLUSTRATION. Schematic Representation of the Clinical Implications of the Present Study Findings *These thresholds are simply the medians of the LV function variables in the present study and have not been validated prospectively in an independent patient population. This algorithm should only be applied conceptually to support the notion that, among patients with ischemic LV systolic dysfunction, the benefit of surgical revascularization is greater when the disease process is more advanced (see text for more detail). CAD= coronary artery disease; EF= ejection fraction; ESVI= end-systolic volume index. Panza et al. Page 19 J Am Coll Cardiol . Author manuscript; available in PMC 2015 August 12. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Panza; J Am CollCardiol2014; 64:553 Extent of Disease May Predict Benefit Figure 3. Kaplan-Meier rate estimates of all-cause mortality among patients with 2–3 (top panel) and 0–1 (bottom panel) prognostic factors In each panel, study patients are divided according to the treatment arm (CABG or OMT) to which they were randomized. Panza et al. Page 14 J Am Coll Cardiol. Author manuscript; available in PMC 2015 August 12. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Panza et al. Page 17 J Am Coll Cardiol. Author manuscript; available in PMC 2015 August 12. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Panza; J Am CollCardiol2014; 64:553 Is Ischemia Testing Relevant? Panza; J Am Col Cardiol2013; 61: 1860 Inducible Ischemia vs. Hibernating Myocardium Ling; Circ CV Imaging 2013; 6:363 Does The Presence of Angina Matter? from CABG ( Central Illustration ). Although mortality was lower in patients assigned to CABG who did not have angina, the interaction between assigned treat- ment and angina at baseline was not signi ficant. When crossovers were considered, the observed reduction in mortality with CABG was signi ficant and of similar magnitude in pa tients with and without angina. Finally, as may be expected, CABG improved angina compared with medical therapy alone. These findings have important clin ical implications given the paucity of prior evidence to guide decision mak- ing in patients with angina and LV systolic dysfunction. Among patients with severe LV dysfunction, CABG is associated with an early risk of serious complica- tions, including death (16) .F i n d i n g sf r o mt h i ss t u d y challenge the perceived bene fit-risk balance for CABG in patients with and without angina. Although revascularization should be considered for symptom relief for patients with heart failure and angina recalcitrant to pharmacological therapy, this analysis suggests that insofar as subsequent prognosis is concerned, the presence or absence of angina should not be used as a discriminating factor to decide for or against revascularization as an initial treatment FIGURE 2 Adjusted Cox Proportional Hazards Estimates of the Cumulative Risk of All-Cause Mortality According to Angina Status and Treatment Arm 0.5 0.4 0.3 0.2 0.1 0 Cumulative Risk of All–Cause Death 0.5 0.4 0.3 0.2 0.1 0 Cumulative Risk of All–Cause Death 012345 Years from Randomization 0123 45 Years from Randomization No. at Risk CABG Medical therapy alone 217 225 189 196 175 180 167 161 133 118 74 57 No. at Risk CABG Medical therapy alone 393 377 343 335 311 305 292 272 101 97 207 192 Medical therapy alone CABG Medical therapy alone CABG No Angina at Baseline Angina at Baseline Subgroup Angina at Baseline No Angina at Baseline No. 770 442 Deaths 296 167 Hazard Ratio (95% CI) 0.89 (0.71, 1.13) 0.68 (0.50, 0.94) p Value for Interaction 0.14 0.50 0.75 1.00 1.25 1.50 1.75 2.00 CABG Better Medical Therapy Better AB C The effect of coronary artery bypass graft (CABG) surgery was similar whether the patient had angina (hazard ratio [HR]: 0.89; 95% con fidence interval [CI]: 0.71 to 1.13) or not (HR: 0.68; 95% CI: 0.50 to 0.94) (A and B) (p interaction ¼0.14) (C). Analyses adjusted for left ventricular ejection fraction, age, body mass index (above or below 35 kg/m 2 ), log of creatinine (0 to 0.4), peripheral vascular disease, mitral regurgitation, use of beta-blockers at baseline, and atrial fibrillation/ flutter. TABLE 3 Odds Ratios of Worsening Angina for Patients Treated With CABG Compared With Patients Treated With Medical Therapy Alone Models OR (95% CI) p Value Unadjusted data 0.70 (0.55 –0.89) <0.01 Third principal model * 0.70 (0.55 –0.90) <0.01 Sensitivity analyses 1. Proportional odds model (angina as 3-level categorical variable) † 0.69 (0.55 –0.87) <0.01 2. Third principal model with adjustment for anti-anginal medication post-randomization 0.78 (0.60 –1.00) 0.05 3. Worst-case scenario 0.77 (0.61 –0.98) 0.03 Of the 1,212 patients randomized in STICH, 1,089 with angina assessed at least once after randomization were included in the statistical model. *The model is the final adjusted binary logistic regression model. The model remained stable after internal validation (OR: 0.69; 95% CI: 0.54 to 0.89), and after crossover patients were taken into consideration (OR: 0.57; 95% CI: 0.45 to 0.74; p <0.01). †Proportional odds model de fines angina relief as an ordinal 3-level categorical variable with values representing worsening angina, stable angina, and angina relief. The odds ratio supplied is predicting the probability of angina relief averaging over worsening angina and stable angina. OR ¼odds ratio; other abbreviations as in Tables 1 and 2 . JACC VOL. 66, NO. 19, 2015 Jolic œur et al . NOVEMBER 10, 2015:2092 –100 The STICH Angina Analysis 2097 Jolcoeuret al. J Am CollCardiol2015; e pub IMAGE 1A Study: AIMI-HF Study: RCT Evaluating Standard vs. Advanced Imaging in Patients with Ischemic CM O’Meara E, Mielniczuk LM et al. Trials 2013; 14:332 Can Biomarkers Aid in Decision Making? ZeltJE, Mielniczuk LM, Can J Cardiol2017; 1478-88 Can Biomarkers Aid in Decision Making? ZeltJE, Mielniczuk LM, Can J Cardiol2017; 1478-88 Coronary Disease Spectrum Severe LV dysfunction•Significant scar•Predominant HF symptomsNormal LV function•Significant CAD•Presence of angina •Some degree of LV dysfunction•Mixture of hibernating myocardium•Evidence of ischemia or symptoms of angina Patients with severe CAD:•Only demonstration of viability may be necessaryMild-moderate CAD•Ischemia testing may be of benefit Decision Making for Viability AssessmentsViabilityTesting Unlikely to Add Useful InformationViability Testing May Be HelpfulYounger patientsOlder patientsHFrEFwith >classII anginaHFrEFwith no anginaModerate-severe ischemia on provocativetestingNo evidence of ischemiaEF>40%EF<40%Left main coronary diseaseChronic total occlusionsNo or limited co-morbiditiesSevere/multipleco-morbid disease Kandolin, Mielniczuk Can J Cardiol: in press Decision Making for Revascularization in Heart Failure Velazquez JACC 2015;65: 615-24 Concluding Remarks•Viability testing is not for everyone•To be considered when it may impact management decisions•The field has evolved significantly over 20 years•Over-reliance on viability info not needed to guide decisions•Personalized approaches to revascularization are needed•Future Directions•Role of biomarkers•Method of revascularization•Novel imaging techniques •Heart team and artificial intelligence approaches for complex decisions