HF-Preserved Ejection Fraction

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1 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

2 Disclosures Available online: vigour.ualberta.ca

3 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

4 DEFINITIONS: WHAT IS IT?

5 Different trial/cohort entry criteria Zile et al 2003 Vasan/Levy I-PRESERVE CHARMpreserved PEP-CHF 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 prior hosp <6 months biomarkers +imaging +provocation (all undefined further) NYHA class III/IV and abnormal CXR (pulmonary congestion), ECG (LVH, LBBB) or echocardiogram (LVH, enlarged LA) NYHA class II IV 4 weeks NYHA III/IV in prior 6 months if taking ACE-I Prior cardiac hospitalisation Diuretic 1 week 3 of 9 clinical criteria (e.g. exertional or paroxysmal nocturnal dyspnea, edema, raised JVP etc) and 2 of 4 echo criteria (preserved wall motion, LA enlargement, LVH or Doppler evidence of DD) Cardiac hospitalisation in prior 3 months

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

7 borderline What s in a name? HF-REF HF-PEF <40% >50% DHF HF-PSF Ejection fraction

8 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 Invasive Haemodynamic Measurements mpcw > 12 mmhg or LVEDP > 16 mmhg or t> 48 ms or b > 0.27 TD EIE > > EIE > 8 Biomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ml 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 Biomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ml TD EIE > 8 HFNEF Figure 1: European Society of Cardiology Diagnostic Criteria for Diastolic Heart Failure, 2007.

9 ESC 2012

10 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: >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,

HF-PEF subtypes/clusters A B C D E F 100% men 96% women Men or women 100% women 100% men

5%) 65 years 65 years 70 years 73 years 75 years 82 years Low rates of Afib, renal

Obesity, DM, CAD, anemia average rates of DM, hyperlipidemia, obesity, renal

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

12 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 , 18 FEB 2014 DOI: /eurjhf/hfs072

13 IS IT RISKY?

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

15 THERAPEUTIC OPTIONS

16 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

17 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

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

19 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, % Medications, % Hosp. for HF 72 Natriuretic Peptide 29 ACE-I or ARB 84 Beta-blocker 78 Diuretic 81 S. Shah Circ HF 2012

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

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

22 TOPCAT: Regional Strata US, Canada, Argentina, Brazil HR=0.82 ( ) Placebo: 280/881 (31.8%) Interaction p=0.122 Russia, Rep Georgia HR=1.10 ( ) Placebo: 71/842 (8.4%) Pfeffer, TOPCAT NEJM 2013

23 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= % relative risk reduction for the primary endpoint in favor of spironolactone Pfeffer, TOPCAT NEJM 2013

24 Shah, Circ-HF 2015 TOPCAT: Echo changes? 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.

25 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

26 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 predefined 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

27 HF-PEF and Exercise Pandey, CircHF, 2015

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

29 WHAT S IN THE PIPELINE?

30 HF-PEF and?lcz696 PARAMOUNT HF-PEF with elevated NPs No change in QOL Solomon, Lancet 2012

31 HF-PEF in development Soluble guanylate cyclase modulators Vericiguat SOCRATES- 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*

32 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

33 Acknowledgements

HFpEF, Mito or Realidad?

HFpEF, Mito or Realidad? Ileana L. Piña, MD, MPH Professor of Medicine and Epidemiology/Population Health Associate Chief for Academic Affairs -- Cardiology Montefiore-Einstein Medical Center Bronx, NY