Post on 12-Jan-2017
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
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%)
19McMurray 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 %)
20McMurray NEJM 2014
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
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 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
pean
Jour
nal o
f Hea
rt F
ailu
re 2
015,
17
(Sup
pl. 1
), 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
European Journal of Heart Failure 2015, 17 (Suppl. 1), 5–441 P 1794
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
tens
en e
t al.
Circ
Hea
rt F
ail.
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
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 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
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
://d
x.do
i.org
/10.
1093
/eur
hear
tj/eh
w12
8
43
European Journal of Heart Failure 2015, 17 (Suppl. 1), 5–441 P 1794
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)
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