LCZ696: Changing the Current Treatment of
Systolic Heart Failure
Dr. Edgardo Kaplinsky
Cardiology Unit,Medicine Department,
Hospital Municipal de Badalona
Spain
BIT's 8th Annual International Congress of Cardiology-2016
BARCELONA MAY 28-30, 2016

Heart Failure: large patient population
worldwide
5.1
15.0
4.2
1.0
More than 25.000.000 millions of
patients in the world
Diagnosed HF-rEF patients NYHA II-IV,
in millons1-5
World Health Statistics, World Health Organization 1995
1.0
1 Eur Heart J 2008; 29:2388-2442.
2. Circulation. 2013;127:e6–e245.
3. IJC Heart & Vasculature 6 (2015) 25–31
4. 2002) Coronary heart disease statistics: heart failure supplement. London: British Heart Foundation
5. Circ J. 2008;72(3):489-91
5.1 (2013) 8.5 (2030)
2013 update: a report from the American Heart Association
Mortality rates for HF remain
approximately 50% within
5 years of diagnosis
Circulation.2013; 128: e240-e327

HF: a state of neurohumoral “imbalance”
decreased
adaptive
mechanisms
increased
maladaptive
mechanisms
Natriuretic peptides,
adrenomedullin
bradikinin,
substance P

Kaye and Krum Nature Reviews Drug Discovery 2007; 6: 127–139
Mechanisms of progression in heart failure

Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26;
Pandey. J Am Soc Hypertens 2008;2:210–6; Von Lueder et al. Pharmacol Ther 2014 [Epub ahead of print];
Potter. FEBS J 2011;278:1808–17; Lumsden et al. Curr Pharm Des 2010;16:4080–8; Mangiafico et al. Eur
Heart J 2013;34:886–93
Endocrine response to HF: Natriuretic peptides
Stimulated by the increase of cardiac wall stress: (volume and/or pressure overload)
Binding to receptor: causes conversion of GTP to cGMP (raises intracellular cGMP)
Metabolized by Neprilysin
 Origin: atrial cells
 Measurable (plasma)
 Origin: atrial /ventricular cells
 Measurable (plasma)
 Origin endothelial cells
 Non-measurable (plasma)
Local action -clearance of NP
Bone growth regulation
ANP – BNP

Metabolism of NPs and other vasoactive peptides by NEP1–9
1. Erdos, Skidgel. FASEB J 1989;3:145–51; 2. Levin et al. N Engl J Med 1998;339;321–8; 3. Stephenson et al. Biochem J 1987;243:183–7; 4. Lang et al. Clin Sci 1992;82:619–23; 5. Kenny et al. Biochem J
1993;291:83–8; 6. Skidgel et al. Peptides 1984;5:769–76; 7. Abassi et al. Metabolism 1992;41:683–5; 8. Murphy et al. Br J Pharmacol 1994;113:137–42; 9. Jiang et al. Hypertens Res 2004;27:109–17; 10.
Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9; 11. Richards et al. J Hypertens 1993;11:407–16; 12. Ferro et al. Circulation 1998;97:2323–30
NPs
Endothelin
Substance P
Bradykinin
Ang II
Adrenomedullin
Inactive
metabolites
NEP inhibition clinical
implications:
 NEP substrates may have
biological opposing actions10
 The total effect of the inhibition
depends on the net effect of the
individual metabolized
substrates 10
 The benefits of increasing the NPs
system may be lost by increasing
Ang II11
 A simultaneous suppression of
the RAAS is necessary 2,11,12
Calcitonin gene-related
peptide
Neprilysin has many substrates that are
metabolized with different levels of affinity
NEP
 NEP: Zinc-dependent metalloproteinase
which is found on a large variety of normal
tissues (abundant in kidneys)
1MME membrane metallo-endopeptidase [ Homo sapiens (human) ]
http://www.ncbi.nlm.nih.gov/gene/4311

7
Candoxatril
Neprilysin therapeutic targeting:
inhibition alone
First neprilysin inhibitor available orally : dose-dependent
increase in ANP and natriuresis
Concomitant Increase of angiotensin II concentrations
No reduction of BP in patients with hypertension and systemic
vascular or pulmonary resistance in patients with HF
Vardeny et al. J Am Coll Cardiol HF 2014;2:663–70
Neprilysin
Inhibition alone
Angiotensin II Endogenous peptides
No benefit

8
Neprilysin therapeutic targeting:
dual inhibition ACE-neprilysin
Trials:
IMPRESS
OVERTURE
OCTAVE
Omapatrilat First dual acting drug: neprilysin and ACE inhibition. More potent
than candoxatril (lowering BP and improving hemodynamics in HF)
No substantial clinical benefit versus enalapril
Excess risk of serious
angioedema
(increased concentration
of bradykinin )
Failure to inhibit
neprilysin for 24 Hs
Simultaneous
enzyme (proteases)
inhibition
Modest (10%) reduction
in risk of CV events

9
Next step: neprilysin inhibition + angiotensin
receptor blockade
Angiotensin II

10
LCZ696: first ARNI (angiotensin receptor
neprilysin inhibitor)
 LCZ696 is a saline-crystalline complex
created by fusion that contains 2 active
parts :,1-3
– Sacubitril (AHU377) – prodrug
metabolized to metabolite LBQ657
which is an active neprilysin inhibitor
– Valsartan : blocks the angiotensin II type-
1 (AT1) receptor
– Both parts are in their anionic forms,
sodium cations and water molecules:
Ratio 1:1 molar
– Offers a higher bioavailability of
valsartan than valsartan given alone (
100 mg =160 mg)1. Bloch, Basile. J Clin Hypertens 2010;12:809–12; 2. Gu et al. J Clin Pharmacol
2010;50:401–14; 3. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
LCZ696 structure

11
LCZ696: simultaneously NEP inhibition (via
LBQ657) and AT1 receptor blockade (via valsartan)
1. Bloch, Basile. J Clin Hypertens 2010;12:809–12; 2. Gu et al. J Clin Pharmacol
2010;50:401–14; 3. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
Vasodilatation
 Blood pressure
 Sympathetic tone
 Aldosterone levels
 Fibrosis
 Hypertrophy
 Natriuresis/diuresis
Inactive fragments
ANP, BNP, CNP, others
vasoactive peptides*
AT1 receptor
Vasoconstriction
 Blood pressure
 Sympathetic tone
 Aldosterone
 Fibrosis
 Hypertrophy
Angiotensinogen
(liver secretion )
Ang I
Ang II
RAAS
LCZ696
SACUBITRIL
(AHU377; prodrug)
Inhibiting
Stimulating
LBQ657
(iNEP inhibitor)
OH
O
HN
O
HO
O
VALSARTAN
N
NHN
N
N
O
OH
O
*Sustratos de neprilisina listados en orden de relativa afinidad por NEP: ANP, CNP, Ang II, Ang I, adrenomedullna, sustancia P, bradiquinina, endotelina-1, BNP
Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42;
Schrier & Abraham N Engl J Med 1999;341:577–85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9;
Feng et al. Tetrahedron Letters 2012;53:275–6

12
• International, multi-center, double-blind, placebo-controlled RCT
• Primary: composite of CV death and/or hospitalization for HF
– LCZ696 200 mg BID
Randomization 1:1
– Enalapril 10 mg BID
PARADIGM-HF
1. to replace ACEi and ARBs (cornerstone of HF treatment)..comparison “head to head”
2. to show an incremental effect on CV death since sample size of the trial was
determined by effect on cardiovascular mortality (not the primary endpoint)
Specifically designed:

13
PARADIGM-HF: pre-specified endpoints
All-cause mortality
Change from baseline in the clinical summary score of the Kansas
City Cardiomyopathy Questionnaire at 8 months
Time to new onset of atrial fibrillation
Time to first occurrence of a protocol-defined decline in renal function
o Secondary:
o primary:
Cardiovascular death
Heart failure hospitalization

14
Inclusion:
• age ≥ 18 y. NYHA class II-IV. HF. LVEF ≤40 % (≤35% amend)
•BNP ≥150 /NT-proBNP ≥600 (pg/mL) or BNP ≥100 / NT-proBNP ≥400 (pg/mL) hosp within 12 mo.
•Guideline-recommended use of beta-blockers and MRA antagonists
•Background ACEi or ARB equivalent to enalapril 10 mg (4 weeks)
•SBP ≥ 100 mm Hg (run-in) / ≥ 95 mmHg (randomization)
•eGFR ≥ 30 ml/min/1.73 m2 / no decrease >25%. (amend to 35%) and K < 5.2 mmol/l
PARADIGM-HF: Prospective comparison of ARNI with ACEi
to Determine Impact on Global Mortality and morbidity in HF
36 hs washing
period
36 hs washing
period

15
PARADIGM-HF: patient disposition
10,521 patients screened at
1043 centers in 47 countries
Did not fulfill criteria
for randomization
(n=2079)
Randomized erroneously
or at sites closed due to
GCP violations (n=43)
8399 patients randomized for ITT analysis
LCZ696 200 mg
BID
(n=4187)
At last visit
375 mg daily
11 lost to follow-up
Enalapril 10 mg
BID
(n=4212)
At last visit
18.9 mg daily
9 lost to follow-up
median 27 months
of follow-up

16
LCZ696
(n=4187)
Enalapril
(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: baseline characteristics

17
PARADIGM-HF: early termination

18
McMurray NEJM 2014
PARADIGM-HF: CV death or HF hospitalization
(Primary Endpoint)
HR = 0.80 (0.73-0.87)
P = 0.0000004
Number needed to treat = 21
(21.8%)
(26.5%)

19
McMurray NEJM 2014
PARADIGM-HF: CV death or HF hospitalization
(Primary Endpoint)
HR = 0.80 (0.71-0.89)
P = 0.00008
Number need to treat = 32
(LCZ696 13.3% vs. Enalapril 16,5 %) (LCZ696 12,8% vs. Enalapril 15,6 %)

20
McMurray NEJM 2014
PARADIGM-HF: death for any cause
(secondary endpoint)
HR = 0.84 (0.76-0.93)
P=0.0009
Patients at Risk
LCZ696
Enalapril
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
1005
994
280
279

21
PARADIGM-HF: secondary endpoints
LCZ696
(n=4187)
Enalapril
(n=4212)
Treatment
effect
P
Value
KCCQ clinical
summary score
at 8 months
– 2.99
± 0.36
– 4.63
± 0.36
Hazard ratio
1.64
(0.63,2-65)
0.001
New onset
atrial fibrillation
84/2670
(3.2%)
83/2638
(3.2%)
Hazard ratio
0.97
(0.72,1.31)
0.84
Protocol-defined
decline in renal
function
94/4187
(2.3%)
108/4212
(2.6%)
Hazard ratio
0.86
(0.65, 1.13)
0.28

22
PARADIGM-HF: safety endpoints
LCZ696
(n=4187)
Enalapril
(n=4212)
P
Value
Prospectively identified adverse events
Symptomatic hypotension 588 388 < 0.001
Serum potassium > 6.0 mmol/l 181 236 0.007
Serum creatinine ≥ 2.5 mg/dl 139 188 0.007
Cough 474 601 < 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 9 NS
Hospitalized; no airway compromise 3 1 NS
Airway compromise 0 0 ----

23
In heart failure with reduced ejection fraction, when
compared with recommended doses of enalapril:
LCZ696 was more effective than enalapril in . . .
• Reducing the risk of CV death and HF hospitalization
• Reducing the risk of CV death by incremental 20%
• Reducing the risk of HF hospitalization by incremental 21%
• Reducing all-cause mortality by incremental 16%
• Incrementally improving symptoms and physical limitations
LCZ696 was better tolerated than enalapril . . .
• Less likely to cause cough, hyperkalemia or renal impairment
• Less likely to be discontinued due to an adverse event
• More hypotension, but no increase in discontinuations
• Not more likely to cause serious angioedema
PARADIGM-HF: Summary of Findings

24
Post Hoc analysis
European Journal of Heart Failure 2015, 17 (Suppl. 1), 5–441 P 1794

25
LVEF: powerful independent predictor of CV outcomes
and mortality in PARADIGM-HF
PARADIGM-HF
(mean LVEF 29,5 ± 6,2 %)
< 17,5% (n:339) ≥27,5% to < 32,5%. (n:2486)
≥17,5% to < 22,5% (n: 930) ≥32,5%. (n: 3143)
≥22,5% to < 27,5% (n:1500))
)
Each 5-point reduction in LVEF was associated with:
9% increased risk of CV death HF hospitalization (HR, 1.09; 95% CI, 1.05–1.13;P<0.001)
9% increased risk for CV death (HR, 1.09; 95% CI, 1.04–1.14).
9% increased risk in HF hospitalization (HR, 1.09;95% CI 1.04–1.14)
7% increased risk in all-cause mortality (HR 1.07; 95% CI 1.03–1.12)
Solomon S. Circ Heart Fail. 2016;9:e002744. DOI: 10.1161/CIRCHEARTFAILURE.115.002744

26
LCZ696: effective across the LVEF spectrum non
modificated by any endpoint
Younger / male / NYHA III/IV Less history of hypertension, MI, or AF
Lower systolic BP > creatinine
More presence of ICD or CRT, More treated with diuretics, digoxin, and a MRA
Lower EF patients
Solomon S. Circ Heart Fail. 2016;9:e002744. DOI: 10.1161/CIRCHEARTFAILURE.115.002744

• Increases with age…..from 13,4 to 14.8 across the age categories
• Less pronounced in PARADIGM-HF than in prior trials (CHARM, SHIFT, DIG)
• Most marked for death from any cause and non-CV death (greatest difference)
than for strictly CV death.
Rate of death and heart failure hospitalization (per 100 patients-year) “gradient”
These findings suggest that “effective disease-modifying
drugs” may have attenuated the age-related gradient in CV
events (Vs. historical studies)
Effect of age in PARADIGM -HF
• Hypotension, renal impairment and hyperkalemia increased in both groups with age
• Differences between treatments were consistent across age categories
• More hypotension but less renal impairment and hyperkalemia with LCZ696
Safety outcomes
Jhund PS.Eur Heart L 36(38):2576-84.
PARADIGM- HF
aged 18-96 (median: 63,4)
6128 (72,9%) <74
1563 (18.6%) 75-79
587 (7.0%) 80-84
121 (1.44%) ≥85
Older
Patients
Western Europe / North America
Female & white in NYHA III-IV
Higher systolic BP & LVEF
Higher creatinine & NPs values

LCZ696: across the spectrum of age
P-value for interaction 0.94
P-value for interaction 0.81
P-value for interaction 0.92
P-value for interaction 0.99
Overall HR
0.80 (0.73, 0.87), P , 0.001
LCZ696 was more beneficial than enalapril across the broad spectrum of age studied in
PARADIGM-HF with a favourable benefit-risk profile in all age groups
7.7
JhundPS.EurHeartL36(38):2576-84.
6.4 6.4
5.1
7.5
5.5
9.2
7.7
9.0
7.2
7.5
6.5
9.0
7.3
12.0
10.5
P=0.84
P=0.79
P=0.74
P=0.84 P=0.80
P=0.87
P=0.87
P=0.81

PARADIGM-HF: mode of death
Desai AS, Eur Heart J 2015 ;36(30):1990-7
17.0%
Of total
19.8%
Of total
13.3%
Of total
16,5%
Of total
n:1546 n:1251 (80,9%) n:561 (44,8%) n:331 (26,5%)
Non-CV death
n:295 (19,1%)
Other -CV death
n:359 (28,6%)
NS
between both
arms
Died vs. alive
(end of trial)
Older, male, Poorer NYHA class
Lower body mass index
Higher HR, creatinine & NPs levels
Other comorbidities (DM, AF, etc)
Died from
HF vs. SD
Lower EF
Higher NPs levels
More AF
6.0%
Of total
7.4%
Of total
3.5%
Of total
4.4%
Of total
37.2% vs. 35.2%
Of death
22.0 % vs. 20.7%
Of death

PARADIGM-HF: causes of CV death
SD vs. Pump failure %: 39,4 vs 20,7 (LCZ696) – 40,0 vs. 22% (Enalapril)

LCZ696: more effective preventing clinical progression of
HF in survivors than enalapril
Intensification of outpatient
therapy
604
(14.3)
520
(12.4)
0.84 (0.74–0.94) /
0.003
Worsening NYHA (≥1 class) 12 mo. 271 (7.4) 225 (6.1) 0.023
ED visit for HF 150 (3.6) 102 (2.4) 0.66 (0.52–0.85) /
0.001
Patients hospitalized for HF 658
(15.6)
537
(12.8)
0.79 (0.71–0.89) /
<0.001
Patients receiving IV positive
inotropic drugs
229 (5.4) 161 (3.9) 0.69 (0.57–0.85)/
<0.001
Patients requiring CRT, VAD or
Cardiac Tx
119 (2.8) 94 (2.3) 0.78 (0.60–1.02) /
0.07
•Reduction in HF hospitalization (evident within the first 30 days after randomization).
•30% lower rate of all (including repeat) visits to ED than the enalapril group (P=0.017).
Enalapril
N:4212
LCZ696
N:4187
Hazard/Rate Ratio (95% CI)
P Value
Packer M. Circulation 2015;131(1):54-61

LCZ696: early effect on biomarkers
Packer M. Circulation 2015;131(1):54-61
Levels of urinary cyclic GMP and plasma
BNP were higher during treatment with
LCZ696 than with enalapril
Patients receiving LCZ696 had consistently
lower levels of NTproBNP (reflecting
reduced cardiac wall stress) and troponin
(reflecting reduced cardiac injury)

33
LCZ696: consistent across all spectrum of SBP
Run-in period: After randomization
Enalapril: 146 of 10513 (1.4%) - 29 of 4212 (0.7%)
LCZ696 : 164 of 9419 (1.74%) - 36 of 4187 (0.9%)
Discontinued
for hypotension
PARADIGM-HF: mean SBP 122 ±15 mmHg
EuropeanJournalofHeartFailure2015,17(Suppl.1),5–441P1794
P interaction p=0.58.

34
LCZ696: lower incidence of renal dysfunction
despite a greater fall in BP
LCZ696 reduced the risk
of CVD/HFH similarly in
patients
with and without
baseline CKD
Damman K, et al. http://eurheartj.oxfordjournals.org
Overall GFR decreased all the study
(48 months).7.7 mL/min/1.73m2 .
PARADIGM-HF
•Baseline GFR: 67.7 mL/min/1.73m2
•36% of patients <60 mL/min/1.73m2 …
Chronic kidney disease (CKD) GFR changed (mL/min/1.73m2):
−0.14 (enalapril)
−0.11 (LCZ696) per month (P=0.01).
Enalapril no CKD
Enalapril CKD
LCZ696 no CKD
LCZ696CKD
HR
0.790 (0.691, 0.902) vs 0.799 (0.711, 0.897),
respectively, P interaction =0.90

35
Post Hoc analysis
European Journal of Heart Failure 2015, 17 (Suppl. 1), 5–441 P 1794
8274 patients
DM or HbA1c
no DM 5367 (65%)
DM 2907 (35%)
2160 (40%)-26% of total
no DM HbA1c <6
2103 (39%)-25% of total
HbA1c 6-<6,4 “pre-DM
1106 (21%)-13% of total
HbA1c >6,5“undiagnosed DM”
4013 (49%) DM
History + HbA1c
Older, often white
Longer HF duration
More obesity
Higher NYHA, BNP
Lower GFR
More edema (diuretics)
Lowest prevalence: LA
……so dysglycemia could be
a harmful marker in HF
1. DM is a risk marker for HF development. Prognosis is worse, once HF develops
2. HF seems to be a state of insulin resistance,(underlying mechanisms not clear)
3. Prevalence and consequences of pre–diabetic dysglycemia in HF are not well studied

SørenL.Kristensenetal.CircHeartFail.2016;9:e002560
no DM: HbA1c <6 pre-DM: HbA1c 6-<6,4
undiagnosed DM HbA1c >6,5 DM
LCZ696: beneficial compared with enalapril, irrespective
of glycemic status
CV death or HF hospitalization p interaction=0.13 CV death p interaction=0.09
HF hospitalization p interaction=0.78 All cause mortality p interaction= 0.06
Kaplan–Meier curves

•Reducing sudden cardiac deaths and deaths from worsening HF
•Preventing clinical progression of surviving patients with HF
•Reducing CV death and HF hospitalizations across
•spectrum of LVEF
•spectrum of age
•spectrum of SBP
•glycemic status
•Attenuating renal dysfunction
PARADIGM-HF: post hoc analysis findings
In heart failure with reduced ejection fraction, when
compared with recommended doses of enalapril:
LCZ696 was more effective than enalapril in . . .

38
European Journal of Heart Failure 2015, 17 (Suppl. 1), 5–441 P 1794
Sacubitril-Valsartan: place in therapy

NYHA II-IV …LVEF ≤ 40 % (≤ 35%)
BNP ≥ 150 or NT-proBNP ≥600 pg/ ml)
BNP ≥ 100 or NT-proBNP ≥400 pg/ml)
+ HFH (previous 12 mo.)
Sacubitril-Valsartan: place in therapy
PARADIGM –HF
(McMurray JJ. N Engl J Med 2014;371:993)
Neprilysin inhibitor and angiotensin II receptor blocker combination to reduce the risk of CV
death and hospitalization for HF in patients with chronic heart failure (NYHA Class II-IV) and
reduced ejection fraction
FDA: JULY-7-2015
The Committee for Medicinal Products for Human Use (CHMP) considers by majority that
the risk-benefit balance of Entresto indicated in adult patients for treatment of symptomatic
chronic HF with reduced ejection fraction is favourable
EMEA: Nov-24-2015
www.fda.gov/NewsEvents/Newsroom/PressAnnouncement /ucm453845.html. Published July 7, 2015. Accessed July 7,2015
www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/004062/WC500197538.pdf

Sacubitril-Valsartan: place in therapy
MAY-11-2016
https://content.onlinejacc.org/article.aspx?articleid=2524644

Sacubitril-Valsartan: place in therapy
MAY-20-2016
http://dx.doi.org/10.1093/eurheartj/ehw128
Starting dose Target dose

Sacubitril-Valsartan: place in therapy
http://dx.doi.org/10.1093/eurheartj/ehw128

43
European Journal of Heart Failure 2015, 17 (Suppl. 1), 5–441 P 1794
Sacubitril-Valsartan: future

44
44
LZC696: global studies phase III/IV
TITRATION: Safety and tolerability of initiating LCZ696 in heart failure patients
(NCT01922089)
TRANSITION: Comparison of pre- and post-discharge initiation of LCZ696 therapy in
HFreF patients after an acute decompensation event (NCT02661217)
PEDIATRICS: Single dose study to evaluate safety, tolerability and pharmacokinetics
of LCZ696 followed by a 52-week study of LCZ696 compared with enalapril in
pediatric patients with heart failure (NCT02678312).
PARADIGM-OPEN LABEL: Safety and Tolerability During Open-label Treatment With
LCZ696 in Patients With CHF and Reduced Ejection Fraction (NCT02226120)
PRESERVED: LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure
and Preserved Left-ventricular Ejection Fraction (NCT00887588)
PARAGON-HF: Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity
and Mortality in Heart Failure Patients With Preserved Ejection Fraction
(NCT01920711)

45
45
LZC696: global studies phase III/IV
PET-Study: To evaluate the effects of Entresto compared to valsartan on cognitive
function as assessed by comprehensive neurocognitive battery and brain amyloid
plaque deposition as assessed by PET imaging in patients with chronic heart failure
with preserved ejection fraction.(Risk-management-plan_summary/human/004062/WC500194315.pdf
PARASAIL: Tolerability of LCZ696 (Sacubitril / Valsartan) in heart failure with reduced
ejection fraction treated in real life setting (NCT02690974)
JAPAN HF: Efficacy and Safety of LCZ696 in japanese patients with chronic heart
failure and reduced ejection fraction (NCT02468232)
PIONEER-HF: Sacubitril/valsartan versus enalapril on effect on NT-PROBNP in
patients stabilized from an acute heart failure episode (NCT02554890)
PARABLE: Asymptomatic patients with elevated natriuretic peptide and elevated
left atrial volume index (NCT026827)
PRIME: Pharmacological reduction of functional ischemic mitral regurgitation
(NCT02687932)

PARADIGM-HF: what does it signify for
one single patient ??

47
European Journal of Heart Failure 2015, 17 (Suppl. 1), 5–441 P 1794
Sacubitril-Valsartan: present & future
….take me to the magic of the
moment on a glory night (glory night)
where the children of tomorrow
dream away (dream away)
in the wind of change .
Wind Of Change, Scorpions..1990