Marco Canepa, MD, PhD

Università degli Studi di Genova

Cardiologia, Ospedale Policlinico San Martino IRCCS

marco.canepa@unige.it

INIBITORI

NEPRILISINA

ARNI: ANGIOTENSIN RECEPTOR

NEPRILYSIN INHIBITORS

ARNI

VALSARTAN

SACUBITRIL

SACUBITRILAT

Sing JSS et al. HEART 2017

PARADIGM-HF. NEJM 2014

PARADIGM-HF Primary endpoint

Ka

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n-M

eie

r E

sti

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tes

of

Cu

mu

lati

ve R

ate

s (

%)

Days After Randomization

Cardiovascular Death or HF hospitalization

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35% STABLE DOSE

of ACEi or ARB

NYHA II-III

INCREASED

BNP or

NT-proBNP

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

PARADIGM-HF Characteristics at baseline

PARADIGM-HF. NEJM 2014

PARADIGM-HF LVEF

Solomon S et al. PARADIGM-HF. CIRC HF 2016

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35% STABLE DOSE

of ACEi or ARB

NYHA II-III BNP≥150 or

NTproBNP≥600

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35% STABLE DOSE

of ACEi or ARB

NYHA II-III BNP≥150 or

NTproBNP≥600

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

PARADIGM-HF SBP trends

PARADIGM-HF. NEJM 2014

PARADIGM-HF Run-In Period & Study Period

PARADIGM-HF. NEJM 2014

N=10521 N=9419

RUN-IN PERIOD STUDY PERIOD

Desai et al. PARADIGM-HF. CIRC HEART FAIL 2016

PARADIGM-HF Dropout during Run-In Period

Desai et al. PARADIGM-HF. CIRC HEART FAIL 2016

PARADIGM-HF Dropout during Run-In Period

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35% STABLE DOSE

of ACEi or ARB

NYHA II-III BNP≥150 or

NTproBNP≥600

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

PARADIGM-HF SBP trends

PARADIGM-HF. NEJM 2014

McMurray JJ et al. PARADIGM-HF. NEJM 2014

PARADIGM-HF AEs and Discontinuation during Study

Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016

PARADIGM-HF Dose Reduction in ARNI vs. ACEi group

Participants with any dose reduction

42% in sacubitril/valsartan 43% in enalapril

NS

Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016

PARADIGM-HF Dose Reduction Predictors

Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016

PARADIGM-HF Dose Reduction & Prognosis

Cardiovascular Death or HF hospitalization

Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016

PARADIGM-HF Dose Reduction & Prognosis ARNI vs. ACEi

Cardiovascular Death or HF hospitalization

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35% STABLE DOSE

of ACEi or ARB

NYHA II-III BNP≥150 or

NTproBNP≥600

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

PARADIGM-HF Minimum required pre-study daily doses

McMurray et al. PARADIGM-HF. EJHF 2013

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35%

TARGET

STABLE DOSE

of ACEi or ARB

NYHA II-III BNP≥150 or

NTproBNP≥600

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

Pellicori P, Clark AL et al. EJHF 2017

1396 ambulatory CHF patients in UK

Pellicori P, Clark AL et al. EJHF 2017

1. LVEF≤40% at baseline

2. LVEF≤40% at fup

3. Alive at fup

4. Available at fup

5. On target dose ACEi/ARB

6. No controindications

7. Symptoms

8. NTproBNP>400

9. NTproBNP>600

Proportion of patients

eligible for ARNI

Only 28% of the 5000 HFrEF patients

in the ESC HF Long-Term Registry are

at ACEi/ARB target dose

- still up-titration

- side effects (symptomatic hypotension

and/or worsening renal function)

- no obvious reason (>30%!)

No loss of the advantage of

sacubitril–valsartan over enalapril for

morbidity and mortality in >40% of

patients in PARADIGM-HF who had

doses reduction of trial medication

during follow-up.

Rather than going to the trouble of

titrating patients to full dose

ACEi/ARB and then switching to an

ARNI, it may be appropriate to

initiate patients on the latter from

the outset.

Pellicori P, Clark AL et al. EJHF 2017

AHA/ACC HF Guidelines. Focused Update 2017

1396 ambulatory CHF patients in UK

Pellicori P, Clark AL et al. EJHF 2017

1. LVEF≤40% at baseline

2. LVEF≤40% at fup

3. Alive at fup

4. Available at fup

On target dose ACEi/ARB

5. No controindications

6. Symptoms

7. NTproBNP>400

8. NTproBNP>600

Proportion of patients

eligible for ARNI

COSTS

BENEFITS

HIGH

LOW

LOW HIGH

56 cp (bid) = 200 €

28 cp (od) = 5 € 28 cp (od) = 10 €

Cost of one-month therapy

with ARNI vs. ACEi/ARB

COSTS

BENEFITS

HIGH

LOW

LOW HIGH

King et al. JACC HF 2014

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35% STABLE DOSE

of ACEi or ARB

NYHA II-III BNP≥150 or

NTproBNP≥600

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

“Three major regulatory authorities [the Food and Drug

Administration (FDA), the European Medicines Agency (EMA),

and the National Institute for Health and Care Excellence

(NICE)] have not suggested that initiation of sacubitril–

valsartan should be restricted to patients with an elevated NT-

proBNP. We believe this is a mistake” .

Natriuretic peptides are powerful prognostic markers . Low

values will identify patients at low risk in whom sacubitril–

valsartan is unlikely to be cost -effective. Even if the relative

reduction in risk is similar, patients at low risk of events will

have a small absolute benefit.

Natriuretic peptides

in the prescription of ARNI

Pellicori P, Clark AL et al. EJHF 2017; Van Veldhuisen et al. JACC 2013

De

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Van Veldhuisen et al. JACC 2013; AHA/ACC 2017 HF Guidelines update

“In our opinion, measuring plasma natriuretic peptides would

be a simple, effective and probably cost -effective strategy

that would reduce prescriptions of sacubitril–valsartan for

patients who had little to gain and greatly increase them in

those most l ikely to benefit . We predict that this would lead to

an overall increase in sacubitril–valsartan use but,

importantly, a greater increase in what we consider

appropriate use”.

Pellicori P, Clark AL et al. EJHF 2017; Van Veldhuisen et al. JACC 2013

Natriuretic peptides

in the prescription of ARNI

PARADIGM-HF Inclusion & Exclusion Criteria

LVEF ≤35% STABLE DOSE

of ACEi or ARB

NYHA II-III BNP≥150 or

NTproBNP≥600

SYMPTOMATIC

HYPOTENSION SBP <100

eGFR <30 K >5.2

SELECTING THE RIGHT PATIENTS

FOR ARNI YES

• HFrEF patients with LVEF≤35%

• NYHA II-III & increased BNP/NT-proBNP

• SBP>100 mmHg

• Tolerating target ACEi/ARB

MAYBE • On low-dose ACEi/ARB

• ACEi/ARB naïve

NO DATA • NYHA IV/stage D HF

• Hospitalized HF

• HFpEF

• NYHA I/asymptomatic LVH

ARNI

UPCOMING CLINICAL STUDIES

Prospective ARNI vs ACE Inhibitor Trial to

DetermIne Superiority in Reducing Heart

Failure Events After MI (PARADISE-MI)

ARNI in Asymptomatic Patients With

Elevated Natriuretic Peptide and Elevated

Left Atrial Volume Index eLEvation

(PARABLE)

Efficacy and Safety of LCZ696 Compared to

Valsartan, on Morbidity and Mortality in

Heart Failure Patients With Preserved

Ejection Fraction (PARAGON-HF)

comParIson Of Sacubitril/valsartaN Versus

Enalapril on Effect on ntpRo-bnp in Patients

Stabilized From an Acute Heart Failure

Episode (PIONEER-HF)

A Randomized, Double-blind Controlled

Study Comparing LCZ696 to Medical

Therapy for Comorbidities in HFpEF Patients

(PARALLAX)

Comparison of Pre- and Post-discharge

Initiation of LCZ696 Therapy in HFrEF

Patients After an Acute Decompensation

Event (TRANSITION)

www.clinicaltrials.gov

TITRATION CONSERVATIVE vs. CONDENSED initiation

Senni et al. TITRATION. EUR J HEART FAILURE 2016

CONDENSED

CONSERVATIVE

Jhund PS et al. PARADIGM-HF. EUR HEART J 2015

ARNI Efficacy According to Age

Shen et al. NEJM 2017

THE BUILDING BLOCKS

OF HFrEF THERAPY

TODAY PROGNOSIS

OF CHRONIC HFrEF

1990 1995 2000 2005 2010 2015 TODAY

TOTAL MORTALITY

SUDDEN DEATH

COMORBIDITIES

MO

RTA

LIT

Y/Y

EA

R

5%

10%