MINERALO CORTICOID RECEPTOR ANATAGONIST ARE IMPORTANT THERAPEUTICS IN HEART FAILURE BUT OFTEN NEGLECTED

1. MRA - The neglected pillar in
HF

3. Heart Failure Prevalence - Expected
to Continue Increasing
1. Mozaffarian D, et al; Circulation 2015;131(4):e29-e322. 2. Global Burden of Disease Study 2013 Collaborators, Lancet. 2015 Nov 28;386(10009):2145-91
For the use only of healthcare
practitioner, hospital, or
laboratory

4. Mean Age 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
Mean Age 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.
For the use only of healthcare
practitioner, hospital, or
laboratory

6. Chronic HF - Associated with a Devastating Burden
Despite the introduction of treatments,
the mortality rate for patients with chronic HF is
about 50% at 5 years post-diagnosis1–7
HRrEF: Heart failure with reduced ejection fraction; HFpEF: Heart failure with preserved ejection fraction; LVEF: left ventricular ejection fraction
1. Owan et al. N Engl J Med 2006;355:251–9; 2. Roger et al. JAMA 2004;292:344–50; 3. Levy et al. N Engl J Med 2002;347:1397–402; 4. McMurray et al. Eur Heart J 2012;33:1787–847; 5. Yancy et al. Circulation
2013;128:e240–327; 6. Loehr et al. Am J Cardiol 2008;101:1016–22; 7. Askoxylakis et al. BMC Cancer 2010;10:105
For the use only of healthcare
practitioner, hospital, or
laboratory

8. What Does Heart Failure Feel Like?
Ventricular dysfunction limits a patient's ability to
perform the routine activities of daily living…..
Increased preload and afterload

10. Thirty years of progress in HFrEF:
Positive drug trials 1986-2001
McMurray JJV. Eur J Heart. 2015;36:3467-70.

14. ALDOSTERONE ANTAGONIST IN
HEART FAILURE
• SPINOLACTONE
• EPLERENONE
• OTHERS

16. AT1R
Liver
Angiotensinogen
Angiotensin I
Angiotensin II
Kidney
Renin
DRI
Chymase
ARB
BK
Breakdown
products
ACTH
K+
Aldosterone
MR
MRA
Corticosteroids
β-blocker
Adrenal gland
DRI, direct renin inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist;
K+ potassium ion; ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone (corticotropin); BK, bradykinin;
AT1R, angiotensin II type 1 receptor; MR, mineralcorticoid receptor
ACE
ACE
inhibitor
─
─
─
─
─
Why mineralocorticoid receptor antagonist
(MRA)?

17. “Triple therapy Triples lifespan.”----JACC: HEART FAILURE VOL. 2, NO. 5, 2014

20. ALDOSTERONE ANTAGONIST IN
HEART FAILURE
•EVIDENCES

21. • NYHA class III or IV (and class IV within past 6 months)
• Treated with an ACE-I (if tolerated) and a loop diuretic
• LVEF <35%
• Potassium-sparing diuretics not permitted. Potassium supplements only if
hypokalemia developed.
• EXCLUSIONS: Serum creatinine concentration >2.5 mg/dl (221 µmol/l) or
serum potassium >5.0 mmol/l.
• After 8 weeks spironolactone dose could be increased to 50 mg once daily
if no hyperkalemia. If hyperkalemia developed at any time, the dose
decreased to 25 mg every other day.
• Study medication withheld if serious hyperkalemia or creatinine >4.0 mg
/dl (354 µmol/l).
RALES
Randomized ALdactone
Evaluation Study

22. RALES
Randomized ALdactone Evaluation Study
1663 patients, NYHA class III-IV, LVEF ≤0.35. ACE-i 95%, digoxin 73%
and beta blockers 10.5%. Mean follow-up 24MTHS months.
Pitt et al. NEJM 1999341:709-17
HR 0.70 (95% CI 0.60-0.82)
P<0.001

23. Eplerenone –(MRA) - aldosterone-antagonist
RALES
EPHESUS
LVSD and HF/
diabetes
after AMI
EMPHASIS-HF
Mild HF
symptoms
(NYHA class II)
Severe HF
symptoms
(NYHA class III/IV)

24. EPLERENONE
• The proposed benefits of MRAs following MI are several-fold. First,
MRAs preserve serum potassium levels and thereby may prevent arrhythmic triggers in a
population vulnerable to lethal arrhythmias.
• More importantly, MRAs favourably influence a myriad of pathways
involved in myocardial remodelling and fibrosis, and improve endothelial dysfunction and
peripheral vascular compliance.
That MRAs reduced markers of haemodynamic stress in the REMINDER Study, specifically in
patients with smaller infarcts, suggests that crude measures of ventricular function such as
ejection fraction and symptomatic heart failure fail to reflect the degree of myocardial
damage and subsequent maladaptive remodelling in many MI patients.

25. EPHESUS Trial
Eplerenone Post-AMI Heart Failure
Efficacy and Survival Study
N Engl J Med 2003;348:1309-21

26. EPHESUS Trial:
674 centers in 37 countries
6,632 patients with acute MI complicated by heart
failure and systolic left ventricular dysfunction
 Acute MI in prior 3-14 days
 Left ventricular dysfunction (EF <40%)
 Heart failure (in non-diabetics but not required for diabetics)
Eplerenone
(n = 3,313)
Placebo
(n = 3,319)
Endpoints (at mean of 16 month follow-up):Primary
1) death from any cause and
2) death or hospitalization from CV causes
Optimal medical therapy
(ACE inhibitors, angiotensin-receptor blockers, diuretics, and beta-blockers,
coronary reperfusion therapy)

27. EPHESUS Trial:
Primary Endpoints
All-cause Mortality
RR 0.85
p=0.008
CV Death or Hospitalization
RR 0.83
p=0.005
Eplerenone Placebo
Eplerenone Placebo
14.4
%
16.7
%
0%
5%
10%
15%
20%
26.7
%
30.0
%
0%
10%
20%
30%
40%
Eplerenone 3-14 days after an acute MI significantly reduced mortality and the
rate of hospitalization for heart failure

28. Eplerenone - Summary of EPHESUS
Eplerenone provided early and sustained survival benefits above
and beyond standard therapies*

29. MI patients — LVEF ≤30%
Early survival benefits
All-cause mortality SCD
43%*†
P=.002
58%*†
P=.008
Eplerenone reduced all-cause mortality and SCD at 30 days
(95% CI, 0.40-0.82)
(N=Eplerenone, 1048 [n=46]; placebo, 1058 [n=80])
(95% CI, 0.22-0.82)
(N=Eplerenone, 1048 [n=13]; placebo, 1058 [n=30])
Prevention of SCD: Pharmacotherapy

30. EMPHASIS-HF
Eplerenone in Mild Patients Hospitalization And
SurvIval Study in Heart Failure

32. • NYHA class II and ≥55 years. CV hospitalization within 6 months or elevated NPs.
• Treated with an ACE inhibitor and beta-blocker unless not tolerated
• LVEF ≤30% (>30 to 35% if QRS duration of >130 msec)
• EXCLUSIONS: eGFR 30 ml per minute per 1.73 m2 or serum potassium >5.0
mmol/l.
• Eplerenone started at 25 mg once daily and increased after 4 weeks to 50 mg
once daily (or started 25 mg on alternate days, and increased to 25 mg daily, if
the eGFR was 30 to 49 ml/min/1.73 m2), provided potassium ≤5.0 mmol/l.
• Dose decreased if potassium 5.5 to 5.9 mmol/l and withheld if ≥6.0 mmol/l
EMPHASIS-HF
Eplerenone in Mild Patients Hospitalization
And SurvIval Study in Heart Failure

33. EMPHASIS-HF: Summary
• The addition of eplerenone to recommended treatment
resulted in a
– 37% reduction in the rate of the composite outcome
of death from cardiovascular causes or hospitalization
for heart failure
– 24% reduction in the all cause mortality
– 23% reduction in the rate of hospitalization from any
cause
– 42% reduction in the rate of hospitalization for heart
failure
• The effect of eplerenone on the primary outcome was
consistent across all prespecified subgroups
• NNT
– To prevent one patient experiencing the primary
endpoint, per year of follow up, is 19
– To postpone one death, per year of follow up, is 51

35. Comparison of Spironolactone and Eplerenone
• Eplerenone is more selective for the MR then spironolactone and not
associated with the sexual side effects associated with spironolactone
such a breast pain and gynecomastia in males and menstrual
irregularities in females (RALES vs Ephesus and Emphasis)
• In patients with Diabetes mellitus spironolactone is associated with an
increase in HbAic and cortisol where's Eplerenone is not (Toutamoto, et
al.)
• Eplerenone has a shorter plasma half life then spironolactone and may
be safer in case of hyperkalemia
B. Pitt, 2015

36. Mild – Moderate HF - Non-HF
AMI
without
HF
REMINDER
(Eplerenone)

37. Combining eplerenone and torsemide
1. Effective control : Eplerenone can be used to increase diuresis in
patients resistant to loop diuretics
2. Anti-aldosterone effect: Eplerenone & Torsemide has proven anti-
aldosterone effect
3. Complimentary action: on K+
4. Improved patient compliance: Availability of the two drugs in a
single tablet can help enhance patient compliance

38. What do the guidelines say?

39. Pharmacological therapy indicated in
potentially all patients with HFrEF
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; EF, ejection fraction; MRA,
mineralocorticoid receptor antagonist; NYHA, New York Heart Association.

40. AHA/ACC 2017 focussed update

41. ESC 2021

42. Overview of the management
of HFrEF
Eur Heart J, ehab368,
https://doi.org/10.1093/eurheartj/ehab368
• Colour code for classes of recommendation:
Green for Class of recommendation I;
Yellow for Class of recommendation IIa
• BTC =bridge to candidacy; BTT=bridge to transplantation;
• CRT-D= cardiac resynchronization therapy with defibrillator;
• CRT-P=cardiac resynchronization therapy with pacemaker;
• DT=destination therapy;
• ICD=implantable cardioverter-defibrillator;
• ISDN=isosorbide dinitrate;
• LBBB=left bundle branch block;
• MCS=mechanical circulatory support;
• MRA=mineralocorticoid receptor antagonist;
• MV=mitral valve; PVI=pulmonary vein isolation;
• SAVR=surgical aortic valve replacement;
• SR=sinus rhythm;
• TAVI=transcatheter aortic valve replacement;
• TEE=transcatheter edge to edge.

43. Therapeutic algorithm of Class I Therapy Indications for a
patient with heart failure with reduced ejection ...
Eur Heart J, ehab368, https://doi.org/10.1093/eurheartj/ehab368
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44. CAUTION

45. Management of Hyperkalemia in Heart Failure
Spironolactone and Eplerenone Dose Adjustment Proposal
João Pedro Ferreira, MD, PHD,et al,Abnormalities of Potassium in Heart Failure, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, VOL. 75,
NO. 22, 2020

46. ALDOSTERONE ATAGONIST IN
OTHER SITUATION
1.HFPeF
2.STEMI
3.RESISTANT HYPERTENSION

49. The REMINDER trial
Primary End Point: CV mortality, re-hospitalisation
or extended stay for HF, sustained VT or fibrillation,
EF≤40% after 1 month or BNP>200pg/ml
placebo
Randomized
Double blind
N=612
Eplerenone
25-50mg od
STEMI in the first 24hrs
6 month FU minimum

50. REMINDER - Primary Endpoint
PRIMARY ENDPOINT: Time to first occurrence of CV mortality, re-hospitalization or extended initial hospital
stay due to diagnosis of HF or sustained ventricular tachycardia or ventricular fibrillation, as well as at 1 month
post randomization: LVEF ≤ 40% or elevated BNP / NT-proBNP
HR [95% CI] = 0.581 [0.449, 0.753]
P = <0.0001
Eplerenone
Placebo

51. HF with Preserved Ejection Fraction
51

52. 52

53. HR=0.82 (0.69-0.98)
p=0.02
6
HR=1.10 (0.79-1.51)
p=0.57
6
interaction
P=0.122
US, Canada,
Argentina, Brazil
Russia, Rep Georgia

54. TOPCAT

56. Characteristics Outcomes
Guideline-Directed Medical
Therapies
Older
Age
Male
Sex
CAD Morbidity Mortality ACEI ARB ARNI BB MRA
HFpEF
(LVEF>50%)
+++ + ++ ++ ++ X
☑️
(IIB)
? x
☑️
(IIB)
HFmrEF
(LVEF 40-
50%)
++ ++ +++ ++/+++ ++ ?
☑️
(IIB)
? ?
☑️
(IIB)
HFrEF
(LVEF<40%)
+ +++ +++ +++ +++
☑️
(I)
☑️
(I)
☑️
(I)
☑️
(I)
☑️
(I)
Characterization of HFpEF, HFmrEF, and HFrEF
Heart Failure
Hsu, J.J. et al. J Am Coll Cardiol HF. 2017;5(11):763–71.

60. Eplerenone & resistant hypertension
Conclusion-
In patients with drug-resistant hypertension, the add-on use of eplerenone was
effective in lowering BP, especially home and ambulatory awake BP.
Furthermore, endothelial function was improved by eplerenone without causing
significant adverse effects.

62. Resistant
Hypertension
Mild HF
LVSD
Post MI
LVSD
AMI without
heart failure
Moderate HF
LVSD
Severe HF
LVSD
MRA
Eplerenone
Increasing Horizon for MRA…
HFpEF

63. Summary and conclusions
• Today, we have a large base of clinical evidence to support
the use of aldosterone antagonists (AAs) in patients with
varying degrees of heart failure with reduced ejection
fraction (HFrEF).. .
• Adverse events are predictable (expected as a result of
blocking the RAAS), rarely serious in appropriately
selected and carefully monitored patients and the
benefit/risk ratio is very favorable in these patients.
• MRAs are one of the key quartet of disease-modifying
drugs in HFrEF (i.e. along with an ACEi/ARB, beta-blocker
or neprilysin inhibitor).

64. Summary and conclusions
• MRA have been studied and also found to be
useful in HPpEF,Resistant hypertension and
even STEMI
• Underutilization of Aldosterone Antagonists
suggest a significant misstep in treatment
considering the impact this class of drugs has
on morbidity, mortality and readmission rates
in HFrEF.

65. Thank you.