Detailed discussion on Heart Failure with Preserved Ejection Fraction By DR. Vaibhav Yawalkar, Interventional Cardiologist MD, DM

1. Heart Failure with Preserved
Ejection Fraction –
Current Concepts
Dr. Vaibhav Yawalkar
MD, DM Cardiology

2. Heart Failure is a clinical syndrome characterized
by typical
Symptoms (e.g. breathlessness, ankle swelling
and fatigue) that may be accompanied by
Signs (e.g. elevated jugular venous pressure,
pulmonary crackles and peripheral oedema)
Caused by a structural and/or functional cardiac
abnormality, resulting in a reduced cardiac output
and/or elevated intracardiac pressures at rest or
during stress.
Heart Failure: Definition

3. HF: Classification

4. New Classification of Heart Failure
HFrEF HFmrEF HFpEF
symptoms
(+/- signs)
symptoms
(+/- signs)
symptoms
(+/- signs)
LVEF < 40% LVEF 40-49% LVEF ≥ 50%
1. Elevated (NT-pro)BNP
2. Relevant structural
heart disease (LVH or
LAE) +/- diastolic
dysfunction
1. Elevated (NT-pro)BNP
2. Relevant structural
heart disease (LVH or
LAE) +/- diastolic
dysfunction
Identifying HFmrEF as a separate group will stimulate research into
underlying characteristics, pathophysiology and treatment
of this population
Ponikowski P et al. 2016 ESC HF Guidelines
Eur Heart J 2016 & Eur J Heart Fail 2016

5. Heart Failure – Global Prevalence
Ponikowski, P, et al. Heart Failure – preventing disease and death worldwide. 2014. Available at:
http://www.escardio.org/communities/HFA/Documents/whfa-whitepaper.pdf , 2014.
North America
Canada
USA
1.5%
1.9%
Europe
France
UK
~1.2%
2.2%
1.3%
Asia
China 1.3%
Japan 1%
Malaysia 6.7%
Singapore 4.5%
Latin America
No population-based
estimates
Adapted from Ponikowski et al,
2014
*HF or swollen limbs
Africa
No population-
based estimates
Middle East
Oman 0.5%
Australasia
Australia* 1.3%

6. 1. Mozaffarian D et al. Circulation. 2015;131(4):e29-e322.
2. Mosterd A et al. Heart. 2007;93(9):1137-1146.
3. http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Chronic-Conditions/Downloads/2012Chartbook.pdf
4. Cowie MR et al. Oxford PharmaGenesis; 2014. http://www.oxfordhealthpolicyforum.org/AHFreport. Accessed February 18, 2015.
5. Fauci AS et al. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.
6. Cook C et al. Int J Cardiol. 2014;171(3):368-376.
NUMBER of PATIENTS
21 MILLION adults worldwide are
living with heart failure
This number is expected to
rise.1,2
REHOSPITALISATION
Heart failure is the NUMBER 1
cause of hospitalisation for
patients aged >65 years.4
MORTALITY
50% of heart failure patients die
within 5 years from diagnosis.5
COMORBIDITIES: The vast
majority of HF patients has 3 or
more comorbidities 3
ECONOMIC BURDEN
In 2012, the overall worldwide
cost of heart failure was nearly
$108 BILLION.6
The burden of heart failure

7. Heart Failure In
India

8. J Pract Cardiovasc Sci 2016 ;2:28-35.

9. MeanAge of Patients: 53 Years
In-Hospital Mortality: 30.8%
Post Discharge Mortality (6 months): 26.3%
Heart Failure – A Bigger Challenge in India
Global
India
MeanAge of Patients: 73 Years
In-Hospital Mortality: 3.8%
Post Discharge Mortality (6 months): 8.6%
Patients With Heart Failure In India
• Affected at a Younger Age
• Have a Very High Mortality Both In-Hospital and also After Discharge
Seth S, et al. J Pract Cardiovasc Sci 2015;1:35-8.

11. Heart Failure
Clinical Features

12. HF staging system
High Risk for Developing HF
Hypertension
CAD
Diabetes mellitus
Family history of cardiomyopathy
Asymptomatic HF
Previous MI
LV systolic dysfunction
Asymptomatic valvular disease
Symptomatic HF
Known structural heart disease
Shortness of breath and fatigue
Reduced exercise tolerance
Refractory
End-Stage HF
Marked symptoms at rest
despite maximal
medical therapy
A
B
C
D
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

13. Clinical Features: Symptoms

14. Clinical Features: Signs

15. Pathogenesis &
Pathophysiology

16. Pathogenesis of HF
• HF begins after an index event which produces an initial
decline in pumping capacity of the heart.
• After initial decline in pumping capacity, a variety of
compensatory mechanisms are activated, including the
adrenergic system, the RAAS and the cytokine systems.
• In the short term, these systems are able to restore CV
function to a normal homeostatic range, and the patient
remains asymptomatic.
• With time, however, the sustained activation of these
systems can lead to secondary end-organ damage within
the ventricle, with worsening LV remodeling and
subsequent cardiac decompensation.
• As a result of these changes, patients undergo the
transition from asymptomatic to symptomatic heart
failure

18. Pathophysiology of HF
In the patient with HFrEF, contractility is
depressed, Ees is low, and the end-
systolic pressure volume
relationship is accordingly shallow
With progressive LV dysfunction , LV
filling pressure increases and stroke
volume gradually decrease.
(Frank-Starling curves)

19. Pathophysiology of HF

20. Diagnosis of
Heart Failure

21. Diagnosis of Heart Failure
2 Major
OR
1 Major
+
2 Minor

22. NormalAbnormal
Diagnosis of HF

23. Heart Failure with
Preserved Fraction

24. HFpEF vs HFrEF
• Poorly understood
• Increasing in prevalence
• No definitive treatments
• High morbidity/mortality
• Common in females
• Common in Elderly
• More Co-morbidities
• More non-cardiovascular Deaths
• Well studied
• Decreasing in prevalence
• Many proven treatments
• Decreasing morbidity
• Decreasing mortality

25. Prevalence of HFpEF
The Cardiovascular Health Study
67%
10%
23%
Women
Normal (55%)
Mildly Reduced
(45% - 54%)
Moderately (30-44%)
or severely reduced
(< 30%)
Kitzman, et. al.Am. J. Cardiol. 87:413-419 (2001)
27%
31%
42%
Men
4,842 community-dwelling elderly (>66 yr) subjects; CHF prevalence 8.8%
80% had normal EF(>45%)

27. • Prevalence of HFpEF among patients with a discharge diagnosis of
HF increased from 38% to 54% from 1987–20011
• Increasing prevalence of HFpEF may be a consequence of growing
recognition, population aging and increases in hypertension and
obesity2
Patientswithpreserved
ejectionfraction(%)
70
60
50
40
30
20
0
1986 1990 1994 1998 2002
r=0.92, p<0.001
1. Owan et al. N Engl J Med 2006;355:251–9
2. Blanche et al. Swiss Med Wkly 2010;140:66–72
Increasing HFpEF prevalence trends
50 %

28. In a retrospective study of 451 patients with HF in Sweden, time from
diagnosis to first post-diagnosis CV or HF-related hospitalization was
not significantly different between HFpEF and HFrEF (p=0.49 and
p=0.08, respectively)
Wikstrom et al. ESC 2011 Gothenburg,
Sweden, May 21–24, 2011
HFpEF & HFrEF: Similar initial hospital rates
Time to first CV hospitalization Time to first HF hospitalization
1.00
0.75
0.50
0.25
0
0 200 400 600 800 1,000
Time (days)
Survivaldistributionfunction
1.00
0.75
0.50
0.25
0
0 200 400 600 800 1,000
Time (days)
Survivaldistributionfunction
HFpEF (LVEF >45%)
HFrEF (LVEF ≤45%)
Wikstrom et al. ESC 2011 Gothenburg, Sweden, 21–24 May 2011

29. HFpEF survival rates are not improving
• Owan et al. N Engl J Med 2006;355:251–9
Patients with HFpEF (LVEF ≥50%)Survival
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5
Year
p=0.36
1987–1991
1992–1996
1997–2001
Survival
1.0
0.8
0.6
0.4
0.2
0
Patients with HFrEF (LVEF <50%)
0 1 2 3 4 5
Year
1987–1991
1992–1996
1997–2001
p=0.005
Current annual
Mortality = 10-30%

30. Pathophysiology of
HFpEF

31. Does HFpEF exist as a distinct entity ?

32. • Antecedent and comorbid
diseases create hemodynamic
and metabolic load that causes
sympathetic and RAAS activation
& parasympathetic suppression
• Create a pro-inflammatory and
profibrotic milieu
• Results in recruitment of
circulating hematopoietic
progenitor cells, altered
endothelial function, increased
ROS & ECM fibrosis
• Cardiomyocyte calcium and
energetic regulation,
myofilament structure and
function also altered
Pathogenesis of HFpEF

33. Pathogenesis of HFpEF
• Concentric hypertrophy or
remodeling at the LV and
cardiomyocyte level
• Increased in LV wall thickness with
no change in volume;
cardiomyocytes have increased
diameter but no change in length
• Titin phosphorylation
• ECM : Increased fibrillar collagen
and interstitial fibrosis

34. Pathogenesis of HFpEF
• Titin phosphorylation in
HFpEF
• ↓↓ PKG/PKA
Phosphorylation
• ↑↑ PKC Phosphorylation

35. • The diastolic pressure-volume
relationship (DPVR) in patients
with HFpEF is shifted upward and
to the left, such that for any given
LV volume, pressure is higher in
HFpEF, indicating decreased
distensibility (increased stiffness).
• In patients with HFrEF, the DPVR
is shifted to the right, indicating
increased distensibility.
Pathogenesis of HFpEF: DPVR

36. Pathogenesis of HFpEF: Myocardial Stiffness
• As sarcomere length increases, the slope increases most rapidly in the HTN(+)HFpEF group.
• Patients with HTN(+)HFpEF had an increase in total myocardial stiffness as indicated by a leftward shift in
the stress vs. sarcomere length relationship.
• No significant differences between HTN(-)HFpEF vs. control patients
• Hypertension in the absence of HFpEF, did not alter passive myocardial stiffness.

37. LV Diastolic Pressure Volume Curve
• Four patterns of diastolic pressure-volume relationship
(DPVR)
• In the most prevalent pattern in HFpEF, represented by
curve B, the DPVR is shifted upward and to the left,
indicating reduced distensibility, where LV pressure is
increased at any LV volume.
• In patients with HFpEF, when relaxation is markedly
prolonged and diastole is abbreviated, as shown in
curve A, LV diastolic pressure falls throughout diastole
but remains increased.
• In curve C, pericardial constraint causes a parallel
upward shift in the DPVR.
• DPVR in patients with HFrEF typically is characterized
by curve D, in which eccentric remodeling results in a
shift of the DPVR to the right, representing an increase
in distensibility.
Most
Prevalent

38. LV End-systolic elastance & Vasodilator response
Differential effects of vasodilator therapy
• In HFpEF, the end-systolic pressure volume
relationship is steep, Ees is high, and reductions
in arterial afterload or elastance (Ea) from acute
vasodilator therapy lead to dramatic reductions
in systolic blood pressure (SBP) and modest
increases in stroke volume.
• In the patient with HFrEF, contractility is
depressed, Ees is low, and the end-systolic
pressure volume relationship is accordingly
shallow. Thus the same degree of vasodilation
(reduction in Ea) causes much less reduction in
SBP and much more increase in forward SV.

39. Diastolic Dysfunction & LV stiffness
is prevalent in HFpEF

44. *PAT – Peripheral Arterial Tonometry
*PAT–PeripheralArterialTonometry

46. Although pulmonary venous HTN contributes to
PH, it does not fully account for the severity of PH
in HFpEF

47. Novel Paradigm in pathogenesis of HFpEF
Walter J. Paulus et al JACC Feb 2013
The role of endothelial oxidative
stress in myocardial remodeling in
HFpEF, HFrEF and advanced HFrEF.
The inflammatory state due to
various co-morbidities may result
in altered coronary microvascular
endothelial function
• Increased ROS
• Reduced NO bioavailability,
cGMP, and protein kinase G
activity
• Increased interstitial fibrosis
• Hypo-phosphorylation of titin
ultimately resulting in HFpEF

48. Menopause-Related Estrogen Decrease and the
Pathogenesis of HFpEF
Potential mechanisms of E2(Estradiol) action
preventing development of HFpEF
• HFpEF is a condition
predominantly of
postmenopausal women.
• Menopause-related E2 decline
might contribute to HFpEF
onset.
• E2 regulates several pathways
involved in the pathogenesis of
HFpEF.
• Targets for the prevention and
therapy of HFpEF may prove
useful

49. Diagnosis of
HFpEF

50. Understanding “Diastolic HF” in 2004
Aurigemma G, et al. NEJM 2004
“HFpEF = Diastolic Dysfunction”

51. Understanding “HFpEF” in 2019
Kitzman D, Shah SJ. JACC 2016; Borlaug B. Nat Rev Cardiol
“HFpEF = Systemic Inflammation & comorbidities driven pathogenesis”

54. Reddy Y et al., Circulation 2018;138:861-870
HFpEF Diagnosis: A Score approach

55. HFpEF diagnosis: A score approach
Reddy Y et al., Circulation 2018;138:861-870

56. *EACVI Representatives.
HFpEF, heart failure with preserved ejection fraction.
The new ESC/HFA 2019 diagnostic algorithm:
“How to diagnose HFpEF –The HFA-PEFF Diagnostic
Algorithm”
An updated Consensus Statement of the Heart Failure Association (HFA) of the European
Society of Cardiology
Burkert Pieske, Carsten Tschöpe, Rudolf de Boer, Alan Fraser*, Stefan Anker, Donal Ewan,
Frank Edelmann, Michael Fu, Marco Guazzi, Carolyn Lam, Patrizio Lancelotti*, Vojtech
Melenovsky, Daniel Amando Morris, Eike Nagel, Elisabeth Pieske-Kraigher, Piotr
Ponikowski, Ramachandran Vasan, Scott Solomon, Frans Rutten, Petar Seferovic, Adriaan
Voors, Frank Ruschitzka, Walter Paulus, Gerasimos Filippatos
European Heart Journal, ESC 2019

57. HF-PEFF Algorithm

58. HF-PEFF Algorithm – Step 1 (P)

59. HF-PEFF Algorithm – Step 2 (E)

60. HF-PEFF Algorithm – Step 2 (E)
Major: 2 points; Minor: 1 point
Exclusion: ≤1 point; Diagnostic: ≥5 point; Grey zone: 2-4 points

61. HF-PEFF Algorithm – Step 3 (F1)

62. Example : Indeterminate diagnosis with SCORE
Echocardiography at Rest and during Exercise
Patient R.W., 74 y: HF, NYHA class III
Functional parameters during Exercise
E/e´ mean 20.4 – TR 3.3 m/s
Functional parameters at Rest:
E/e´mean 13.6, TR 2.6 m/s

63. HF-PEFF Algorithm – Step 3 (F1)

64. Step 3 (F1): Functional tests –
Invasive hemodynamics at rest ± exercise

65. HF-PEFF Algorithm – Step 4 (F2)

66. Amyloidosis HOCM
Myocarditis
M. Fabry
Hyperaldosteronism Aortic stenosis (mimics HFpEF)
Examples of specific aetiologies

67. Summary: What is new in diagnosing HFpEF?
• HFpEF is frequent, often overlooked, and heterogeneous
• Heart failure (and HFpEF!) can be objectivated
• The ESC/HFA diagnostic PEFF Algorithm provides a novel tool for a
stepwise approach in the assessment of suspected HFpEF
• Key elements are: a new diagnostic SCORE, and inclusion of non-
invasive or invasive exercise tests
• Workup for specific aetiologies is required in specific situations

68. Prognostic
Parameters in HFpEF

69. LV filling pressure predicts decompensation
• Patients with HFpEF have increased LV diastolic pressure (indexed as
ePAD), further increases in pressure leads to ADHF
• Both baseline LV diastolic filling pressure and changes in filling pressure are
sensitive predictors of future ADHF events

70. LV filling pressure predicts Mortality
Both baseline LV diastolic filling pressure and changes in
filling pressure are sensitive predictors of all-cause mortality

71. • LA Volume
• Grade of LVDD
• LVH
All predicts future HF events
Parameters of cardiac structure and function

72. Increased E/e’ ratio TR jet velocity
Both increased the risk of heart failure hospitalization and CV mortality

73. Biomarkers in HFpEF
• Higher the baseline value of NT-proBNP, the higher the rate of the
primary and HF endpoints.
• Change from baseline values of NT-proBNP have significant prognostic
value and predict morbidity and mortality outcomes.

74. Management
of HFpEF

78. CHARM-Preserved1 PEP-CHF2
I-PRESERVE3
1. Yusuf S et al., Lancet 2003; 2. Massie BM et al., N Engl J Med 2008;
3. Cleland JJ et al., Eur Heart J 2006; 4. Pitt et al. N Engl J Med 2014
TOPCAT4
Trials with RAAS inhibitors in HFpEF

79. TOPCAT
• Primary endpoint (CV death, CHF hospitalization, or
resuscitated cardiac arrest): spironolactone vs. placebo:
18.6% vs. 20.4%, HR 0.89, 95% CI 0.77-1.04, p = 0.14
• CV mortality: 9.3% vs. 10.2%, p = 0.35; CHF
hospitalizations: 12.0% vs. 14.2%, p = 0.042
• Hyperkalemia: 18.7% vs. 9.1%, p < 0.001; renal failure
also was higher in the spironolactone arm
Trial design: Patients with heart failure with preserved ejection fraction (HFpEF)
were randomized to spironolactone (initiated at 15 mg/day; median dose 25
mg/day) or placebo. Patients were followed for 6 years.
Results
Conclusions
Pitt B, et al. N Engl J Med 2014;370:1383-92
(p = 0.14)
Spironolactone
(n = 1,722)
Primary endpoint
• Spironolactone was not superior to placebo for CV
outcomes in HFpEF patients (majority on ACEI/ARB)
• Significantly higher rate of hyperkalemia and renal
failure in patients treated with spironolactone
• Reduction in CHF hospitalizations with
spironolactone is hypothesis generating and
deserves further study
0
25
50
18.6 20.4
Placebo
(n = 1,723)
%

80. Summary of Major Trials

81. Novel Targets for HFpEF treatment
 Neprilysin inhibition with ARNI
 Interatrial Shunt Device
 Implantable hemodynamic Monitor
 Activation of NO/cGMP pathway
 SGLT2 Inhibitors

88. • In patients with HFpEF, ARNI reduced NT-proBNP, a marker associated with
worse outcomes, to a greater extent than valsartan after 12 weeks of therapy.
• This reduction became evident at 4 weeks and was sustained to 36 weeks,
though the between group difference was no longer significant.
• There was reduction in left atrial size, indicative of reverse left atrial
remodeling, and improvement in NYHA class after 36 weeks
• ARNI was well tolerated.
• ARNI may have beneficial effects ,study is hypothesis generating
PARAMOUNT HF: CONCLUSIONS

96. • In patients with HFpEF, when comparing sacubitril/valsartan to valsartan the
former led to modest non-significant "13%” reduction in the primary outcome
overall, which was driven mainly by a reduction in first and recurrent HF
hospitalizations
• Secondary analyses showed improvement in various measures of symptoms,
quality of life, and renal function
• Use of an ARB as an active comparator rather than placebo, may have
attenuated overall treatment effect of ARNI
• Data suggested heterogeneity in the treatment response, with suggestion of
greater benefit in women and in individuals with lower LVEF (<57%)
PARAGON HF: CONCLUSIONS

98. Device therapy
for HFpEF

99. Transcatheter Intracardiac Shunt Device
Provides Sustained Clinical Benefit at
One Year in Heart Failure with Preserved or
Mildly Reduced Ejection Fraction:
The REDUCE LAP Heart Failure Trial
David M Kaye MD, PhD
on behalf of the REDUCE LAP HF Investigators
99

100. • The magnitude of the exercise - mediated rise in PCWP in HFPEF is
related to both symptoms and outcome.
100
Implications of Elevated LA Pressure in HFPEF
SURVIVAL
Dorfs EHJ 2014
SYMPTOMS
0 100 200 300
0
200
400
600
Workload corrected PCWP
(mmHg/W/kg)
Sixminutewalk(meters)
r= -0.47
p<0.001
REDUCE LAP-HF Unpublished data
| | | | | | | |
||||||
2 4 6 8 10 12 14 16
100
90
80
70
60
50
Work corrected
PCWP>25.5 mmHg/W/kg
Work corrected
PCWP<25.5 mmHg/W/kg
p=0.03
YearsSurvival(%)

101. • Computer simulation demonstrated that an 8mm interatrial shunt
device (IASD®) would provide acute LA decompression during exercise
Left Atrial Decompression: IASD Rationale
Inter-atrial Shunt Therapy in HFPEF?
LA pressure
RA pressure
Kaye et al JCardFail 2014

102. CAUTION Investigational device. Limited by Federal (or United States) law to investigational use
InterAtrial Shunt Device - Mode of Action
102
X
Elevated LV filling
pressures (Elevated LAP)
Pulmonary Venous
hypertension
Pulmonary Congestion &
Dyspnea (rest/exercise)
Transcatheter interatrial shunt device

103. 103
REDUCE LAP-HF Trial
Hasenfuß G et al: Lancet 2016; 387: 1298–304
Inclusion Criteria (n=64):
Open label
LVEF ≥ 40%,
NYHA class II-IV
Elevated PCWP
≥ 15 mmHg (rest) or
≥ 25 (supine bicycle exercise)
6 month outcomes
& reduced exercise PCWP*MLWHF - Minnesota living with heart failure questionnaire
*6MWT – 6 Minutes walk test

104. REDUCE-LAP Summary
• Implantation of an interatrial shunt device appears to be safe with an acceptable
MACCE rate through one year of follow-up.
• Interatrial shunt device patency was maintained through one year
• The clinical and hemodynamic benefit observed 6 months after implant was
sustained through one year, with no evidence of adverse sequelae
• Meaningful improvements in NHYA class, exercise capacity and QOL
• Clinically meaningful reduction in normalized PCWP
• Randomised trials are required and ongoing to determine the value of this novel
strategy for the management of HFPEF.
104

105. CHAMPION – IHM derived PAP guided Therapy
• Hospitalization for heart failure: 0.32 events
per patient per 6 months in the treatment
group vs. 0.44 events per patient per 6
months in the treatment group (p = 0.0002)
• During the open access period, control
patients experienced a 48% reduction in
hospitalization for heart failure compared
with control patients during the randomization
period (p < 0.0001)
Trial design: Patients with recent hospitalization for heart failure were implanted with a
pulmonary artery pressure monitor and randomized so that providers received daily
pulmonary artery pressure information for 6 months (n = 270) vs. control (n = 280).
Results
Conclusions
• Among individuals with recent hospitalization
for heart failure, the use of an implantable
device to provide daily pulmonary artery
hemodynamic information was beneficial
• This device resulted in a reduction in
hospitalization for heart failure
Abraham WT, et al. Lancet 2016;387:453-61
Pulmonary artery
monitoring
Control
Events/patient
(p = 0.0002)
0.32
0.44

108. (Vericiguat)
Change in LA Volume Change in NT-proBNP

109. • In patients with advanced HFpEF after recent HF
decompensation, vericiguat up to a target dose of 10 mg
was safe and well tolerated
• Vericiguat did not change the primary endpoints, NT-
proBNP or LAV at 12 weeks compared with placebo
• Vericiguat was associated with clinically important
improvements in patients’ health status and quality of life
• This sGC stimulator in HFpEF warrant further study,
possibly with higher doses, longer follow-up, and
additional endpoints
SOCRATES PRESERVED CONCLUSIONS

110. event-driven outcome trial on CV death /HF hospitalization
2 arms / 1 dose (10 mg)VICTORIAPhase III - HFrEF1
Phase IIb - HFpEF1
Design similarities
• Randomization within 6
months after HF event
• Elevated NT-proBNP /
BNP
• 2-week titration
intervals, repeated
titration options
LVEF 45%
≥45%
<45%
Jun
2018
750
enrolled
Ancillary studies: Genetics / BMx /Accelerometry
KCCQ-PLS
3 arms / 10 + 15 mg
VITALITY-
HFpEF
Armstrong PW et al. JACC Heart Fail. 2018
Parallel Conduct of VITALITY with VICTORIA

111. (VITALITY ,Vericiguat in HFpEF : (Preliminary Results)

112. SGLT2
Inhibitors

113. HHF, Hospitalisationfor HeartFailure
MacDonaldMR et al. Eur HeartJ 2008;29:1377
0
0.5
20
CV death or HHF in patients with and without diabetes according to ejection
fraction category
60
40
0 1 1.5 2
Follow-up (years)
2.5 3 3.5
HFrEF: adjusted HR 1.60
(95% CI 1.4, 1.77)
p<0.0001
HFpEF: adjusted HR 2.0
(95% CI 1.70, 2.36)
p<0.0001
HFrEF
HFpEF
HFrEF
HFpEF
Cumulativeincidence(%)
DiabetesNon-diabetes
Diabetes is Associated with Worse Outcomes

114. Gerich JE. Diabet Med. 2010;27:136–142.
48
SGLT1
SGLT2
~ 10%
~ 90%
When blood glucose
increases above the
renal threshold
(~ 10 mmol/l or 180
mg/dL), the capacity
of the transporters is
exceeded, resulting in
urinary glucose
excretion
Filtered glucose load >
180 g/day
Renal glucose re-absorption in patients with hyperglycaemia

115. SGLT2 inhibitors
reduce glucose
re-absorption in
the proximal
tubule, leading to
urinary glucose
excretion* and
osmotic diuresis
*Loss of ~ 80 g of glucose/day (~ 240 cal/day).
Gerich JE. Diabet Med. 2010;27:136–142.
49
SGLT1
Filtered glucose load
> 180 g/day
Urinary glucose excretion via SGLT2 inhibition
SGLT2
inhibition

116. EMPEROR-Preserved1 EMPEROR-Reduced2 Dapa-HF3
Sample size 4126 2850* 4500
Key inclusion
criteria
Patients with chronic HF†
Elevated NT-proBNP
eGFR ≥20 ml/min/1.73 m2
HFpEF (LVEF >40%) HFrEF (LVEF ≤40%)
Time to first event of adjudicated CV death or
adjudicated HHF
Symptomatic HFrEF†
Elevated NT-proBNP
eGFR ≥30 ml/min/1.73 m2
HFrEF (LVEF ≤40%)
Primary
endpoint
Time to first occurrence of CV
death, HHF or urgent HF visit
Key secondary
endpoints
Individual components of primary endpoint
All-cause mortality
All-cause hospitalisation
Time to first occurrence of sustained reduction of
eGFR
Change from baseline in KCCQ
Total number of HHF or CV
death
All-cause mortality
Composite of ≥50% sustained
eGFR decline ESRD or renal
death
Change from baseline in KCCQ
Start date
Expected
completion date
March 2017
June 2020
March 2017
June 2020
February 2017
Published
*NT-proBNP-basedenrichment of the populationwith patients at higher severityof HF; †NYHA class II–IV
eGFR, estimatedGlomerularFiltrationRate; ESRD, End-Stage Renal Disease;HF, HeartFailure; HHF, Hospitalisationfor Heart Failure;KCCQ, KansasCity CardiomyopathyQuestionnaire;
LVEF, Left Ventricular Ejection Fraction; NT-proBNP,N-terminal Pro−B-typeNatriureticPeptide;SGLT2, Sodium-Glucoseco-Transporter-2
1. ClinicalTrials.govNCT03057951;2. ClinicalTrials.govNCT03057977;3. ClinicalTrials.govNCT03036124
Randomised Controlled Trials of
SGLT2 Inhibitors in HF

117. Summary
EMPEROR-Reduced1 and EMPEROR-Preserved2 trials follow on from
EMPA- REG OUTCOME in patients with T2D and established CV disease
The EMPEROR trials are the first dedicated outcomes trials
of empagliflozin for the treatment of chronic heart failure
The EMPEROR HF clinical trial programme will provide insights into
the safety and efficacy of empagliflozin in patients with HFpEF and
HFrEF, both with and without T2D, receiving current standard of care
1. ClinicalTrials.govNCT03057977;2. ClinicalTrials.govNCT03057951
EMPEROR-Reduced & EMPEROR-Preserved
Heart Failure Outcome Trials

120. Guidelines
ESC 2016

121. ACC 2017

122. • 50% of HF patients have HFPEF , prevalence is increasing & survival has not
improved
• Pathophysiology/Etiology is complex and multifactorial, comorbidities can
contribute
• Most patients with HFpEF have diastolic dysfunction, so do asymptomatic
elderly people. There occurs definite transition from mere diastolic dysfunction
to HFpEF
• Diagnosis is challenging and validated algorithms for diagnosis are lacking.
New HFA-PEFF algorithm uses objective parameters for diagnosis
Summary and Conclusions

123. • HFpEF has been notoriously hard to treat. No single agent has been identified
as being effective in improving CV outcomes
• Current management: Loop diuretics, risk factor control ,treating co-morbidities,
Physical activity and exercise training. HFpEF phenotype based treatment.
• Neprilysin inhibition strategy has failed to achieve statistically significant benefit,
though benefit was noted in lower range LVEF (<57%) & in women.
• New pharmacological approaches under investigation:
 Soluble Guanylate cyclase stimulation
 SGLT2 Inhibitors
• New devices and interventions
 Interatrial Shunt
 Implantable hemodynamic monitoring based therapy
Summary and Conclusions

124. Thank you