sacubitril valsartan ek

LCZ696: Changing the Current Treatment of Systolic Heart Failure

Dr. Edgardo KaplinskyCardiology Unit,Medicine Department,

Hospital Municipal de BadalonaSpain

BIT's 8th Annual International Congress of Cardiology-2016BARCELONA MAY 28-30, 2016

http://www.bitcongress.com/icc2016/europe/

http://www.bitcongress.com/icc2016/europe/

Heart Failure: large patient population worldwide

5.1

15.0

4.21.0

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) 25–314. 2002) Coronary heart disease statistics: heart failure supplement. London: British Heart Foundation5. 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 diagnosisCirculation.2013; 128: e240-e327

HF: a state of neurohumoral “imbalance”

decreased adaptive

mechanismsincreased

maladaptivemechanisms

SNS + RAAS stimulation

Endogenous vasoactive peptides

Vasoconstriction (afterload) Water & sodium retention

Cardiac hypertrophy & fibrosis>HR and contractility

Vasodilation (< vascular tone)

< Neurohormonal activation

>Natriuresis / diuresis< Cardiac fibrosis & hypertrophy

Natriuretic peptides, adrenomedullinbradikinin, 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

Inactivemetabolites

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:IMPRESSOVERTUREOCTAVE

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

Neprilysin

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

OHN

O

HO

O

VALSARTAN

N

NHNN

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 BIDRandomization 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 disposition10,521 patients screened at1043 centers in 47 countries

Did not fulfill criteriafor 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 visit375 mg daily

11 lost to follow-up

Enalapril 10 mg BID

(n=4212)

At last visit18.9 mg daily

9 lost to follow-up

median 27 monthsof follow-up

16

LCZ696(n=4187)

Enalapril(n=4212)

Age (years) 63.8 ± 11.5 63.8 ± 11.3Women (%) 21.0% 22.6%Ischemic cardiomyopathy (%) 59.9% 60.1%LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9%Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15Heart rate (beats/min) 72 ± 12 73 ± 12N-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

18McMurray 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%)


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 %)


PARADIGM-HF: death for any cause (secondary endpoint)

HR = 0.84 (0.76-0.93)P=0.0009

Patients at Risk

LCZ696Enalapril

41874212

40564051

38913860

32823231

24782410

17161726

1005994

280279

21

PARADIGM-HF: secondary endpoints

LCZ696(n=4187)

Enalapril(n=4212)

Treatmenteffect

PValue

KCCQ clinical summary score

at 8 months– 2.99± 0.36

– 4.63± 0.36

Hazard ratio1.64

(0.63,2-65)0.001

New onsetatrial fibrillation

84/2670(3.2%)

83/2638(3.2%)

Hazard ratio0.97

(0.72,1.31)0.84

Protocol-defined decline in renal

function94/4187(2.3%)

108/4212(2.6%)

Hazard ratio0.86

(0.65, 1.13)0.28

22

PARADIGM-HF: safety endpoints

LCZ696(n=4187)

Enalapril(n=4212)

PValue

Prospectively identified adverse eventsSymptomatic hypotension 588 388 < 0.001Serum potassium > 6.0 mmol/l 181 236 0.007Serum creatinine ≥ 2.5 mg/dl 139 188 0.007Cough 474 601 < 0.001

Discontinuation for adverse event 449 516 0.02Discontinuation for hypotension 36 29 NSDiscontinuation for hyperkalemia 11 15 NSDiscontinuation for renal impairment 29 59 0.001

Angioedema (adjudicated)Medications, no hospitalization 16 9 NSHospitalized; no airway compromise 3 1 NSAirway 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 limitationsLCZ696 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 AFLower systolic BP > creatinineMore 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 AmericaFemale & white in NYHA III-IVHigher systolic BP & LVEFHigher creatinine & NPs values

LCZ696: across the spectrum of age

P-value for interaction 0.94




Overall HR 0.80 (0.73, 0.87), P , 0.001

LCZ696 was more beneficial than enalapril across the broad spectrum of age studied inPARADIGM-HF with a favourable benefit-risk profile in all age groups

7.7

Jhun

d PS

.Eur

Hea

rt L

36(

38):2

576-

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%)

NSbetween both

arms

Died vs. alive (end of trial)

Older, male, Poorer NYHA classLower body mass indexHigher HR, creatinine & NPs levelsOther comorbidities (DM, AF, etc)

Died from HF vs. SD

Lower EFHigher NPs levelsMore AF

6.0%Of total

7.4%Of total 3.5%

Of total4.4%

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).

EnalaprilN:4212

LCZ696N: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 randomizationEnalapril: 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

Euro

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Jour

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015,

17

(Sup

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), 5–

441

P 17

94

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


8274 patientsDM or HbA1c

no DM 5367 (65%)

DM 2907 (35%)

2160 (40%)-26% of totalno DM HbA1c <6

2103 (39%)-25% of total HbA1c 6-<6,4 “pre-DM

1106 (21%)-13% of total HbA1c >6,5“undiagnosed DM”

INTERN

ATION

ALDIABETES EXPERT COM

MITTEE CRITERIA 4013 (49%) DM

History + HbA1c

Older, often whiteLonger HF duration

More obesityHigher NYHA, BNP

Lower GFRMore 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 develops2. 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

Søre

n L.

Kris

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2016

;9:e

0025

60

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=0.09HF 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


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 therapyPARADIGM –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


MAY-11-2016

https://content.onlinejacc.org/article.aspx?articleid=2524644

https://content.onlinejacc.org/article.aspx?articleid=2524644


MAY-20-2016

http://dx.doi.org/10.1093/eurheartj/ehw128

Starting dose Target dose



http

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/10.

1093

/eur

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8


43


Sacubitril-Valsartan: future

4444

LZC696: global studies phase III/IVTITRATION: 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)

4545

LZC696: global studies phase III/IVPET-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)

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Risk-management-plan_summary/human/004062/WC500194315.pdf



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

47


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

sacubitril valsartan ek

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