Skip Navigation

European Journal of Heart Failure 2008 10(2):201-213; doi:10.1016/j.ejheart.2008.01.002
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (11)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by De Luca, L.
Right arrow Articles by Gheorghiade, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Luca, L.
Right arrow Articles by Gheorghiade, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2008 European Society of Cardiology

Overview of emerging pharmacologic agents for acute heart failure syndromes

Leonardo De Lucaa, Alexandre Mebazaab, Gerasimos Filippatosc,*, John T. Parissisd, Michael Böhme, Adriaan A. Voorsf, Markku Niemineng, Faiez Zannadh, Andrew Rhodesi, Ali El-Banayosyj, Kenneth Dicksteink and Mihai Gheorghiadel

a Department of Cardiovascular Sciences, European Hospital Rome, Italy
b Department of Anesthesiology and Critical Care Medicine, Lariboisiere Hospital University Paris 7 Diderot, France
c Department of Cardiology, Athens University Athens, Greece
d Heart Failure Unit, Attikon University Hospital Athens, Greece
e Division of Cardiology, Medizinische Universitätsklinik Homburg/Saar, Germany
f Department of Cardiology, University Medical Center Groningen, The Netherlands
g Division of Cardiology, University Central Hospital Helsinki, Finland
h Inserm, Clinical Investigation Center, University Henri Poincaré Nancy, France
i Department of Intensive Care, St George Hospital London, UK
j Department of Cardiovascular Surgery, Heart Center NRW, Ruhr University Bochum Bad Oeynhausen, Germany
k Division of Cardiology, University of Bergen, Stavanger University Hospital Stavanger, Norway
l Division of Cardiology, Northwestern University Chicago, IL, USA

* Corresponding author. Department of Cardiology, Heart Failure Unit Athens University Hospital Attikon, Athens, 12461, Greece. Tel.: +30 6944 479926; fax: +30 210 5832195. E-mail address: geros{at}otenet.gr (G. Filippatos).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Conclusion
 References
 
Background: Several therapies commonly used for the treatment of acute heart failure syndromes (AHFS) present some well-known limitations and have been associated with an early increase in the risk of death. There is, therefore, an unmet need for new pharmacologic agents for the early management of AHFS that may improve both short- and long-term outcomes.

Aim: To review the recent evidence on emerging pharmacologic therapies in AHFS.

Methods: A systematic search of peer-reviewed publications was performed on MEDLINE, EMBASE and Clinical Trials.gov from January 1990 to August 2007. The results of unpublished or ongoing trials were obtained from presentations at national and international meetings and pharmaceutical industry releases. Bibliographies from these references were also reviewed, as were additional articles identified by content experts.

Results: Cumulative data from large studies and randomised trials suggest that therapies with innovative mechanisms of action may safely and effectively reduce pulmonary congestion or improve cardiac performance in AHFS patients.

Conclusion: Some investigational agents for the management of AHFS are able to improve haemodynamics and/or clinical status. In spite of these promising findings, no new agent has demonstrated a clear benefit in terms of long-term clinical outcomes compared to placebo or conventional therapies.

Key Words: Acute heart failure • New medical treatment

Received October 4, 2007; Revised November 15, 2007; Accepted January 2, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Conclusion
 References
 
Acute heart failure syndromes (AHFS) represent a heterogeneous group of disease states with different clinical presentations, prognosis, and various management strategies [1]. In contrast to chronic heart failure, guideline recommendations in AHFS largely reflect expert consensus with limited documentation of the effects of pharmacological therapy on clinical outcome.

A practical approach to differentiating AHFS patients, which relies on systolic blood pressure (SBP) levels at the time of presentation [2,3], enables the identification of three groups of patients with different risk for subsequent morbidity and mortality:

  1. Patients presenting with hypertension are more likely to be female and have preserved systolic function. Their in-hospital mortality rate is approximately 2%, with 5% mortality and 30% readmission rates within 60-90 days of discharge.
  2. Patients in the normotensive group tend to have a lower left ventricular ejection fraction (LVEF) and signs and symptoms of pulmonary/systemic congestion (oedema) before and at the time of admission. The in-hospital mortality rate is approximately 3%, with 7% mortality and 30% readmission rates within 60-90 days of discharge.
  3. Patients with low SBP levels (≤120 mm Hg) at the time of presentation (approximately 5-10% of total admissions for AHFS), generally have a low LVEF, and have a history of HF. The mortality rate is approximately 7% during hospitalisation and 14% within 60-90 days of discharge.

These three patient groups not only differ prognostically but also require appropriately tailored pharmacologic treatments (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1 Current and investigational pharmacologic agents for the treatment of AHFS

 
Most patients with AHFS with high or normal SBP at admission present with pulmonary and/or systemic congestion and relatively normal cardiac output, and their early management is mostly directed at correcting high LV filling pressure and/or after load. In contrast, in patients hospitalised with AHFS who present with low SBP, first-line therapies are targeted at low cardiac output in addition to congestion [1].

Some pharmacologic agents commonly used for the treatment of AHFS present some well-known limitations and have been associated with an early increase in the risk of death [4-8]. Consequently, there is an unmet need for new agents tailored to AHFS patients presenting with congestion or low cardiac output that can safely improve haemodynamics, symptoms and possibly long-term survival.

The aim of this paper is therefore to review recent evidence on emerging pharmacological therapies in AHFS and to summarise evidence of clinical benefit.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Conclusion
 References
 
2.1. Search strategy
We performed a systematic search of peer-reviewed publications through MEDLINE, EMBASE and Clinical Trials.gov from January 1990 to August 2007 using the following keywords: acute heart failure, congestion low cardiac output, pharmacologic therapies, vasopressin antagonists, adenosine antagonists, renal natriuretic peptides, endothelin antagonists, istaroxime, metabolic modulators, cardiac myosin activators, nesiritide and levosimendan.

Additionally, a manual search was conducted through previous reviews, meta-analyses, presentations at national and international meetings and pharmaceutical industry releases on new pharmacologic therapies for AHFS. All references were screened for eligible studies. We excluded from the analysis any reference regarding chronic HF, refractory HF and cardiogenic shock.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Conclusion
 References
 
3.1. Investigational agents for AHFS patients presenting with congestion and normal to high SBP
Medical treatments for this group of patients primarily target pulmonary (i.e., increased pulmonary capillary wedge pressure [PCWP]) and/or systemic congestion. Pharmacologic agents that are commonly used as first-line approach in this setting include diuretics and vasodilators (e.g., nitroglycerin, nitroprusside). Although these therapies are effective in reducing fluid overload and acutely relieve symptoms, they have been associated with short-term adverse clinical outcomes, especially when used at high dosages [5-8]. Given these limitations, a variety of new agents are under investigation for the treatment of congestion in the setting of AHFS.

3.1.1. Vasopressin antagonists
Vasopressin levels are inappropriately high in both acute and chronic HF [9,10]. Along with activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, nonosmotic release of vasopressin is thought to represent a maladaptive response that is central to the pathophysiology of HF [11].

Vasopressin appears to play a pivotal role in the development of hyponatraemia, a powerful predictor of poor outcome [12-14]. Accordingly, vasopressin antagonism seems to represent a potentially beneficial approach to both acute and chronic HF.

Two types of vasopressin receptors have been identified: V1 (V1a, V1b) and V2 receptors. V1a receptors are present on the vascular wall and mediate vasoconstriction, whereas stimulation of V2 receptors located in the kidneys promotes water re-absorption [15].

The 2 most extensively investigated vasopressin antagonists are conivaptan (a dual V1a/V2 receptor antagonist) and tolvaptan (an oral, selective antagonist of the V2 receptor).

An experience with a single-dose intravenous administration of conivaptan in patients with advanced systolic HF demonstrated that short-term antagonism of V1a and V2 receptors produced favourable haemodynamic effects and a brisk increase in urine output. Compared with placebo, conivaptan significantly increased urine output in a dose-dependent manner and decreased PCWP and right atrial pressure, without significant changes in heart rate, blood pressure, cardiac index, and systemic and pulmonary vascular resistance [16].

One small-scale study demonstrated a reduction in congestion, decrease in body weight, and correction of hyponatraemia with tolvaptan [17].

The Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial [18] firstly evaluated the short- and intermediate-term effects of tolvaptan in the setting of AHFS. Three-hundred-nineteen patients with LVEF ≤0.40 admitted for worsening HF associated with systemic congestion were randomised to receive 30, 60, or 90 mg/day of oral tolvaptan or placebo, in addition to standard therapy including diuretics, continued for up to 60 days. This study included both acute and chronic end points: change in body weight at 24 h and worsening HF (defined as death, hospitalisation, or unscheduled visits for HF) at 60 days. Tolvaptan therapy decreased body weight without changes in heart rate or blood pressure, serum potassium, or worsening renal function. However, there were no differences in worsening HF at 60 days between the tolvaptan and placebo groups.

The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) [19,20] was an international, multicenter, randomised, double-blind, placebo-controlled study of oral tolvaptan in patients with low LVEF (≤0.40) who were hospitalised with worsening HF (NYHA class III-IV symptoms) and systemic congestion. Patients were randomised to once-daily tolvaptan 30 mg or placebo for a minimum of 60 days. The EVEREST program consisted of the main study and 2 identical embedded studies (study A and study B). The main study, which included 4133 patients, was designed to assess the effect of tolvaptan on clinical outcomes and had 2 co-primary end points: (1) time to all-cause mortality, and (2) time to first occurrence of cardiovascular mortality or HF hospitalisation [19].

During a median follow-up of 9.9 months, there was no difference between tolvaptan and placebo in terms of all-cause mortality or heart failure-related morbidity (Fig. 1). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalisation, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of patient-assessed dyspnoea at day 1, body weight at day 1, and oedema at day 7. In addition, in patients with hyponatraemia, serum sodium levels significantly increased. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups [19].


Figure 01
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Kaplan-Meier analysis of all-cause mortality in the EVEREST trial (modified from [19]).

 
In the embedded studies designed to assess the short-term effect of tolvaptan, the primary end point was the patient-assessed global clinical status (on the seventh inpatient day or discharge, whichever occurred earlier), and the secondary end point was quality of life evaluated at outpatient week 1 [20].

These studies demonstrated that oral tolvaptan in addition to standard therapy including diuretics improved many heart failure signs and symptoms, whereas improvements in global clinical status were not different between groups. Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension [20].

The aggregate findings of the EVEREST program demonstrate that tolvaptan relieves some symptoms associated with AHFS and has no demonstrable evidence of harm such as worsening of renal failure, but importantly, it does not reduce mortality or HF-related morbidity at 1 year.

Recently, a multicenter, randomised, double-blind, placebo-controlled trial evaluating the effect of long-term administration of tolvaptan (30 mg/day) on reducing left ventricular end-diastolic volume in patients with HF and reduced systolic function, has been published [21]. After 1 year of tolvaptan therapy, there was a small and not significant reduction in LV volume, compared to placebo. In addition, although tolvaptan was not associated with serious side effects (generally similar to placebo) and no important change in laboratory parameters, non-prespecified outcome data favoured therapy with this selective V2 receptor antagonist, with a reduction in the combined end point of mortality and HF hospitalisation [21].

In summary, vasopressin antagonists have the potential to promote free water excretion without compromising renal function. However, further studies are needed in order to evaluate the role of these agents in different subsets of AHFS patients, perhaps as characterized by hyponatraemia.

3.1.2. Adenosine antagonists
A1-receptors located in the afferent arteriole and proximal tubule in kidneys contribute to mediation of afferent arteriolar vasoconstriction and tubuloglomerular feedback, modulating glomerular filtration rate, and enhancing sodium re-absorption by the proximal tubule. [22,23] (Fig. 2). Experimental studies suggest that A1-receptor antagonism induces diuresis and natriuresis without exerting adverse effects on cardiac and renal functions, providing a potential therapeutic tool for AHFS [23-27].


Figure 02
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 A1-receptors in the afferent arteriole and proximal tubule in kidneys.

 
A crossover study of 12 patients with clinically stable HF (NYHA class III-IV) compared the effects of furosemide and BG9719 (also called CVT-124), a highly selective A1-receptor antagonist, on renal function [26]. The 2 agents effectively induced natriuresis, although the doses of the 2 drugs used in this study did not cause equivalent excretion of sodium and water. Furosemide caused a 25% decrease in glomerular filtration rate, but BG9719 preserved the baseline glomerular filtration rate. Another clinical study investigated the renal effects of BG9719 alone or in addition to furosemide [27]. A total of 63 patients with HF on standard therapy including ACE inhibitors randomly received placebo or 1 of 3 doses of BG9719 (infused over 7 h to yield target serum concentrations) on one day and the same medication plus furosemide on a separate day. BG9719 alone increased urine output, sodium excretion, and glomerular filtration rate. Addition of BG9719 to furosemide augmented urine output and, notably, restored the glomerular filtration rate to the level seen with the placebo infusion, suggesting a renoprotective effect against a furosemide-induced decline in glomerular filtration rate.

Recently, a randomised, double-blind, placebo-controlled study of another adenosine receptor antagonist (BG9928) was conducted in patients with HF and systolic dysfunction who were receiving standard therapy [28]. A total of 50 patients were randomised to receive different dosages of BG9928, which is an orally active, potent, and selective inhibitor of the A1 adenosine receptor, or placebo for 10 days. BG9928 increased sodium excretion compared with placebo, and natriuresis was maintained over 10 days without causing kaliuresis or reducing renal function. Patients who received 15, 75, or 225 mg of BG9928 had a reduction in body weight compared with placebo at the end of study [28].

SLV320 is another selective and potent adenosine A1 antagonist with a selectivity factor of at least 200 versus other adenosine receptor subtypes. It inhibits phosphodiesterase 4 (PDE4), while it has no effect on the other PDE isoenzymes tested to date. Experimental and phase I studies demonstrated a dose-related increase in mean urinary output and mean sodium excretion for the three SLV320 treatment groups over the 0-6-hour post-dosing period [29].

The pilot phase of the PROTECT (Placebo-Controlled Randomized Study of the selective A1 adenosine receptor antagonist KW-3902 for patients hospitalised with acute HF and volume Overload to assess Treatment Effect on Congestion and renal funcTion) trial ran from July 2006 to February 2007 and involved 304 patients. During this pilot phase, patients were randomised, in a double-blind manner, to treatment with placebo or one of three doses of KW-3902, another selective adenosine A1 antagonist, given as a daily infusion over 4 h for up to 3 days following hospitalisation for AHFS. KW-3902 improved dyspnoea, decreased the likelihood of worsening HF events in hospital and improved renal function [30]. The next phase of the PROTECT study is currently underway and will evaluate the effect of KW-3902IV, in addition to intravenous loop diuretics (such as furosemide) on HF signs and symptoms, renal function, and safety in approximately 1200 patients hospitalised with AHFS. The ongoing REACH UP (Placebo-Controlled Randomized Study of KW-3902 for Subjects Hospitalized With Worsening Renal Function and Heart Failure Requiring IV Therapy) trial is aimed to evaluate the effect of KW-3902IV, in addition to standard therapy, on worsening HF and worsening renal function, and on deaths or rehospitalisations for HF or worsening renal function, and to estimate and compare within-trial medical resource utilization and direct medical costs between subjects treated with KW 3902IV versus placebo.

A1-agonism appears to represent another potential therapeutic avenue in HF treatment, displaying a different mechanism of action than that of A1-antagonism. In an experimental model of cardiac hypertrophy induced by pressure overload, activation of the A1-receptor was shown to attenuate myocardial hypertrophy and myocardial dysfunction [31].

It is important to highlight that adenosine might have beneficial effects on LV hypertrophy attenuation and heart function improvement. Therefore, inhibiting adenosine effect might worsen LV hypertrophy. Studies on renal function should therefore use A1-receptor blockade, and evaluate heart function and heart size.

3.1.3. Ularitide
Urodilatin is a renal natriuretic peptide that belongs to the family of atrial or A-type natriuretic peptides (ANP). It is produced in renal tubular cells, is secreted luminally, and subsequently binds to luminally located receptors downstream in the nephron, leading to an increase in intracellular concentration of cyclic guanosine monophosphate and thereby contributing to regulation of sodium and water excretion [32]. Ularitide is a synthetic analogue of urodilatin.

In studies involving small cohorts of patients with HF, administration of urodilatin produced favourable haemodynamic effects and enhanced diuresis and natriuresis without neurohormonal activation [33,34].

The possible role of ularitide as a short-term infusion for the treatment of AHFS was studied in the Safety and Efficacy of an Intravenous Placebo-Controlled Randomised Infusion of Ularitide in a Prospective Double-Blind Study in Patients with Symptomatic Decompensated Chronic Heart Failure (SIRIUS) I [35] and SIRIUS II [36] trials. In SIRIUS I [35], 24 patients hospitalised with AHFS (NYHA class III-IV), received a continuous 24-hour intravenous infusion of ularitide at 3 doses or placebo. Haemodynamics were invasively measured at 6, 24, and 30 h after the start of the 24-hour study drug infusion. Ularitide infusion appeared to have beneficial symptomatic, haemodynamic (PCWP and cardiac index), and neurohumoral effects. In a subsequent phase II trial (SIRIUS II), 221 patients with HF and dyspnoea at rest or on minimal exertion were randomised to receive a 24-hour infusion of ularitide at 1 of 3 dose levels (7.5, 15, or 30 ng/kg/min) or placebo in addition to standard therapy [36]. The 2 higher doses produced favourable haemodynamic effects that were rapid and sustained for 24 h, reductions in N-terminal-pro-BNP over 24 h, and the greatest improvements in self-assessed dyspnoea. The most frequent adverse event in all of the ularitide groups was a decrease in blood pressure (5%), with the mean systolic blood pressure decreasing by up to 15 mm Hg with the 30 ng dose. Mortality at day 30 trended lower in favour of ularitide: there were 7 deaths in the placebo group, 1 in the highest-dose ularitide group, and 2 deaths in each of the other groups [36] (Fig. 3).


Figure 03
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Rates of total mortality and adverse events in the SIRIUS II trial.

 
The Ularitide Global Evaluation in Acute Decompensated Heart Failure (URGENT) trial, a phase 3, randomised, double-blind, placebo-controlled study of ularitide in the treatment of patients with AHFS is expected to begin soon. This study will randomise 3000 patients from North and South America, Europe, and Australia to ularitide or placebo plus standard therapy within 24 h of hospital admission for AHFS. The main end points will be dyspnoea and the visual analogue scale, as well as safety data in terms of morbidity and mortality, not only during hospitalisation but also after discharge. These data will define the role, if any, of ularitide in the treatment of AHFS.

3.1.4. Endothelin antagonists
Endothelin-1 is one of the most potent vasoconstrictors known, production by vascular tissue, contributes to neurohormonal activation and plays a central role in the pathophysiology of HF [37]. Endothelin-1 plasma concentration in patients with AHFS independently predicts adverse clinical outcomes [38,39].

Several endothelin antagonists have been developed, such as bosentan, darusentan, and tezosentan (a non-selective endothelin-A/B antagonist designed for intravenous administration) [40].

Tezosentan for the treatment of AHFS has been studied in the Randomized Intravenous Tezosentan (RITZ) program that consists of the 2 pivotal trials (RITZ-1 [41] and RITZ-2 [42]) and the 2 safety trials (RITZ-4 [43] and RITZ-5 [44]), as well as the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study (VERITAS) [45].

Although the RITZ-2 trial showed haemodynamic and symptomatic benefits of tezosentan compared with placebo, the RITZ-1 trial demonstrated no advantage of tezosentan over placebo in terms of dyspnoea and time to worsening HF or death. It was suggested that the inconsistency between the data from the 2 trials might be related to differences in the study population (RITZ-2 patients were more acutely ill and had invasive haemodynamic monitoring, whereas RITZ-1 excluded patients with pulmonary artery catheter) and in the dose of tezosentan used (higher in RITZ-1, as suggested by a relatively high incidence of adverse hypotensive events) [41,42].

The 2 safety trials showed that tezosentan was relatively safe in high-risk patients with AHFS associated with acute coronary syndromes (RITZ-4) or with acute cardiogenic pulmonary oedema leading to respiratory failure (RITZ-5). However, neither RITZ-4 nor RITZ-5 demonstrated clinical benefit of tezosentan compared with placebo [43,44] (Fig. 4).


Figure 04
View larger version (11K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Primary end point of the RITZ-4 trial (modified from [43]).

 
VERITAS was a large-scale international trial designed to study the effects of tezosentan added to conventional therapy in patients with AHFS who were hospitalised with dyspnoea at rest [45]. The 2 primary end points were the change in dyspnoea over the first 24 h of treatment and the incidence of death or worsening HF at 7 days. This trial was discontinued because of the low probability of achieving a significant treatment effect, after a recommendation based on prespecified rules by the Data Safety and Monitoring Board.

Accordingly, clear evidence to support the use of endothelin antagonists in the management of AHFS is still lacking.

3.2. Investigational agents for AHFS patients presenting with low SBP with or without congestion
Patients with AHFS presenting with low cardiac output (AHFS/LO) are characterized by poor end-organ perfusion, manifesting as hypotension and prerenal azotaemia. These individuals generally have advanced/end-stage HF refractory to therapy or de novo HF (e.g., a large myocardial infarction [MI], acute mitral insufficiency). They often require invasive haemodynamic monitoring and positive inotropic therapy.

An ideal pharmacologic agent for treating AHFS/LO should mainly increase cardiac output and improve symptoms. This increase in cardiac output should not be associated with further reduction in blood pressure, increased myocardial oxygen consumption, decreased coronary perfusion (particularly in patients with CAD), myocardial damage (apoptosis, necrosis), arrhythmia, or worsening renal function.

Conventional inotropic agents, such as dobutamine and/or milrinone, are the cornerstones of treatment for patients with AHFS/LO, providing short-term symptomatic alleviation and haemodynamic improvement. However, most inotropic agents are associated with adverse effects, including increased ventricular ectopy, tachyarrhythmia, ischaemia, increased myocardial oxygen consumption, and hypotension, especially at high doses. Short-term use of these agents has been also associated with increased post-discharge mortality, particularly in patients with coronary artery disease [46].

Recent research is focused on developing new agents that may improve cardiac output safely and promptly as a bridge therapy to stabilize critically ill patients until definitive and life-saving therapy can be undertaken.

3.2.1. Istaroxime
Istaroxime is a novel compound that has both positive inotropic and lusitropic properties [47-50]. Its positive inotropism is due to its ability to inhibit Na-K ATPase located at the sarcolemma, producing cytosolic calcium accumulation. Its positive lusitropism results from its ability to stimulate sarcoplasmic reticulum calcium ATPase, leading to rapid sequestration of cytosolic calcium into the sarcoplasmic reticulum during diastole, which promotes myocardial relaxation [47-50].

Experimental and small human studies have shown that istaroxime improves myocardial contractility, haemodynamics and diastolic relaxation without inducing proarrhythmic or ischaemic effects [47,51-55].

The ongoing Haemodynamic Effects of Istaroxime, a Novel Lusitropic Agent, in Patients with Left Ventricular Systolic Dysfunction Hospitalized with Exacerbation of Chronic HF (HORIZON-HF) trial is a phase 2, randomised, double-blind, placebo-controlled, dose-escalation exploratory study. Its primary objective is to determine the minimum effective dose of istaroxime in patients requiring hospitalisation for chronic HF (NYHA class I-III) caused by idiopathic dilated cardiomyopathy or coronary artery disease/hypertension and LV systolic dysfunction (LVEF ≤0.40). Efficacy will be measured as the change in PCWP from baseline to the last assessment at 6 h of intravenous infusion. The desirable pharmacokinetic characteristics of istaroxime (activity in short time, no accumulation, and rapid washout) lead to the expectation that its use for long-term infusion may be effective without increasing myocardial oxygen consumption or heart rate, thus representing a unique positive luso-inotropic agent that is potentially applicable to the treatment of AHFS/LO.

3.2.2. Cardiac myosin activators
Cardiac myosin is a cytoskeletal motor protein that mediates the adenosine triphosphate-dependent generation of cardiac contraction. Cardiac myosin activators (such as CK-0689705, 116 CK-1122534 [56,57], and CK-1827452 [58,59]) are recently discovered small molecules that have been found to directly stimulate the activity of the cardiac myosin motor protein, thereby improving cardiac contractility in the absence of changes in intracellular calcium concentration.

In vitro and in vivo studies of these compounds have indicated their therapeutic potential for HF. They increase the fractional shortening in ventricular myocytes in a dose-dependent manner [57,60]. CK-0689705 increases contractility in ventricular myocytes from rats with HF [60]. CK-1827452 has been shown to enhance cardiac contractility in a rat model of HF [59] and to improve cardiac function and output, as well as haemodynamics in a dog model [58]. CK-1827452 is currently in a phase 1 clinical trial to study its role as a potential treatment for AHFS. This dose-escalation clinical trial in healthy volunteers is designed to identify the maximum tolerated dose of a 6-hour intravenous infusion of CK-1827452 and to evaluate its effect on LV function using serial echocardiograms. CK-1827452 seems to increase systolic time more than the rate of developed pressure, as with traditional inotropes.

Whether cardiac myocyte activators induce an associated increase in oxygen consumption remains to be investigated.

3.2.3. Metabolic modulators
Free fatty acids are the preferred metabolic substrate used by heart muscle to produce energy [61]. Notably, during the ischaemic conditions associated with reduced oxygen availability, high levels of free fatty acid catabolites in a relatively anaerobic milieu may have detrimental effects on the myocardium, including direct inhibition of glucose oxidation leading to intracellular accumulation of lactate and, ultimately, reduction of myocardial contractility. In addition, a high concentration of free fatty acid intermediates has been found to be associated with increased ventricular arrhythmias and diastolic dysfunction [62-66].

Metabolic modulators were initially developed as an attractive choice of co-treatment, in addition to optimal therapy, for patients with recurrent episodes of angina who are not candidates for revascularization (particularly the elderly) [67]. However, optimization of cardiac energetics could benefit not only ischaemic, but also non-ischaemic cardiomyopathy. Several studies in HF patients without significant coronary artery disease have revealed regional myocardial hypoperfusion, attributed to increased oxygen demand from tachycardia and heightened wall stress, and decreased oxygen supply due to endothelial dysfunction and elevated filling pressures [68-70].

Relaxin is an insulin-related polypeptide hormone of human reproduction [71]. It stimulates the generation of nitric oxide and cyclic AMP and has a variety of biological activities including vasodilation, induction of collagen breakdown, stimulation of atrial natriuretic peptide secretion, regulation of fluid balance and prevention of platelet aggregation [71]. Some reports show that plasma relaxin is increased in HF [72] and that relaxin mRNA is expressed in the myocardium in proportion to the severity of cardiac decompensation. However, recent controlled studies have failed to demonstrate a prognostic value of relaxin in HF patients [73]. The ongoing randomised, double-blind RELAX-AHF trial is comparing different doses of relaxin versus placebo, to determine its efficacy and safety for the treatment of patients hospitalised with AHFS.

Perhexiline is an inhibitor of carnitine palmitoyl transferase-1, an enzyme critical to mitochondrial uptake of free fatty acids, thus shifting myocardial substrate of utilization from free fatty acids to carbohydrates (Fig. 5). It also acts as a mild calcium channel antagonist, although this property is not apparent at therapeutic concentrations [74,75]. Early trials showed that perhexiline was an effective compound to relieve anginal symptoms and improve exercise tolerance [76]. Unfortunately, subsequent studies demonstrated that perhexiline has a narrow therapeutic index and is associated with adverse effects such as hepatotoxicity [77] and peripheral neuropathy [78]. Although no data from large-scale acute-setting studies of this agent are available, a small randomised, double-blind, 8-week trial [79] showed significant improvement in peak exercise oxygen consumption, quality of life, LVEF, resting and peak stress myocardial function, and skeletal muscle energetics, when plasma concentrations of 150-600 ng/mL were maintained. Currently available therapeutic monitoring tools have generated renewed interest in perhexiline because they may provide a safe and effective strategy to avoid toxicity. Other available carnitine palmitoyl transferase-1 inhibitors include trimetazidine, ranolazine, and etomoxir, but, to date, there are no clinical data available for the application of these drugs to the AHFS.


Figure 05
View larger version (29K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Mechanism of action of perhexiline.

 
3.3. Recently approved agents for AHFS
Available evidence suggests that early treatment of patients admitted with AHFS is critical because the short-term use of pharmacologic agents may affect long-term morbidity and mortality.

A major challenge in AHFS is the development of effective short-term surrogate end points for assessing new drugs, and re-evaluating clinical trial design. In fact, the studies to date have been small to moderate short-term haemodynamic or symptom-focused designs, constructed primarily to meet regulatory requirements.

The International Working Group on AHFS previously proposed a stage-based approach for conducting future trials in this field [1]: the emergency treatment phase (stage A), the in-hospital management phase (stage B), and discharge-planning (stage C). An existing paradox is that research in AHFS is based on stage B trials [1], conducted during the hospitalisation phase, when often symptoms such as dyspnoea are markedly reduced or abolished. Conversely, conducting stage A trials (during the initial presentation at the Emergency Department or even before arrival to hospital) may enable testing of new drugs during an early phase, when PCWP is still high, renal function preserved, and before any conventional agents have been administered (e.g. high dose IV diuretics).

Nesiritide and levosimendan are two drugs for the treatment of AHFS which have recently been approved by the FDA and EMEA, respectively. However, the safety and efficacy of these agents have recently been questioned and nesiritide has not been approved by EMEA and levosimendan has not been approved by FDA. In fact, although previous studies demonstrated that these new therapies improve haemodynamic parameters, recent meta-analyses and randomised trials suggest that they may increase or have comparable impact on long-term mortality, compared to conventional drugs.

3.3.1. Nesiritide
Nesiritide is a recombinant form of human brain natriuretic peptide (BNP) that exerts vasodilatory effects on arterial, venous, and coronary vessels, leading to increased cardiac output.

Studies of nesiritide in the treatment of AHFS have documented beneficial effects on haemodynamics (reductions in PCWP and systemic vascular resistance and increases in cardiac output) and symptoms, compared with placebo [80,81].

The Vasodilatation in the Management of Acute Congestive Heart Failure (VMAC) trial was a large, multicenter, randomised, double-blind, controlled trial designed to compare the haemodynamic and clinical effects and safety of intravenous nesiritide and intravenous nitroglycerin added to standard care in 489 patients hospitalised for dyspnoea at rest due to AHFS [82]. Patients were randomised to receive nesiritide (n=204), nitroglycerin (n=143), or placebo (n=142) for 3 h. After 3 h, nesiritide reduced PCWP to a significantly greater degree than did nitroglycerin or placebo. Nesiritide significantly improved dyspnoea compared with placebo but resulted in no significantly different improvement in dyspnoea compared with nitroglycerin. After 24 h, the mean reduction in PCWP was significantly greater in the nesiritide group than in the nitroglycerin group, but there was no significant difference in dyspnoea between the 2 groups. Adverse events (most commonly headache) occurred significantly less frequently with nesiritide than with nitroglycerin. There was no significant difference in 6-month mortality rates in the nesiritide group compared with the nitroglycerin group.

As mentioned before, the safety and efficacy of nesiritide has recently been questioned [83]. Concerns have emerged about the possible adverse effects of nesiritide therapy on renal function [84] and short-term mortality, in comparison with standard diuretic and vasodilator therapies [85,86].

Recently, the BNP-CARDS (B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome) trial randomised 75 consecutive patients with AHFS and baseline renal dysfunction to receive nesiritide (0.01 µg/kg/min with or without a 2-µg/kg bolus) or placebo (5% dextrose in water) for 48 h in addition to usual care [87]. There were no significant differences in the increase in serum creatinine by 20% and change in serum creatinine between the two groups. In addition, there were no significant differences in the secondary end points of change in weight, intravenous furosemide use, discontinuation of the infusion due to hypotension, or 30-day death/hospital readmission [87]. A possible explanation for the disparate findings between this and previous studies is the use of a bolus dose. It is plausible that any positive or neutral effects of nesiritide on glomerular filtration rate might be overcome by significant hypotension occurring with the bolus dose, possibly accounting for some of the worsened renal function seen in other retrospective analyses. Another possible difference between the results of this trial and previous observations are the timing of the nesiritide infusion initiation and the dose of infusion used.

Data from the second Follow-Up Serial Infusions of Nesiritide in Advanced Heart Failure (FUSION-2) trial have recently been presented [88]. The trial randomised 911 patients to receive nesiritide as a 2-µg/kg bolus followed by a 0.01-µg/kg/min infusion for 4 to 6 h or a matching placebo regimen, once or twice a week for 12 weeks. Inclusion in the trial required being in NYHA class 3 or 4 with an LVEF <40% and a history of at least two prior hospitalisations for HF within the past year. Patients in NYHA class 3 were only recruited if their creatinine clearance was <60 mL/min. No outpatient IV inotropic or vasodilator therapy was allowed during the study. At the end of the study, there were no significant differences in rates of the primary end point of all-cause mortality or cardiovascular or cardiorenal hospitalisation or in rates of its individual component events. Nor were there significant outcome differences for any of a long list of subgroups defined by age, sex, comorbidities, renal and LV function, and NYHA functional class [88]. Notably, this trial was ultimately underpowered to render any firm conclusions about the safety and clinical effects of nesiritide, say observers, because clinical events were fewer than anticipated.

The ongoing Acute Study of Clinical Effectiveness of Nesiritide in Subjects With Decompensated Heart Failure (ASCEND-HF) trial is a phase 3, randomised, double-blind, placebo-controlled study.

The primary objective of this study is to evaluate whether treatment with nesiritide improves patient outcomes (as measured by reduction in the composite of HF rehospitalisation and all-cause mortality through 30 days) and HF symptoms (as measured by subject self-assessed Likert dyspnoea scale at 6 h after study drug initiation) compared to placebo, when administered in addition to other standard therapies in patients with AHFS. The co-primary end points are: 1) the composite of HF rehospitalisation and all-cause mortality through 30 days; and 2) subject self-assessed dyspnoea symptom at 6 h. Eligible subjects must be hospitalised with a primary diagnosis of AHFS, or experience AHFS while already hospitalised for another reason. Approximately 7000 subjects (3500/arm) will be enrolled in this study.

3.3.2. Levosimendan
Calcium sensitizing agents are a unique class of positive inotropic drugs that include levosimendan, pimobendan, senazodan, EMD-53998, and its enantiomer, ED-57033 [89]. These drugs seem to exert a dose-dependent calcium sensitizing mechanical enhancement on the failing heart via a variety of biochemical mechanisms, including the enhancement of troponin-C affinity for calcium, the direct stabilization of the calcium-induced conformation of troponin-C, or the action distal to the troponin-C molecule [89]. However, some molecules such as pimobendan, EMD-53398, senazodan and possibly levosimendan may act as phosphodiesterase inhibitors at therapeutic doses, causing a deleterious increase of intracellular cyclic AMP. This effect seems to be an essential limitation for the use of these particular drugs clinically [89].

Levosimendan is the most studied calcium sensitizer and has recently been introduced in many countries for the treatment of AHFS. Levosimendan acts via two complementary mechanisms [90]. It enhances contractility by improving cardiac myofilament response to intracellular calcium and it reduces the cardiac workload by opening ATP-dependent potassium channels for dilation of blood vessels [90]. Indeed levosimendan-induced decrease in right and left ventricular afterload may be beneficial in failing hearts [90,91]. Furthermore, levosimendan differs from classic inotropes because of its ability to improve myocardial efficiency without increasing myocardial oxygen demand, its antistunning properties, its effects on coronary blood flow, and its lack of negative lusitropic effects [90,91].

Data from several trials suggest that levosimendan appears to improve haemodynamics, symptoms and neurohormonal response [92-94] in AHFS and to possibly prolong survival in some subsets of patients.

For instance, in the Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure Due to an Acute Myocardial Infarct (RUSSLAN) study [95], and in the Levosimendan Infusion Versus Dobutamine (LIDO) study [96], levosimendan was associated with haemodynamic improvements and in secondary and post-hoc analyses with a lower risk of death compared to dobutamine and/or placebo in post-MI or low-output HF patients.

The recent REVIVE-1 and -2 (Randomized Evaluations of Levosimendan) and SURVIVE (Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) trials showed that levosimendan was superior to placebo or dobutamine, respectively, in producing clinical improvement and beneficial neurohormonal modulation (as expressed by the reduction in plasma BNP) in patients with AHFS [97-99]. However, levosimendan failed to lead in a reduction of in-hospital and 6-month mortality compared with dobutamine (SURVIVE: primary end point) in these patients. More specifically, in the REVIVE-2 study [97], 90-day all-cause mortality was 15.1% in the levosimendan group and 11.6% among placebo-treated patients (p=0.210); this numerical increase in deaths in the levosimendan group was associated with the higher incidence of hypotensive episodes than in the placebo group.

The SURVIVE trial [99] randomised 1327 patients with ADHF and a left ventricular ejection fraction of 30% or less, who required intravenous inotropic therapy because of insufficient response to intravenous diuretics and/or vasodilators. All patients received standard treatment and were randomised to the addition of either a 12-µg/kg bolus of levosimendan followed by a stepped dose regimen of 0.1-0.2 µg/kg/min infusion for a maximum of 24 h or dobutamine at a dose of at least 5 µg/kg/min for at least 24 h. The primary end point in the SURVIVE trial (all-cause mortality at 6 months) showed similar results for both levosimendan and dobutamine (26.2% and 27.9%, respectively; p=0.401) (Fig. 6).


Figure 06
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 Effect of dobutamine and levosimendan treatment on all-cause mortality during 180 days following the start of study drug infusion in the SURVIVE trial (modified from [99]).

 
Interestingly SURVIVE shows that levosimendan induced a much greater decrease in BNP compared to dobutamine, over the first week of treatment [99].

Levosimendan is currently in clinical use in several countries (excluding US) and is indicated in patients with symptomatic low cardiac output HF secondary to cardiac systolic dysfunction without severe hypotension [100]. Further studies are clearly warranted in order to identify proper dosages and timing of infusion, and the subset of patients who may benefit more from this agent (i.e. patients with AHF who are on b-blockers).


   4. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Conclusion
References
 
In spite of promising findings, no new agent has demonstrated a clear benefit in terms of long-term clinical outcomes compared to placebo or conventional therapies.

Since recent studies demonstrated that early management may influence long-term outcomes, a major challenge in AHFS trials remains the development of appropriate surrogate end points for evaluating the efficacy of these new pharmacologic therapies.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Conclusion
 References
 

  1. Gheorghiade M., Zannad F., Sopko G., et al. Acute heart failure syndromes: current state and framework for future research. Circulation (2005) 112:3958–3968.[Free Full Text]
  2. Gheorghiade M., Abraham W., Albert N., et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA (2006) 296:2217–2226.[Abstract/Free Full Text]
  3. Filippatos G., Zannad F. An introduction to acute heart failure syndromes: definition and classification. Heart Fail Rev (2007) 12:87–90.[CrossRef][Web of Science][Medline]
  4. Shin D.D., Brandimarte F., De Luca L., et al. Review of current and investigational pharmacologic agents for acute heart failure syndromes. Am J Cardiol (2007) 99:4A–23A.[Web of Science][Medline]
  5. Bayram M., De Luca L., Massie M.B., Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol (2005) 96:47–58.
  6. Cotter G., Metzkor E., Kaluski E., et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet (1998) 351:389–393.[CrossRef][Web of Science][Medline]
  7. Hasselblad V., Stough W.G., Shah M.R., et al. Relation between diuretic dose and outcome in a heart failure population: results of the ESCAPE trial [abstract]. J Card Fail (2005) 11:S157.
  8. Cohn J.N., Franciosa J.A., Francis G.S., et al. Effect of shortterm infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veterans Administration cooperative study. N Engl J Med (1982) 306:1129–1135.[Abstract]
  9. Szatalowicz V.L., Arnold P.E., Chaimovitz C., Bichet D., Schrier R.W. Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N Engl J Med (1981) 305:263–266.[Web of Science][Medline]
  10. Riegger G.A.J., Liebau G., Kochsiek K. Antidiuretic hormone in congestive heart failure. Am J Med (1982) 72:49–52.[CrossRef][Web of Science][Medline]
  11. Schrier R.W., Abraham W.T. Hormones and hemodynamics in heart failure. N Engl J Med (1999) 341:577–585.[Free Full Text]
  12. Klein L., O'Connor C.M., Leimberger J.D., et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study. Circulation (2005) 111:2454–2460.[Abstract/Free Full Text]
  13. Gheorghiade M., Abraham W.T., Albert N.M., et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J (2007) 28:980–988.[Abstract/Free Full Text]
  14. Gheorghiade M., Rossi J.S., Cotts W., et al. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE trial. Arch Intern Med (2007) 167:1998–2005.[Abstract/Free Full Text]
  15. Goldsmith S.R. Vasopressin: a therapeutic target in congestive heart failure? J Card Fail (1999) 5:347–356.[CrossRef][Web of Science][Medline]
  16. Udelson J.E., Smith W.B., Hendrix G.H., et al. Acute hemodynamic effects of conivaptan, a dual V1A and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation (2001) 104:2417–2423.[Abstract/Free Full Text]
  17. Gheorghiade M., Niazi I., Ouyang J., et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation (2003) 107:2690–2696.[Abstract/Free Full Text]
  18. Gheorghiade M., Gattis W.A., O'Connor C.M., et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA (2004) 291:1963–1971.[Abstract/Free Full Text]
  19. Konstam M.A., Gheorghiade M., Burnett J.C. Jr., et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA (2007) 297:1319–1331.[Abstract/Free Full Text]
  20. Gheorghiade M., Konstam M.A., Burnett J.C. Jr., et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA (2007) 297:1332–1343.[Abstract/Free Full Text]
  21. Udelson J.E., McGrew F.A., Flores E., et al. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J Am Coll Cardiol (2007) 49:2151–2159.[Abstract/Free Full Text]
  22. Modlinger P.S., Welch W.J. Adenosine A1 receptor antagonists and the kidney. Curr Opin Nephrol Hypertens (2003) 12:497–502.[Web of Science][Medline]
  23. Gottlieb S.S. Renal effects of adenosine A1-receptor antagonists in congestive heart failure. Drugs (2001) 61:1387–1393.[CrossRef][Web of Science][Medline]
  24. Givertz M.M., Massie B.M., Fields T.K., Pearson L.L., Dittrich H.C. CKI-201 and CKI-202 Investigators. The effects of KW-3902, an adenosine A1-receptor antagonist, on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. J Am Coll Cardiol (2007) 50:1551–1560.[Abstract/Free Full Text]
  25. Dittrich H.C., Gupta D.K., Hack T.C., et al. The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment. J Card Fail (2007) 13:609–617.[CrossRef][Web of Science][Medline]
  26. Gottlieb S.S., Skettino S.L., Wolff A., et al. Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure. J Am Coll Cardiol (2000) 35:56–59.[Abstract/Free Full Text]
  27. Gottlieb S.S., Brater D.C., Thomas I., et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation (2002) 105:1348–1353.[Abstract/Free Full Text]
  28. Greenberg B., Thomas I., Banish D., et al. Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure results of a placebo-controlled, dose-escalation study. J Am Coll Cardiol (2007) 50:600–606.[Abstract/Free Full Text]
  29. Kalk P., Eggert B., Relle K., et al. The adenosine A(1) receptor antagonist SLV320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure. Br J Pharmacol. (2007) 151:1025–1032.[CrossRef][Web of Science][Medline]
  30. Metra M., Cotter G. Placebo-controlled randomized study of the selective A1 adenosine receptor antagonist KW-3902 for patients hospitalized with acute HF and volume Overload to assess Treatment Effect on Congestion and renal funcTion (PROTECT) pilot study. Late-breaking Clinical Trials. Heart Failure Congress, Annual Meeting, Hamburg, Germany (2007) 9–12. June.
  31. Liao Y., Takashima S., Asano Y., et al. Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. Circ Res (2003) 93:759–766.[Abstract/Free Full Text]
  32. Forssmann W., Meyer M., Forssmann K. The renal urodilatin system: clinical implications. Cardiovasc Res (2001) 51:450–462.[Abstract/Free Full Text]
  33. Kentsch M., Ludwig D., Drummer C., Gerzer R., Muller-Esch G. Haemodynamic and renal effects of urodilatin bolus injections in patients with congestive heart failure. Eur J Clin Invest (1992) 22:662–669.[Web of Science][Medline]
  34. Elsner D., Muders F., Muntze A., Kromer E.P., Forssmann W.G., Riegger G.A. Efficacy of prolonged infusion of urodilatin [ANP-(95-126)] in patients with congestive heart failure. Am Heart J (1995) 129:766–773.[CrossRef][Web of Science][Medline]
  35. Mitrovic V., Luss H., Nitsche K., et al. Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial. Am Heart J (2005) 150:1239.[Medline]
  36. Mitrovic V., Seferovic P.M., Simeunovic D., et al. Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J (2006) 27:2823–2832.[Abstract/Free Full Text]
  37. Teerlink J.R. The role of endothelin in the pathogenesis of heart failure. Curr Cardiol Rep (2002) 4:206–212.[CrossRef][Medline]
  38. Aronson D., Burger A.J. Neurohumoral activation and ventricular arrhythmias in patients with decompensated congestive heart failure role of endothelin. PACE Pacing Clin Electrophysiol (2003) 26:703–710.[CrossRef][Medline]
  39. Aronson D., Burger A.J. Neurohormonal prediction of mortality following admission for decompensated heart failure. Am J Cardiol (2003) 91:245–248.[CrossRef][Web of Science][Medline]
  40. Gheorghiade M., De Luca L., Bonow R.O. Neurohormonal Inhibition in heart failure: insights from recent clinical trials. Am J Cardiol (2005) 96(suppl):3L–9L.[Web of Science][Medline]
  41. Teerlink J.R., Massie B.M., Cleland J.G.F., Tzivoni D. for the RITZ-1 Investigators. A double-blind, parallel-group, multi-center, placebocontrolled study to investigate the efficacy and safety of tezosentan in reducing symptoms in patients with acute decompensated heart failure [abstract]. Circulation (2001) 104:II–526.
  42. Torre-Amione G., Young J.B., Colucci W.S., et al. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol (2003) 42:140–147.[Abstract/Free Full Text]
  43. O'Connor C.M., Gattis W.A., Adams K.F. Jr., et al. Tezosentan in patients with acute heart failure and acute coronary syndromes: results of the Randomized Intravenous TeZosentan Study (RITZ-4). J Am Coll Cardiol (2003) 41:1452–1457.[Abstract/Free Full Text]
  44. Kaluski E., Kobrin I., Zimlichman R., et al. RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study. J Am Coll Cardiol (2003) 41:204–210.[Abstract/Free Full Text]
  45. McMurray J.J., Terlink J., Cotte G., et al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA (2007) 298:2009–2019.[Abstract/Free Full Text]
  46. Abraham W.T., Adams K.F. Jr., Fonarow G.C., et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol (2005) 46:57–64.[Abstract/Free Full Text]
  47. Micheletti R., Mattera G.G., Rocchetti M., et al. Pharmacological profile of the novel inotropic agent (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744). J Pharmacol Exp Ther (2002) 303:592–600.[Abstract/Free Full Text]
  48. De Munari S., Cerri A., Gobbini M., et al. Structure based design and synthesis of novel potent Na+/K+-ATPase inhibitors derived from a 5{alpha},14 {alpha}-androstane scaffold as positive inotropic compounds. J Med Chem (2003) 56:3644–3654.
  49. Rocchetti M., Besana A., Mostacciuolo G., Ferrari P., Micheletti R., Zaza A. Diverse toxicity associated with cardiac Na+/K+ pump inhibition: evaluation of electrophysiological mechanisms. J Pharmacol Exp Ther (2003) 305:765–771.[Abstract/Free Full Text]
  50. Rocchetti M., Besana A., Mostacciuolo G., et al. Modulation of sarcoplasmic reticulum function by Na+/K+ pump inhibitors with different toxicity: digoxin and PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride]. J Pharmacol Exp Ther (2005) 313:207–215.[Abstract/Free Full Text]
  51. Adamson P.B., Vanoli E., Mattera G.G., et al. Hemodynamic effects of a new inotropic compound, PST-2744, in dogs with chronic ischemic heart failure. J Cardiovasc Pharmacol (2003) 42:169–173.[CrossRef][Web of Science][Medline]
  52. Barassi P., Ferrandi M., Bianchi G., Ferrari P. Istaroxime stimulates SERCA2a activity in animal and human failing heart preparations [abstract]. J Card Fail (2005) 11:S154.
  53. Mattera G.G., Lo Giudice P., Loi F.M.P., et al. Istaroxime: a new luso-inotropic agent for heart failure. Am J Cardiol (2007) 99:S33–S40.[CrossRef]
  54. Sabbah H.N., Imai M., Cowart D., Amato A., Carminati P., Gheorghiade M. Hemodynamic properties of a new-generation positive luso-inotropic agent for the acute treatment of advanced heart failure. Am J Cardiol (2007) 99:S41–S46.
  55. Ghali J.K., Smith W.B., Torre-Amione G., et al. A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function. Am J Cardiol (2007) 99:S47–S56.
  56. Cleland J.G., Coletta A.P., Clark A.L. Clinical trials update from the Heart Failure Society of America meeting: FIX-CHF-4, selective cardiac myosin activator and OPT-CHF. Eur J Heart Fail (2006) 8:764–766.[Abstract/Free Full Text]
  57. Niu C, Anderson R, Cox D, et al. The cardiac myosin activator, CK-1122534, increases contractility in adult cardiac myocytes without altering the calcium transient. In: Presented at the 44th Annual Meeting of the American Society of Cell Biology (2004) Washington, DC. December 4-8.
  58. Malik F, Elias KA, Finer JT, et al. Direct activation of cardiac myosin by CK-1827452 improves cardiac function in a dog heart failure model. In: Presented at the 9th Annual Scientific Meeting of the Heart Failure Society of America (2005) Boca Raton, Florida. September 18-21.
  59. Anderson RL, Sueoka SH, Rodriguez HM, et al. In vitro and in vivo efficacy of the cardiac myosin activator CK-1827452. In: Presented at the 45th Annual Meeting of the American Society of Cell Biology (2005) San Francisco, California. December 10-14.
  60. Niu C, Cox D, Lee K, et al. Cellular responses of the myosin activator CK-0689705 in normal and heart failure models. In: Presented at the 44th Annual Meeting of the American Society of Cell Biology (2004) Washington, DC. December 4-8.
  61. Stanley W.C., Lopaschuk G.D., Hall J.L., McCormack J.G. Regulation of myocardial carbohydrate metabolism under normal and ischemic conditions: potential for pharmacological interventions. Cardiovasc Res (1997) 33:243–257.[Free Full Text]
  62. Taegtmeyer H., Roberts A.F., Raine A.E. Energy metabolism in reperfused heart muscle: metabolic correlates to return of function. J Am Coll Cardiol (1985) 6:864–870.[Abstract]
  63. Depre C., Vanoverschelde J.L., Taegtmeyer H. Glucose for the heart. Circulation (1999) 99:578–588.[Free Full Text]
  64. Lopaschuk G.D., Wambolt R.B., Barr R.L. An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts. J Pharmacol Exp Ther (1993) 264:135–144.[Abstract/Free Full Text]
  65. Murnaghan M.F. Effect of fatty acids on the ventricular arrhythmia threshold in the isolated heart of the rabbit. Br J Pharmacol (1981) 73:909–915.[Web of Science][Medline]
  66. Kennedy J.A., Kiosoglous A.J., Murphy G.A., Pelle M.A., Horowitz J.D. Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J Cardiovasc Pharmacol (2000) 36:794–801.[CrossRef][Web of Science][Medline]
  67. Cole P.L., Beamer A.D., McGowan N., et al. Efficacy and safety of perhexiline maleate in refractory angina. Circulation (1990) 81:1260–1270.[Abstract/Free Full Text]
  68. Treasure C.B., Vita J.A., Cox D.A., et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation (1990) 81:772–779.[Abstract/Free Full Text]
  69. Unverferth D.V., Magorien R.D., Lewis R.P., Leier C.V. The role of subendocardial ischemia in perpetuating myocardial failure in patients with nonischemic congestive cardiomyopathy. Am Heart J (1983) 105:176–179.[CrossRef][Web of Science][Medline]
  70. van den Heuvel A.F., van Veldhuisen D.J., van der Wall E.E., et al. Regional myocardial blood flow reserve impairment and metabolic changes suggesting myocardial ischemia in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol (2000) 35:19–28.[Abstract/Free Full Text]
  71. Kupari M., Mikkola T.S., Turto H., Lommi J. Is the pregnancy hormone relaxin an important player in human heart failure? Eur J Heart Fail (2005) 7:195–198.[Abstract/Free Full Text]
  72. Dschietzig T., Richter C., Bartsch C., et al. The pregnancy hormone relaxin is a player in human heart failure. Faseb J (2001) 15:2187–2195.[Abstract/Free Full Text]
  73. Fisher C., Berry C., Blue L., Morton J.J., McMurray J. N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Heart (2003) 89:879–881.[Abstract/Free Full Text]
  74. Barry W.H., Horowitz J.D., Smith T.W. Comparison of negative inotropic potency, reversibility, and effects on calcium influx of six calcium channel antagonists in cultured myocardial cells. Br J Pharmacol (1985) 85:51–59.[Web of Science][Medline]
  75. Jeffrey F.M., Alvarez L., Diczku V., Sherry A.D., Malloy C.R. Direct evidence that perhexiline modifies myocardial substrate utilization from fatty acids to lactate. J Cardiovasc Pharmacol (1995) 25:469–472.[Web of Science][Medline]
  76. Horowitz J.D., Mashford M.L. Perhexiline maleate in the treatment of severe angina pectoris. Med J Aust (1979) 1:485–488.[Web of Science][Medline]
  77. Roberts R.K., Cohn D., Petroff V., Seneviratne B. Liver disease induced by perhexiline maleate. Med J Aust (1981) 2:553–554.[Web of Science][Medline]
  78. Bouche P., Bousser M.G., Peytour M.A., Cathala H.P. Perhexiline maleate and peripheral neuropathy. Neurology (1979) 29:739–743.[Abstract/Free Full Text]
  79. Lee L., Campbell R., Scheuermann-Freestone M., et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation (2005) 112:3280–3288.[Abstract/Free Full Text]
  80. Mills R.M., LeJemtel T.H., Horton D.P., et al. Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol (1999) 34:155–162.[Abstract/Free Full Text]
  81. Colucci W.S., Elkayam U., Horton D.P., et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med (2000) 343:246–253.[Abstract/Free Full Text]
  82. Publication Committee for the VMAC [Vasodilatation in the Management of Acute CHF] Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA (2002) 287:1531–1540.[Abstract/Free Full Text]
  83. Topol E.J. Nesiritide—not verified. N Engl J Med (2005) 353:113–116.[Free Full Text]
  84. Sackner-Bernstein J.D., Skopicki H.A., Aaronson K.D. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation (2005) 111:1487–1491.[Abstract/Free Full Text]
  85. Sackner-Bernstein J.D., Kowalski M., Fox M., Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA (2005) 293:1900–1905.[Abstract/Free Full Text]
  86. Aaronson K.D., Sackner-Bernstein J.D. Risk of death associated with nesiritide in patients with acutely decompensated heart failure [research letter]. JAMA (2006) 296:1465–1466.[Free Full Text]
  87. Witteles R.M., Kao D., Christopherson D., et al. Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol (2007) 50:1835–1840.[Abstract/Free Full Text]
  88. Cleland J.G., Coletta A.P., Clark A.L. Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet. Eur J Heart Fail (2007) 9:740–745.[Abstract/Free Full Text]
  89. Parissis J.T., Farmakis D., Nieminen M. Classical inotropes and new cardiac enhancers. Heart Fail Rev (2007) 12:149–156.[CrossRef][Web of Science][Medline]
  90. De Luca L., Colucci W.S., Nieminen M.S., Massie B.M., Gheorghiade M. Evidence-based use of levosimendan in different clinical settings. Eur Heart J (2006) 27:1908–1920.[Abstract/Free Full Text]
  91. Parissis J., Filippatos G., Farmakis D., Adamopoulos S., Paraskevaidis I., Kremastinos D. Levosimendan for the treatment of acute heart failure syndromes. Exp Opin Pharmacother (2005) 6(15):2741–2751.[CrossRef][Web of Science][Medline]
  92. Nieminen M.S., Akkila J., Hasenfuss G., et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol (2000) 36:1903–1912.[Abstract/Free Full Text]
  93. Slawsky M.T., Colucci W.S., Gottlieb S.S., et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation (2000) 102:2222–2227.[Abstract/Free Full Text]
  94. Parissis J., Panou F., Famakis D., et al. Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure. Am J Cardiol (2005) 96:423–426.[CrossRef][Web of Science][Medline]
  95. Moiseyev V.S., Poder P., Andrejevs N., et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction: a randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J (2002) 23:1422–1432.[Abstract/Free Full Text]
  96. Follath F., Cleland J.G., Just H., et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomized double-blind trial. Lancet (2002) 360:196–202.[CrossRef][Web of Science][Medline]
  97. Packer M., Colucci W.S., Fisher L. Development of a comprehensive new endpoint for the evaluation of new treatments for acute decompensated heart failure: results with levosimendan in the REVIVE-1 study (Abstract). J Card Fail (2003) 9:S61.
  98. Packer M. The Randomized multicenter EValuation of Intravenous leVosimendan Efficacy-2 (REVIVE-2) trial. In: Late-breaking Clinical Trials (2005) Dallas, TX: American Heart Association, Annual Scientific Session. 13–16. November.
  99. Mebazaa A., Nieminen M.S., Packer M., et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA (2007) 297:1883–1891.[Abstract/Free Full Text]
  100. Nieminen M.S., Bohm M., Cowie M.R., et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure. The task force on acute heart failure of the European Society of Cardiology. Eur Heart J (2005) 26:384–416.[Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 EuropaceHome page
F. Zannad, N. Agrinier, and F. Alla
Heart failure burden and therapy
Europace, November 1, 2009; 11(suppl_5): v1 - v9.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
D. S. Silverberg, D. Wexlerb, A. Iaina, and D. Schwartz
The role of correction of anaemia in patients with congestive heart failure: A short review
Eur J Heart Fail, September 1, 2008; 10(9): 819 - 823.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. Gheorghiade, J. E.A. Blair, G. S. Filippatos, C. Macarie, W. Ruzyllo, J. Korewicki, S. I. Bubenek-Turconi, M. Ceracchi, M. Bianchetti, P. Carminati, et al.
Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: A Randomized Controlled Trial in Patients Hospitalized With Heart Failure
J. Am. Coll. Cardiol., June 10, 2008; 51(23): 2276 - 2285.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (11)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by De Luca, L.
Right arrow Articles by Gheorghiade, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Luca, L.
Right arrow Articles by Gheorghiade, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?