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 HFPEF 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
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
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
of 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?
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
HF-REF
<40%
borderline
What’s in a name?
HF-PEF
>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/ m2
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’ > 15
15 > EIE’ > 8
Biomarkers
NT-proBNP > 220 pg/ml
or
BNP > 200 pg/ml
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/m2
or LVMI > 122 g/m2 (♀); >149 g/m2 (♂)
Or Atrial Fibrillation
HFNEF
Figure 1: European Society of Cardiology Diagnostic Criteria for Diastolic Heart Failure, 2007.
TD
EIE’ > 8
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
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
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:
– Symptomatic Heart
Failure
– Age ≥ 50
– LVEF ≥ 45%
– stratified according to:
• HF Hospitalization within
the past year, or
• Elevated natriuretic
peptides
• 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
– 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
Eligibility Stratum, %
65 (54, 79)
Hosp. for HF
Natriuretic Peptide
72
29
ACE-I or ARB
Beta-blocker
Diuretic
84
78
81
Medications, %
S. Shah Circ HF 2012
TOPCAT: Primary outcome
351/1723 (20.4%)
(CV Death, HF Hosp, or
Resuscitated Cardiac Arrest)
320/1722 (18.6%)
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:
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, 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 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
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
cyclase modulators
Diabetes drugs
Vericiguat
SGLT2
SOCRATESPreserved
multiple
ARNI
MRA
Mitochondria fxn
LCZ696
Spironolactone
Bendavia
PARAGON
SPRINT
Mito-HFPEF
Exercise
Diet
Diet
Aerobic, anaerobic
Overall diet
Low sodium
multiple
DASH-DHF2
SODIUM-HF*
Supplements
Supplements
Epicatechin (cocoa)
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