©2017 MFMER | 3686275-1

ICD for NICM All in the Past?

Win K. Shen, MD

Mayo Clinic Arizona

Controversies and Advances in CV Diseases

Cedars-Sinai Heart Institute, 2017

©2017 MFMER | 3686275-2

DISCLOSURE

Relevant Financial Relationship(s)

None

Off Label Usage

None

©2017 MFMER | 3686275-3

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

Objectives

©2017 MFMER | 3686275-4

©2011 MFMER | 3134946-4

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%

©2017 MFMER | 3686275-5

Would you recommend ICD?

1. Yes

2. No

©2017 MFMER | 3686275-6

©2011 MFMER | 3134946-6

* Guidelines: GDMT, exclude reversible transient causes of LV dysfunction (no change in VT guideline 2017)

* Optimal GDMT ≥ 3-9 months: a CMS rule

Primary SCD in Non-ischemic, LVEF ≤ 35%

NYHA

Disease

I II, III IV

Nonischemic* IIB I X

Indications for ICD (guidelines 2012)

©2017 MFMER | 3686275-7

DANISH Trial: NICM, EF ≤ 35%, NYHA II, III, IVa 1,116 patients eligible for randomization

Køber L et al. NEJM 2016; 375:1221-30.

19 had preexisting CRT 626 had indication for CRT 471 did not have indication for CRT

645 underwent randomization 471 underwent randomization

323 assigned to

control group

322 assigned to

ICD group

237 assigned to

control group

234 assigned to

ICD group

• 6 did not undergo

ICD implantation

• 1 Had

unsuccessful

implantation

• 5 withdrew consent

• 19 had ICD extracted

or deactivated

• 8 did not undergo

ICD implantation

• 1 died before

implantation

• 1 had unsuccessful

implantation

• 6 withdrew consent

• 11 had ICD extracted

or deactivated • 306 remained without ICD

during trial

• 17 underwent

ICD implantation

during trial

• 15 had arrhythmia

• 2 underwent implantation at

physician request

303 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

209 had ICD

throughout trial

©2017 MFMER | 3686275-8

DANISH Trial: Time-to-Event

Køber L et al. NEJM 2016; 375:1221-30.

Cu

mu

lati

ve

E

ven

t R

ate

Hazard ratio, 0.87 (95% CI 0.68–1.12)

P=0.28

0 1 2 3 4 5 6 7 8

Cu

mu

lati

ve

E

ven

t R

ate

Hazard ratio, 0.77 (95% CI 0.57–1.05)

P=0.10

Cu

mu

lati

ve

E

ven

t R

ate

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

Hazard ratio, 0.50 (95% CI 0.31–0.82)

P=0.005

0 1 2 3 4 5 6 7 8

0 1 2 3 4 5 6 7 8

Sudden Cardiac Death

Cardiovascular Death Death from Any Cause

Years Years

Years

Control group

ICD group

Control group

ICD group

Control group

ICD group

~ 4-5%/yr ~ 2-3 %/yr

~ 1 – 1.6 %/yr

©2017 MFMER | 3686275-9

CMS Announcement: May 30, 2017

• Reopening national coverage analysis to reconsider indications for ICDs!!

©2017 MFMER | 3686275-10

Non-ischemic CM DEFINITE, EF < 36%, NYHA I-III, NSVT or PVCs (47% had < 90 days from dx to randomization; excluded reversible causes)

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6

Pro

bab

ilit

y o

f

su

rviv

al

Survival (yr)

ICD group

Standard therapy

Kadish et al, NEJM 2004

At risk (no.)

229 218 140 77 41

229 210 131 67 32

P=0.08

©2017 MFMER | 3686275-11

SCD-HeFT: ICD vs. Amio vs. Medical RX EF ≤ 35%, NYHA II-III, NICM 48%

0.0

0.1

0.2

0.3

0.4

0.5

0 12 24 36 48 60

Mo

rtality

rate

Months of follow-up

Amiodarone (240 deaths;

5-yr event rate 0.340)

Placebo (244 deaths;

5-yr event rate 0.36)

Bardy et al, NEJM 2005

At risk (no.)

845 772 715 484 280 97

847 797 724 505 304 89

829 778 733 501 304 103

HR (97.5% CI) P Amiodarone vs placebo 1.06 (0.86-1.30) 0.53 ICD therapy vs placebo 0.77 (0.62-0.96) 0.007

ICD therapy (182 deaths;

5-yr event rate 0.289)

©2017 MFMER | 3686275-12

NICM Primary SCD Prevention by ICD: Meta-Analysis Total Mortality

Al-Khatib: JAMA Cardiol 2(6): 685, 2017

No. of events No. of events

Source (Trial name)

Duration of follow-up (mo)

ICD group

Control group

ICD group

Control group HR (95% CI) HR (95% CI) Weight (%)

Bänsch et al, 2002 (CAT)

66.0 13 17 50 54 0.81

(0.38-1.71) 7.9

Køber et al, 2016 (DANISH)

67.6 58 65 234 237 0.83

(0.58-1.19) 34.0

Kadish et al, 2004 (DEFINITE)

29.0 28 40 229 229 0.65

(0.40-1.06) 18.6

Bardy et al, 2005 (SCD-HeFT)

45.5 71 95 424 417 0.73

(0.52-1.02) 39.6

Total 170 217 937 937

Fixed effect model 0.75

(0.61-0.93)

Random-effects model 0.75

(0.61-0.93)

Overall P=0.008

Heterogeneity, I2=0%; 2=0; P=0.87

0.50 1.00 2.00

©2017 MFMER | 3686275-13

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)

64 Year-Old Woman

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What Would You Recommend?

1. CRT-P

2. CRT-D

©2017 MFMER | 3686275-15

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 120-149 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 120-149 Sinus Any

IIB ≤35% II Non LBBB ≥150 Sinus Any

2012 ACCF/AHA/HRS Focused Update; 2013 ACCF/AHA HF Guidelines

©2017 MFMER | 3686275-16

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 0.5 – 0.8 points, EF ~ 0.04 – 0.06

• Average decrease in Mn Living with Heart Failure Score of approx 10 points

• 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)

Improvement in 70% of patients

©2017 MFMER | 3686275-17

COMPANION (NYHA III, IVa, NICM 44%) Death from Any Cause

50

60

70

80

90

100

0 90 180 270 360 450 540 630 720 810 900 990 1,080

Days after randomization

Event-free survival

(%)

Bristow et al: NEJM, 2004

No. at risk

Pharmacologic 308 284 255 217 186 141 94 57 45 25 4 2

therapy

CRT-P 617 579 520 488 439 355 251 164 104 60 25 5

CRT-D 595 555 517 470 420 331 219 148 95 47 21 1

Pharmacologi

c therapy

(77 events) CRT-P

(131 events, P=0.059)

CRT-D

(105 events, P=0.003)

©2017 MFMER | 3686275-18

CRT-D vs CRT-P: All-Cause Mortality

Sérgio et al: J Am Heart Assoc. 2015;4:e002539 doi: 10.1161

Study or subgroup Log hazard ratio) SE Weight

Hazard ratio

IV, random, 95% CI

Hazard ratio

IV, random, 95% CI

Morani 2013 -0.215 0.244 12.5% 0.81 (0.50, 1.30)

Kutyifa 2014 -0.357 0.166 27.1% 0.70 (0.51, 0.97)

Looi 2014 -0.411 0.258 11.2% 0.66 (0.40, 1.10)

Reitan 2015 -0.734 0.273 10.0% 0.48 (0.28, 0.82)

Witt -0.301 0.138 39.2% 0.74 (0.56, 0.97)

Total (95% CI) 100.0% 0.70 (0.59, 0.83)

Heterogeneity: Tau2=0.00; Chi2=2.45, df=4 (P=0.65); I2=0%

Test for overall effect: Z=4.18 (P<0.00001)

0.5 0.7 1 1.5 2

Favors CRT-D Favors CRT-P

Study or subgroup Log hazard ratio) SE Weight

Hazard ratio

IV, random, 95% CI

Hazard ratio

IV, random, 95% CI

Morani 2013 -0.579 0.209 23.8% 0.56 (0.37, 0.84)

Kutyifa 2014 -0.02 0.152 32.9% 0.98 (0.73, 1.32)

Looi 2014 -0.231 0.299 14.7% 0.79 (0.44, 1.43)

Reitan 2015 -0.654 0.447 7.6% 0.52 (0.22, 1.25)

Witt -0.041 0.231 21.0% 0.96 (0.61, 1.51)

Total (95% CI) 100.0% 0.79 (0.61, 1.02)

Heterogeneity: Tau2=0.00; Chi2=6.20, df=4 (P=0.18); I2=36%

Test for overall effect: Z=1.78 (P=0.07)

0.5 0.7 1 1.5 2

Favors CRT-D Favors CRT-P

Non-ischemic cardiomyopathy

Ischemic cardiomyopathy

©2017 MFMER | 3686275-19

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, 1.060 12.36

SCD-HeFT 0.73 (0.50, 1.07) 20.28

COMPANION 0.50 (0.29, 0.88) 9.53

DANISH 0.87 (0.68, 1.12) 47.14

Subtotal (I2=0.0%; P=0.565) 0.77 (0.64, 0.91) 100.00

CRT-D vs. CRT-P

COMPANION 0.50 (0.29, 0.88) 43.28

DANISH (CRT) 0.91 (0.64, 1.29) 56.72

Subtotal (I2=68.7%; P=0.074) 0.70 (0.39, 1.26) 100.00

ICD vs. GDMT

CAT 0.83 (0.45, 1.52) 11.99

AMIOVIRT 0.87 (0.31, 2.42) 4.21

DEFINITE 0.65 (0.40, 1.06) 18.71

SCD-HeFT 0.73 (0.50, 1.07) 30.70

DANISH (No CRT) 0.83 (0.58, 1.19) 34.40

Subtotal (I2=0.0%; P=0.937) 0.76 (0.62, 0.94) 100.00

All-Cause Mortality: NICM ICD and CRT-D vs Medical Therapy for Primary SCD Prevention

0.2 0.6 1 1.8 5 Favors device Favors no device

Note: weights are from random effects analysis Golwala et al: Circ 135(2): 201, 2017

©2017 MFMER | 3686275-20

DANISH Trial: Subgroup Analysis, All-Cause Mortality

Køber, et al: N Engl J Med; 375:1221, 2016

Hazard Ratio (95% CI) ICD Group Control Group

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 m2

73 ml/min/1.73 m2

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

Subgroup P Value for

Interaction

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

23/156 108/404

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 40/113

100/425 5/21

12/55 14/59

120/514 11/46

65/237 66/323

0.009

0.66

0.06

0.69

0.86

0.71

0.73

0.63

0.60

0.30

0.80

0.71

0.73

P Value

0.51 (0.29-0.92) 0.75 (0.48-1.16) 1.19 (0.81-1.73)

1.03 (0.57-1.87) 0.85 (0.64-1.12)

0.59 (0.38-0.91) 0.99 (0.73-1.36)

0.87 (0.62-1.22) 0.79 (0.54-1.14)

0.88 (0.64-1.21) 0.82 (0.55-1.23)

0.92 (0.63-1.35) 0.81 (0.58-1.13)

0.88 (0.54-1.43) 0.81 (0.61-1.09)

0.90 (0.66-1.22) 0.79 (0.51-1.21)

0.85 (0.63-1.31) 0.92 (0.57-1.50)

0.92 (0.68-1.24) 0.76 (0.48-1.20)

0.88 (0.66-1.17) 0.59 (0.13-2.71) 0.68 (0.29-1.63) 1.02 (0.47-2.20)

0.88 (0.68-1.14) 0.88 (0.36-2.20)

0.83 (0.58-1.19) 0.91 (0.64-1.29) 0.87 (0.68-1.12)

0.02 0.19 0.38

0.92 0.24

0.02 0.96

0.42 0.21

0.42 0.33

0.68 0.21

0.61 0.17

0.48 0.27

0.26 0.74

0.58 0.24

0.37 0.50 0.39 0.96

0.34 0.79

0.31 0.59 0.28

no. of events/total no.

0.25 0.50 1.00 2.00

ICD Better Control Better

©2017 MFMER | 3686275-21

Trends in the Rate of Sudden Death Across Trial Groups Over Time

1

2

3

4

5

6

7

8

9

10

N Engl J Med 2017;377:41-51

Year of randomization

An

nu

al

rate

of

su

dd

en

death

(per

100 p

ati

en

t-yr)

Control group

Experimental-therapy group

Slope (per decade), -1.22 per 100 patient-yr; P=0.02

CORONA PARADIGM-HF

EMPHASIS-HF GISSI-HF

RALES

MERIT-HF BEST

RALES

BEST CIBIS-II

CIBIS-II

Val-HeFT

MERIT-HF

SCD-HeFT SCD-HeFT

CHARM-Added

CHARM-Alternative

CHARM-Added

CHARM-Alternative

Population 3000

1000

©2017 MFMER | 3686275-22

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

Take Home Message

©2017 MFMER | 3686275-23

ICD in NICM All in the Past?

Cedars 2017

©2017 MFMER | 3686275-24

Win K. Shen, MD

Mayo Clinic Arizona

Controversies and Advances in CV Diseases

Cedars-Sinai Heart Institute, 2017

ICD for NICM All in the Past?