1130412-Updated Heart Failure Medical Therapy.pdf

Updated Heart Failure
Medical Therapy
高雄醫學大學附設中和紀念醫院
心臟血管內科
林宗憲
12:40-13:10
Conflict of interest: Nil

Type of HF HFrEF HFmrEF HFpEF
Criteria
1 Symptoms±Signsa Symptoms±Signsa Symptoms±Signsa
2 LVEF ≤ 40% LVEF 41-49%b LVEF ≥ 50%
3 - - Objective evidence of cardiac structural and/or
functional abnormalities consistent with the
presence of LV diastolic dysfunction/raised LV
filling pressures, including raised natriuretic
peptidesc
2
Definition of heart failure with reduced ejection fraction, mildly reduced
ejection fraction and preserved ejection fraction
2021 ESC Guidelines for the diagnosis and treatment of
acute and chronic heart failure
HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricle; LVEF,
left ventricular ejection fraction
a Signs may not be present in the early stage of HF (especially in HFpEF) and in optimally treated patients
b For the diagnosis of HFmrEF, the presence of other evidence of structural heart disease (e.g. increased left atrial size, LV hypertrophy or echocardiographic measure of impaired LB filling_ makes the
diagnosis more likely
c for the diagnosis of HFpEF, the greater the number of abnormalities present, the higher the likelihood of HFpEF
Eur Heart J. 2021 Sep 21;42(36):3599-3726.

Acta Cardiol Sin 2023;39:361390

Heart failure presents with multiple signs and symptoms, and
varies between patients
1. McMurray JJV et al. Eur Heart J 2012;33:1787; 2. Borlaug B et al. Circ Heart Fail 2010;3:588
Breathlessness
Common symptoms1 Common signs1
Paroxysmal nocturnal dyspnoea
Orthopnoea
Reduced exercise tolerance
Laterally displaced apex beat
Third heart sound (gallop rhythm)
Pulmonary rales
Elevated jugular venous pressure
Fatigue, tiredness, increased
time to recover after exercise
Ankle swelling Cardiac murmur
Hepatojugular reflux
4

Many common heart failure signs and symptoms are present only
in patients with advanced HFpEF (LVEF > 50%)
1. McMurray JJV et al. Eur Heart J 2012;33:1787; 2. Borlaug B et al. Circ Heart Fail 2010;3:588
Breathlessness
Common symptoms1 Common signs1
Paroxysmal nocturnal dyspnoea
Orthopnoea
Reduced exercise tolerance
Laterally displaced apex beat
Third heart sound (gallop rhythm)
Pulmonary rales
Elevated jugular venous pressure
Fatigue, tiredness, increased
time to recover after exercise
Ankle swelling Cardiac murmur
Hepatojugular reflux
In early HFpEF, often
patients present only with
exertional symptoms2
These non-specific and widely
prevalent symptoms, especially
in the elderly population, can
make it difficult to differentiate
HFpEF from other disorders
5

CHF with
Moderate
symptoms
CHF with
Severe
symptoms
CHF with
Mild
symptoms
Post-MI HF
LV Dysfunction
CONSENSUS
(enalapril)
AIRE / SAVE / TRACE
(ramipril / captopril / trando)
COPERNICUS
(carvedilol)
CAPRICORN
(carvedilol)
RALES
(spironolactone)
NYHA III / IV
EPHESUS
(eplerenone)
SOLVD Treatment
(enalapril)
US Carvedilol / MERIT / CIBIS
(carvedilol / metoprolol / bisoprolol)
ELITE (Losartan)
ValHeft / CHARM
(Valsartan / Candesartan)
OPTIMAAL
(Losartan)
VALIANT (Valsartan)
ACE-I
Beta
Blocker
Aldosterone
Blocker
ARB
EMPHASIS-HF
(eplerenone)
NYHA II CHF
Heart Failure
Study Data along the HF Spectrum
ACE-I: Angiotensin Converting Enzyme-Inhibitor
ARB: Angiotensin II Receptor Blocker

AC
AC
Gi
Gi Gs
Gs
Muscarinic
receptor
IK
Noradrenaline
Acetylcholine
ICa,L
ICa,T
-receptor
Sinus node cell
f-channel
Mode of action

K Swedberg, M Komajda, et al. Lancet. 2010;376:875-885.
Primary Composite Endpoint
( CV death or hospitalization for worsening HF )
0 6 12 18 24 30 Months
40
30
20
10
0
Ivabradine
Placebo
Cumulative
frequency (%)
Coralan n=793 (14.5%PY)
Placebo n=937 (17.7%PY)
HR = 0.82
- 18%
- 18%
p<0.0001
3M

1.00
Primary composite end point
Cardiovascular mortality
Hospitalization for worsening HF
Death from HF
All-cause mortality
All-cause hospitalization
Any cardiovascular hospitalization
0.76 0.68-0.85
0.83 0.71-0.97
0.70 0.61-0.80
0.61 0.46-0.81
0.83 0.72-0.96
0.82 0.75-0.90
0.79 0.71-0.88
0.20
Hazard
ratio
1.20
0.40 0.60 0.80
Favors
95% CI
N = 4150
64% of SHIFT population P-value
Effect of Coralan on major outcomes in
patients with HR  75bpm
Effect of Coralan on major outcomes in
patients with HR  75bpm
Bohm M, Borer J, et al. Clin Res Cardiol. 2013;102(1):11-22.
<0.0001
0.0166
<0.0001
0.0006
0.0109
<0.0001
<0.0001
<0.0001
0.0006

N Engl J Med. 2014 Sep 11;371(11):993-1004

Angiotensin–Neprilysin Inhibition
PARAGON-HF
Total Hospitalizations for HF and Death from
CV Causes
LCZ696, sacubitril-valsartan
McMurray JJV et al. N Engl J Med 2014;371:993 ; Solomon S et al. N Engl J Med 2019; 381:1609-1620
14
PARADIGM-HF
CV Death or HF Hospitalization
RR, 0.87 (0.75–1.01)
P=0.06
12.8%/year
9.69%/year
(21.8%/27 months)
RR, 0.87 (0.75–1.01)
P=0.06
12.8%/year

Circulation. 2020 Feb 4;141(5):352-361.

Influence of EF on outcomes in TOPCAT
CV, cardiovascular; EF, ejection fraction; HF, heart failure; LVEF, left ventricular ejection fraction
Dashed lines represent 95% CI; primary outcome: composite of CV death, aborted cardiac arrest, or hospitalization for HF
Solomon S, et al, Eur Heart J. 2016;37:455–462.
• Treatment effect of spironolactone as a
function of EF in TOPCAT (patients
with LVEF ≥45% [range 44% to 85%];
N=3444)
A post-hoc analysis of the TOPCAT study
40 50 60 70 80
40 50 60 70 80
40 50 60 70 80
40 50 60 70 80
0.5
1
1.5
2
2.5
0.5
1
1.5
2
2.5
0.5
1
1.5
2
2.5
0.5
1
1.5
2
2.5
Treatment
effect
incidence
rate
ratio
Treatment
effect
incidence
rate
ratio
Treatment
effect
incidence
rate
ratio
Treatment
effect
incidence
rate
ratio
Primary outcome HF hospitalization
CV death All-cause death
Conclusion
• In patients with HFpEF enrolled in
TOPCAT, patient characteristics and
outcomes varied substantially by LVEF
• The potential efficacy of
spironolactone was
greatest at the lower end of
the LVEF spectrum

Story of SGLT2 inhibition in heart failure
Normal
ventricular
function
End-stage
heart
failure
Preclinical
(subclinical) stage
of the disease
Clinical stage of
the disease
Detectable cardiac
involvement
0 Years 10 Years 18-20 Years
HF prevention HF treatment
CANVAS Program
2017
CREDENCE
2019
DECLARE-TIMI 58
2019
EMPA-REG OUTCOME
2015
DAPA-HF
2019
DELIVER HFpEF
EMPEROR-Preserved
EMPEROR-Reduced
2020
EMPULSE
EMPACT-MI
DAPA-MI
VERTIS-CV
2020
Type 2 diabetes Diabetes and non-diabetes
Dates indicate the year of publication of primary results from each trial.
HF, heart failure; SGLT2, sodium-glucose co-transporter-2
Adapted from Bhatt DL et al. Cell Metab 2019;30:847
18

Primary endpoint: First adjudicated CV death or
hospitalisation for heart failure
Placebo
Empagliflozin
Days after randomisation
Estimated
cumulative
incidence
function
(%)
HR 0.75
(95% CI 0.65, 0.86)
p<0.001
Empagliflozin:
361 patients with event
Rate: 15.8/100 patient-years
Placebo:
462 patients with event
40
30
20
10
0
90 180 270 360 450 540 630 720 810
0
Patients at risk
Placebo
Empagliflozin
1867 1715 1612 1345 1108 854 611 410 224 109
1863 1763 1677 1424 1172 909 645 423 231 101
NNT = 19
RRR
25%
ARR
5.2%
Cox regression model including covariates age, baseline eGFR, geographic region, baseline diabetes status, sex, LVEF and treatment
CV, cardiovascular; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; ARR, absolute risk reduction; RRR, relative risk reduction. NNT: Number needed to treat
Data on file

Time to first event analysis of all-cause mortality, heart failure hospitalization
or emergent/urgent care visit for worsening heart failure
Circulation. 2021 Jan 26;143(4):326-336.
20

Subgroup analysis by 5 eGFR categories:
Key clinical outcomes
21 Zannad F et al. Circulation 2020. 10.1161/CIRCULATIONAHA.120.051685
Empagliflozin Placebo
P-value for
trend
n with event/N
analysed (%)
Rate per
100 PY
n with event/N
analysed (%)
Rate per
100 PY HR (95% CI) HR (95% CI)
Adjudicated HHF or CV death
Overall 361/1863 (19.4) 15.8 462/1867 (24.7) 21.0 0.75 (0.65, 0.86) 0.12
eGFR ≥90 31/229 (13.5) 10.7 55/220 (25.0) 21.4 0.51 (0.33, 0.80)
eGFR 60 to <90 128/740 (13.5) 14.1 169/740 (22.8) 19.3 0.73 (0.58, 0.92)
eGFR 45 to <60 80/433 (18.5) 14.9 108/467 (23.1) 19.3 0.76 (0.57, 1.02)
eGFR 30 to <45 87/345 (25.2) 21.1 96/349 (27.5) 22.9 0.92 (0.69, 1.23)
eGFR <30 35/115 (30.4) 25.2 33/90 (36.7) 38.3 0.68 (0.42, 1.09)
First and recurrent HHF (number of events)*
Overall 388 553 0.70 (0.58, 0.85) 0.06
eGFR ≥90 25 75 0.35 (0.19, 0.63)
eGFR 60 to <90 132 192 0.70 (0.51, 0.96)
eGFR 45 to <60 88 135 0.71 (0.48, 1.06)
eGFR 30 to <45 102 109 0.99 (0.65, 1.50)
eGFR <30 41 42 0.59 (0.28, 1.23)
Composite kidney outcome†
Overall 30/1863 (1.6) 1.6 58/1867 (3.1) 3.1 0.50 (0.32, 0.77) 0.74
eGFR ≥90 1/229 (0.4) 0.4 4/220 (1.8) 1.8 Not calculated‡
eGFR 60 to <90 12/740 (1.6) 1.6 22/740 (3.0) 3.0 0.52 (0.26, 1.05)
eGFR 45 to <60 9/433 (2.1) 2.0 12/467 (2.6) 2.5 0.88 (0.37, 2.11)
eGFR 30 to <45 5/345 (1.4) 1.4 15/349 (4.3) 4.3 0.33 (0.12, 0.90)
eGFR <30 3/115 (2.6) 2.5 5/90 (5.6) 6.6 Not calculated‡
Favours placebo
Favours drug
0.25 0.50 1.00 2.00

N Engl J Med. 2021 Jan 14;384(2):117-128.

FOR INTERNAL USE ONLY. STRICTLY CONFIDENTIAL. DO NOT COPY, DETAIL OR DISTRIBUTE EXTERNALLY.
26
Empagliflozin is not indicated for treatment of hospitalization of heart failure or renal outcome.
EMPULSE
HFE, heart failure event; HHF, hospitalisation for heart failure; CV, cardiovascular; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score; KCCQ-TSS,
Kansas City Cardiomyopathy Questionnaire - Total Summary Score; NTproBNP, N-terminal pro b-type natriuretic peptide
1. ClinicalTrials.gov. NCT04157751 (accessed Aug 2020); 2. Packer et al. NEJM 2020. DOI: 10.1056/NEJMoa2022190.
PRIMARY ENDPOINT
• Net clinical benefit (composite of
death, HFE, time to first HFE and change
in KCCQ-TSS after 90 days of treatment)
SELECT SECONDARY ENDPOINTS
• Change in NT-proBNP
• Change in KCCQ-TSS
• Days alive and out of hospital
• Time to CV death or HHF
Acute HHF;
stabilized
(N~500)
1:1
EMPULSE1,2
Empagliflozin 10 mg
Placebo
Randomisation
Days
15 30
90
Follow-up
Empagliflozin in stabilized acute HF
Aim: Assess whether in-hospital administration of empagliflozin results in improvements in HF-related clinical
events and patient-reported outcomes
Population: Patients hospitalised for acute HF (de novo or decompensated CHF) who have been stabilised
2021 AHA

0.25 0.5 1 2 4
• Patients treated with empagliflozin were 36% more likely to experience a clinical benefit* compared
with patients on placebo
Primary endpoint
Numbers reflect percentage of comparisons. For the components of the win ratio these numbers do not reflect randomized comparisons. *Composite of death, number of HFEs, time to first HFE and
change from baseline in KCCQ-TSS after 90 days of treatment. **HFE includes hospitalizations for heart failure, urgent heart failure visits, and unplanned outpatient visits. CI, confidence interval;
HFE, heart failure event; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire total symptom score.
6.4%
6.4%
27.5%
0.6%
7.7%
4.0%
39.7%
35.9%
0.2%
10.6%
7.2%
53.9%
Ties, none of the
previous
KCCQ-TSS
Time to HFE**
HFE** frequency
Time to death
Clinical benefit*
Favors placebo Favors empagliflozin 10 mg
Stratified
win ratio: 1.36
(95% CI: 1.09, 1.68)
p=0.0054
Death:
Empagliflozin: 4.2%
Placebo: 8.3%
HF event:
Empagliflozin 10.6%
Placebo 14.7%
Empagliflozin winner Placebo winner Ties

Primary endpoint by subgroup continued
CI, confidence interval; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction;
NT-proBNP, N-terminal pro b-type natriuretic peptide.
1 Empagliflozin Placebo
Win ratio (95% CI)
Interaction
p-value
n with event/total N
All patients 265 265 1.36 (1.09, 1.68)
NT-proBNP at baseline, pg/ml 0.7904
<Median 125 130 1.36 (0.99, 1.85)
≥Median 130 126 1.44 (1.06, 1.96)
eGFR (CKD-EPI) at baseline, ml/min/1.73 m2 0.7562
<60 161 145 1.38 (1.04, 1.83)
≥60 88 106 1.48 (1.04, 2.13)
Atrial fibrillation/flutter at baseline 0.1129
No 123 133 1.68 (1.22, 2.32)
Yes 142 132 1.18 (0.88, 1.59)
Baseline LVEF, % 0.9008
≤40 182 172 1.35 (1.04, 1.75)
>40 76 92 1.39 (0.95, 2.03)
Empagliflozin better
Placebo better
0.25 0.5 1 2 4

32
EMPEROR-Preserved study design
Empagliflozin is currently not indicated for treatment of heart failure with preserved ejection fraction.
*Randomized, double-blind, placebo-controlled trial.
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HFpEF, heart failure with preserved ejection fraction;
HHF, hospitalization for heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; OD, once daily; T2D, type 2 diabetes.
Anker S et al. N Engl J Med. 2021 Oct 14;385(16):1451-1461.
Phase III trial* in patients with HFpEF
Aim: To investigate the safety and efficacy of empagliflozin versus placebo in patients with HF
with preserved ejection fraction
Population: T2D and non-T2D, aged ≥18 years, chronic HF (NYHA class II–IV)
Median follow-up 26.2 months
EMPEROR-Preserved
LVEF >40%
5988 patients
Placebo
Empagliflozin 10 mg OD
CONFIRMATORY KEY SECONDARY ENDPOINTS
• First and recurrent adjudicated HHF
• Slope of change in eGFR (CKD-EPI) from baseline
COMPOSITE PRIMARY ENDPOINT
• Time to first event of adjudicated CV death or
adjudicated HHF

33
Inclusion criteria Exclusion criteria
• Age ≥18 years
• Chronic HF NYHA class II−IV
• LVEF >40%
• NT-proBNP:
• >300 pg/mL in patients without AF
• >900 pg/mL in patients with AF
• Structural changes in the heart (increases
in left atrial size or left ventricular mass) or
HHF within 12 months of screening
• MI, coronary artery bypass graft surgery
or other major CV surgery, stroke or TIA
≤90 days before visit
• Heart transplant recipient, or listed for
heart transplant
• Acute decompensated HF
• SBP ≥180 mmHg at randomization
• Symptomatic hypotension and/or SBP
<100 mmHg
• eGFR <20 mL/min/1.73 m2 or requiring
dialysis
EMPEROR-Preserved:
Inclusion and exclusion criteria
Further criteria apply
AF, atrial fibrillation; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HHF, hospitalization for heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction;
NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; TIA, transient ischaemic attack.
Anker S et al. N Engl J Med. DOI: 10.1056/NEJMoa2107038

34
25
20
15
10
5
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Empagliflozin demonstrated a clinically meaningful 21% RRR in the composite
primary endpoint of CV death or HHF
Estimated
cumulative
incidence
(%)
Months since randomization
Patients at risk
Placebo
Empagliflozin
2991
2997
2888
2928
2786
2843
2706
2780
2627
2708
2424
2491
2066
2134
1821
1858
1534
1578
1278
1332
961
1005
681
709
400
402
HR: 0.79
(95% CI: 0.69, 0.90)
p<0.001
Empagliflozin:
415 (13.8%) patients with event
Placebo:
511 (17.1%) patients with event
NNT*=31
RRR
21%
ARR
3.3%
Placebo
Empagliflozin
*During a median trial period of 26 months. ARR, absolute risk reduction; CI, confidence interval; CV, cardiovascular; HHF, hospitalization for heart failure; HR, hazard ratio;
NNT, number needed to treat; RRR, relative risk reduction. Anker S et al. N Engl J Med. DOI: 10.1056/NEJMoa2107038.

EMPEROR-Preserved: Time of first statistical significance in time-to-first-event
analysis of CV death, HHF or emergent/urgent heart failure visit requiring IV
treatment for worsening heart failure
35
To determine the time point when statistical significance was reached and maintained for the first time, Cox regression models were fitted and sequentially censoring at increasing number of days since
randomization, yielding a continuous display of hazard ratios with confidence bands.
CI, confidence interval; CV, cardiovascular; HHF, hospitalization for heart failure; HR, hazard ratio; IV, intravenous
Packer M et al. Circulation. 2021;144:1284.
0 15 30 45 60 75 90 105
Study day
0.0156
0.0313
0.0625
0.25
1
4
16
Hazard
ratio
(95%
Cl)
180
120 135 150 165
Statistical significance achieved for
the first time and maintained
Placebo
better
Empagliflozin
better
0.125
0.5
2
8
Day 18

Circulation. 2023 Sep 26;148(13):1011-1022.

STEP-HFpEF trial design
Semaglutide 2.4 mg s.c. once weekly
Placebo s.c. once weekly
Week 0
Randomisation
Week 16
End of dose escalation
0.25 mg
0.5 mg
1.0 mg
0.5 mg
0.25 mg
1.0 mg
1.7 mg
Week 52
End of treatment
Randomised participants
Adults ≥18 years,
BMI ≥30 kg/m2
N=529
Week 57
Follow-up
Follow-up
SOC treatment, plus:
1.7 mg
6MWD, 6-minute walk distance; BMI, body mass index; CV, cardiovascular; echo, echocardiographic; HbA1c, glycated haemoglobin; HF, heart failure; HFpEF, heart failure with preserved ejection fraction;
KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SBP, systolic blood pressure; s.c., subcutaneous;
– Elevated left ventricular filling pressures (invasively measured)
– Elevated natriuretic peptide levels and structural echocardiographic
abnormalities
– HF hospitalisation (previous 12 months) and ongoing requirement
for diuretics and/or structural echocardiographic abnormalities
Key inclusion criteria
• LVEF ≥45%, NYHA functional class II–IV, KCCQ-CSS <90 points, 6MWD
≥100 metres, and ≥1 of the following:
Key exclusion criteria
• Prior/planned bariatric surgery
• Recent self-reported weight change >5 kg (11 lbs)
• Recent adverse CV event or HF hospitalisation
• SBP of >160 mmHg at screening
• HbA1c ≥6.5% or known medical history of diabetes
SOC, standard of care; STEP, Semaglutide Treatment Effect in People with obesity.
Kosiborod MN, et al. Presented at the European Society of Cardiology Congress, 25–28 August 2023.

3
-2
8
13
18
-4 0 4 8 12 16 24 28 32 40 44 48 56
Change from baseline to week 52 in KCCQ-CSS
Dual primary endpoints
Mean
change
in
KCCQ-CSS
(points)
20 36
Time since randomisation (weeks)
Participants
52 52*
Sema 2.4 mg 263 249 225 243 263
Placebo 266 242 217 237 266
16.6 points
8.7 points
ETD: 7.8 points
95% CI: 4.8 to 10.9
p<0.001
p=0.0000006
Semaglutide 2.4 mg Placebo
56.7
Overall mean baseline
KCCQ-CSS (points)
Data are for the treatment policy estimand. *Data are estimated mean changes from baseline to week 52 for the treatment policy estimand using ANCOVA and an imputation approach for missing data.
ANCOVA, analysis of covariance; CI, confidence interval; ETD, estimated treatment difference; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; sema, semaglutide.

-20
-15
-10
-5
0
-4 24 32 40 48 56
Change from baseline to week 52 in body weight
Dual primary endpoints
Data are for the treatment policy estimand. *Data are estimated mean changes from baseline to week 52 for the treatment policy estimand using ANCOVA and an imputation approach for missing data.
ANCOVA, analysis of covariance; CI, confidence interval; ETD, estimated treatment difference; sema, semaglutide.
Mean
change
in
body
weight
(%)
0 4 8 12 16 20 28 36 44
Time since randomisation (weeks)
–13.3%
–2.6%
ETD: –10.7%
95% CI: –11.9 to –9.4
p<0.001
p<0.0000001
Sema 2.4 mg 263 255 254 250 246 252 239 243 240 246 263
Placebo 266 259 249 250 243 246 243 239 233 242 266
52 52*
Semaglutide 2.4 mg Placebo
108.4
Overall mean baseline
body weight (kg)
Participants

2022 AHA/ACC/HFSA
Stage A
At-Risk for HF
Stage B
Pre-HF
Stage C and D
Stage C: Symptomatic HF and Stage D: Advanced HF
HFrEF: LVEF ≤40%
Diuretics
as needed
Class 1
ARNI in NYHA
II-III;
ACEI or ARB in NYHA
II-IV
Class 1
Beta-blocker
Class 1
MRA
Class 1
SGLT2i
Class 1
Hydral-nitrates for
NYHA III-IV in
African American pts
Class 1
SGLT2i in pts with DM
Class 1
SGLT2i in pts with DM
Class 1
ACEI
Class 1
ARB if ACEI intolerant
Class 1
Beta-blocker
Class 1
HFmrEF: LVEF 41-
49%
Diuretics, as needed
Class 1
SGLT2i
Class 2a
ACEI, ARB, ARNI
Class 2b
Beta-blocker
Class 2b
MRA
Class 2b
GDMT
of major
medication
classes
HFpEF: LVEF ≥50%
Diuretics, as needed
Class 1
SGLT2i
Class 2a
ARNI
Class 2b
ARB
Class 2b
MRA
Class 2b
ACC = American College of Cardiology; ACEI = angiotensin-converting enzyme inhibitor; ADA = American Diabetes Association; AHA = American Heart Association; ARB = angiotensin-receptor blocker; ARNI = angiotensin-receptor neprilysin inhibitor; DM = diabetes mellitus; GDMT = guideline-directed medical therapy; HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart
failure
with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HFSA = Heart Failure Society of America; Hydral-nitrates: hydralazine and isosorbide dinitrate; LVEF = left ventricular ejection
fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; SGLT2i = sodium-glucose cotransporter 2 inhibitor.
Adapted from JACC. Guidelines and clinical documents. Management of heart failure guideline hub. Central illustration. JACC website.
European Heart Journal (2023) 00, 1–13 https://doi.org/10.1093/eurheartj/ehad195

歐美心臟科指引建議:
SGLT2i治療心衰竭不論EF高低
42
aDapagliflozin or empagliflozin are specified in the ESC guidelines.
1. McDonagh TA et al. Eur Heart J. 2021;42(36):3599-3726; 2. McDonagh TA et al. Online ahead of print. Eur Heart J. 2023;
3. Heidenreich PA et al. J Am Coll Cardiol. 2022;79(17):e263-e421; 4. Kittleson MM et al. J Am Coll Cardiol.
2023;81(18):1835-1878.
HF type COR LOE COR LOE
HFrEF (LVEF ≤40%) I A 1 A
HFmrEF (LVEF 41-49%) I A 2a B-R
HFpEF (LVEF ≥50%) I A 2a B-R
2023 ACC Expert Consensus Decision Pathway considers
SGLT2 inhibitors first-line for the treatment of HFpEF4

J Am Coll Cardiol. 2024 Apr 16;83(15):1444-1488.

J Am Coll Cardiol. 2023 May 9;81(18):1835-1878.

48
Acta Cardiol Sin 2023;39:361-390

Finerenone is a Selective, nonsteroidal
Mineralocorticoid Receptor Antagonist (MRA) *
Spironolactone Eplerenone Finerenone
*Most of the available evidence exploring these differences is available for the nonsteroidal MRA finerenone. Other nonsteroidal MRAs have different physicochemical and pharmacological properties, but corresponding comparisons
within this class are pending due to missing data; #observed in HF patients; ‡in healthy volunteers
BP, blood pressure; CKD, chronic kidney disease; CNS, central nervous system; HF, heart failure; LVEF, left ventricular ejection fraction; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; T2D, type 2 diabetes;
TFDA, Taiwan Food and Drug Administration
1. Kintscher U, et al. Br J Pharmacol 2022;179:3220–3234; 2. Kolkhof P, et al. Curr Opin Nephrol Hypertens 2015;24:417–424; 3. Kolkhof P, et al. Handb Exp Pharmacol. 2017;243:271-305; 4. Pfizer Pharmaceuticals Co., Ltd. ALDACTONE®
(spironolactone) Prescription Information. 2021. https://info.fda.gov.tw/MLMS/H0001D3.aspx?LicId=02022610 [accessed 14 November 2022]; 5. Pfizer Pharmaceuticals Co., Ltd. INSPRA® (eplerenone). Prescription Information. 2020.
https://info.fda.gov.tw/MLMS/H0001D3.aspx?LicId=02024305 [accessed 14 November 2022]; 6. Bayer Taiwan Co., Ltd. KERENDIA® (finerenone) Prescription Information. 2023.
https://mcp.fda.gov.tw/im_detail_1/%E8%A1%9B%E9%83%A8%E8%97%A5%E8%BC%B8%E5%AD%97%E7%AC%AC028325%E8%99%9F and
https://mcp.fda.gov.tw/im_detail_1/%E8%A1%9B%E9%83%A8%E8%97%A5%E8%BC%B8%E5%AD%97%E7%AC%AC028326%E8%99%9F [accessed 20 April 2023]
Structural properties Flat (steroidal) Flat (steroidal) Bulky (nonsteroidal)
Potency to MR +++ + +++
Selectivity to MR + ++ +++
CNS penetration + + –
Half-life Long (>20 h)# Medium/short (4–6 h)# Short (2–3 h)‡
Active metabolites ++ – –
Sexual side effects ++ (+) –
Effect on BP +++ ++ +
Tissue distribution Kidney > heart (at least 6-fold)2,3 Kidney > heart (~3-fold)2,3 Balanced kidney : heart (1:1)2,3
Indication (TFDA) Edema, hypertension, PA4 HFrEF post-AMI, chronic HFrEF、
Hypertension5 CKD associated with T2D6
Kerendia (finerenone)1
Kerendia (finerenone)1
Steroidal MRAs1
Steroidal MRAs1

Albuminuria categories (mg albumin/g creatinine)1
A1
Normal to mildly
increased
A2
Moderately
increased
A3
Severely
increased
0–29 30–299 ≥300–≤5000
GFR
categories
(ml/min/1.73
m
2
)
G1 >90
G2 60–89
G3a 45–59
G3b 30–44
G4 15–29
G5 <15
3
4
Finerenone in reducing kidney failure
and disease progression
(N=5734)
2
Finerenone in reducing CV mortality
and morbidity
(N=7437) Prespecified
pooled analysis
(N=13,171)
Finerenone was Investigated in Phase III Clinical Trial
Program in Patients with Early CKD (Stage 1–2) and More
Advanced CKD (Stage 3–4) and T2D
G1: high and optimal; G2: mild; G3a: mild-to-moderate; G3b: moderate-to-severe; G4: severe; G5: kidney failure
CKD, chronic kidney disease; GFR, glomerular filtration rate; T2D, type 2 diabetes
1. KDIGO. Kidney Int Suppl 2013;3:1–150; 2. Bakris GL, et al. N Engl J Med 2020;383:2219–2229; 3. Pitt B, et al. N Engl J Med 2021;2021:385-2252; 4. Agarwal R, et al. Eur Heart J 2022;43:474–484

The FIDELITY Analysis Showed Significant Risk Reductions in
Both CV and kidney outcomes with Finerenone
*ESKD or an eGFR <15 ml/min/1.73 m2; events were classified as renal death if: (1) the patient died; (2) kidney replacement therapy had not been initiated despite being clinically indicated; and (3) there was
no other likely cause of death; #cumulative incidence calculated by Aalen–Johansen estimator using deaths due to other causes as competing risk; ‡number of patients with an event over a median of 3.0 years
of follow-up; §at-risk subjects were calculated at start of time point. CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; HHF, hospitalisation for heart failure; HR hazard ratio; MI,
myocardial infarction; NNT, number needed to treat
Agarwal R, et al. Eur Heart J 2022;43:474–484
reduced risk of CV morbidity and
mortality vs placebo
14%
Kidney composite
CV composite
No. at risk§
Finerenone
Placebo
6519
6507
6360
6330
6202
6125
6009
5938
5273
5184
4207
4147
3065
2969
2187
2135
1087
1082
0 6 12 18 24 30 36 42 48
25
10
15
20
0
5
Cumulative
incidence
(%)
#
Months since randomisation
Finerenone: 825/6519 (12.7)‡
Placebo: 939/6507 (14.4%)‡
HR=0.86; 95% CI 0.78–0.95
p=0.0018
NNT after 3 years = 46
(95% CI 29–109)
0 6 12 18 24 30 36 42 48
25
5
15
20
0
10
Cumulative
incidence
(%)
Months since randomisation
Finerenone: 360/6519 (5.5%)‡
Placebo: 465/6507 (7.1%)‡
Finerenone
Placebo
6519
6507
6291
6292
6107
6071
5848
5815
5027
4949
3973
3932
2815
2798
2024
1988
959
962
No. at risk
HR=0.77; 95% CI 0.67–0.88
p=0.0002
NNT after 3 years = 60
(95% CI 38–142)
reduced risk of CKD progression*
vs placebo
23%
Time to CV death, non-fatal MI, non-fatal stroke, or HHF Time to kidney failure,* sustained ≥57% decrease in
eGFR from baseline, or kidney-related death

*Composite of time to first onset of CV death, non-fatal MI, non-fatal stroke, or hospitalisation for HF
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction
Agarwal R, et al. Eur Heart J 2022;43:474–484
Outcome Finerenone
(n=6519)
Placebo
(n=6507)
Hazard ratio (95% CI) p-
value
n (%) n per
100
PY
n (%) n per
100 PY
Composite CV outcome* 825 (12.7) 4.34 939 (14.4) 5.01 0.86 (0.76–0.95) 0.0018
Hospitalisation for HF 256 (3.9) 1.31 325 (5.0) 1.68 0.78 (0.66–0.92) 0.0030
CV death 322 (4.9) 1.61 364 (5.6) 1.84 0.88 (0.76–1.02) 0.0922
Non-fatal MI 173 (2.7) 0.88 189 (2.9) 0.97 0.91 (0.74–1.12) 0.3601
Non-fatal stroke 198 (3.0) 1.01 198 (3.0) 1.02 0.99 (0.82–1.21) 0.9460
Favours finerenone Favours placebo
0.5 1.0 2.0
Also, Significantly Reduce 22% Hospitalization for
Heart Failure (HHF)

The MOONRAKER HF Trial Program will Generate Data for
Finerenone in HF Across Clinical Settings
Finerenone is not indicated for the treatment of heart failure.
CV, cardiovascular; HHF, hospitalization for heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction;
HFrEF, heart failure with reduced ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal pro–B-type natriuretic peptide
1. Agarwal R, et al. Eur Heart J 2022;43:474–484; 2. Bayer. https://clinicaltrials.gov/ct2/show/NCT04435626 [accessed 06 June 2023]; 3. Bayer AG. https://clinicaltrials.gov/ct2/show/NCT06008197 [accessed 24 August 2023]; 4. Bayer AG.
https://www.clinicaltrials.gov/study/NCT06024746; 5. Bayer AG. https://www.clinicaltrials.gov/study/NCT06033950
 Patients with symptomatic
HFmr/pEF
 Primary outcome: number of
CV deaths and HF events up
to month 42
 Prespecified pooled analysis of
FIDELIO-DKD and FIGARO-DKD
 Patients with CKD and T2D
 CV composite outcome:
time to CV death, non-fatal MI,
non-fatal stroke or HHF
1
2016 2020 2022
2021 2024
2023 2025
2
6
5
3
4

The HF Trial Program Aims to Address Key Evidence &
Implementation Gaps for Finerenone in Patients with HF
Finerenone is not indicated for the treatment of heart failure.
HF, heart failure; HFrEF, heart failure with reduced ejection fraction; SGLT-2i, sodium-glucose co-transporter-2 inhibitor; sMRA, steroidal mineralocorticoid receptor antagonist
1. Bayer AG. https://clinicaltrials.gov/ct2/show/NCT06008197 [accessed 24 August 2023]; 2. Bayer AG. https://www.clinicaltrials.gov/study/NCT06024746; 3. Bayer AG. https://www.clinicaltrials.gov/study/NCT06033950
Early, in-hospital
initiation of finerenone in
patients with HF
Efficacy and safety for
combined use of
finerenone and
SGLT-2i
Simultaneous initiation
of finerenone and
SGLT-2i early in high-risk
patients
Efficacy and safety of
finerenone in patients
with HFrEF intolerant of
or not eligible
for sMRAs
1 2 3

Conclusion
• HFrEF (LVEF  40%)
- -blocker, ACEI/ARB, MRA
- ARNI
- SGLT2i
• HFmrEF & HFpEF
- SGLT2i first
- ARNI & MRI
• Peri-AHF
- SGLT2i & Vericiguat
• Wait GLP1-RA & finerenone (FINEARTS) trial

1130412-Updated Heart Failure Medical Therapy.pdf

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