1

Disclosure:I am a consultant, research investigator for Abbott (CardioMEMS, HeartMate3)

2

Learning Objectives:

1. Recognize high risk of mortality in heart failure.

2. Appreciate when to consider advanced therapy.

3. Apply new pharmacologic therapy appropriately.

Advanced Heart Failure

What is advanced heart failure?

What’s new with pharmacotherapy?

What’s new with device technology?

When to refer to heart failure specialist?

3

Case Presentation

76 yo MICM diagnosed 1996CABG 1998 & 2010Former smoker, moderate COPD, mild PVD

Six months ago was able to play 18 holes of golf

Four months ago developed AF with RVRFailed catheter ablation

Four hospital admissions in the last 3 months

ICD shock requiring admission

Inappropriate for afib with RVR

Now on Bumex 2 mg BID

Lisinopril held due to rising creatinine

Case Presentation

4

Case Presentation

Unable to climb a flight of stairs, trouble with ADLs on “bad” days

Na 129, BUN 20, Creat 1.6 (GFR 50)AST 35/ALT 42, Bili 1.6

What is this patient’s 12 month mortality risk? a. 20%b. 30%c. 50%d. 80%

Peura Cook JL, et. al. Circulation 2012; 126(22):2648-2667

5

Risk Stratification

Table 6. Prognostic Determinants in Advanced HFDemographic

Advanced ageMale gender

ClinicalFrequent hospitalizations (>1 in past 6 months)Advanced NYHA class (III or IV)Intolerance to neurohormonal antagonistsIncreased diuretic requirement HypotensionFailed CRTInotrope dependenceCo-morbidities (diabetes, anemia, COPD, etc.)

LaboratoryHyponatremiaRenal insufficiency (BUN/serum creatinine)Hepatic insufficiencyElevated neurohormones, natriuretic peptides, troponins, CRP

Doppler-echo and right heart catheterizationLow LV EF (<30%)Mitral regurgitation/increased LA volumeIncreased filling pressure (PCWP >16 mmHg or RAP>12 mmHg)Low RV EFIncreased pulmonary vascular resistance

Functional capacityInability to perform an exercise testLow peak VO2 (<12-14 ml/kg/min)Increased ventilatory response to exercise (VE/VCO2 slope)Low 6-minute walk test distance (<300 m)

Peura Cook JL, et. al. Circulation 2012; 126(22):2648-2667

ESC HF Guidelines. Eur J Heart Fail 2012;14:803-69.

Class IIIa

Class IIIb

6

NYHA Class: Predicts Mortality

Case PresentationNYHA III-IV

Hillege H L et al. Circulation 2000;102:203-210

Renal Function: Predicts Mortality

Case PresentationGFR 50

7

Hillege H L et al. Circulation 2000;102:203‐210

Renal Function: Predicts Mortality

Case PresentationGFR 50, NYHA III-IV

Betablocker

Mineralocorticoidreceptor

antagonist

Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction

ACEinhibitor

Angiotensinreceptorblocker

Drugs that inhibit the renin-angiotensin system have modest effects on

survival

Based on results of SOLVD-Treatment, CHARM-Alternative,COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

10%

20%

30%

40%

0%

% D

ecre

ase

in M

ort

alit

y

8

Med Intolerance: Predicts Mortality

Case PresentationStopped ACEI

<50% 12 mo survival

Med Intolerance: Predicts Mortality

9

Neuberg, et al. AHJ 2002;144:31-36

Diuretic Dose: Predicts MortalityDiuretic (high)Lasix > 80 mg/dBumex > 2 mg/d

ACEI (high)Lisinopril > 10 mg/d (or equivalent)

High diureticLow ACEI

High/ High 

Low/ Low

Low diureticHigh ACEI

Case PresentationBumex 2 mg BID, no ACEI

High diureticLow ACEI

40% 12 mo Mortality

Serum Na: Predicts Mortality

Case PresentationNa 129

80% 12 mo Mortality

10

Serum Na: Predicts Mortality

ICD Shock: Predicts Mortality

Borne R, JAMA IM 2013;173:859-865 Proietti R 2015; Canadian J Card 31: 270-277

Case PresentationICD shock for Afib

11

Adapted from Thorvaldsen T et. Al. JACC 2014; 63:661-671Abraham W et al Lancet 2011:377:658-66

Median Transplant survival

12

Median VAD survival5

Abraham WT et al Lancet 2011;377:658-66

CardioMEMS

Implantable hemodynamic

monitoring system

12

23

Adamson et al Circ Heart Fail. 2014 Nov;7(6):935‐44

CHAMPION CohortHF hospitalization at 17.6 months

Decreased by 50%

CHAMPION CohortHF hospitalization at 17.6 months

Decreased by 50%

Cu

mu

lati

ve H

F H

osp

ital

izat

ion

s

Days After Implant

p<0.0001

Abraham W et al Lancet 2011:377:658-66Goldberg et al, HRS 2015, Boston Abstract AB36-02.

CardioMEMS: CHAMPION

HF Hospitalization by Diuretic Management Strategy

NYHA III, hospital admission within last 12 months

Patients with HFpEF and HFrEF

13

CHAMPION: 18 month follow-up

Abraham WT et al Lancet 2016;387:453-61

CHAMPION: 18 month follow-up

Abraham WT et al Lancet 2016;387:453-61

14

Desai et. al. Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in “Real-World” Clinical Practice. JACC 2017;69:2357-65

HF Related Cost Reduction6 months -$7,43312 months -$11,260

Case Presentation

Due to multiple risk factors patient needs advanced care

Would you refer patient for CardioMEMS?Surgical therapy evaluation?Hospice?

What is this patients actual mortality risk?

15

Heart Failure Statistics

New Cases: 550,000NYHA Class IV (Stage D): 70,000Deaths: 50,000Health care costs:

$30 billion annually$70 billion by 2030

Hospitalization = 80% costs

NEJM 1998;339:1522-1533. NEJM, 2001;345:1435-1443

At 40 years old……

Lifetime risk of developing HF is 1 in 5

5 year mortality ≈50% Olmsted County Study

1 year mortality 29.6% Medicare Beneficiaries

Mozaffarian D Circulation 2015; 131:434-441.

16

Perhaps we underestimate HF death risk

But, do we really believe these numbers?

Mozaffarian D Circulation 2015; 131:434-441.

Enormous evidence from clinical trials……Absolute Risk Kaplan-Meier Curves

Mortality: RALES 1999Medical Rx v. Spironolactone, NYHA III-IV, EF <35%

Pitt, B RALES NEJM 1999;341:709-17

NYHA class III 70%IV 30%

Death 2 yrs35% Rx

40% Placebo

17

Mortality: SCD-HeFT 2005Medical Rx v. Amio v. ICD, NYHA II-III, EF <35%

Bardy GH, et al NEJM 2005 352;3: 225-237.

NYHA III

Death 2 yrs22% Placebo18% ICD

Mortality: PARADIGM-HFEnalapril 10 BID to LCZ696 200 mg BID, NYHA II-IV, EF <40%, BNP >150

Death 2 yrs15% Enalapril

11% LCZ696

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One Enzyme — Neprilysin — DegradesMany Endogenous Vasoactive Peptides

Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neprilysin

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Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter

Maladaptive Mechanisms in Heart Failure

Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention

Neprilysin Neprilysininhibition

• NYHA class II-IV heart failure

• LV ejection fraction ≤ 40% 35%

• BNP ≥ 150 (or NT-proBNP ≥ 600), but one-third lower if hospitalized for heart failure within 12 months

• Any use of ACE inhibitor or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg daily for at least 4 weeks

• Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists

• Systolic BP ≥ 95 mm Hg, eGFR ≥ 30 ml/min/1.73 m2

and serum K ≤ 5.4 mEq/L at randomization

PARADIGM-HF: Entry Criteria

20

LCZ696(n=4187)

Enalapril(n=4212)

Age (years) 63.8 ± 11.5 63.8 ± 11.3

Women (%) 21.0% 22.6%

Ischemic cardiomyopathy (%) 59.9% 60.1%

LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3

NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9%

Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15

Heart rate (beats/min) 72 ± 12 73 ± 12

N-terminal pro-BNP (pg/ml) 1631 (885-3154) 1594 (886-3305)

B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465)

History of diabetes 35% 35%

Digitalis 29.3% 31.2%

Beta-adrenergic blockers 93.1% 92.9%

Mineralocorticoid antagonists 54.2% 57.0%

ICD and/or CRT 16.5% 16.3%

PARADIGM-HF: Baseline Characteristics

0

16

32

40

24

8

Enalapril(n=4212)

360 720 10800 180 540 900 1260

Days After Randomization

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

41874212

39223883

36633579

30182922

22572123

15441488

896853

249236

LCZ696Enalapril

Patients at Risk

1117

Kap

lan

-Mei

er E

stim

ate

of

Cu

mu

lati

ve R

ates

(%

)

21

0

16

32

40

24

8

Enalapril(n=4212)

360 720 10800 180 540 900 1260

Days After Randomization

41874212

39223883

36633579

30182922

22572123

15441488

896853

249236

LCZ696Enalapril

Patients at Risk

1117

Kap

lan

-Mei

er E

stim

ate

of

Cu

mu

lati

ve R

ates

(%

)

914

LCZ696(n=4187)

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

0

16

32

40

24

8

Enalapril(n=4212)

360 720 10800 180 540 900 1260

Days After Randomization

41874212

39223883

36633579

30182922

22572123

15441488

896853

249236

LCZ696Enalapril

Patients at Risk

1117

Kap

lan

-Mei

er E

stim

ate

of

Cu

mu

lati

ve R

ates

(%

)

914

LCZ696(n=4187)

HR = 0.80 (0.73-0.87)P = 0.0000002

Number needed to treat = 21

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

22

LCZ696(n=4187)

Enalapril(n=4212)

Hazard Ratio

(95% CI)

PValue

Primary endpoint

914(21.8%)

1117(26.5%)

0.80(0.73-0.87)

0.0000002

Cardiovascular death

558(13.3%)

693(16.5%)

0.80(0.71-0.89)

0.00004

Hospitalization for heart failure

537(12.8%)

658(15.6%)

0.79(0.71- 0.89)

0.00004

PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components

10%

Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current

Inhibitors of the Renin-Angiotensin System

20%

30%

40%

ACEinhibitor

Angiotensinreceptorblocker

0%

% D

ecre

ase

in M

ort

alit

y

18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trialEffect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensinneprilysininhibition

15%

23

Risk factors SBP ≤90mmHg Creat ≥1.8 Hgb ≤ 12 RAS antagonist intoleranceBeta blocker intolerance

Risk Factors 1‐yr Survival

0 90%

1 79%

2 60%

3‐5 39%

Transplant 90%

VAD 81%

Risk Factors 1‐yr Survival

0 90%

1 79%

2 60%

3‐5 39%

Transplant 90%

VAD 81%

HeartWare Ventricular Assist Device

24

HeartMate III Ventricular Assist Device

25

26

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24

Pat

ien

ts w

ith

Eve

nt-

free

Su

rviv

al (

%)

Months Since Implantation

Primary End Point Analysis (ITT)

Survival at 2 years free of disabling stroke (>3 mRS) or

reoperation to replace or remove a malfunctioning device

Superiority AnalysisHazard ratio, 0.46 (95% CI, 0.31-0.69)

P<0.001 by log-rank test

80.5% 73.6

%

56.4%

87.3%

84.4% 77.9

%

HeartMate II

HeartMate 3

51

Functional Status and Quality of Life

*P‐value between treatment arms over time**P‐value for treatment over time

52

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Thank You