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

• Available online: vigour.ualberta.ca

Disclosures

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- preserved 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 NYHA class II–IV ≥ 4 weeks Diuretic ≥ 1 week biomarkers +imaging +provocation (all undefined further) NYHA class III/IV and abnormal CXR (pulmonary congestion), ECG (LVH, LBBB) or echocardiogram (LVH, enlarged LA) NYHA III/IV in prior 6 months if taking ACE-I 3 of 9 clinical criteria (e.g. exertional or paroxysmal nocturnal dyspnea, edema, raised JVP etc) and 2

• f 4 echo criteria

(preserved wall motion, LA enlargement, LVH or Doppler evidence of DD)

Prior cardiac hospitalisation Cardiac hospitalisation in prior 3 months

What’s in a name?

Ejection fraction <40% >50% HF-REF HF-PEF

Zile: +Framingham Vasan: +SSx + biomarkers + imaging +provocative ESC CHARM-p I-preserve PEP-CHF

Zile Circulation 2003 Vasan Circulation 2000 ESC EHJ 2007

What’s in a name?

Ejection fraction <40% >50% HF-REF HF-PEF

borderline

DHF HF-PSF

Symptoms and signs of heart failure Normal of mildly left ventricular systolic function LVEF > 50% And LVEDVI < 97 ml/ m2 Evidence of abnormal LV relaxation. Filling, diastolic distensibility and diastolic stiffness

Invasive Haemodynamic Measurements mPCW > 12 mmHg

• r LVEDP > 16 mmHg
• r t> 48 ms
• r b > 0.27

TD EIE’ > 15 15 > EIE’ > 8 Biomarkers NT-proBNP > 220 pg/ml

• r

BNP > 200 pg/ml Biomarkers NT-proBNP > 220 pg/ml

• r

BNP > 200 pg/ml ECHO-bloodflow Doppler E/A>50 yr < 0.5 and DT>50 yr > 280 ms

• r Ard-Ad > 30 ms
• r LAVI > 40 ml/m2
• r LVMI > 122 g/m2 (♀); >149 g/m2 (♂)

Or Atrial Fibrillation TD EIE’ > 8 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

100% men

65 years

Low rates of Afib, renal disease, valvular disease

B

96% women

65 years

low rates of AF, renal dysfunction, and valvular disease

C

Men or women

70 years

Obesity, DM, CAD, anemia

D

100% women

73 years

average rates of DM, hyperlipidemia,

• besity, renal

insufficiency

E

100% men

75 years

lower BMI, +AF +CAD.

F

mostly women (77.5%)

82 years

lower BMI +AF, valvular disease, renal dysfunction, and anemia.

Kao, EJHF 2015 I-PRESERVE, CHARM-P data No difference in symptoms, SBP, BNP across groups

HF-PEF: causation or association?

European Journal of Heart Failure Volume 14, Issue 7, pages 713-715, 18 FEB 2014 DOI: 10.1093/eurjhf/hfs072

RULE-OUT: Anemia COPD Obesity Deconditioning from other medical illness …

IS IT RISKY?

MAGGIC Collaborative

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

Heartfailurerisk.org

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

Desai, Rationale and design, Am Heart J 2011 Pfeffer, TOPCAT NEJM 2013 Pfeffer Circulation 2014

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%

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

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

(CV Death, HF Hosp, or Resuscitated Cardiac Arrest)

320/1722 (18.6%) 351/1723 (20.4%)

Pfeffer, TOPCAT NEJM 2013

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

TOPCAT: Placebo event rates

Pfeffer, TOPCAT NEJM 2013

HR=0.82 (0.69-0.98) HR=1.10 (0.79-1.51)

Interaction p=0.122

US, Canada, Argentina, Brazil Russia, Rep Georgia Placebo: 280/881 (31.8%) Placebo: 71/842 (8.4%)

TOPCAT: Regional Strata

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?

Shah, Circ-HF 2015 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.

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

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

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*

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