A PARADIGM SHIFT IN HEART FAILURE TREATMENT PARADIGM HF

1. DR.PRAVEEN NAGULA

2. ANGIOTENSIN Receptor –NEPRILYSIN Inhibition
versus
ENALAPRIL in HeartFailure
John J.V.McMurray M.D. et al,NEJM, Aug 30,2014
Original article
Does the concept succeed ?

3. Prospective Comparison of ARNI [Angiotensin Receptor -
Neprilysin Inhibitor] with ACEI [Angiotensin Converting
Enzyme Inhibitor] to Determine Impact on Global
Mortality and Morbidity in Heart Failure Trial.
“A new day in HEART FAILURE,
a step closer to taking the FAILURE out of HEART FAILURE”

4.  Angiotensin –Converting Enzyme Inhibitors (ACEI) have been
the cornerstone of the treatment for heart failure and a reduced
ejection fraction for nearly 25yrs.
 Comparison of the Angiotensin Receptor –Neprilysin Inhibitor
LCZ696 with Enalapril in heart failure patients with a reduced
ejection fraction.

5.  Membrane metallo endopeptidase /neutral
endopeptidase/CD10/CALLA
 Encoded by MME gene.
 Zinc dependent metalloproteinase
 Cleaves peptides at the amino side of hydrophobic residues and
inactivates several peptide hormones including
glucagon,enkephalin,subtance P,neurotensin,oxytocin,bradykinin.
 Abundant in kidney.

6. One Enzyme — Neprilysin — Degrades
Many Endogenous Vasoactive Peptides
Endogenous
vasoactive peptides
(natriuretic peptides, adrenomedullin,
bradykinin, substance P,
calcitonin gene-related peptide)
Neprilysin
Inactive metabolites

7. Neprilysin Inhibition Potentiates Actions of
Endogenous Vasoactive Peptides That Counter
Maladaptive Mechanisms in Heart Failure
Endogenous
vasoactive peptides
(natriuretic peptides, adrenomedullin,
bradykinin, substance P,
calcitonin gene-related peptide)
Inactive metabolites
Neurohormonal
activation
Vascular tone
Cardiac fibrosis,
hypertrophy
Sodium retention
Neprilysin
Neprilysin
inhibition

8. Processing of angiotensin peptides by angiotensin-converting enzyme (ACE), ACE2, and
neprilysin (NEP) as part of the renin-angiotensin system.
Klingler D , and Hardt M Circ Cardiovasc Genet. 2012;5:265
Copyright © American Heart Association, Inc. All rights reserved.

10.  Dual inhibitor of both ACE and NEP and aminopeptidaseA .
 Rx of HTN and HF.
 In HTN ,decreases both SBP and DBP more than ACEI.
 In HF, decreases risk of death or hospitalization for HF.
 Serious adverse effects –angioedema.
Trials
 IMPRESS
 OVERTURE
 OCTAVE - in HTN

11.  Consists of the Neprilysin inhibitor Sacubitril (AHU 377) and the
ARB Valsartan.
 AHU 377 – LBQ 657 (active compound)
 Combined inhibition of ACE and Neprilysin –angioedema.
 It has hemodynamic and neurohormonal effects greater than those
of ARB alone.
 Small pilot studies proved it efficacy with minimal adverse
effects.

12.  Double blinded trial
 8442 pts
 Class II,III,IV HF and EF  40%
 LCZ696(200 mg bd) or Enalapril (10 mg bd)
 The above are in addition to recommended therapy.

13.  Composite of death from cardiovascular causes or
hospitalization for HF.
The trial was designed to detect a difference in the rates
of death from cardiovascular causes.

15. PARADIGM-HF: Patient Disposition
10,521 patients screened at
1043 centers in 47 countries
Did not fulfill criteria
for randomization
(n=2079)
Randomized erroneously
or at sites closed due to
GCP violations (n=43)
8399 patients randomized for ITT analysis
LCZ696 (n=4187)
At last visit
375 mg daily
11 lost to follow-up
Enalapril (n=4212)
At last visit
18.9 mg daily
9 lost to follow-up
median 27 months
of follow-up

18.  Trial was stopped early.
 Median follow up of 27 months.
LCZ 696 Enalapril Hazard ratio P value
Primary outcome 914 pts (21.8%) 1117 pts (26.5%) 0.84 <0.001
deaths 711(17.0%) 835 pts (19.8%) 0.84 <0.001
CV death 558 (13.3%) 693(16.5%) 0.80 <0.001
Risk of
hospitalization
due to HF
Reduction by 21% <0.001
Symptoms and
physical
limitations of HF
=0.001

22. Higher proportion of patients
 Hypotension
 Nonserious angioedema
Lower proportions
 Renal impairement
 Hyperkalemia
 Cough

24.  The inhibition of both the Angiotensin II Receptor and Neprilysin with
LCZ696 was more effective than ACEI with Enalapril in
 Reducing the risk of death from CV causes
 Hospitalization for HF
 Risk of death from any cause
 Reducing symptoms and physical limitations of HF.
 These advantages were highly significant and clinically important
(the drug compared was enalapril 10 mg bd* proven drug for
mortality benefit in HF).

25.  Mean dose of enalapril that was used in this trial was 18.9 mg daily
(higher than dose used in CONSENSUS trial 16.6mg) or similar to
the dose used in (SOLVD trial 18.4mg).
 Results were different compared to that of OVERTURE trial.
[Enalapril vs Omapatrilat (a drug that inhibits ACE, neprilysin,
aminopeptidase P)].
Omapatrilat was given once daily.

26.  Greater vasodilatory effect of LCZ696 was repsonsible for
increased rate of symptomatic hypotension.
 The increases in serum creatinine and renal imapirement
because of hypotension were less in LCZ 696 group than in
Enalapril.
Were they true/consistent ?
 They were consistent with effects observed in experimental
studies and trials on omapatrilat.

27.  Main safety concern of Omapatrilat – life threatening
angioedema –due to inhibition of three enzymes responsible for
the degradation of bradykinin.
 LCZ696 does not inhibit ACE or aminopeptidase P,was not
assosciated with increased risk of serious angioedema in our
study.

28. LCZ696 was superior to Enalapril in reducing the risks
of death and of hospitalization for heart failure.

29. Drugs That Reduce Mortality in Heart
Failure With Reduced Ejection Fraction
Beta
blocker
Mineralocorticoid
receptor
antagonist
ACE
inhibitor
Angiotensin
receptor
blocker
Drugs that inhibit the
renin-angiotensin system
have modest effects on
survival
Based on results of SOLVD-Treatment, CHARM-Alternative,
COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF
0%
10%
20%
30%
40%
% Decrease in Mortality

30. Angiotensin Neprilysin Inhibition With LCZ696
Doubles Effect on Cardiovascular Death of Current
Inhibitors of the Renin-Angiotensin System
10%
20%
30%
40%
ACE
inhibitor
Angiotensin
receptor
blocker
0%
% Decrease in Mortality
18%
20%
Angiotensin
neprilysin
inhibition
15%
Effect of ARB vs placebo derived from CHARM-Alternative trial
Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial
Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

31. Vasopeptidase
inhibitors
NEUTRAL
ENDOPEPTIDASE
inhibitors
Candoxatril Ecadotril Ilepatril
Dual
inhibitors
ACE +NEP
SAMPATRILAT
FASIDOTRIL
GEMOPATRILAT
OMAPATRILAT
ARB +NEP
LCZ696
(Valsartan
+Sacubitril)

32. • CHF II-IV - SOLVD trial
• CHF IV - CONSENSUS trial Enalapril
Candesartan • CHARM trial
• Metoprolol – MERIT HF trial
• Bisoprolol – CIBIS II
• Carvedilol - COPERNICUS
B blockers
• Spironolactone – RALES
• Eplerenone – EMPHASIS -HF
Aldosterone
blockers
Omapatrilat • OVERTURE trial