HEART FAILURE TREATMENT

1. Heart Failure Buzz:
Fantastic 4, Fabulous 5 and
Flight of 6
HF, heart failure.
Dr Awadhesh Sharma, DM, FACC, FSCAI, FISC, FICCM
Associate Professor of Cardiology
LPS Institute Of Cardiology
GSVM Medical College, Kanpur, UP

2. Disease Progression
Cardiac
Function
&
QoL
Hospitalisations for ADHF
HF – A Chronic condition interspersed with acute Episodes
Truby LK, Rogers JG. Advanced Heart Failure: Epidemiology, Diagnosis, and Therapeutic Approaches. JACC Heart Fail. 2020 Jul;8(7):523-536.

3. The incidence of HF is soaring in India, but it
may be underestimated
HF, heart failure.
Ref.: Savarese G and Lund LH. Card Fail Rev. 2017 Apr;3(1):7-11.
Portugal
USA
1–2
1.5–1.9
China 1.3
Japan 1
India 0.12–0.44
Malaysia 6.7
Singapore 4.5
South America 1
Australia 1–2
0.1–0.2
0.1–0.2
0.9
0.05–0.17
0.2
Spain 2.1
Germany 1.6–1.8
Sweden 1.8–2.2
Italy 1.44
UK
0.39–0.44
0.39
0.27
Netherlands
0.38
0.31–0.39
0.5 0.4 0.3 0.2 0.1 1 2 3 4 5 Prevalence(%)
Incidence (%)

4. 1 out of every 3 patients readmitted at least once over 1 year
Hospital readmissions at 1 year
HF, heart failure; HFrEF, heart failure with reduced ejection
fraction; HFpEF, heart failure with preserved ejection fraction.
Ref.: Harikrishnan S, et al. Am Heart J. 2017 Jul;189:193-199.
30.2%
1-year hospital
readmission rate
24.4%
Readmitted once
5.8%
Readmitted more than once
Similar across gender
Men (30.3%), Women (30.9%)
Similar irrespective of
ejection fraction
HFrEF (30.1%), HFpEF (31.6%)
India witnesses a huge HF hospitalization
burden

5. Increasing mortality in HF patients across the HF
spectrum in India
HF, heart failure; HFrEF, heart failure with reduced ejection
fraction; HFpEF, heart failure with preserved ejection fraction.
Ref.: Harikrishnan S, et al. Am Heart J. 2017 Jul;189:193-199.
HF patients die within
1 year during their
productive life years
Mortality rate per 100 person years
of follow-up
1/3
 HFrEF-43.8%
 HFpEF-35.7%

6. Current available therapies for
heart failure- Fantastic Four

7. ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor
antagonist.
Ref.: Sindone A. How to welcome the fantastic four. Available [online] URL: https://www.csanz.edu.au/wp-
content/uploads/2023/09/CSANZ_Speaker_Series_Heart_Failure.pdf As accessed on 4th Jan 2024.
In 2013, there were
3 main pillars of heart failure therapy
ACEi or ARB Beta-blocker MRA

8. ARNI changed the face of HF treatment
In 2014, Sacubitril/Valsartan, a new class of drug comprising an angiotensin
receptor-neprilysin inhibitor (ARNI) was tested against Enalapril in HFrEF patients
New evidence for HF treatment with ARNI after a decade
HF, heart failure; HFrEF, heart failure with reduced ejection fraction; ARNI, angiotensin receptor-neprilysin
inhibitor; PARADGIM-HF, Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with
Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in
Heart Failure.
Ref.: Marcondes-Braga. ABC Heart Fail Cardiomyop. 2022;2(1):31-5.
PARADIGM-HF

9. PARADIGM-HF: The largest clinical trial in HFrEF
CV death/HF hospitalization, primary composite outcome.
HF, heart failure; CV, cardiovascular; CI, confidence interval; HR, hazard ratio; HFrEF, heart failure with reduced
ejection fraction; PARADGIM-HF, Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with
Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart
Failure.
Sacubitril/valsartan
keeps HFrEF
patients out of
hospital, helps
them live longer
26.5
16.5
15.6
21.8
13.3 12.8
0
5
10
15
20
25
30
Primary composite CV death HF hospitalization
Number
of
events
(%)
by
treatment
Enalapril Sacubitril/valsartan
HR 0.80
(95% Cl, 0.71-0.89) HR 0.79
(95% Cl, 0.71-0.89)
HR 0.80
(95% Cl, 0.73-0.87)
20%
reduction
P<0.001
P<0.001
P<0.001
20%
reduction
21%
reduction

10. ESC, European Society of Cardiology; ACEi, angiotensin converting enzyme inhibitor; HF, heart failure; HFrEF, heart
failure with reduced ejection fraction; HFA, Heart Failure Association; HFSA, Heart Failure Society of America; MRA,
mineralocorticoid receptor antagonist; ARNI, angiotensin receptor–neprilysin inhibitor; ACC, American College of
Cardiology; AHA, American Heart Association; ARB, angiotensin receptor blocker;
CV, cardiovascular; ACCF, American College of Cardiology Foundation; NYHA, New York Heart Association.
Ref.: 1. Ponikowski P, et al. Kardiol Pol. 2016;74(10):1037-1147; 2. Yancy CW, et al. Circulation. 2016 Sep
Change in guidelines after decades

11. ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor
antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitors.
Ref.: Sindone A. How to welcome the fantastic four. Available [online] URL: https://www.csanz.edu.au/wp-
content/uploads/2023/09/CSANZ_Speaker_Series_Heart_Failure.pdf As accessed on 4th Jan 2024.
Now, in 2024, there are
4 main pillars of heart failure therapy
ARNI Beta-blocker MRA SGLT2i
The Fantastic Four

12. SGLT2, Sodium-glucose cotransporter-2.
Ref.: Packer M, et al. Eur J Heart Fail. 2021;23:882-894.
New guidelines focus is on adding drugs rapidly
Rapid Evidence-Based Sequencing of Foundational Drugs for HFrEF
Conventional Sequencing Rapid Sequencing
Step 1 ACE inhibitor or angiotensin receptor blocker
Beta-blocker
Mineralocorticoid receptor antagonist
Angiotensin receptor neprilysin inhibitor
SGLT2 inhibitor
Step 2
Step 3
Step 4
Step 5
Up titration to target doses at each step
Typically requires 6 months or more
Beta-blocker SGLT2 inhibitor
Angiotensin receptor neprilysin inhibitor
All 3 step achieved within 4 weeks
Up titration to target doses thereafter
Step 1
Step 2
Step 3
Mineralocorticoid receptor antagonist

13. ACEi, angiotensin-converting enzyme inhibitor; ARB,
angiotensin ii receptor blocker; ARNi, angiotensin-receptor-
neprilysin inhibitor; BB, beta-blocker; CV, cardiovascular; HF,
heart failure; HFrEF, heart failure with reduced ejection
fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i,
sodium glucose cotransporter 2 inhibitor.
Risk reduction and expected lifetime benefit of comprehensive disease-
modifying therapy in chronic HFrEF
Comprehensive
therapy
(ARNI + BB + MRA + SGLT2i)
CV death + HF hospitalization
62%
47%
44%
50%
CV death
All-cause mortality
68%
HF hospitalization
V/S
Conventional
therapy
(ACEi/ARB + BB)
Projected event-free survival at age
55 years
8.3 additional years of event-free
survival

14. HF, heart failure.
Ref.: Fatima K , et al. European Journal of Heart Failure (2023)
25, 1477–1480. doi:10.1002/ejhf.3005
While there has been considerable
success in the past two decades in
developing HF therapies, there remain
significant unmet needs for improved
implementation to address the
substantial residual risk

15. Fabulous 5-Vericiguat
HF, heart failure.

16. 16
37.8
13.9
29.1
42.4
40.1
16.9
33.6
12.9
25.9
38.3
35.9
16
0
5
10
15
20
25
30
35
40
45
Primary composite
(CV death/HFH)
CV death HFH Total HFH HFH or all-cause
mortality
All-cause mortality
Event
rate
(events/100
PY)
Placebo
Vericiguat
HR=0.93
(0.81–1.06)*
HR=0.90
(0.81–1.00)*
p=0.048
HR=0.91
(0.84–0.99)*
p=0.02#
HR=0.90
(0.83–0.98)*
p=0.02#
HR=0.95
(0.84–1.07)*
p=0.38#
‡
ARR=4.2
HR=0.90
(0.82–0.98)*
p=0.02
Worsening symptoms requiring hospitalization or IV diuretic use in the outpatient setting. For patients with multiple events, only the first event contributing to the composite endpoint is counted.
*HR (vericiguat over placebo) and 95% CI from Cox proportional hazard model controlling for stratification factors (defined by region and race). #From log rank test stratified by the stratification factors
defined by region and race. ‡Patients could have been hospitalized more than once. Based on data up to the primary completion date (18 June 2019).
ARR, absolute rate reduction; CI, confidence interval; CV, cardiovascular; HFH, heart failure hospitalization; HR, hazard ratio; IV, intravenous; PY, patient-years.
1. Armstrong PW et al. N Engl J Med. 2020;382:1883–1893.
The primary composite outcome, total HFH and the composite of HFH or all-cause mortality
were significantly reduced with vericiguat vs placebo
ARR=1.0
ARR=3.2
ARR=4.1
ARR=4.2
Vericiguat improved both primary and secondary outcomes in patients with chronic and
worsening HF in VICTORIA

17. Vericiguat is recommended for patients with HFrEF following a worsening
HF event1–3
17
* Level of evidence B from a randomized trial.
# A conditional recommendation is provided because vericiguat has not yet been approved for this indication in Canada.
ACC, American College of Cardiology; ACEi, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ARNi, angiotensin receptor–neprilysin inhibitor; CCS, Canadian Cardiovascular Society; CHFS, Canadian Heart
Failure Society; CV, cardiovascular; ESC, European Society of Cardiology; GDMT, guideline-directed medical therapy; HF, heart failure; HFH, heart failure hospitalization; HFrEF, heart failure with reduced ejection fraction; HFSA, Heart
Failure Society of America; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; sGC, soluble guanylate cyclase.
References: 1. McDonald M et al. Can J Cardiol 2021;37:531–546; 2. Heidenreich PA et al. Circulation 2022; https://doi.org/10.1016/j.jacc.2021.12.012; 3. McDonagh TA et al. Eur Heart J 2021;42:3599–3726.
Recommendation
Class of
recommendation
Level of evidence
AHA/ACC/HFSA 2022 guidelines2
In selected high-risk patients with HFrEF and recent worsening of HF already on GDMT,
an oral sGC stimulator (vericiguat) may be considered to reduce HFH and CV death
2b B–R*
ESC 2021 guidelines3
Vericiguat may be considered in patients in NYHA class II–IV who have had worsening HF
despite treatment with an ACEi (or ARNi), a beta blocker and an MRA to reduce the risk
of CV mortality or HFH
IIb B
CCS/CHFS 2021 guidelines1
We recommend that vericiguat, an oral sGC stimulator, be considered in addition to
optimal HF therapies for HFrEF patients with worsening symptoms and HFH in the past 6
months, to reduce the risk of subsequent HFH
Conditional#
Moderate quality

18. Flight of 6- Intravenous Iron
therapy
HF, heart failure.

19. Iron deficiency
• Iron deficiency is an emerging problem in chronic HF, affecting half of
the patients.
• A decreased iron status is associated with disease severity (as
assessed by NYHA functional class and NT-proBNP level), the
presence of anemia and female sex.
• Iron Deficiency is a strong and independent predictor of outcome.
• Inclusion of Iron Deficiency provides additive prognostic value when
added to a prediction model with established risk factors.

20. 2021 ESC Guidelines for
the diagnosis and
treatment of acute and
chronic heart failure

22. Conclusion
•Quadruple medical therapy (ARNI, BB, MRA, SGLT2 inhibitor), titrated to maximally
tolerated or target doses, is foundational therapy.
•Rapid sequence or simultaneous initiation of quadruple medical therapy is an
evidence-based strategy.
•Early upfront use of vericiguat should be considered among patient with WHF.
•Intravenous iron should be administered to patients with iron deficiency.

23. Thank You
Keep Smiling,
90% of your Heart Problems will resolve automatically.