Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.
Konstam MA(1), Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K,
Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of
Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST)
(1)Division of Cardiology, Tufts-New England Medical Center, Boston, Mass, USA.
Curr Cardiol Rep. 2008 May;10(3):166-7.
JAMA. 2007 Mar 28;297(12):1374-6.
Curr Heart Fail Rep. 2009 Mar;6(1):3-4.
CONTEXT: Vasopressin mediates fluid retention in heart failure. Tolvaptan, a
vasopressin V2 receptor blocker, shows promise for management of heart failure.
OBJECTIVE: To investigate the effects of tolvaptan initiated in patients
hospitalized with heart failure.
DESIGN, SETTING, AND PARTICIPANTS: The Efficacy of Vasopressin Antagonism in
Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven,
randomized, double-blind, placebo-controlled study. The outcome trial comprised
4133 patients within 2 short-term clinical status studies, who were hospitalized
with heart failure, randomized at 359 North American, South American, and
European sites between October 7, 2003, and February 3, 2006, and followed up
during long-term treatment.
INTERVENTION: Within 48 hours of admission, patients were randomly assigned to
receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for
a minimum of 60 days, in addition to standard therapy.
MAIN OUTCOME MEASURES: Dual primary end points were all-cause mortality
(superiority and noninferiority) and cardiovascular death or hospitalization for
heart failure (superiority only). Secondary end points included changes in
dyspnea, body weight, and edema.
RESULTS: During a median follow-up of 9.9 months, 537 patients (25.9%) in the
tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98;
95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for
the mortality difference was within the prespecified noninferiority margin of
1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart
failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group
patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end
points of cardiovascular mortality, cardiovascular death or hospitalization, and
worsening heart failure were also not different. Tolvaptan significantly improved
secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and
day 7 edema. In patients with hyponatremia, serum sodium levels significantly
increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was
not improved at outpatient week 1, but body weight and serum sodium effects
persisted long after discharge. Tolvaptan caused increased thirst and dry mouth,
but frequencies of major adverse events were similar in the 2 groups.
CONCLUSION: Tolvaptan initiated for acute treatment of patients hospitalized with
heart failure had no effect on long-term mortality or heart failure-related
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00071331
PMID: 17384437 [PubMed - indexed for MEDLINE]
Int J Cardiol. 2002 Nov;86(1):1-4.
Omapatrilat--the story of Overture and Octave.
Int J Cardiol. 2003 Sep;91(1):113.
At the American College of Cardiology in March two major trials were presented.
The publicity surrounding the two could not have been more different. The LIFE
demonstrated clear superiority of losartan-based therapy over atenolol-based
therapy for the treatment of hypertension. It was published the same week in the
Lancet and received major press coverage all over the world. The OVERTURE
(Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events)
study in contrast received a subdued reception, very little publicity and is yet
to be published. 5770 NYHA class II-IV heart failure patients (LVEF
10 mg BD of Enalapril or 40 mg once a day Omapatrilat. The primary end-point of
all cause mortality or heart failure related hospitalisation did not differ
significantly: 914/2884 for Enalapril and 914/2886 for Omapatrilat (hazard ratio
0.94, CI's 0.86-1.03, P=0.187). Mortality was also similar: 509 for Enalapril and
477 for Omapatrilat (hazard ratio 0.94, CI's 0.83-1.07, P=0.339). Omapatrilat was
as good as Enalapril but not better. The worrying trend was however, that
angioedema was more common with Omapatrilat; 24 (0.8%) versus 14 cases (0.5%).
The OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril)
study was also presented at this time. 25,267 hypertensives were randomised to
Omapatrilat or enalapril and a difference of approximately 3 mmHg in favour of
Omapatrilat was seen. Significantly more cases of angioedema were seen with
Omapatrilat, 274 (2.17%) compared to 86 (0.68%) with enalapril. Overall death
rates were similar, 0.18% for enalapril and 0.15% for Omapatrilat. All adverse
events werehttps://www.blogger.com/blogger.g?blogID=8343526887863586538#editor/target=post;postID=1531264929101084479 similar, 51.0% for Omapatrilat and 50.4% for enalapril. The rates of
angioedema were much higher in blacks, 5.54% for Ompatrilat and 1.62% for
enalapril and for smokers, 3.93% for Omapatrilat and 0.81% for enalapril. We were
left with a drug that was, for heart failure, not superior to an ACE inhibitor
already off patent, and, as an anti-hypertensive, with an angioedema rate more
than double that of an ACE inhibitor in a large head to head comparison. The
medical community will be watching to make sure these data are published in full
in the medical literature in a timely fashion, in the order of end-points
specified in the protocol and with appropriate emphasis on the logical points of
PMID: 12243845 [PubMed - indexed for MEDLINE]
N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014Aug 30.
Angiotensin-neprilysin inhibition versus enalapril in heart failure.
McMurray JJ(1), Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL,
Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and
(1)From the British Heart Foundation (BHF) Cardiovascular Research Centre,
University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); the Department of
Clinical Sciences, University of Texas Southwestern Medical Center, Dallas
(M.P.); the Division of Cardiovascular Medicine, Brigham and Women's Hospital,
Boston (A.S.D., S.D.S.); Novartis Pharmaceuticals, East Hanover, NJ (J.G.,
M.P.L., A.R.R., V.C.S.); Institut de Cardiologie de Montréal, Université de
Montréal, Montreal (J.L.R.); the Department of Molecular and Clinical Medicine,
University of Gothenburg, Gothenburg, Sweden (K.S.); National Heart and Lung
Institute, Imperial College London, London (K.S.); and the Medical University of
South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston
Nat Rev Cardiol. 2014 Nov;11(11):618.
Perspect Infirm. 2015 Jan-Feb;12(1):61.
N Engl J Med. 2014 Dec 11;371(24):2336-7.
N Engl J Med. 2014 Dec 11;371(24):2335-6.
N Engl J Med. 2014 Dec 11;371(24):2335.
G Ital Cardiol (Rome). 2014 Dec;15(12):651-5.
N Engl J Med. 2014 Sep 11;371(11):1062-4.
N Engl J Med. 2014 Dec 11;371(24):2336.
BACKGROUND: We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with
enalapril in patients who had heart failure with a reduced ejection fraction. In
previous studies, enalapril improved survival in such patients.
METHODS: In this double-blind trial, we randomly assigned 8442 patients with
class II, III, or IV heart failure and an ejection fraction of 40% or less to
receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose
of 10 mg twice daily), in addition to recommended therapy. The primary outcome
was a composite of death from cardiovascular causes or hospitalization for heart
failure, but the trial was designed to detect a difference in the rates of death
from cardiovascular causes.
RESULTS: The trial was stopped early, according to prespecified rules, after a
median follow-up of 27 months, because the boundary for an overwhelming benefit
with LCZ696 had been crossed. At the time of study closure, the primary outcome
had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients
(26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95%
confidence interval [CI], 0.73 to 0.87; P<0 .001="" 711="" a="" br="" of="" patients="" total="">receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio
for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0 .001="" br="" of="" these="">patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular
causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0 .001="" as="" br="" compared="" with="">enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by
21% (P<0 .001="" and="" br="" decreased="" heart="" limitations="" of="" physical="" symptoms="" the="">failure (P=0.001). The LCZ696 group had higher proportions of patients with
hypotension and nonserious angioedema but lower proportions with renal
impairment, hyperkalemia, and cough than the enalapril group.
CONCLUSIONS: LCZ696 was superior to enalapril in reducing the risks of death and
of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF
ClinicalTrials.gov number, NCT01035255.).
PMID: 25176015 [PubMed - indexed for MEDLINE]
Clin Sci (Lond). 1993 Jul;85(1):19-26.
Renal and hormonal effects of chronic inhibition of neutral endopeptidase (EC 18.104.22.168) in normal man.
O'Connell JE(1), Jardine AG, Davies DL, McQueen J, Connell JM.
(1)MRC Blood Pressure Unit, Western Infirmary, Glasgow, U.K.
1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC
22.214.171.124), which cleaves the cardiac hormone atrial natriuretic peptide, raises
endogenous levels of the hormone. Short-term administration of inhibitors causes
natriuresis and diuresis in normal and hypertensive subjects; we report here the
effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg)
given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a
placebo-controlled cross-over study. 2. Candoxatril administration caused a
transient natriuresis on day 1 of treatment, but this was not sustained, and
cumulative sodium excretion at the end of the study was not altered by active
therapy [1720 +/- 40 versus 1734 +/- 57 (placebo) mmol; means +/- SEM];
exchangeable body sodium content was similarly unchanged. However, urinary cyclic
GMP excretion was elevated throughout the active treatment phase when compared
with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide
could not be demonstrated, platelet atrial natriuretic peptide binding sites were
reduced by active treatment [23 +/- 3 versus 39 +/- 4 (placebo) fmol/10(9); P <
0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril
treatment. After 10 days of therapy subjects were given incremental infusions of
angiotensin II (2, 4 and 8 ng min-1 kg-1) followed by phenylephrine. Although
active therapy had not altered basal plasma concentrations of active renin and
angiotensin II, levels of angiotensin II during infusion of the octapeptide were
higher during the active phase.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 8149689 [PubMed - indexed for MEDLINE]
Nephrol Dial Transplant. 2014 Aug 18. pii: gfu269. [Epub ahead of print]
Neprilysin inhibition in chronic kidney disease.
Judge P(1), Haynes R(1), Landray MJ(1), Baigent C(1).
(1)Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield
Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
Despite current practice, patients with chronic kidney disease (CKD) are at
increased risk of progression to end-stage renal disease and cardiovascular
events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential
to improve outcomes for patients with CKD. NEPi enhances the activity of
natriuretic peptide systems leading to natriuresis, diuresis and inhibition of
the renin-angiotensin system (RAS), which could act as a potentially beneficial
counter-regulatory system in states of RAS activation such as chronic heart
failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting
enzyme inhibitors but were associated with unacceptable rates of angioedema and,
therefore, withdrawn. However, one such agent (omapatrilat) showed promise of
NEP/RAS inhibition in treating CKD in animal models, producing greater reductions
in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with
isolated RAS inhibition. A new class of drug called angiotensin receptor
neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown
substantial benefits in trials in hypertension and HF. In CKD, HF is common due
to a range of mechanisms including hypertension and structural heart disease
(including left ventricular hypertrophy), suggesting that ARNi could benefit
patients with CKD by both retarding the progression of CKD (hence delaying the
need for renal replacement therapy) and reducing the risk of cardiovascular
disease. LCZ696 is now being studied in a CKD population.
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.
PMID: 25140014 [PubMed - as supplied by publisher]
Diabetologia. 2003 Jul;46(7):961-71. Epub 2003 Jun 28.
Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy.
Davis BJ(1), Johnston CI, Burrell LM, Burns WC, Kubota E, Cao Z, Cooper ME, Allen
(1)Diabetic Complications Group, Baker Heart Research Institute, P.O. Box 6492,
Melbourne, 8008 Victoria, Australia.
AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the
mortality and morbidity is still high. As other hormonal factors are involved,
inhibition of vasopeptidases could further reduce progression. We studied dual
inhibition of angiotensin converting enzyme and neutral endopeptidase in a model
of progressive diabetic renal injury. The major endpoints were reductions in
systemic blood pressure, albuminuria and renal structural injury.
METHODS: Diabetic spontaneously hypertensive rats were treated with the ACE
inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor
omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks.
In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal
structural injury was assessed by measurement of the glomerulosclerotic (GS)
index and tubulointerstitial area (TI). The expression of transforming growth
factor beta, beta-inducible gene-h3 and nephrin were also quantitated.
RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10,
greater attenuation of albuminuria was afforded by oma10, with a complete
amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP
binding and this was associated with less albuminuria and prevention of GS, TI
area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction
in nephrin expression was restored by both drugs.
CONCLUSION/INTERPRETATION: These findings suggest that other vasoactive
mechanisms in addition to angiotensin II are important in the prevention of
diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage
over blockade of the RAS alone in the treatment of diabetic renal disease.
PMID: 12838387 [PubMed - indexed for MEDLINE]
Eur J Heart Fail. 2015 Feb 6. doi: 10.1002/ejhf.232. [Epub ahead of print]
Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction.
Voors AA(1), Gori M, Liu LC, Claggett B, Zile MR, Pieske B, McMurray JJ, Packer
M, Shi V, Lefkowitz MP, Solomon SD; for the PARAMOUNT Investigators.
(1)Department of Cardiology, University Medical Centre Groningen, University of
Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
BACKGROUND: Increases in serum creatinine with renin-angiotensin-aldosterone
system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents.
The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves
clinical outcome patients with heart failure with reduced ejection fraction, and
pilot data suggest potential benefit in heart failure with preserved ejection
fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed.
METHODS AND RESULTS: A total of 301 HFpEF patients were randomly assigned to
LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function
[creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary
albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of
treatment. Worsening renal function (WRF) was determined as an serum creatinine
increase of >0.3 mg/dL and/or >25% between two time-points. Mean eGFR at baseline
was 65.4 ± 20.4 mL/min per 1.73 m(2) . The eGFR declined less in the LCZ696 group
than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m(2) ; P = 0.002). The
incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group
(18%) at any time-point, but this difference was not statistically significant (P
= 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group
(2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0
mg/mmol; P for difference between groups = 0.016).
CONCLUSION: In patients with HFpEF, therapy with LCZ696 for 36 weeks was
associated with preservation of eGFR compared with valsartan therapy, but an
increase in UACR.
© 2015 The Authors European Journal of Heart Failure © 2015 European Society of
PMID: 25657064 [PubMed - as supplied by publisher]