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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