HF-Preserved Ejection Fraction Justin A. Ezekowitz, MBBCh MSc FRCPC - PowerPoint PPT Presentation

HF-Preserved Ejection Fraction Justin A. Ezekowitz, MBBCh MSc FRCPC FACC FESC FAHA Associate Professor, University of Alberta Co-Director, Canadian VIGOUR Centre Cardiologist, Mazankowski Alberta Heart Institute 14 March 2016

Disclosures • Available online: vigour.ualberta.ca

HF – preserved ejection fraction • No therapy specifically recommended for HF- PEF with “strong” recommendation • Complicated phenotype (s) and trial design (s) • Different patient demographics • Many pharmacologic and non-pharmacologic interventions have been tried

DEFINITIONS: WHAT IS IT?

Different trial/cohort entry criteria Zile et al 2003 Vasan/Levy I-PRESERVE CHARM- PEP-CHF preserved none none >60 yrs >18 yrs >70 yrs EF>50% EF>50% EF>45% EF>40% EF>40% Framingham Sx Signs and symptoms + NYHA class II – IV with NYHA class II –IV ≥ 4 Diuretic ≥ 1 week prior hosp <6 months weeks biomarkers +imaging NYHA class III/IV and NYHA III/IV in prior 6 3 of 9 clinical criteria +provocation (all abnormal CXR months if taking ACE-I (e.g. exertional or undefined further) (pulmonary paroxysmal nocturnal congestion), ECG dyspnea, edema, (LVH, LBBB) or raised JVP etc) and 2 echocardiogram (LVH, of 4 echo criteria enlarged LA) (preserved wall motion, LA enlargement, LVH or Doppler evidence of DD) Prior cardiac Cardiac hospitalisation hospitalisation in prior 3 months

What’s in a name? HF- R EF HF- P EF >50% CHARM-p I-preserve <40% PEP-CHF ESC Zile: +Framingham Vasan: +SSx + biomarkers + imaging +provocative Zile Circulation 2003 Ejection fraction Vasan Circulation 2000 ESC EHJ 2007

What’s in a name? HF- R EF HF- P EF borderline <40% >50% DHF HF-PSF Ejection fraction

Symptoms and signs of heart failure Normal of mildly left ventricular systolic function LVEF > 50% And LVEDVI < 97 ml/ m 2 Evidence of abnormal LV relaxation. Filling, diastolic distensibility and diastolic stiffness TD Biomarkers Invasive EIE ’ > 15 15 > EIE ’ > 8 NT-proBNP > 220 pg/ml Haemodynamic or Measurements Biomarkers BNP > 200 pg/ml mPCW > 12 mmHg NT-proBNP > 220 pg/ml or LVEDP > 16 mmHg or or t> 48 ms BNP > 200 pg/ml or b > 0.27 TD EIE ’ > 8 ECHO-bloodflow Doppler E/A >50 yr < 0.5 and DT >50 yr > 280 ms or Ard-Ad > 30 ms or LAVI > 40 ml/m 2 or LVMI > 122 g/m 2 ( ♀ ); >149 g/m 2 ( ♂ ) Or Atrial Fibrillation HFNEF Figure 1: European Society of Cardiology Diagnostic Criteria for Diastolic Heart Failure, 2007.

ESC 2012

Does BNP help for Diagnosis? Figure 1. Distribution of Patients in the 5 LVEF Groups for BNP. The following divisions were made: low: 0 to 250 pg/ml; middle: 251 to 750 pg/ml; and high: &gt;750 pg/ml. The proportion is depicted in stacked bars. BNP = B-type natriuretic peptide; LVEF = left ... Dirk J. van Veldhuisen, et al JACC Volume 61, Issue 14, 2013, 1498 – 1506

HF-PEF subtypes/clusters A B C D E F mostly 96% Men or 100% 100% men 100% men women women women women (77.5%) 65 years 65 years 70 years 73 years 75 years 82 years low rates of AF, average rates of lower BMI +AF, Low rates of renal DM, valvular Afib, renal Obesity, DM, lower BMI, +AF dysfunction, hyperlipidemia, disease, renal disease, CAD, anemia +CAD. and valvular obesity, renal dysfunction, valvular disease disease insufficiency and anemia. No difference in symptoms, SBP, BNP across groups Kao, EJHF 2015 I-PRESERVE, CHARM-P data

HF-PEF: causation or association? RULE-OUT: Anemia COPD Obesity Deconditioning from other medical illness … European Journal of Heart Failure Volume 14, Issue 7, pages 713-715, 18 FEB 2014 DOI: 10.1093/eurjhf/hfs072

IS IT RISKY?

MAGGIC Collaborative Heartfailurerisk.org MAGGIC). (2012). EHJ doi:10.1093/eurheartj/ehr254 Pocock, S. J., (2013). EHJ doi:10.1093/eurheartj/ehs337

THERAPEUTIC OPTIONS

Tried and failed Reduced Preserved Beta-blockers Multiple J-DHF, SENIORS ARB Valsartan, candesartan CHARM-P, I-PRESERVE ACE Multiple PEP-CHF Digoxin DIG DIG-preserved PDE5 (sildenafil) RELAX-HF Statins GISSI-HF, CORONA GISSI-HF MRA RALES, EMPHASIS TOPCAT, Aldo-DHF Alagebrium Small RCT Nitrates V-HeFT NEAT Exercise HF-ACTION Small RCT

TOPCAT • International, multi-center, double-blind, placebo-controlled RCT • NIH Sponsored • Significant CAN involvement: Sites, Exec, Country Leaders • Randomization, 1:1 – Spironolactone, 15, 30, 45 mg daily – matching placebo • Primary: CV death, HF hosp, or aborted cardiac arrest • Assumed: 3-year placebo rate of 17.4% Desai, Rationale and design, Am Heart J 2011 Pfeffer, TOPCAT NEJM 2013 Pfeffer Circulation 2014

TOPCAT: Eligibility criteria • Inclusion: • Major Exclusion: – Symptomatic Heart – eGFR<30 mL/min/1.7m2 Failure – potassium ≥5 mmol/L – Age ≥ 50 – uncontrolled – LVEF ≥ 45% hypertension, AF with rate > 90/min, recent – stratified according to: ACS, restrictive, • HF Hospitalization within infiltrative, or the past year, or hypertrophic • Elevated natriuretic cardiomyopathy peptides – BNP ≥100 pg/mL – NT- proBNP ≥360 pg/mL Desai, Rationale and design, Am Heart J 2011 Pfeffer, TOPCAT NEJM 2013

TOPCAT: Baseline characteristics N=3445 pts Age, median (IQR), years 67 (61-76) Female, % 52 Ejection Fraction, median, % 56 Diabetes, % 33 Atrial Fibrillation, % 35 eGFR, median, IQR 65 (54, 79) Eligibility Stratum, % Hosp. for HF 72 Natriuretic Peptide 29 Medications, % ACE-I or ARB 84 Beta-blocker 78 Diuretic 81 S. Shah Circ HF 2012

TOPCAT: Primary outcome 351/1723 (20.4%) 320/1722 (18.6%) Resuscitated Cardiac Arrest) (CV Death, HF Hosp, or Pfeffer, TOPCAT NEJM 2013

TOPCAT: Placebo event rates Placebo: 280/881 (31.8%) US, Canada, Argentina, Brazil 12.6 per 100 pt-yr Russia, Rep Georgia Placebo: 71/842 (8.4%) 2.3 per 100 pt-yr Pfeffer, TOPCAT NEJM 2013

TOPCAT: Regional Strata Placebo: US, Canada, Argentina, 280/881 (31.8%) 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, TOPCAT NEJM 2013

TOPCAT: Regional Strata • Fully adjusted model for primary endpoint including region and other variables: – HR 0.85, 95%CI 0.73 to 0.99, p=0.043 – “ 15% relative risk reduction for the primary endpoint in favor of spironolactone ” Pfeffer, TOPCAT NEJM 2013

TOPCAT: Echo changes? 12 -18 months of spironolactone therapy was not associated with improvement in LV structure or function in HFpEF. Reduction in LA volume at follow-up was associated with a lower risk of primary endpoint. Shah, Circ-HF 2015

TOPCAT: Safety • Doubling in the rate of hyperkalemia: • 9.1% in the placebo group • 18.7% in the spironolactone group – no deaths due to hyperkalemia • Fewer events of hypokalemia • No renal failure leading to dialysis

CCS HF-PEF Recommendation Recommendation • We suggest that in individuals with HFpEF, an elevated natriuretic peptide level, serum potassium < 5.0 mmol/L and an eGFR ≥30 ml/min, a mineralocorticoid receptor antagonist like spironolactone should be considered, with close surveillance of serum potassium and creatinine. – Weak Recommendation, Low Quality of Evidence Values and Preferences • This recommendation is based upon a pre-specified subgroup analysis of the TOPCAT trial, which includes analysis of the pre- defined outcomes according to admission NT-BNP level, as well as the corroborating portion of the trial conducted within North and South America. Moe, Ezekowitz CJC 2014

HF-PEF and Exercise Pandey, CircHF, 2015

CCS HF-PEF Recommendation • TBA: exercise for HF-PEF? • Would you not send a patient with HF to cardiac rehabilitation?

WHAT’S IN THE PIPELINE?

HF-PEF and ?LCZ696 PARAMOUNT HF-PEF with elevated NPs No change in QOL Solomon, Lancet 2012

HF-PEF in development Soluble guanylate Vericiguat SOCRATES- cyclase modulators Preserved Diabetes drugs SGLT2 multiple ARNI LCZ696 PARAGON MRA Spironolactone SPRINT Mitochondria fxn Bendavia Mito-HFPEF Exercise Aerobic, anaerobic multiple Diet Overall diet DASH-DHF2 Diet Low sodium SODIUM-HF* Supplements Epicatechin (cocoa) Supplements Resveratrol REV-HF*

Summary 1. Definitions: apply what is clinically relevant EF>50% +/- Sx +/- signs + ?BNP 2. Spironolactone may offer benefit 3. Don ’ t forget about exercise 4. New therapies on horizon

Acknowledgements