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

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 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 HFpEF PEP-CHF CHARM-Preserved I-PRESERVE TOPCAT

Wrong patient? Wrong therapy? TOPCAT Placebo: 280/881 (31.8%) US, Canada, Argentina, Brazil HR=0.82 (0.69-0.98) Interaction p=0.122 Placebo: 71/842 (8.4%) Russia, Rep Georgia HR=1.10 (0.79-1.51) Pfeffer Circ 2015; 131: 34-42

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 TAPSE TAPSE/PASP p<0.001 p<0.001 p=0.019 p=0.019 TAPSE TAPSE/PASP → RV strain not predictive Bosch Eur J HF 2017

RV dysfunction & mortality Gorter Eur J Heart Fail 2016

β -agonists in HFpEF/PH Mads J. Andersen et al. Circ Heart Fail. 2015;8:542-550

Volume overload: Obese HFpEF Masaru-Obokata Circulation 2017

Borlaug Circ HF 2017

Role for SGLT2i: EMPEROR-Preserved Mechanism 1 − 4 Possible cardio−renal effects 5,6 SGLT2 inhibition 1,2 CV/renal outcomes observed in EMPA-REG OUTCOME 7,8 Cardiac function Osmotic Preload diuresis Afterload Cardiometabolic efficiency Metabolism CV death Arrhythmia Glucose removal Na+ Hospitalisation Sodium Arterial wall removal for heart failure structure/function Renal function Renal events 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 OUTCOME 8

Asian vs White HF Singapore Asians vs Swedish whites Bank, … Lam. JACC HF 2016

ASIAN-HF Registry 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 http://www.clinicaltrials.gov/ct2/show/NCT01633398?term=ASIAN+HF&rank=1 22 Lam CS Eur J Heart Fail 2013

Comorbidity clusters in ASIAN-HF 23 CONFIDENTIAL 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 HFpEF (n=20) and controls (n=8) studied with conductance catheter and endomyocardial biopsy Role of TGF β 1 in transdifferentiation of fibroblasts to myofibroblasts, ↑collagen synthesis Positive correlation between cardiac collagen, inflammatory cells, and diastolic dysfunction suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction Westerman Circ Heart Fail 2011

Interleukin-1 blockade in HFpEF: D-HART Pilot Trial Cross-over RCT in 12 HFpEF with plasma CRP>2 mg/l Van Tassell Am J Cardiol 2014

D-HART 2 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 Van Tassell Circulation. 2017;136:A17709

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

Cardiomyocyte stiffness & low myocardial cGMP-PKG activity Franssen JACC HF 2015 Van Heerebeek Circulation 2012

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

SOCRATES-Preserved Primary endpoints No effect on log NT-proBNP or LAV at 12 weeks vs placebo Placebo 1.25 2.5 2.5 to 2.5 to 2.5 to Placebo 1.25 2.5 2.5 to 2.5 to 2.5 to mg mg 5 mg 10 mg 10 mg mg mg 5 mg 10 mg 10 mg 0.20 2 Change in left atrial volume (mL) 0 Change in log-NT-proBNP (pg/mL) 0.10 – 2 0.00 – 4 – 0.10 – 6 – 0.20 Placebo 1.25 mg 2.5 mg 2.5 to 5 mg 2.5 to 10 mg Pooled dose groups Data are mean ± standard error for the per-protocol analysis set Presented by B. Pieske at HF Congress 2016

SOCRATES-Preserved Pre-specified exploratory endpoint: Patient-reported health status Change from baseline in KCCQ clinical summary score Change from week 4 in KCCQ clinical summary score at week 12 25 Placebo 1.25 2.5 2.5 to 2.5 to Placebo 1.25 2.5 2.5 to 2.5 to Placebo 1.25 2.5 2.5 to 2.5 to mg mg 5 mg 10 mg mg mg 5 mg 10 mg mg mg 5 mg 10 mg 20 Change in KCCQ-CSS 15 Change in KCCQ-CSS 10 10 Minimum Clinically Important Difference = 5 points 5 5 0 0 Week 4 Week 12 Placebo 1.25 mg 2.5 mg 2.5 to 5 mg 2.5 to 10 mg Data are mean ± standard error for the full analysis set excluding those subjects with incorrectly assigned doses Presented by B. Pieske at HF Congress 2016

Systemic & myocardial signaling in HFpEF Sanjiv J. Shah et al. Circulation. 2016;134:73-90

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

PARAMOUNT PARAMOUNT : LCZ696 vs valsartan in chronic HFpEF • 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 LCZ696 Valsartan LCZ696 vs (geometric mean) (n=134) (n=132) valsartan Baseline, pg/mL 783 862 (95% CI) (670, 914) (733, 1,012) 0.77* (0.64, 0.92) Week 12, pg/mL 605 835 p=0.005 (95% CI) (512, 714) (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. Solomon et al. Lancet 2012;380:1387 – 95

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 HF PAH No PH „pure“ „typical“ „atypical“ Normal RV Function Severity of PH DPG PVR Cpc-PH Ipc-PH Severe PH Moderate PH RV Function Normal RV Function Targeted No Perhaps No PAH Therapy PH Therapy Numerous AMBITION RELAX (JAMA 2013) Guazzi 2011 Hoendermis PAH RCTs Ex-PAS NEAT (NEJM 2015) COMPERA 2015 EHJ 2015 Cpc-PH: Combined post- and pre-capillary PH Ipc-PH: Isolated post-capillary PH

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