All in the Past? Win K. Shen, MD Mayo Clinic Arizona Controversies and Advances in CV Diseases Cedars-Sinai Heart Institute, MFMER

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1 ICD for NICM All in the Past? Win K. Shen, MD Mayo Clinic Arizona Controversies and Advances in CV Diseases Cedars-Sinai Heart Institute, MFMER

2 DISCLOSURE Relevant Financial Relationship(s) None Off Label Usage None 2017 MFMER

3 Objectives ICD for Non-Ischemic Cardiomyopathy Case discussion A patient with narrow QRS: ICD or no ICD, and when? A patient with LBBB: CRT-D or CRT-P? Why the question? Evidence-based discussion Guidelines, emergent data and take home message 2017 MFMER

4 62 Year-Old Woman A 62 year-old woman was admitted to the hospital for evaluation of SOB, PND and orthopnea. She was found to be in heart failure. EKG showed SR 90 bpm, QRSD 104 ms. Echo showed an EF of 26%. Angiogram showed no significant CAD. Work up for cardiomyopathy was unrevealing. She responded to diuretics. Her discharge medications included metoprolol, valsartan, lasix and K supplement She had no signs of heart failure at 3-month follow up. Her functional class was NYHA II. A repeat echo showed the EF was 32% 2011 MFMER 2017 MFMER

5 Would you recommend ICD? 1. Yes 2. No 2017 MFMER

6 Primary SCD in Non-ischemic, LVEF 35% Indications for ICD (guidelines 2012) NYHA I II, III IV Disease Nonischemic* IIB I X * Guidelines: GDMT, exclude reversible transient causes of LV dysfunction (no change in VT guideline 2017) * Optimal GDMT 3-9 months: a CMS rule 2011 MFMER 2017 MFMER

7 DANISH Trial: NICM, EF 35%, NYHA II, III, IVa 1,116 patients eligible for randomization 19 had preexisting CRT 626 had indication for CRT 471 did not have indication for CRT 645 underwent randomization 471 underwent randomization 322 assigned to ICD group 323 assigned to control group 234 assigned to ICD group 237 assigned to control group 8 did not undergo ICD implantation 1 died before implantation 1 had unsuccessful implantation 6 withdrew consent 11 had ICD extracted or deactivated 303 had ICD throughout trial Køber L et al. NEJM 2016; 375: remained without ICD during trial 17 underwent ICD implantation during trial 15 had arrhythmia 2 underwent implantation at physician request 6 did not undergo ICD implantation 1 Had unsuccessful implantation 5 withdrew consent 19 had ICD extracted or deactivated 209 had ICD throughout trial 227 remained without ICD during trial 10 underwent ICD implantation during trial 9 had arrhythmia 1 underwent implantation at physician request 2017 MFMER

8 Cumulative Event Rate DANISH Trial: Time-to-Event Cumulative Event Rate Cumulative Event Rate Death from Any Cause Hazard ratio, 0.87 (95% CI ) P= Cardiovascular Death Hazard ratio, 0.77 (95% CI ) P= Control group ICD group Years ~ 4-5%/yr ~ 2-3 %/yr Sudden Cardiac Death Hazard ratio, 0.50 (95% CI ) P=0.005 Control group ICD group Years Køber L et al. NEJM 2016; 375: Control group 0.0 ICD group Years ~ %/yr 2017 MFMER

9 CMS Announcement: May 30, 2017 Reopening national coverage analysis to reconsider indications for ICDs!! 2017 MFMER

10 Non-ischemic CM DEFINITE, EF < 36%, NYHA I-III, NSVT or PVCs (47% had < 90 days from dx to randomization; excluded reversible causes) Probability of survival ICD group Kadish et al, NEJM 2004 P= Survival (yr) At risk (no.) Standard therapy 2017 MFMER

11 Mortality rate SCD-HeFT: ICD vs. Amio vs. Medical RX EF 35%, NYHA II-III, NICM 48% HR (97.5% CI) P Amiodarone vs placebo 1.06 ( ) 0.53 ICD therapy vs placebo 0.77 ( ) Amiodarone (240 deaths; 5-yr event rate 0.340) ICD therapy (182 deaths; 5-yr event rate 0.289) Placebo (244 deaths; 5-yr event rate 0.36) 0.0 Bardy et al, NEJM Months of follow-up At risk (no.) MFMER

12 NICM Primary SCD Prevention by ICD: Meta-Analysis Total Mortality No. of events No. of events Source (Trial name) Bänsch et al, 2002 (CAT) Køber et al, 2016 (DANISH) Kadish et al, 2004 (DEFINITE) Bardy et al, 2005 (SCD-HeFT) Duration of follow-up (mo) ICD group Control group ICD group Control group HR (95% CI) HR (95% CI) Weight (%) 0.81 ( ) 0.83 ( ) 0.65 ( ) 0.73 ( ) Total Fixed effect model Random-effects model Overall P= ( ) 0.75 ( ) Heterogeneity, I 2 =0%; 2 =0; P= Al-Khatib: JAMA Cardiol 2(6): 685, MFMER

13 64 Year-Old Woman 64 year-old woman has idiopathic DM for 4 years. Despite medical therapy, she now has progressive exertional dyspnea walking 2-3 blocks. Most recent EF was 27%, LVEDD/ESD: 62/52. She has been treated with carvedilol, valsartan, lasix, niacin. She is referred to you for consideration of CRT. EKG is shown, QRSD 144 msec. (Ht 5 1, Wt 96 Kg) 2017 MFMER

14 What Would You Recommend? 1. CRT-P 2. CRT-D 2017 MFMER

15 CRT Indications Class LVEF NYHA class IVCD pattern QRS (ms) Rhythm Disease IA (B) 35% II, III, IVa LBBB 150 Sinus Any IIA 35% II, III, IVa LBBB Sinus Any IIA 35% III, IVa Non LBBB 150 Sinus Any IIA 35% II, III, IVa V pacing or QRS criteria+ rate control AF Any IIA 35% II, III, IVa V pacing >40% NA Sinus Any IIB 30% I LBBB 150 Sinus Ischemia IIB 35% III, IVa Non LBBB Sinus Any IIB 35% II Non LBBB 150 Sinus Any 2012 ACCF/AHA/HRS Focused Update; 2013 ACCF/AHA HF Guidelines 2017 MFMER

16 Outcomes of CRT Trials Improvement in 6 minute walk test, 20% Improvement of O2 consumption, 10 15% Improvement in NYHA functional class - most trials approx points, EF ~ Average decrease in Mn Living with Heart Failure Score of approx 10 points Improvement in 70% of patients Fairly consistent on secondary endpoint of decreased hospitalization for CHF, 35 50% All cause mortality COMPANION: CRT-D, 36% relative reduction (p 0.003) CRT-P, 24% relative reduction (p 0.059) CARE-HF: CRT-P 36% relative reduction (p < 0.002) 2017 MFMER

17 COMPANION (NYHA III, IVa, NICM 44%) Death from Any Cause Event-free survival (%) Pharmacologi c therapy (77 events) CRT-P (131 events, P=0.059) CRT-D (105 events, P=0.003) ,080 Days after randomization No. at risk Pharmacologic therapy CRT-P CRT-D Bristow et al: NEJM, MFMER

18 CRT-D vs CRT-P: All-Cause Mortality Ischemic cardiomyopathy Study or subgroup Log hazard ratio) SE Weight Hazard ratio IV, random, 95% CI Morani % 0.81 (0.50, 1.30) Kutyifa % 0.70 (0.51, 0.97) Looi % 0.66 (0.40, 1.10) Reitan % 0.48 (0.28, 0.82) Witt % 0.74 (0.56, 0.97) Total (95% CI) 100.0% 0.70 (0.59, 0.83) Heterogeneity: Tau 2 =0.00; Chi 2 =2.45, df=4 (P=0.65); I 2 =0% Test for overall effect: Z=4.18 (P< ) Non-ischemic cardiomyopathy Study or subgroup Log hazard ratio) SE Weight Hazard ratio IV, random, 95% CI Morani % 0.56 (0.37, 0.84) Kutyifa % 0.98 (0.73, 1.32) Looi % 0.79 (0.44, 1.43) Reitan % 0.52 (0.22, 1.25) Witt % 0.96 (0.61, 1.51) Total (95% CI) 100.0% 0.79 (0.61, 1.02) Heterogeneity: Tau 2 =0.00; Chi 2 =6.20, df=4 (P=0.18); I 2 =36% Test for overall effect: Z=1.78 (P=0.07) Hazard ratio IV, random, 95% CI Favors CRT-D Favors CRT-P Hazard ratio IV, random, 95% CI Favors CRT-D Favors CRT-P Sérgio et al: J Am Heart Assoc. 2015;4:e doi: MFMER

19 All-Cause Mortality: NICM ICD and CRT-D vs Medical Therapy for Primary SCD Prevention Study HR (95% CI) Weight (%) ICD/CRT-D vs. GDMT CAT 0.83 (0.45, 1.52) 7.92 AMIOVIRT 0.87 (0.31, 2.42) 2.78 DEFINITE 0.65 (0.40, SCD-HeFT 0.73 (0.50, 1.07) COMPANION 0.50 (0.29, 0.88) 9.53 DANISH 0.87 (0.68, 1.12) Subtotal (I 2 =0.0%; P=0.565) 0.77 (0.64, 0.91) CRT-D vs. CRT-P COMPANION 0.50 (0.29, 0.88) DANISH (CRT) 0.91 (0.64, 1.29) Subtotal (I 2 =68.7%; P=0.074) 0.70 (0.39, 1.26) ICD vs. GDMT CAT 0.83 (0.45, 1.52) AMIOVIRT 0.87 (0.31, 2.42) 4.21 DEFINITE 0.65 (0.40, 1.06) SCD-HeFT 0.73 (0.50, 1.07) DANISH (No CRT) 0.83 (0.58, 1.19) Subtotal (I 2 =0.0%; P=0.937) 0.76 (0.62, 0.94) Note: weights are from random effects analysis Golwala et al: Circ 135(2): 201, Favors device Favors no device 2017 MFMER

20 DANISH Trial: Subgroup Analysis, All-Cause Mortality Subgroup Age <59 yr 59 to <68 yr 68 yr Sex Female Male NT-proBNP <1177 pg/ml 1177 pg/ml LV ejection fraction <25% 25% Estimated GFR <73 ml/min/1.73 m 2 73 ml/min/1.73 m 2 NYHA functional class II III IV Heart failure duration <18 mo 18 mo Hypertension No Yes Diabetes No Yes Permanent atrial fibrillation No Yes Cause of heart failure Idiopathic Valvular Hypertension Other Preexisting pacemaker No Yes CRT No Yes Overall ICD Group Control Group no. of events/total no. 17/167 36/173 67/216 22/151 98/405 32/266 57/292 70/264 50/292 75/272 45/283 52/297 68/259 31/254 89/301 78/375 42/181 87/457 33/99 83/421 37/135 90/424 4/20 13/62 13/50 108/500 12/56 58/234 62/322 34/181 50/202 47/177 23/ /404 74/268 88/290 65/242 66/318 80/278 50/280 54/300 77/260 36/277 95/283 87/392 44/167 95/448 36/112 91/447 40/ /425 5/21 12/55 14/59 120/514 11/46 65/237 66/323 Hazard Ratio (95% CI) ICD Better Control Better 0.51 ( ) 0.75 ( ) 1.19 ( ) 1.03 ( ) 0.85 ( ) 0.59 ( ) 0.99 ( ) 0.87 ( ) 0.79 ( ) 0.88 ( ) 0.82 ( ) 0.92 ( ) 0.81 ( ) 0.88 ( ) 0.81 ( ) 0.90 ( ) 0.79 ( ) 0.85 ( ) 0.92 ( ) 0.92 ( ) 0.76 ( ) 0.88 ( ) 0.59 ( ) 0.68 ( ) 1.02 ( ) 0.88 ( ) 0.88 ( ) 0.83 ( ) 0.91 ( ) 0.87 ( ) P Value P Value for Interaction Køber, et al: N Engl J Med; 375:1221, MFMER

21 Annual rate of sudden death (per 100 patient-yr) Trends in the Rate of Sudden Death Across Trial Groups Over Time RALES BEST RALES Slope (per decade), per 100 patient-yr; P=0.02 Population MERIT-HF BEST CIBIS-II Val-HeFT MERIT-HF SCD-HeFT CIBIS-II SCD-HeFT CHARM-Added CHARM-Alternative CHARM-Added CHARM-Alternative GISSI-HF CORONA Control group Experimental-therapy group EMPHASIS-HF PARADIGM-HF Year of randomization N Engl J Med 2017;377: MFMER

22 Take Home Message ICD for NICM: All in the Past? Not yet!! ICD vs. GDMT: CAT, DEFINITE, SCD-HeFT, DANISH Mortality benefit not shown from each trial individually Together, mortality was reduced by 23%, significant CRT-D vs. CRT-P: COMPANION, DANISH, Non-RCT A trend towards mortality reduction in favor of CRT-D Patient population is heterogeneous CRT-D for younger patients, less comorbidity, NYHA II 2017 MFMER

23 ICD in NICM All in the Past? Cedars MFMER

24 ICD for NICM All in the Past? Win K. Shen, MD Mayo Clinic Arizona Controversies and Advances in CV Diseases Cedars-Sinai Heart Institute, MFMER