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Sacubitril/Valsartan: Why, Who, When, How?
Akshay S. Desai MD, MPH

Director, Heart Failure Disease Management
Cardiovascular Division
Brigham and Women’s Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, MA
Disclosures: Honoraria and Research Support from Novartis, CEC Chair for
PARADIGM-HF, Lead Investigator EVALUATE-HF
Neprilysin as a
Therapeutic Target
• Neprilysin is responsible for the breakdown of a
number of endogenous vasoactive peptides, Natriuretic Peptides
including the natriuretic peptides Adrenomedullin
Bradykinin
• Inhibition of neprilysin potentiates the action of Substance P
those peptides (angiotensin II)
• Because angiotensin II is also a substrate for

neprilysin, neprilysin inhibitors must be co- Neprilysin
administered with a RAAS blocker
• The combination of a neprilysin inhibitor and an Inactive

ACE-inhibitor is associated with unacceptably fragments
high rates of angioedema
Sacubitril/Valsartan (LCZ696):
A first-in-class angiotensin/neprilysin
inhibitor (ARNi)
LCZ696
LCZ696 is a novel
crystalline complex
consisting of the
molecular moieties of
valsartan and sacubitril
in an equimolar ratio
Dissociates
at low pH
Sacubitril Valsartan
↓
LBQ657
Neprilysin Inhibitor + ARB

PARADIGM-HF: Entry Criteria
Key Inclusion Criteria Key Exclusion Criteria

• Chronic HF NYHA class II–IV with LVEF ≤40% • History of angioedema
(which was amended to ≤35% one year after • eGFR <30 mL/min/1.73 m2
study started) and:
• Serum potassium >5.2 mmol/L
– BNP ≥150 pg/mL (or NT-proBNP ≥ 600) OR
• Symptomatic hypotension,
– BNP ≥100 pg/mL (or NT-proBNP ≥ 400) + HF
SBP <100 mmHg
hospitalization last 12 months
• Current acute decompensated HF
• Stable on ACEI or ARB (dosage equivalent to
enalapril ≥10 mg/d)
for 4 weeks
• β-blocker for 4 weeks, unless not tolerated
• Optimized dosing of background HF medications
(MRA)
McMurray et al. NEJM 2014

PARADIGM-HF Study Design
Randomization
Single-blind run-in period Double-blind period
(N=10,521) (N=8399)
19.7% Attrition
LCZ696 200 mg
Sacubitril/Valsartan BID
97/103 mg BID
Enalapril LCZ696
(1:1 randomization)
10 mg 100 mg 200 mg Median Follow up 27 Months
BID BID BID
Enalapril 10 mg BID
2 weeks 1-2 weeks 2-4 weeks
Predictors of Run-in
Noncompletion
• Lower eGFR
• Higher NT-proBNP
• Lower Systolic BP
• Ischemic cause of heart Failure
Those who dropped out share many characteristics with those who were randomized
Overweighting patients similar to those who dropped out does not alter study results
Desai et al. Circulation 2016

PARADIGM-HF: Baseline Characteristics
LCZ696 Enalapril
(n=4187) (n=4212)
Age (years) 63.8 ± 11.5 63.8 ± 11.3
Women (%) 21.0% 22.6%
Ischemic cardiomyopathy (%) 59.9% 60.1%
LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3
NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9%
Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15
Heart rate (beats/min) 72 ± 12 73 ± 12
N-terminal pro-BNP (pg/ml) 1631 (885-3154) 1594 (886-3305)
B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465)
History of diabetes 35% 35%
Digitalis 29.3% 31.2%
Beta-adrenergic blockers 93.1% 92.9%
Mineralocorticoid antagonists 54.2% 57.0%
ICD and/or CRT 16.5% 16.3%
PARADIGM-HF: CV Death or HF
Hospitalization (Primary Endpoint)
40
1117 (26.5%)
Enalapril
Kaplan-Meier Estimate of
32 (n=4212) 914 (21.8%)

Cumulative Rates (%)
24
LCZ696
15% at 1 yr (n=4187)
16
HR = 0.80 (0.73-0.87)
8 P = 0.0000004
Number needed to treat = 21
0
0 180 360 540 720 900 1080 1260
Patients at Risk Days After Randomization
LCZ696 4187 3922 3663 3018 2257 1544 896 249
Enalapril 4212 3883 3579 2922 2123 1488 853 236
McMurray et al. NEJM 2014
Other Key Endpoints
↓16%
↓20%
↓21%
McMurray, NEJM 2014; Desai et al. European Heart Journal 2015

Doubling of Survival over
ACE/ARB
Angiotensin
receptor ACE LCZ 696
blocker inhibitor
0%
% Decrease in Mortality
15%
10%
20%
Neprilysin inhibition 16%
30%
40% Estimated 1-2 year increase in life expectancy with LCZ696 over enalapril
McMurray et al. EHJ 2015; Claggett, et al NEJM 2015

Consistent Benefits Across a
Spectrum of HF Severity
CV death or HF hospitalisation
Enalapril LCZ696
RATE PER100 PATIENT YEARS
25
20
15
10
5
0
1 2 3 4 5
QUINTILE OF MAGGIC RISK SCORE
Increasing risk of CV death/HF hospitalization
Simpson J, et al. JACC 2015
Heart Failure Progression
Time to First HF Hospitalization Cumulative HF Hospitalizations
(first 30 days)
Fewer LCZ696-treated patients experienced worsening HF symptoms or required intensification of

medical treatment, emergency department evaluation, intensive care, or inotropic support for HF
Packer M, et al. Circulation 2015

Impact on Readmissions
PARADIGM-HF: Safety
LCZ696 Enalapril P
(n=4187) (n=4212) Value
Prospectively identified adverse events
Symptomatic hypotension 588 (14%) 388 (9.2%) < 0.001
Serum potassium > 6.0 mmol/l 181 (4.3%) 236 (5.6%) 0.007
Serum creatinine ≥ 2.5 mg/dl 139 (3.3%) 188 (4.5%) 0.007
Cough 474 (11.3%) 601 (14.3%) < 0.001
Discontinuation for adverse event 449 516 0.02
Discontinuation for hypotension 36 29 NS
Discontinuation for hyperkalemia 11 15 NS
Discontinuation for renal impairment 29 59 0.001
Angioedema (adjudicated)
Medications, no hospitalization 16 (0.3%) 9 (0.2%) NS
Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) NS
Airway compromise 0 0 ----
Guideline Update
COR LOE Recommendations

I B-R ACEi OR ARB OR ARNI in conjunction with beta-blockers + MRA
(where appropriate) is recommended for patients with chronic HFrEF
to reduce morbidity and mortality.
I B-R In patients with chronic, symptomatic HFrEF NYHA class II or III who
tolerate and ACE inhibitor or ARB, replacement by an ARNI is
recommended to further reduce morbidity and mortality
III B-R ARNI should NOT be administered concomitantly with ACEi or within
36 hours of last ACEi dose
III C=EO ARNI should NOT be administered to patients with a history of
angioedema
Yancy, et al. Circulation 2016

A New Paradigm?
Optimize ‘standard regimen’ first?
Timing of introduction of spironolactone?
Different approach in African Americans?
Jhund P, McMurray J. Heart 2016

How to Initiate?
• Initiation
– 36 hour gap between discontinuation of ACE and initiation of
sacubitril/valsartan
• Dosing
Population Initial Dose
Routine 49/51 mg twice daily
Low dose ACE/ARB
ACE/ARB naïve
eGFR<=30 mL/min/m2
24/26 mg twice daily
Moderate Hepatic Impairment (Child-Pugh Class B)
Elderly
• Titration
– Double dose every 2-4 weeks until target dose of 97/103 mg twice daily is
reached
Summary:
Selecting Patients for Sacubitril/Valsartan
• Yes
– NYHA II-III subjects tolerating ACE/ARB
• Maybe
– Subjects on low dose ACE/ARB
– ACE/ARB naïve subjects
• No Data
– Stage D HF
– Hospitalized HF patients
– HF with Preserved EF
Thank You!
www.brighamandwomens.org/heart

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Sacubitril/Valsartan: Why, Who, When, How?

Akshay S. Desai MD, MPH

• Because angiotensin II is also a substrate for

• The combination of a neprilysin inhibitor and an Inactive

Neprilysin Inhibitor + ARB

Key Inclusion Criteria Key Exclusion Criteria

McMurray et al. NEJM 2014

Desai et al. Circulation 2016

32 (n=4212) 914 (21.8%)

McMurray, NEJM 2014; Desai et al. European Heart Journal 2015

McMurray et al. EHJ 2015; Claggett, et al NEJM 2015

Fewer LCZ696-treated patients experienced worsening HF symptoms or required intensification of

Packer M, et al. Circulation 2015

COR LOE Recommendations

Yancy, et al. Circulation 2016

Timing of introduction of spironolactone?

Different approach in African Americans?

Jhund P, McMurray J. Heart 2016

Routine 49/51 mg twice daily

Low dose ACE/ARB

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