physiology to development of new treatments Carolyn S.P. Lam, MBBS, - - PowerPoint PPT Presentation

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physiology to development of new treatments Carolyn S.P. Lam, MBBS, - - PowerPoint PPT Presentation

Aug 16, 2022 135 likes •695 views

Groningen Heart Failure Satellite Symposium HFpEF: From understanding the physiology to development of new treatments Carolyn S.P. Lam, MBBS, PhD, MRCP, FAMS, FESC, FACC Senior Consultant Cardiologist, National Heart Centre Singapore

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HFpEF: From understanding the physiology to development

  • f 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

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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.

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ESC Guidelines 2016

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

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What hasn’t worked? What may still work?

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Outcomes Trials in HFpEF

CHARM-Preserved PEP-CHF I-PRESERVE TOPCAT

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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%)

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What hasn’t worked? What may still work?

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

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What may still work? Potential targets in HFpEF

  • 1. Hemodynamic targets

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

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LV diastolic dysfunction

Population-based age-, sex-, body size- adjusted

Lam Circulation 2007

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Left atrial hypertension: REDUCE-LAP HF I (Phase 2)

Shah Circulation 2017

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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

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Pulmonary hypertension: CHAMPION

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

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RV-PA coupling

p=0.019 →RV strain not predictive TAPSE TAPSE/PASP p<0.001 p=0.019 TAPSE TAPSE/PASP p<0.001

Bosch Eur J HF 2017

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Gorter Eur J Heart Fail 2016

RV dysfunction & mortality

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

β-agonists in HFpEF/PH

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Volume overload: Obese HFpEF

Masaru-Obokata Circulation 2017

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Borlaug Circ HF 2017

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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

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Asian vs White HF

Bank, … Lam. JACC HF 2016

Singapore Asians vs Swedish whites

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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),

  • bservational study of Asian patients with Stage C HF; all with

detailed characterization (echo, ECG) and adjudicated outcomes

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Comorbidity clusters in ASIAN-HF

CONFIDENTIAL 23 Tromp PLOS Medicine 2018

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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

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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

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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

  • f fibroblasts to

myofibroblasts, ↑collagen synthesis

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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

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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

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Molecular targets

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

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Cardiomyocyte stiffness & low myocardial cGMP-PKG activity

Franssen JACC HF 2015 Van Heerebeek Circulation 2012

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Molecular targets

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

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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

Change in log-NT-proBNP (pg/mL)

0.20 0.10 0.00 –0.10 –0.20

Change in left atrial volume (mL)

2 –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-Preserved

Primary endpoints

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

Presented by B. Pieske at HF Congress 2016

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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 5 15 25 20 10 5 Week 4 Week 12

Minimum Clinically Important Difference = 5 points

Change in KCCQ-CSS Change in KCCQ-CSS

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-Preserved

Pre-specified exploratory endpoint: Patient-reported health status

Presented by B. Pieske at HF Congress 2016

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

Systemic & myocardial signaling in HFpEF

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Molecular targets

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

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  • 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=0.005 Week 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

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Molecular targets

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

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Sildenafil in HFpEF-PH: Guazzi

Guazzi et al., Circulation 2011

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Sildenafil in HFpEF (regardless of PH): RELAX

Redfield MM et al., JAMA 2013

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Hoendermis Eur Heart J 2015

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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 PH Ipc-PH: Isolated post-capillary PH

Targeted PAH Therapy

Moderate PH Normal RV Function Severe PH RV Function

Ipc-PH Cpc-PH

DPG PVR

PAH

AMBITION Ex-PAS Numerous PAH RCTs „pure“ „typical“ „atypical“

Severity of PH

Hoendermis EHJ 2015 Guazzi 2011 COMPERA 2015

No Perhaps

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Molecular targets

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

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Passive myocardial stiffness, titin & collagen in HTN+HFpEF

Zile Circulation 2015

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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

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Molecular targets

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

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

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

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