The Myths of Heart Failure with Preserved Ejection

Fraction: A misunderstood disease in search

of a therapyScott D. Solomon, MD

The Edward D. Frohlich Distinguished Chair Professor of Medicine

Harvard University Director, Noninvasive Cardiology Brigham and Women’s Hospital

DISCLOSURES

• Dr. Solomon has received research Support from Abbott, Amgen, Bayer, Boston Scientific, Daichi-Sankyo, Novartis, NHLBI, NCI, and has consulted for Novartis, Bayer

The Two Faces of Heart Failure

HFrEF HFpEF

Heart Failure Definition• The inability to provide adequate cardiac

output to the body at rest or with exertion, or to do so only in the setting of elevated cardiac filling pressures.

•Clinically: A clinical syndrome characterized by breathlessness, fatigue and edema caused by an abnormality of the heart

-E. Braunwald modified by B. Borlaug and M. Redfield

Distribution of EF in Hospitalized Patients With Heart Failure

EF 4

0-50

%

Fonarow G et al. JACC. 2007; 50:768-777.

EF ≥

50

%

OPTIMIZE-HF Registry, N=41,267

EF ≤

40

%

Similar Signs and Symptoms in Patients with HFpEF and HFrEF

HFpEFHFrEF

35

30

25

20

15

10

5

0

%

Edema Orthop- nea

PND Restdyspnea

S3 Crackles JVP>6 cm

Cardio-megaly

CHARM Investigators

MYTH #1

HFpEF is very benign compared with HFrEF

Bello et al. CHARM. Circ HF 2014

Survival rates have improved for HFrEF, but not for HFpE F

• The survival rate among patients with a discharge diagnosis of HFpEF has not changed significantly over time1

– Among patients with HFrEF, the likelihood of survival increased from 1987 to 2001

Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0

Patients with reduced ejection fraction Patients with preserved ejection fraction

0 1 2 3 4 5 Year

1987–1991 1992–1996 1997–2001

Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0 0 1 2 3 4 5

Year

p=0.005 p=0.36

1987–1991 1992–1996 1997–2001

▪ Advances in the management of patients with HFrEF have resulted in a significant extension of life expectancy, but this is not the case for patients with HFpEF2

1. Owan et al. N Engl J Med 2006;355:251–9; 2. Blanche et al. Swiss Med Wkly 2010;140:66–729

Myth # 2: HFpEF is a Collection of Comorbidities and NOT a Disease!

Bhatia et al. NEJM 2006

HFrEF HFpEF P-value

Age 71.8 ± 12

75.4 ± 11.5 < 0.001

Hypertension 49.2% 55.1% 0.005

Atrial Fibrillation 23.6% 31.8% < 0.001

COPD 13.2% 17.7% 0.002

Anemia 9.9% 21.1% < 0.001

HF Hospitalization and Mortality Higher in HFpEF than in Studies of Similar Comorbidity

0

17,5

35

52,5

70

ACCORD ACTION PEACE HOPE ALLHAT CHARM-P

MortalityHF Hosp

MYTH #3

HFpEF is Caused by Diastolic Dysfunction

Age Dependence of Myocardial Relaxation Velocity in Normals

40 50 60 70 80 904

8

12

16

20

24

Age (Years)

Late

ral E

' (cm

/sec

)

Henein et al. EHJ. 2002;23:162–171.

High Prevalence of Diastolic Dysfunction Regardless of Clinical Status

0

12,5

25

37,5

50

Healthy Co-Morbid HFpEF

5,52,31,6

424242 4341

26

10

15

30

NormalMild DDModerate DDSevere DD

• No DM, HTN, CHD, HF

n = 371 n = 4,555 n = 474

E’ = 7.5 ± 1.9, E/E’ = 9.1 ± 3.0 NT-proBNP = 90 (83,97)

E’ = 6.9 ± 1.9, E/E’ = 10.2 ± 3.8 NT-proBNP = 120 (116, 123)

E’ = 6.7 ± 1.9, E/E’ = 11.2 ± 4.7 NT-proBNP = 209 (188, 232)

Shah et al AHA 2012

Diastolic Dysfunction is Ubiquitous with Aging and Cannot Account for HFpEF

Myth # 5: Systolic Function is Normal in HFpEF

Longitudinal Strain most likely represents Function of subendocardial myofiber bands

Shah A. & Solomon SD. Myocardial Deformation Imaging. Circulation 2012

Myocardial Strain in Normals, HTN, HFpEF and HFrEF

Normal (n=50)

Hypertension and Diastolic dysfunction

(n=300)PARAMOUNT1

(n=~200) MADIT-CRT2 (n=1077)

-34-32-30-28-26-24-22-20-18-16-14-12-10

-8-6-4-20

Myo

card

ial S

train

(%)

Longitudinal Strain Circumferential Strain

TOPCAT3

(n=~438)

1Kraigher-Krainer E, JACC 2013 2Knappe D, Circ HF 2011 3 TOPCAT Unpublished

No HF HFpEF HFrEF

GLS was the BEST Predictor of Outcome in HFpEF in TOPCAT Trial

LVEF

Left Atrial Volume

Global Longitudinal Strain

LV Mass

E/E'

Age

0.8 1 1.2 1.4 1.6 1.8 2

Hazard Ratio for Primary Outcome (per 1 SD)

Univariate Multivariate

P < 0.001 P = 0.005

P < 0.001 P = 0.017

P < 0.001 P = 0.025

P < 0.001 P = 0.001

P = 0.009 P = 0.083

P = 0.081 P = 0.70

TOPCAT Unpublished Data

MYTH #5

There is no Evidenced Based Treatment for HFpEF

THIS ONE IS TRUE!

Outcomes Trials in HFpEFCHARM-Preserved PEP-CHF

I-PRESERVE TOPCAT

Spironolactone

Placebo

HR = 0.89 (0.77 – 1.04) p=0.138

351/1723 (20.4%)

320/1722 (18.6%)

TOPCAT: 1°Outcome (CV Death, HF Hosp, or Resuscitated Cardiac Arrest)

Pfeffer et al. NEJM 2014;370(15):1383-92

HR=0.82 (0.69-0.98)

HR=1.10 (0.79-1.51)

Interaction p=0.122

US, Canada, Argentina, Brazil

Russia, Rep Georgia

Placebo: 280/881 (31.8%)

Placebo: 71/842 (8.4%)

TOPCAT: Results by Region

Pfeffer MA et al. Circulation. 2015 Jan 6;131(1):34-42

TOPCAT: Benefit of Spironolactone Diminishes with Increasing Ejection Fraction

Solomon SD et al. Eur Heart J. 2015

Primary Outcome HF Hospitalization

2012 ESC Guidelines for Heart Failure Treatment

• No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HF-PEF.

• Diuretics are used to control sodium and water retention and relieve breathlessness and oedema as in HF-REF.

• Adequate treatment of hypertension and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in patients with AF (see Section

Current Treatment of HFpEF

•Symptomatic Treatment with Diuretics

• Treatment of Hypertension

•Rate control in Atrial Fibrillation (? Maintain SR)

• Treat Ischemia

• ? Spironolactone

Soluble Guanylate Cyclase stimulator Heart Failure Studies: The SOCRATES Program

SOCRATES-REDUCED SOCRATES-PRESERVED

Design

2 Phase II, randomized, parallel-group, placebo-controlled, double-blind,

dose finding phase IIb studies of 4 dose regimens of the oral sGC stimulator vericiguat over 12 weeks

Inclusion Criteria

Worsening chronic heart failure requiring hospitalization (or IV diuretic for HF) with initiation after clinical stabilization

LVEF <45% LVEF ≥45% Left atrial (LA) enlargement

Primary Outcome

NT-proBNP at 12 weeks

NT-proBNP / LA vol. at 12 weeks (split α: each p<0.025)

Enrollment 410 patients in 5 arms 470 patients in 5 arms

Study status FPFV Nov 29, 2013 FPFV Nov 6, 2013

CT.gov ID NCT01951625 NCT01951638

SOCRATES-Preserved: Primary ResultsNo reduction in log-NT-proBNP or in LAV at week 12

compared with placebo

Data are mean ± standard error for the per-protocol analysis sets

Placebo 1.25 mg 2.5 mg 2.5 to 5 mg 2.5 to 10 mg Pooled dose groups

0.20

0.10

0.00

–0.10

–0.20

Cha

nge

in le

ft at

rial v

olum

e (m

L) 2

0

–2

–4

–6

Placebo 1.25 mg

2.5 mg

2.5 to 5 mg

2.5 to 10 mg

Pooled2.5/5/10

mg

Placebo 1.25 mg

2.5 mg

2.5 to 5 mg

2.5 to 10 mg

Pooled2.5/5/10

mg

NEAT-HFpEF: No Difference in Primary or Secondary Endpoints

(including 6 min walk, QOL, NT-proBNP)

Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) vs. placebo in crossover design

AT1 receptor

Angiotensinogen (liver secretion)

Angiotensin I

Angiotensin II

NH

N

NN

N

O

OH

O

Valsartan

OH

ONH

OOH

O

Renin Angiotensin System

Vasoactive Peptide System

Vasodilation ! blood pressure ! sympathetic tone !aldosterone levels ! fibrosis ! hypertrophy Natriuresis/Diuresis

Inactive fragments

XNeprilysin

Vasoconstriction " blood pressure " sympathetic tone " aldosterone " fibrosis " hypertrophy

X

Heart Failure

LCZ696pro-BNP

NT-pro BNP

ANP BNP CNP

Adrenomedullin Bradykinin Substance P (angiotensin II)

Sacubitril (AHU377)↓

LBQ657

LCZ696 is a novel crystalline complex

consisting of the molecular moieties of valsartan and sacubitril in an equimolar

ratio

LCZ696 – A first-in-class Angiotensin Receptor Neprilysin Inhibitor – Simultaneously Inhibits NEP and the RAS

PARAMOUNT: Study Design

Primary objective NT pro-BNP reduction from baseline at 12 weeks

Secondary objectives

▪ Echocardiographic measures of diastolic function, left atrial size, LV size and function, PASP ▪ HF symptoms, Clinical composite assessment and Quality of life (KCCQ) ▪ Safety and tolerability

LCZ696 100 mg BID

LCZ696 50 mg BID

Valsartan 40 mg BID

1 week 10 weeks2 weeks

Placebo run-in

Discontinue ACEI or ARB therapy one day prior to randomization

LCZ696 200 mg BID

Valsartan 80 mg BID Valsartan 160 mg BID

1 week

Prior ACEi/ARB use discontinued

6 month extension

Baseline randomization visit and visit at end of 12 weeks of core study

Week Visit

-21

0 2

213 4

127

4 865 8 9 10 11

18 24 30 36

Clinicaltrials.gov NCT00887588

301 patients randomized

Solomon et al. ESC Hotline 2012 Lancet 2012

PARAMOUNT: Significant Improvement in Several Domains

Weeks Post Randomization

LCZ696

Valsartan

0 5 10 200

300

400

500

600

700

800

900

1000

NTp

roB

NP

(pg/

ml)

LCZ696/Valsartan: 0.77 (0.64, 0.92) P = 0.005

p = 0.063

12

783 (670,914)

862 (733,1012) 835 (710, 981)

605 (512, 714)

Left Atrial Volume

12 Weeks 36 Weeks

-6 -5 -4 -3 -2 -1 0 1 2

Cha

nge

in L

eft A

trial

Vol

ume

(ml)

Valsartan LCZ696

P = 0.18 P = 0.003

Worsened Unchanged Improved

LCZ696 Valsartan LCZ696 Valsartan 0 10 20 30 40 50 60 70 80 90

100 110

Per

cent

of P

atie

nts

Week 12 Week 36

P = 0.11 P = 0.05

Improvement in NT-proBNP Improvement in Left Atrial Size

Improvement in NYHA Class

Solomon et al. Lancet 2012

Target patient population: ∼4,600 patients with symptomatic HF (NYHA Class II–IV) and LVEF ≥45%

up to 2 weeks ~240 weeks

Valsartan 160 mg BID

LCZ696 200 mg BIDLCZ696 100 mg BID

On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs)

Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events)

Valsartan 80 mg BID*Screening

3–8 weeks

Active run-in period

Double-blind treatment periodRandomization 1:1

Steering Cmt: S. Solomon, co-Chair, J. McMurray, Co-Chair, I. Anand, F. Zannad, A. Maggioni, M. Packer, M. Zile, B. Pieske, J. Rouleau, M. Redfield, C. Lam, D. Van Veldhuisen, F. Martinez, J. Ge, H. Krum, M. Pfeffer

SPRINT: BP Lowering Reduces Adverse Outcomes

HF Hospitalization Reduced 38%

SPRINT Investigators. N Engl J Med 2015

Heart Failure Hospitalizations Reduced Substantial with the SGLT-2 Inhibitor Empaglifozin

Fitchett et al. Eur Heart J 2016

Effect of Exercise Training on Measures of Diastolic Function

Edelmann F…. Pieske B JACC 2011

• Primary endpoint – Change in 6MWT at week 24

• Secondary endpoints – Change in biomarkers for iron deficiency, renal function, cardiac function, NYHA functional

class, PGA and QoL – Overall safety over the treatment period

FAIR-HFpEFDesign

• Design: Multicentre, randomized (1:1), double-blind, placebo-controlled • Main inclusion criteria:

– NYHA class II / III, LVEF ≥ 45% – SR: BNP/NT-proBNP >100/>300 pg/mL or MRproANP>120 mmol/L (if in AF, twice) – 6MWT < 450m – Iron deficiency: serum ferritin <100 µg/L or TSAT <20% – Hb: 9.0–14.0g/dL

Placebo

n=200Screening

R

D0

1° EP: 6MWT

W4 W12 W20 W24

FCM up to 2000mg (2x1000mg)

Treatment continues if ID is not corrected

Inter-Atrial Shunt Device - Concept

• Abnormal LV relaxation results in elevated Left Atrial Pressure (LAP) and pulmonary edema

• Transcatheter implant to create a small1 permanent interatrial shunt

• Shunt allows blood to move from the higher pressure LA to the lower pressure more compliant right side, reducing LAP without compromising LV cardiac output

1 Qp:Qs ratio (Pulmonary to Systemic flow ratio): 1.2-1.3

Inter-Atrial Shunt Device1 - MOA

1 PCWP at rest is predictor of mortality (Dorfs, EHJ 2014)

Elevated LV filling pressures (Elevated LAP)

Pulmonary Venous hypertension (Elevated PCWP1)

Pulmonary edema, Dyspnea at rest/exercise

XHypothesis

41

6 months Effectiveness

endpoints

Hasenfuβ, et al The Lancet Vol 387 March 26, 2016

42

6 months Efficacy Endpoints

Hasenfuβ, et al The Lancet Vol 387 March 26, 2016

Conclusions• HFpEF is alive, and not well.

• It is a heterogeneous disorder, associated with comborbidities but accounts for half of heart failure

• The cardiac phenotype is broader than we previously thought

• Diastolic dysfunction CANNOT account for the disorder and abnormalities of systole are becoming more recognized

• There is no “evidenced-based” therapy currently, but there are promising potential therapies being tested