DR.PRAVEEN NAGULA

JOURNAL CLUB

ANGIOTENSIN Receptor –NEPRILYSIN Inhibition

versus

ENALAPRIL in HeartFailure

PARADIGM –HF trial

John J.V.Mc Murray M.D. et al,NEJM, Aug 30,2014

Original article

Does the concept succeed ?

PARADIGM –HF trialProspective 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”

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.

Back ground

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.

What is Neprilysin?

One Enzyme — Neprilysin — DegradesMany Endogenous Vasoactive Peptides

Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

NeprilysinNeprilysin

Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter

Maladaptive Mechanisms in Heart Failure

Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention

NeprilysinNeprilysinNeprilysininhibition

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.

Dual inhibitor of both ACE and NEP and aminopeptidase A .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.

TrialsIMPRESS OVERTUREOCTAVE - in HTN

Omapatrilat

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.

LCZ696

Double blinded trial8442 ptsClass II,III,IV HF and EF 40% LCZ696(200 mg bd) or Enalapril (10 mg bd)The above are in addition to recommended therapy.

Methods

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.

Primary outcome

10,521 patients screened at1043 centers in 47 countries10,521 patients screened at1043 centers in 47 countries

Did not fulfill criteriafor randomization

(n=2079)

Randomized erroneously or at sites closed due to GCP violations (n=43)

8399 patients randomized for ITT analysis8399 patients randomized for ITT analysis

LCZ696 (n=4187)

At last visit

375 mg daily 11 lost to follow-up

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

Enalapril (n=4212)

At last visit

18.9 mg daily 9 lost to follow-up

median 27 monthsof follow-up

PARADIGM-HF: Patient Disposition

Trial was stopped early.Median follow up of 27 months.

Results

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

Higher proportion of patients HypotensionNonserious angioedema

Lower proportionsRenal impairementHyperkalemiaCough

What is the rate of adverse effects compared to enalapril?

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 HFRisk of death from any causeReducing 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).

DISCUSSION

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.

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.

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.

LCZ696 was superior to Enalapril in reducing the risks

of death and of hospitalization for heart failure.

CONCLUSIONS

Betablocker

Mineralocorticoidreceptor

antagonist

Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction

ACEinhibitor

Angiotensinreceptorblocker

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

10%

20%

30%

40%

0%

% D

ecre

ase

in M

ort

alit

y

10%

Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current

Inhibitors of the Renin-Angiotensin System

20%

30%

40%

ACEinhibitor

Angiotensinreceptorblocker

0%

% D

ecre

ase

in M

ort

alit

y

18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trialEffect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensinneprilysininhibition

15%

Vasopeptidase inhibitors

NEUTRAL ENDOPEPTIDASE

inhibitors

Candoxatril Ecadotril Ilepatril

Dual inhibitors

ACE +NEP

SAMPATRILAT

FASIDOTRIL

GEMOPATRILAT

OMAPATRILAT

ARB +NEP

LCZ696

(Valsartan +Sacubitril)

•CHF II-IV - SOLVD trial

•CHF IV - CONSENSUS trial

Enalapril•C

HARM trial

Candesartan

•Metoprolol – MERIT HF trial

•Bisoprolol – CIBIS II

•Carvedilol - COPERNICUS

B blockers

•Spironolactone – RALES

•Eplerenone – EMPHASIS -HF

Aldosterone blockers

•OVERTURE trial

Omapatrilat

Trial evidence for mortality benefit of drugs in HF

Thank You