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