Angiotensin Receptor-Neprilysin Inhibition in Chronic Heart Failure
Milton Packer, MD
University of Texas Southwestern Medical Center,Dallas, Texas
Disclosures for Presenter
Within past 3 years (related to any aspect of heart failure):
Consultant to: AMAG, Amgen, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Daiichi, Janssen, Novartis, Sanofi
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
orta
lity
Angiotensin II
Adverse effects onheart and blood vessels
ACE inhibitorsor angiotensin
receptor blockers
What Is the Problem With Current Inhibitorsof the Renin-Angiotensin System?
Pharmacologicalantagonism
Angiotensin II
Adverse effects onheart and blood vessels
ACE inhibitorsor angiotensin
receptor blockersPharmacological
antagonism
Biologicalantagonism
What Is the Problem With Current Inhibitorsof the Renin-Angiotensin System?
Endogenous Peptide Antagonists of Angiotensin II and Other Maladaptive Mechanisms
Natriuretic peptidesBradykinin
AdrenomedullinEnkephalinsSubstance P
Calcitonin gene-related peptideVasoactive intestinal polypeptide
Which should we boost?
Natriuretic peptidesBradykinin
AdrenomedullinEnkephalinsSubstance P
Calcitonin gene-related peptideVasoactive intestinal polypeptide
Neprilysin(NEP)
Inactive metabolites
One Enzyme — Neprilysin — DegradesMany Endogenous Vasoactive Peptides
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 toneCardiac fibrosis,
hypertrophySodium retention
Neprilysin Neprilysininhibition
Omapatrilat
Dual inhibitor of ACE and neprilysin
Enalapril 10 mg BID
(based on dosing usedin heart failure)
Design of the OVERTURE Trial (n=5770)
Omapatrilat 40 mg QD
(based on dosing usedIn hypertension)
Baseline
2.5 mg BID
5 mg BID
10 mg QD
20 mg QD
Prior ACE inhibitordiscontinued
Randomization
0
0.2
0.4
0.6
1.0
0 3 219 12 18
0.8
6 15 24
Omapatrilat
Months
HR = 0.94 (0.86-1.03)P = 0.187
OVERTURE: Death or Hospitalizations ForHeart Failure (Primary Endpoint)
Omapatrilat given once daily, but dual effects did not persist for 24 hours
Enalapril
% E
vent
Fre
e Su
rviv
al
Effects of Omapatrilat in the OCTAVE Trial
Incidence of angioedema in25,302 patients with hypertension
2.17% vs 0.68%Omapatrilat ACE inhibitor
Some of the cases were life-threatening
Omapatrilat: Dual Inhibitor of ACE and Neprilysin
Omapatrilat
Inhibition ofcarboxypeptidase
(ACE)
Inhibition ofendopeptidase
(neprilysin)
Inhibition ofaminopeptidase
Omapatrilat
Inhibition ofACE
Inhibitionof NEP
(AHU 377)
Inhibition ofaminopeptidase
Angiotensinreceptor blockade
(valsartan)
LCZ696
Evolution of the Concept of Angiotensin Receptor Neprilysin Inhibition
A Comparison of Angiotensin Receptor-Neprilysin Inhibition (ARNI) With ACE Inhibition
in the Long-Term Treatment of Chronic Heart Failure With a Reduced Ejection Fraction
John J.V. McMurray, Milton Packer, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau,
Victor C. Shi, Scott D. Solomon, Karl Swedberg and Michael R. Zile for the PARADIGM-HF Investigators and Committees
Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and
morbidity in Heart Failure trial (PARADIGM-HF)
SPECIFICALLY DESIGNED TO REPLACE CURRENT USE OF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS AS
THE CORNERSTONE OF THETREATMENT OF HEART FAILURE
Aim of the PARADIGM-HF Trial
LCZ696400 mg daily
Enalapril20 mg daily
• Largest clinical trial ever in chronic heart failure
• Designed prior to obtaining any Phase I or II data in patients with heart failure.
• Carried out without any Phase II “proof-of-concept” or dose-finding study
• First trial designed to evaluate the effect of a drug on cardiovascular mortality in 15 years.
PARADIGM-HF
PARADIGM-HF Was Designed to Show Incremental Effect on Cardiovascular Death
The sample size of the trial was determined by effect on cardiovascular mortality, not the primary endpoint
The Data Monitoring Committee was allowed to stop the trial only for a compelling effect on cardiovascular
mortality (in addition to the primary endpoint)Difference in cardiovascular mortality of 15% between
LCZ696 and enalapril was prospectively identified as being clinically important (n=8000 yielded 80% power)
Primary endpoint was cardiovascular death or hospitalization for heart failure, but PARADIGM-HF
was designed as a cardiovascular mortality trial
0
16
32
40
24
8
Enalapril(n=4212)
360 720 10800 180 540 900 1260Days After Randomization
41874212
39223883
36633579
30182922
22572123
15441488
896853
249236
LCZ696Enalapril
Patients at Risk
1117
Kap
lan-
Mei
er E
stim
ate
ofC
umul
ativ
e R
ates
(%)
914
LCZ696(n=4187)
HR = 0.80 (0.73-0.87)P = 0.0000002
Number needed to treat = 21
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
Enalapril(n=4212)
LCZ696(n=4187)
HR = 0.80 (0.71-0.89)P = 0.00004
Number need to treat = 32
Kap
lan-
Mei
er E
stim
ate
ofC
umul
ativ
e R
ates
(%)
Days After Randomization
41874212
40564051
38913860
32823231
24782410
17161726
1005994
280279
LCZ696Enalapril
Patients at Risk
360 720 10800 180 540 900 12600
16
32
24
8
693
558
PARADIGM-HF: Cardiovascular Death
PARADIGM-HF: All-Cause Mortality
41874212
40564051
38913860
32823231
24782410
17161726
1005994
280279
LCZ696Enalapril
Enalapril(n=4212)
LCZ696(n=4187)
HR = 0.84 (0.76-0.93)P<0.0001
Kap
lan-
Mei
er E
stim
ate
ofC
umul
ativ
e R
ates
(%)
Days After RandomizationPatients at Risk
360 720 10800 180 540 900 12600
16
32
24
8
835
711
LCZ696 was also more effective than enalapril in . . .• Reducing the risk of a heart failure hospitalization by
incremental 21%• Incrementally improving symptoms and physical
limitations of heart failure
LCZ696 was better tolerated than enalapril . . .• Less likely to cause cough, hyperkalemia or renal
impairment or be discontinued for an adverse event• More hypotension, but no increase in
discontinuations• No increase in risk of serious angioedema
PARADIGM-HF: Additional Findings
PARADIGM-HF: A Few Questions
To Which Patients With Heart Failure Can the Results of PARADIGM-HF Be Applied?
To Which Patients With Heart Failure Can the Results of PARADIGM-HF Be Applied?
• The patients enrolled in the PARADIGM-HF trial were very typical of patients with chronic heart failure in the community.
• The advantage of LCZ696 was seen across all prespecified and relevant subgroups.
• The findings of the trial can be generalized to all patients taking an ACE inhibitor or ARB or who have not shown hypotension-related intolerance to these drugs.
Is the Advantage of LCZ696 Over ACE Inhibition Meaningful?
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
orta
lity
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%
Was The Right Dose of Enalapril Usedas Comparator?
Was The Right Dose of Enalapril Usedas Comparator?
• The dose of enalapril used in the PARADIGM-HF trial (18.9 mg daily) was higher than in any other trial of this ACE inhibitor in heart failure.
• Doses of enalapril > 20 mg daily have not been shown to be more effective, but such extremely high doses produce more adverse effects, particularly on renal function.
Can the Results of One Trial Really Be Enough to Change Clinical Practice?
We Normally Require Replication of Findings Before Changing Clinical Practice
Number of Trials With
P < 0.05 Showing Efficacy
P Value Required in a Single Trial to
Provide Same Strength of Evidence
PARADIGM-HF Effect on Primary
Endpoint
PARADIGM-HF Effect on
Cardiovascular Death
1 0.05
2 0.00125
3 0.000042
4 0.0000016
5 0.00000006
Based on formula (0.05)n ÷ n
0.0000002
0.00004
Can We Replicate the Effects of LCZ696Using Some Other Approach?
Administer B-type natriuretic peptide• Long-term infusions of nesiritide are ineffective
Add a neprilysin inhibitor• Neprilysin inhibition alone is ineffective
Add a neprilysin inhibitor to an ACE inhibitor• Combination leads to serious angioedema
Add a neprilysin inhibitor to an ARB• Failure to maintain dual inhibition in proper ratio for
24 hours produces no benefit (OVERTURE)
Can We Replicate the Effects of LCZ696Using Some Other Approach?
For the last 25 years, the magnitude of the effect of ACE inhibitors on cardiovascular mortality (18%) has created an ethical mandate for their use in all patients with chronic heart failure who could tolerate treatment with these drugs.
The finding that LCZ696 has an 20% greater effect on cardiovascular mortality than ACE inhibitors strongly supports the conclusion that LCZ696 should replace current use of ACE inhibitors and angiotensin receptor blockers in the management of chronic heart failure.
Clinical Importance of the Findingsof the PARADIGM-HF Trial
ACE inhibitors orangiotensin receptor
blockers
Beta-adrenergicblockers
Mineralocorticoidreceptor
antagonists
Angiotensin receptor-neprilysin inhibition
(LCZ696)
Beta-adrenergicblockers
Mineralocorticoidreceptor
antagonists
The Present The Near Future
PARADIGM-HF Trial Is Poised to Change Clinical Practice in Heart Failure