HFpEF: From understanding the physiology to development of … · 2019-12-16 · HFpEF: From...

HFpEF: From understanding the physiology to development

of new treatments

Groningen Heart Failure Satellite Symposium

Carolyn S.P. Lam, MBBS, PhD, MRCP, FAMS, FESC, FACC

Senior Consultant Cardiologist, National Heart Centre Singapore

Professor, Duke-National University of Singapore

Rosalind Franklin Fellow, University Medical Centre Groningen

Director, Clinical & Translational Research Office at NHCS

Affiliate Member, SingHealth Duke-NUS Institute of Precision Medicine (PRISM)

Scientific Advisor to the Clinical Trials Coordinating Centre (CTCC) at SingHealth

Disclosures

I am supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; have received research support from Boston Scientific, Bayer, Thermofisher, Medtronic, and Vifor Pharma; and have consulted for Bayer, Novartis, Takeda, Merck, Astra Zeneca, Janssen Research & Development, LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Roche, and Amgen.

ESC Guidelines 2016

“No treatment has yet been shown, convincingly, to reduce morbidity and

mortality in patients with HF-PEF.”

What hasn’t worked?

What may still work?

Outcomes Trials in HFpEFCHARM-Preserved PEP-CHF

I-PRESERVE TOPCAT

Pfeffer Circ 2015; 131: 34-42

Wrong patient? Wrong therapy?

TOPCAT

HR=0.82 (0.69-0.98)

HR=1.10 (0.79-1.51)

US, Canada,

Argentina, Brazil

Russia, Rep Georgia

Interaction p=0.122

Placebo:

280/881 (31.8%)

Placebo:

71/842 (8.4%)

What hasn’t worked?

What may still work?

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

What may still work?

Potential targets in HFpEF

1. Hemodynamic targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

LV diastolic dysfunction

Population-based age-, sex-, body

size- adjusted

Lam Circulation 2007

Left atrial hypertension:

REDUCE-LAP HF I (Phase 2)

Shah Circulation 2017

Pulmonary Hypertension

High prevalence & prognostic impact of PH in HFpEF suggest an important pathophysiologic role

Lam C.S. et al J Am Coll Cardiol. 2009;53:1119-26

Pulmonary hypertension:

CHAMPION

Philip B. Adamson et al. Circ Heart Fail. 2014

RV-PA coupling

p=0.019

→RV strain not predictive

TAPSE TAPSE/PASP

p<0.001p=0.019

TAPSE TAPSE/PASP

p<0.001

Bosch Eur J HF 2017

Gorter Eur J Heart Fail 2016

RV dysfunction & mortality

Mads J. Andersen et al. Circ Heart Fail. 2015;8:542-550

β-agonists in HFpEF/PH

Volume overload: Obese HFpEF

Masaru-Obokata Circulation 2017

Borlaug Circ HF 2017

SGLT2, sodium-glucose co-transporter-2

1. Heise T et al. Diabetes Obes Metab 2013;15:613; 2. Heise T et al. Clin Ther 2016;38:2265; 3. Ferrannini G et al. Diabetes Care 2015;38:1730; 4. Briand F et al.

Diabetes 2016;65:2032; 5. Heerspink HJ et al. Circulation 2016;134:752; 6. Inzucchi S et al. Diab Vasc Dis Res 2015;12:90; 7. Zinman B et al. N Engl J Med

2015;373:2117; 8. Wanner C et al. N Engl J Med 2016;375:323

Empagliflozin is not indicated for the treatment of heart failure or renal disease; empagliflozin is not indicated in all countries for CV risk reduction.

The pathways shown represent not yet proven hypotheses and may not apply to individual patients

The effects shown for renal function is based on the long-term results of empagliflozin versus placebo in EMPA-REG OUTCOME8

Renal events

CV death

Hospitalisation

for heart failure

Arrhythmia

Afterload

Preload

Cardiometabolic

efficiency

Arterial wall

structure/function

Cardiac function

Mechanism1−4 Possible cardio−renal effects5,6 CV/renal outcomes observed in

EMPA-REG OUTCOME7,8

Renal function

SGLT2 inhibition1,2

Glucose

removal

Na+

removal

Metabolism

Sodium

Osmotic

diuresis

Role for SGLT2i:

EMPEROR-Preserved

Asian vs White HF

Bank, … Lam. JACC HF 2016

Singapore Asians vs Swedish whites

22

ASIAN-HF Registry

http://www.clinicaltrials.gov/ct2/show/NCT01633398?term=ASIAN+HF&rank=1

Lam CS Eur J Heart Fail 2013

Prospective multinational (11 regions), multicenter (46 sites),

observational study of Asian patients with Stage C HF; all with

detailed characterization (echo, ECG) and adjudicated outcomes

Comorbidity clusters in ASIAN-HF

CONFIDENTIAL23

Tromp PLOS Medicine 2018

What may still work?

Potential targets in HFpEF

1. Hemodynamic targets

2. Molecular targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

Endothelial dysfunction:

Highly prevalent in HFpEF

Prevalence of endothelial dysfunction (RHI<2.0): 0% in controls, 28% in HTN, 42% in HFPEF

Borlaug JACC 2010

Cardiac inflammation & fibrosis in

human HFpEF

Westerman Circ Heart Fail 2011

HFpEF (n=20) and controls (n=8) studied with

conductance catheter and endomyocardial biopsy

Positive correlation between cardiac collagen, inflammatory cells,

and diastolic dysfunction suggests a direct influence of

inflammation on fibrosis triggering diastolic dysfunction

Role of TGFβ1 in

transdifferentiation

of fibroblasts to

myofibroblasts,

↑collagen synthesis

Interleukin-1 blockade in HFpEF:

D-HART Pilot Trial

Van Tassell Am J Cardiol 2014

Cross-over RCT in 12 HFpEF with plasma CRP>2 mg/l

D-HART 2

Van Tassell Circulation. 2017;136:A17709

Placebo-controlled RCT of 31 stable HFpEF pts with CRP>2 mg/l

- Anakinra 100 mg daily vs placebo for 12 weeks failed to improve

peak VO2 or VE/VCO slope, but improved exercise time

Molecular targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

Cardiomyocyte stiffness & low

myocardial cGMP-PKG activity

Franssen JACC HF 2015Van Heerebeek Circulation 2012

Molecular targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

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

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

groups

Chan

ge in log-

NT

-pro

BN

P(p

g/m

L)

0.20

0.10

0.00

–0.10

–0.20

Chan

ge in left

atr

ial vo

lum

e (

mL)

2

0

–2

–4

–6

Placebo 1.25

mg

2.5

mg

2.5 to

5 mg

2.5 to

10 mg

2.5 to

10 mg

Placebo 1.25

mg

2.5

mg

2.5 to

5 mg

2.5 to

10 mg

2.5 to

10 mg

SOCRATES-PreservedPrimary endpoints

No effect on log NT-proBNP or LAV at 12 weeks vs

placebo

Presented by B. Pieske at HF Congress 2016

Data are mean ± standard error for the full analysis set excluding those subjects with incorrectly assigned doses

Change from baseline in KCCQ clinical summary score Change from week 4 in KCCQ clinical summary score

at week 12

10

0

5

15

25

20

10

0

5

Week 4 Week 12

Minimum Clinically Important Difference = 5 points

Chan

ge in K

CC

Q-C

SS

Chan

ge in K

CC

Q-C

SS

Placebo 1.25 mg 2.5 mg 2.5 to 5 mg 2.5 to 10

mg

Placebo 1.25

mg

2.5

mg

2.5 to

5 mg

2.5 to

10 mg

Placebo 1.25

mg

2.5

mg

2.5 to

5 mg

2.5 to

10 mg

Placebo 1.25

mg

2.5

mg

2.5 to

5 mg

2.5 to

10 mg

SOCRATES-PreservedPre-specified exploratory endpoint:

Patient-reported health status

Presented by B. Pieske at HF Congress 2016

Sanjiv J. Shah et al. Circulation. 2016;134:73-90

Systemic & myocardial signaling in

HFpEF

Molecular targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

• Reduction in NT-proBNP from baseline to Week 12 was

significantly greater with LCZ696 (200 mg BID)

compared with valsartan (160 mg BID) (p=0.005)

NT-proBNP(geometric mean)

LCZ696(n=134)

Valsartan(n=132)

LCZ696 vs valsartan

Baseline, pg/mL(95% CI)

783(670, 914)

862(733, 1,012) 0.77*

(0.64, 0.92)p=0.005Week 12, pg/mL

(95% CI)605

(512, 714)835

(710, 981)

*0.77=ratio of the change from baseline treatment effect between LCZ696 and

valsartan. LCZ696 reduced NT-proBNP 23% more than valsartan with a p

value of 0.005.

PARAMOUNT

Solomon et al. Lancet 2012;380:1387–95

PARAMOUNT:

LCZ696 vs valsartan in chronic HFpEF

Molecular targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

Sildenafil in HFpEF-PH: Guazzi

Guazzi et al., Circulation 2011

Sildenafil in HFpEF

(regardless of PH): RELAX

Redfield MM et al., JAMA 2013

Hoendermis Eur Heart J 2015

PAH vs. PH in Heart Failure: Spectrum of

Phenotypes and Therapeutic Consequences

No

PH Therapy

HF

RELAX (JAMA 2013)

NEAT (NEJM 2015)

No PH

Normal RV Function

Cpc-PH: Combined post- and pre-capillary PHIpc-PH: Isolated post-capillary PH

Targeted

PAH Therapy

Moderate PHNormal RV Function

Severe PHRV Function

Ipc-PHCpc-PH

DPG

PVR

PAH

AMBITION

Ex-PAS

Numerous

PAH RCTs

„pure“ „typical“ „atypical“

Severity of PH

Hoendermis

EHJ 2015

Guazzi 2011

COMPERA 2015

NoPerhaps

Molecular targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

Passive myocardial stiffness,

titin & collagen in HTN+HFpEF

Zile Circulation 2015

PIROUETTE trial

Title The Efficacy and Safety of Pirfenidone in Patients With HFpEF

Type Phase II randomised, double-blind, placebo-controlled

Rationale • Pirfenidone is an anti-fibrotic treatment of idiopathic lung fibrosis [ASCEND & CAPACITY]• Pre-clinical models have shown attenuation of myocardial fibrosis. HFpEF patients have shown some benefit with

anti-fibrotic meds (ACE and ARBs). • Will a selected population of HFpEF patients with high levels of myocardial fibrosis benefit from Pirfenidone?

Study arms 2 arms: Treatment (Pirfenidone, 800mg) vs. control (Placebo) for 12 months

1∘outcome Reduction in myocardial fibrosis, as measured from change in ECM volume (CMR)

2∘outcome • Changes in LV mass, volume, function, strain, torsion, structure (Echo and CMR)• Change in biomarker levels (NT-proBNP, hsTnT)• Patient QoL, 1yr-All-cause mortality, CV mortality, HF hospitalization

Inclusion Ct • Male/female ≥ 40yrs old• HFpEF (one symptom at Visit 0 & one sign in last 12 months, EF ≥ 45%) • BNP ≥ 100 pg/ml or NTproBNP ≥ 300 pg/ml• Myocardial fibrosis, defined as ECM volume > 27% by CMR

Exclusion Ct • MI, CABG, PCI, AF, prolonged QT• COPD, anemia, severe obesity, eGFR <30, history of liver impairment• Pericardial constriction or infiltrative cardiomyopathy, congenital/valvular heart disease• Hypersensitivity, other investigational drug usage, fluvoxamine usage within 28days, pregnancy• Any med condition (IOI) likely to prevent compliance

Stay tuned till ‘Jan 2019…

Christopher Miller (Manchester Uni), NIHR(UK), Liverpool University, Roche Therapeutics

Molecular targets

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

Lam, Voors, de Boer, Solomon,

van Veldhuisen

Eur Heart J 2018 accepted

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted

Lam, Voors, de Boer, Solomon, van Veldhuisen Eur Heart J 2018 accepted