The Myths of Heart Failure with Preserved Ejection Fraction: A misunderstood disease in search of a therapy Scott 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. -E. Braunwald modified by B. Borlaug and M. Redfield Clinically: A clinical syndrome characterized by breathlessness, fatigue and edema caused by an abnormality of the heart
Distribution of EF in Hospitalized Patients With Heart Failure OPTIMIZE-HF Registry, N=41,267 EF 40 % EF 40-50 % EF 50 % Fonarow G et al. JACC. 2007; 50:768-777.
% 35 30 Similar Signs and Symptoms in Patients with HFpEF and HFrEF HFrEF HFpEF 25 20 15 10 5 0 Edema Orthop- nea PND Rest dyspnea S 3 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 time 1 Among patients with HFrEF, the likelihood of survival increased from 1987 to 2001 1.0 0.8 Patients with reduced ejection fraction 1987 1991 1992 1996 1997 2001 1.0 0.8 Patients with preserved ejection fraction 1987 1991 1992 1996 1997 2001 Survival 0.6 0.4 Survival 0.6 0.4 0.2 p=0.005 0 0 1 2 3 4 5 Year 0.2 p=0.36 0 0 1 2 3 4 5 Year 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 HFpEF 2 9 1. Owan et al. N Engl J Med 2006;355:251 9; 2. Blanche et al. Swiss Med Wkly 2010;140:66 72
Myth # 2: HFpEF is a Collection of Comorbidities and NOT a Disease! HFrEF HFpEF P-value Age 71.8 ± 75.4 ± 11.5 < 0.001 Hypertension 12 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 Bhatia et al. NEJM 2006
HF Hospitalization and Mortality Higher in HFpEF than in Studies of Similar Comorbidity 70 52,5 Mortality HF Hosp 35 17,5 0 ACCORD ACTION PEACE HOPE ALLHAT CHARM-P
MYTH #3 HFpEF is Caused by Diastolic Dysfunction
Age Dependence of Myocardial Relaxation Velocity in Normals 24 20 Lateral E' (cm/sec) 16 12 8 4 40 50 60 70 80 90 Age (Years) Henein et al. EHJ. 2002;23:162 171.
High Prevalence of Diastolic Dysfunction Regardless of Clinical Status 50 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) 42 42 43 41 42 37,5 25 30 26 12,5 0 15 10 5,5 1,6 2,3 Healthy n = 371 Co-Morbid n = 4,555 HFpEF n = 474 No DM, HTN, CHD, HF Normal Mild DD Moderate DD 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 Myocardial Strain (%) 0-2 -4-6 -8-10 -12-14 -16-18 -20-22 -24-26 -28-30 -32-34 Normal (n=50) Hypertension and Diastolic dysfunction (n=300) 1 Kraigher-Krainer E, JACC 2013 2 Knappe D, Circ HF 2011 3 TOPCAT Unpublished No HF HFpEF HFrEF PARAMOUNT 1 (n=~200) TOPCAT 3 (n=~438) Longitudinal Strain Circumferential Strain MADIT-CRT 2 (n=1077)
GLS was the BEST Predictor of Outcome in HFpEF in TOPCAT Trial Univariate Multivariate Age P < 0.001 P = 0.005 E/E' P < 0.001 P = 0.017 LV Mass P < 0.001 P = 0.025 Global Longitudinal Strain P < 0.001 P = 0.001 Left Atrial Volume P = 0.009 P = 0.083 LVEF P = 0.081 P = 0.70 0.8 1 1.2 1.4 1.6 1.8 2 Hazard Ratio for Primary Outcome (per 1 SD) TOPCAT Unpublished Data
MYTH #5 There is no Evidenced Based Treatment for HFpEF
THIS ONE IS TRUE!
Outcomes Trials in HFpEF CHARM-Preserved PEP-CHF I-PRESERVE TOPCAT
TOPCAT: 1 Outcome (CV Death, HF Hosp, or Resuscitated Cardiac Arrest) 351/1723 (20.4%) Placebo Spironolactone HR = 0.89 (0.77 1.04) p=0.138 320/1722 (18.6%) Pfeffer et al. NEJM 2014;370(15):1383-92
TOPCAT: Results by Region US, Canada, Argentina, Brazil HR=0.82 (0.69-0.98) Placebo: 280/881 (31.8%) Interaction p=0.122 Placebo: 71/842 (8.4%) Russia, Rep Georgia HR=1.10 (0.79-1.51) Pfeffer MA et al. Circulation. 2015 Jan 6;131(1):34-42
TOPCAT: Benefit of Spironolactone Diminishes with Increasing Ejection Fraction Primary Outcome HF Hospitalization Solomon SD et al. Eur Heart J. 2015
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 Design SOCRATES-REDUCED SOCRATES-PRESERVED 2 Phase II, randomized, parallel-group, placebo-controlled, doubleblind, dose finding phase IIb studies of 4 dose regimens of the oral sgc stimulator vericiguat over 12 weeks Inclusion Criteria Primary Outcome Worsening chronic heart failure requiring hospitalization (or IV diuretic for HF) with initiation after clinical stabilization LVEF <45% NT-proBNP at 12 weeks LVEF 45% Left atrial (LA) enlargement 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 Results No reduction in log-nt-probnp or in LAV at week 12 compared with placebo 0.20 0.10 0.00 0.10 Placebo 1.25 mg 2.5 mg 2.5 to 5 mg 2.5 to 10 mg Pooled 2.5/5/10 mg Change in left atrial volume (ml) 2 0 2 4 Placebo 1.25 mg 2.5 mg 2.5 to 5 mg 2.5 to 10 mg Pooled 2.5/5/10 mg 0.20 Placebo 1.25 mg 2.5 mg 2.5 to 5 mg 2.5 to 10 mg Pooled dose groups 6 Data are mean ± standard error for the per-protocol analysis sets
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
LCZ696 A first-in-class Angiotensin Receptor Neprilysin Inhibitor Simultaneously Inhibits NEP and the RAS Vasoactive Peptide System pro-bnp LCZ696 Heart Failure Renin Angiotensin System Angiotensinogen (liver secretion) ANP BNP CNP Adrenomedullin Bradykinin Substance P (angiotensin II) Vasodilation! blood pressure! sympathetic tone!aldosterone levels! fibrosis! hypertrophy Natriuresis/Diuresis NT-pro BNP Neprilysin X Inactive fragments Sacubitril (AHU377) LBQ657 O HO HN O OH O LCZ696 is a novel crystalline complex consisting of the molecular moieties of valsartan and sacubitril in an equimolar ratio Valsartan O N N N N O OH NH X Angiotensin I Angiotensin II AT 1 receptor Vasoconstriction " blood pressure " sympathetic tone " aldosterone " fibrosis " hypertrophy
PARAMOUNT: Study Design Placebo run-in Discontinue ACEI or ARB therapy one day prior to randomization LCZ696 50 mg BID Valsartan 40 mg BID LCZ696 100 mg BID Valsartan 80 mg BID 301 patients randomized LCZ696 200 mg BID Valsartan 160 mg BID Prior ACEi/ARB use discontinued Week Visit -2 1 2 weeks 0 2 1 2 3 4 1 week 1 week 10 weeks 4 8 12 18 24 30 36 5 6 7 8 9 10 11 6 month extension 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 Baseline randomization visit and visit at end of 12 weeks of core study Clinicaltrials.gov NCT00887588 Solomon et al. ESC Hotline 2012 Lancet 2012
PARAMOUNT: Significant Improvement in Several Domains Improvement in NT-proBNP Improvement in Left Atrial Size NTproBNP (pg/ml) 1000 900 800 700 600 500 400 300 862 (733,1012) 835 (710, 981) 783 (670,914) p = 0.063 Valsartan LCZ696 LCZ696/Valsartan: 0.77 (0.64, 0.92) P = 0.005 605 (512, 714) Change in Left Atrial Volume (ml) 2 1 0-1 -2-3 -4-5 -6 12 Weeks 36 Weeks P = 0.18 P = 0.003 200 0 5 10 12 Weeks Post Randomization Improvement in NYHA Class W U LCZ696 Valsartan Solomon et al. Lancet 2012
Target patient population: 4,600 patients with symptomatic HF (NYHA Class II IV) and LVEF 45% Randomization 1:1 Double-blind treatment period Screening Active run-in period Valsartan 80 mg BID* LCZ696 100 mg BID LCZ696 200 mg BID Valsartan 160 mg BID On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs) up to 2 weeks 3 8 weeks ~240 weeks Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events) 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
FAIR-HFpEF Design 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 FCM up to 2000mg (2x1000mg) Treatment continues if ID is not corrected Screening R n=200 1 EP: 6MWT Placebo D0 W4 W12 W20 W24 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
Inter-Atrial Shunt Device - Concept Abnormal LV relaxation results in elevated Left Atrial Pressure (LAP) and pulmonary edema Transcatheter implant to create a small 1 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 Device 1 - MOA Hypothesis Elevated LV filling pressures (Elevated LAP) X Pulmonary Venous hypertension (Elevated PCWP 1 ) Pulmonary edema, Dyspnea at rest/exercise 1 PCWP at rest is predictor of mortality (Dorfs, EHJ 2014)
6 months Effectiveness endpoints 41 Hasenfuβ, et al The Lancet Vol 387 March 26, 2016
6 months Efficacy Endpoints 42 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