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European Heart Journal: Acute Cardiovascular

http://acc.sagepub.com/content/early/2014/11/21/2048872614560504The online version of this article can be found at:

 DOI: 10.1177/2048872614560504

published online 20 November 2014European Heart Journal: Acute Cardiovascular CareBouvaist and Thierry H Le Jemtel

Pierre V Ennezat, Merrill Stewart, Rohan Samson, Nadia Bouabdallaoui, Sylvestre Maréchaux, Carlo Banfi, HélèneRecent therapeutic trials on fluid removal and vasodilation in acute heart failure

  

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EUROPEANSOCIETY OFCARDIOLOGY ®

Introduction

Acute heart failure (AHF) is a heterogeneous and complex syndrome that associates central and/or peripheral fluid accumulation to a variable degree of end organ hypoperfu-sion.1,2 In contrast to the treatment of chronic heart failure (CHF), the treatment of AHF has not progressed over the past few decades.3,4 The syndrome of AHF heralds a poor prognosis and a high likelihood of recurrence requiring re-hospitalisations.5 In most instances AHF is related to pro-gressive deterioration of CHF. Accordingly, hospitalisation for AHF should be viewed as an opportunity to optimise the medical regimen (adjustment of loop diuretic therapy, initia-tion of aldosterone receptor antagonism, titration of angio-tensin-converting enzyme inhibition and beta-adrenergic blockade), and to consider cardiac resynchronisation ther-apy or referral for cardiac transplantation or mechanical circulatory support.6 The syndrome of AHF comprises activation of multiple systems/pathways (neuro-hormonal, immune, inflammatory) in multiple organs (heart, kidney,

liver, gastrointestinal tract and endothelium) that make man-agement complex, and result in an unfavourable long-term

Recent therapeutic trials on fluid removal and vasodilation in acute heart failure

Pierre V Ennezat1, Merrill Stewart2, Rohan Samson2, Nadia Bouabdallaoui3, Sylvestre Maréchaux4, Carlo Banfi5, Hélène Bouvaist1 and Thierry H Le Jemtel2

AbstractRecent therapeutic trials regarding the management of acute heart failure (AHF) failed to demonstrate the efficacy of newer therapeutic modalities and agents. Low- versus high-dose and continuous administration of furosemide were shown not to matter. Ultrafiltration was not found to be more efficacious than sophisticated diuretic therapy including dose-adjusted intravenous furosemide and metolazone. Dopamine and nesiritide were not shown to be superior to current therapy. Tezosentan and tovalptan had no effect on mortality. The development of rolofylline was terminated due to adverse effect (seizures). Lastly, preliminary experience with serelaxin indicates a mortality improvement at six months that remains to be confirmed. The disappointing findings of these recent trials may reflect the lack of efficacy of newer therapeutic modalities and agents. Alternatively the disappointing findings of these recent trials may be in part due to methodological issues. The AHF syndrome is complex with many clinical phenotypes. Failure to match clinical phenotypes and therapeutic modalities is likely to be partly responsible for the disappointing findings of recent AHF trials.

KeywordsAcute heart failure, fluid removal, vasodilating agents, future directions

Date received: 1 August 2014; accepted: 14 October 2014

1 Cardiology Department, Centre Hospitalier Universitaire de Grenoble, France

2 Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana, USA

3 Department of Cardiovascular Surgery, La Pitié Salpêtrière Hospital, Paris, France

4 Groupement des Hôpitaux de l’Institut Catholique de Lille, Faculté Libre de Médecine, Cardiology Department, Université Catholique de Lille, Lille, France

5 Division of Cardiovascular Surgery and Geneva Hemodynamic Research Group, Geneva University Hospitals, Geneva, Switzerland

Corresponding author:Pierre V Ennezat, Centre Hospitalier Universitaire de Grenoble, Department of Cardiology, BP 217, 38043 Grenoble Cedex 09, France. Email: ennezat@yahoo.com

560504 ACC0010.1177/2048872614560504European Heart Journal: Acute Cardiovascular CareEnnezat et al.research-article2014

Review

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2 European Heart Journal: Acute Cardiovascular Care

outcome.1,7,8 The use of Forrester classification, electrocar-diogram (EKG) findings, laboratory data and bedside Doppler echocardiography allows for an individualised and tailored therapeutic management in a majority of AHF patient.9,10 However, tailored therapy based on right heart catheterisation findings has not been shown to translate into clinical benefits in randomised trials. Right heart catheterisa-tion may be preferentially performed in patients who fail to improve with standard intravenous loop diuretic and vasodi-lator therapy.11,12 When AHF results from ongoing docu-mented myocardial ischaemia, the treatment needs to be primarily targeted at relief of ischaemia. Systolic blood pres-sure (SBP) has been shown to have a large impact on AHF outcomes. Mortality rate at 2–3 months is 5% in patients when SBP is greater than 160 mm Hg on admission, 7% when SBP is between 120–160 mm Hg and 14% when SBP is lower than 120 mm Hg.13 In addition to blood pressure, the treatment of AHF is adjusted for patient age, heart fail-ure (HF) aetiology, severity and nature of left ventricular (LV) and right ventricular (RV) dysfunction and comorbid conditions (diabetes, chronic renal failure, anaemia, obesity, chronic obstructive pulmonary disease and peripheral vas-cular disease). Initial management aims at relieving pulmo-nary congestion and shortness of breath while assessing patients for end organ hypo-perfusion and causes of acute decompensation (arrhythmias, pulmonary or urinary infec-tions, non-adherence to medical regimen). In the absence of hypotension, first-line therapy consists of loop diuretics and vasodilators. Alternative strategies for fluid removal, like nesiritide, endothelin, vasopressin or adenosine antagonists and veno-venous ultrafiltration, have been disappointing overall.14–17 After a brief overview of essential therapeutic targets in AHF, the present review will focus on recent ran-domised trials of loop diuretic therapy in AHF and newer interventions for fluid removal and cardiac unloading (see Appendix 1 for details of trials).

Therapeutic targets in AHF

The pathophysiology of AHF has been extensively reviewed.4 Besides fluid overload, increased vascular stiff-ness and resistance play a key role in the pathophysiology of AHF.1,7,18 Activation of vaso-constrictive pathways (sympathetic nervous system, angiotensin, endothelin and vasopressin) increases pulmonary and peripheral vascular resistances, aortic impedance and thereby lowers ventricu-lar performance and results in ‘afterload mismatch’.7,18,19 The resulting steep increase in left ventricular (LV) filling pressure and alveolo-capillary barrier damage20 contributes to pulmonary capillary fluid extravasation and pulmonary congestion and thereby hypoxia. Of note, low albumin level may also play a role in alveolar leakage.21 Activation of vasoconstrictive pathways shunts venous blood to the heart, thus increasing right atrial pressure (RAP) and RV

preload. Increased RAP also reduces the pressure gradient across the renal vasculature (mean BP minus RAP) and thereby renal filtration.22 Risk factors for worsening renal function (acute kidney injury) include a background of hypertension and diabetes, a low-pressure gradient across the renal vasculature and the presence of incipient renal disease.23,24 Furthermore acute kidney injury and the devel-opment of loop diuretic resistance impede fluid removal in AHF.25 Patients with AHF usually but not always present with elevated systemic vascular resistances. Patients with large acute myocardial infarction or advanced heart failure may occasionally present in AHF with a systemic inflam-matory syndrome that markedly lowers systemic vascular resistances and requires the use of vasopressor agents to maintain a mean BP≥65 mm Hg.8,26

Fluid accumulates over a period of 1–2 weeks, with steady weight gain that precedes symptomatic deteriora-tion in the majority of AHF patients.27 Alternatively, patients may experience acute symptomatic deterioration without weight gain when heightened sympathetic activa-tion mobilises the venous reservoir into the circulation where the increased effective circulatory volume begets pulmonary congestion.3,7,18 Contributing factors to fluid accumulation such as excessive sodium intake, use of non-steroidal agents and acute kidney injury need to be addressed.

Diuretics

Loop diuretics

The aim of diuretic therapy is steady and progressive fluid removal without deterioration of renal function. Meta-analysis of small and relatively heterogeneous studies sug-gested that continuous administration of loop diuretics results in a more abundant diuresis and has a greater safety profile than bolus administration of loop diuretics.28 However, the Diuretic Optimization Strategies Evaluation (DOSE) trial found no significant difference in efficacy or safety between both approaches in 308 AHF patients.29 The high dose strategy (773 mg/72 h) when compared to the low-dose strategy (358 mg/72 h) was associated with a larger diuresis and favourable effects on secondary end-points at the expense of a transient renal function worsen-ing. The Dopamine in Acute Decompensated Heart Failure II (DAD-HF II) trial showed similar clinical efficacy of (a) high-dose furosemide (20 mg/h for 8 h), (b) low-dose furo-semide (5 mg/h for 8 h), and (c) low-dose furosemide com-bined with low-dose dopamine (5 μg/kg/min) in 161 randomised patients hospitalised for acute decompensated heart failure (ADHF).30 The ubiquitous role of loop diuret-ics in AHF management and the scarcity of relevant data mandate further investigation of their immediate and long-term effects.

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Ennezat et al. 3

Adjunct therapy with thiazide diuretics and aldosterone receptor antagonists

Combination diuretic therapy is often attempted in patients who have failed to respond to loop diuretics despite adequate systemic arterial pressure. Thiazide-type diuretics act on the distal convoluted tubule. When given in combination with a loop diuretic thiazide type diuretics have been reported to enhance diuresis and natriuresis.31 Spironolactone, an aldos-terone receptor antagonist, is often prescribed in combina-tion with loop diuretics with the goal of alleviating potassium depletion. However, the combination of loop diuretics with thiazide type diuretics or aldosterone receptor antagonists has not been evaluated in placebo-controlled therapeutic trials.32

Ultra filtration

Veno-venous ultrafiltration (UF) is an emerging alternative approach to loop diuretic therapy for fluid removal in AHF. It presumably has the following advantages over loop diu-retic therapy: (a) precise rate of fluid removal, (b) greater sodium loss and (c) lesser neuro-hormonal activation.33,34 The pilot Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial compared UF to standard care (furosemide 160 mg) in 40 patients with ADHF. Although fluid removal was greater in the UF arm, weight loss was similar at 24 h in patients who underwent UF and in those who received standard care. Patients who were assigned to UF had also received 80 mg of furosemide.33 The Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial enrolled 200 patients with ADHF.34 The UNLOAD trial showed that UF alone improved weight loss at 48 h (5.0 vs 3.1 kg, p<0.001), decreased the need for vasoactive drugs (3% vs 13%, p=0.02), and reduced the rate of hospital rehospitalisations at 90 days (18% vs 32%, p=0.02) com-pared to diuretic therapy with 181 mg of furosemide over 48 h.34 In contrast the CARRESS study (Effectiveness of Ultrafiltration in Treating People with Acute Decompensated Heart Failure and Cardiorenal Syndrome), a NIHBLI spon-sored trial, randomised 188 patients with ADHF and type 1 cardio-renal syndrome. The use of a stepped pharmaco-logic-therapy algorithm was superior to UF (without diu-retic) for the preservation of renal function at 96 h, with a similar weight loss and a lower rate of adverse events than UF.14 The risks associated with venous access and systemic anticoagulation are UF-related issues that need to be explored in larger patient cohorts. The Aquapheresis versus Intravenous Diuretics and Hospitalizations for Heart Failure (AVOID-HF) trial, which is enrolling 810 patients in 40 sites in the USA, is testing whether UF, as compared with intravenous diuretics before worsening renal function, reduces hospitalisations for ADHF.35 At present, UF may

be considered when loop diuretic therapy fails to resolve fluid accumulation (level of evidence C).36

Vasodilating agents

Low dose dopamine (2 μg/kg/min) produces intra-renal arterial vasodilation mediated by dopaminergic D1 recep-tors stimulation. The use of dopamine at low dose has been advocated to enhance diuresis. In the small Dopamine in Acute Decompensated Heart Failure (DAD-HF) trial low-dose furosemide combined to low-dose dopamine was as effective as high-dose furosemide and associated with a lower rate of worsening renal function.30 The larger DAD-HF II trial failed to find any benefit of adding dopa-mine to furosemide.37 In the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE AHF) trial, low-dose dopamine did not enhance diuresis or improve renal function when added to diuretic therapy in patients with AHF and renal dysfunction.38 In the absence of evidenced based data, intravenous administration of low dose dopa-mine may be viewed as a last attempt at pharmacological fluid removal before veno-venous UF in patients who fail to respond to loop diuretic therapy.10

Nitrates are nitric oxide donors that produce venodila-tion at very low doses, thereby reducing cardiac preload and relieving pulmonary congestion. At higher doses nitrates dilate arteriolar vessels, lower systemic vascular resistance, reduce mitral/aortic regurgitation and improve forward stroke volume in patients with severe LV systolic dysfunction.10,39 Nitrates increased sublingual microvascu-lar perfusion in patients with AHF.40 In a randomised trial, intravenous boluses of high dose isosorbide dinitrate and low dose furosemide were more effective at 12 h than intra-venous boluses of high dose furosemide and low dose isosorbide dinitrate in 104 patients with acute pulmonary oedema.41 Attenuation of haemodynamic benefits have been reported with prolonged administration of nitroglyc-erin. However, concomitant administration of hydralazine may prevent tachyphylaxis to nitroglycerin.42,43 Patients with AHF and minimal or no weight change are the most suitable candidates (reduced venous capacitance and heightened arterial elastance) for combined therapy with low dose furosemide and high dose nitrates. Overall meta-analyses of reports regarding nitrates therapy for AHF did not reveal an increased rate of adverse events.44 Compared to nesiritide, nitroglycerin exerts similar haemodynamic effects and reductions in plasma levels of brain natriuretic peptide (BNP) without affecting renal function.45 Owing to a tolerance phenomenon, up-titration of nitrates is needed over time and increased production of reactive oxygen spe-cies (ROS) may be of concern with prolonged nitrates administration.46 Given these issues prolonged monother-apy with nitrates is not recommended. Short-term therapy with nitrates may be of use in the management of AHF as it lessens the need for loop diuretic therapy.10

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4 European Heart Journal: Acute Cardiovascular Care

Nitroprusside a potent arterial and venous vasodilator is useful in patients with AHF and severe hypertension. When carefully titrated and closely monitored, nitroprusside sel-dom produces thiocyanate toxicity.47,48 Due to the risk of ‘coronary steal’ nitroprusside may be detrimental in patients with recent myocardial infarction.49 Safe nitropusside administration requires invasive monitoring of arterial pressure and serial thiocyanate level determinations.

Morphine is an adjunctive therapy in AHF. Morphine produces venodilation and anxiety relief. However it should be avoided in patients with unclear diagnosis, impaired mental status or respiratory drive.

Nesiritide is a recombinant BNPBNP. Nesiritide pro-duces dose-dependent reductions in filling pressure, sys-temic and pulmonary vascular resistance, while increasing cardiac output in patients with LV systolic dysfunction. Promising results were initially observed in the efficacy trial of the Nesiritide Study Group.50 Compared to placebo and low dose nitroglycerin in the Vasodilatation in the Management of Acute CHF (VMAC) trial nesiritide was associated with a greater decrease in pulmonary capillary wedge pressure at 3 and 24 h.51 When compared to placebo, nesiritide improved dyspnoea at 3 h. However, meta-analy-ses of randomised trials suggested that nesiritide, was asso-ciated with a greater rate of worsening renal function and early death than placebo. The recent large placebo con-trolled Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial showed that nesiritide does not improve dyspnoea and does not affect mortality and morbidity as evidenced by unchanged rate of HF re-hospitalisations and renal func-tion.52 The ROSE-AHF trial evaluated the efficacy low dose nesiritide in patients with AHF and kidney dysfunc-tion (estimated glomerular filtration rate (eGFR) 15–60 ml/min/m²).38 Low-dose nesiritide did not enhance fluid removal or improve renal function when added to loop diu-retic therapy. Accordingly, nesiritide is no longer used in the treatment of HF.

Relaxin-2 is a naturally secreted peptide hormone dur-ing pregnancy. Relaxin-2 dilates systemic and renal vascu-lar beds, and has anti-inflammatory, anti-fibrotic and pro-angiogenic effects. Relaxin exerts its effects through cyclic AMP and nitric oxide stimulation and activation of the endothelin type B receptor.53 Serelaxin, a recombinant form of human relaxin-2, yielded promising haemody-namic and neurohormonal effects in phase II studies. In the larger placebo controlled serelaxin, recombinant human relaxin-2, for treatment of Acute Heart Failure (RELAX-AHF) trial, a 48 h infusion of serelaxin (30 μg/kg/d) improved dyspnoea and resulted in lower 180-day mortal-ity in AHF patients with a SBP greater than 125 mm Hg who were not receiving nitrates or nitroprusside therapy.54 The adequately powered RELAX-AHF2 randomised trial is now assessing the mortality benefit of serelaxin against placebo. Cardiovascular mortality during at 180 days is the

primary endpoint of RELAX-AHF2. Serelaxin has not yet been approved for AHF in the US and Europe.

Tezosentan, a non-selective antagonist of the endothe-lin-1 receptor, was found to reduce LV filling pressure, sys-temic vascular resistances and plasma BNP levels in the Randomized Intravenous TeZosentan (RITZ) trials.55 However the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Study (VERITAS) was prematurely terminated because of a low probability of achieving a significant treatment effect. Compared to pla-cebo, intravenous administration of tesozentan (5 mg/h for 30 min, followed by 1 mg/h for 24–72 h) did not improve dyspnoea or survival, and did not affect the rate of worsen-ing heart failure at seven days.56 Tezosentan is not currently used for AHF.

Tolvaptan and conivaptan are arginine vasopressin receptor antagonists that block V2 and V1a/V2 receptors respectively in the collecting ducts of the nephron. Tovalptan and conivaptan promote the loss of electrolyte free water or aquapheresis.57 Tolvaptan and conivaptan deter the systemic effects of arginine vasopressin in HF that are directly related to HF severity and contribute to vaso-constriction, hyponatraemia, aldosterone release and ven-tricular remodelling.58 Short-term treatment with arginine vasopressin receptor antagonists including tolvaptan and conivaptan improved fluid management and haemodynam-ics.59 Fluid excretion achieved with these agents has been associated with improved renal function and electrolyte balance compared with loop diuretic administration. With tolvaptan, the efficacy of selective vasopressin V2 receptor antagonism was evaluated in the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST) trial.16 Tolvaptan did not alter long term outcome (all-cause mortality, cardiovascular mortality or subsequent HF hospitalisations) despite favourable effects on body weight and serum sodium.16,57 Conivaptan, which combines V1a/V2 receptor antagonism, reduces car-diac loading conditions. The long-term effects of conivap-tan have not been studied.60

Rolofylline is an adenosine A1−receptor antagonist. It blocks A1-adenosine receptors in the renal afferent arteri-oles. Increased intra-renal adenosine concentration has been associated with worsening renal function and diuretic resistance. Hydrolysis of ATP releases free adenosine into the extracellular space. The resulting activation of adeno-sine A1 receptors lowers renal blood flow and glomerular filtration rate (GFR) thereby stimulating release of renal renin. In addition, A1-receptor activation enhances proxi-mal tubular sodium reabsorption. In patients with CHF, A1-receptor antagonists may enhance sodium excretion, and improve diuretic responsiveness while preserving GFR.61,62 Efficacy of rolofylline in patients with AHF and impaired renal function (eGFR ranging from 20–80 ml per min using Cockcroft−Gault equation), was evaluated in the Placebo-Controlled Randomized Study of the Selective A1

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Ennezat et al. 5

Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial.15 Daily intravenous rolofylline (30 mg) for up to three days compared to pla-cebo did not improve symptoms, survival or HF hospitali-sations. The rolofylline development program has been terminated.

Ularitide is the synthetic version of urodilatin, the renal natriuretic peptide (NP) which is released by renal tubular cells and regulates renal sodium and water excretion. Through guanylate cyclase activation ularitide is associated with pre-glomerular vasodilation and post-glomerular vasoconstriction, thereby increasing GFR. In the phase II Safety and Efficacy of an Intravenous Placebo-Controlled Randomized Infusion of Ularitide in a Prospective Double-blind Study (SIRIUS) trial, ularitide at 15 ng/kg/min low-ered serum blood urea nitrogen (BUN), increased cardiac output, and preserved the mean BP-RAP pressure gradient; thereby enhancing renal perfusion.63 Phase III URGENT (n>3000) and Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure (TRUE-AHF) (n=2116) trials are ongoing. Specifically TRUE-AHF is a randomised double blind placebo-controlled trial with two co-primary efficacy endpoints including cardio-vascular mortality for the entire duration of the trial and a composite one at short term (48 h).

Other vasodilators that activate soluble guanylate cyclase like a chimeric natriuretic peptide C-D and cinaciguat exerting potent venous and arterial vasodilation are currently being evaluated.64,65

Negative trials and methodological issues

Overall none of the recent trials of new therapeutic modali-ties have shown a definite improvement over existing thera-pies. Thus at the present time none of the agents under investigation appears to have a clear advantage over current therapy. Such negative results may truly reflect the lack of novel efficacious agents for the pharmacological treatment of AHF. Alternatively the failure to demonstrate the efficacy of novel agents may reflect methodological issues. As above mentioned, AHF is a complex and heterogeneous condition with a multitude of pathological processes, underlying mechanisms, patient phenotypes, de novo versus recurrent AHF and end-organ malfunctions. The likelihood of observ-ing a statistical difference between two interventions is hin-dered by the complexity and heterogeneity of AHF as a given intervention may not benefit the whole AHF popula-tion. Therapies that aim at fluid removal and/or cardiac unloading can only benefit patients who have no systemic hypotension with clear evidence of fluid accumulation. Any attempt at fluid removal or cardiac unloading is likely to be detrimental in patients with hypotension, low cardiac output

and minimal fluid accumulation. Thus better identification of the AHF phenotype that may respond to a given interven-tion is essential to ensure therapeutic success. At the present time novel therapies for AHF are investigated without con-cerns for AHF phenotypes.

More importantly, in none of the above mentioned thera-peutic trials was an effort was made to elucidate the cas-cade of events that led to the acute presentation. It is well accepted that resuming medications consistently results in symptomatic improvement in patients who, non-adherent to medications, are hospitalised for AHF. Assuming that such patients represented a substantial proportion of the therapeutic trial population, this in fact decreased the trial population by half as such patients were likely to respond equally well to the strategies under investigation. In other terms, sample size calculation is blemished by the propor-tion of patients who due to the nature of the intervention at hand are unlikely to experience a beneficial response to the intervention. The negative results of these rigorously con-ducted but inadequately designed trials of fluid removal and vasodilation in AHF were not entirely unexpected.

Conclusion

Fluid retention and excessive cardiac loading conditions are the hallmark of the syndrome of AHF. Management of AHF remains empirical in the absence of evidence based data. Vasodilation and fluid removal are the corner stone of man-agement. Use of a loop diuretic is the preferred modality for fluid removal. Treatment failures are in most instances related to underestimation of fluid retention and premature discontinuation/down-titration of intravenous loop diuretic therapy. Manipulation of excessive cardiac loading condi-tions presently entails oral administration of nitrates or intravenous administration of nitroglycerin or nitroprusside. Tachyphylaxis hinders the use of nitroglycerin and the need for close arterial pressure monitoring hampers the use of nitroprusside. Serelaxin and uralitide are promising endog-enous vasodilatory hormones under investigation for the treatment of AHF. In contrast to past experience, newer tri-als have long-term mortality as the primary endpoint.

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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32. Eng M and Bansal S. Use of natriuretic-doses of spironolac-tone for treatment of loop diuretic resistant acute decompen-sated heart failure. Int J Cardiol 2014; 170: e68–e69.

33. Bart BA, Boyle A, Bank AJ, et al. Ultrafiltration versus usual care for hospitalized patients with heart failure: The Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial. J Am Coll Cardiol 2005; 46: 2043–2046.

34. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007; 49: 675–683.

35. Costanzo MR. Study of heart failure hospitalizations after aquapheresis therapy compared to intravenous (IV) diuretic treatment (AVOID-HF), http://clinicaltrials.gov/ct2/show/NCT01474200

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38. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopa-mine or low-dose nesiritide in acute heart failure with renal dysfunction: The ROSE acute heart failure randomized trial. JAMA 2013; 310: 2533–2543.

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40. Den Uil CA, Lagrand WK, Spronk PE, et al. Low-dose nitroglycerin improves microcirculation in hospitalized patients with acute heart failure. Eur J Heart Fail 2009; 11: 386–390.

41. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosem-ide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998; 351: 389–393.

42. Münzel T, Kurz S, Rajagopalan S, et al. Hydralazine pre-vents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest 1996; 98: 1465–1470.

43. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enal-april with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–310.

44. Wakai A, McCabe A, Kidney R, et al. Nitrates for acute heart failure syndromes. Cochrane Database Syst Rev 2013; 8: CD005151.

45. Chow SL, O’Barr SA, Peng J, et al. Renal function and neurohormonal changes following intravenous infusions of nitroglycerin versus nesiritide in patients with acute decom-pensated heart failure. J Cardiac Fail 2011; 17: 181–187.

46. Gori T and Parker JD. Nitrate tolerance: A unifying hypoth-esis. Circulation 2002; 106: 2510–2513.

47. Mullens W, Abrahams Z, Francis GS, et al. Sodium nitro-prusside for advanced low-output heart failure. J Am Coll Cardiol 2008; 52: 200–207.

48. Linakis JG, Lacouture PG and Woolf A. Monitoring cya-nide and thiocyanate concentrations during infusion of sodium nitroprusside in children. Pediatr Cardiol 1991; 12: 214–218.

49. Cohn JN, Franciosa JA, Francis GS, et al. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure. N Engl J Med 1982; 306: 1129–1135.

50. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesir-itide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med 2000; 343: 246–253.

51. VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA 2002; 287: 1531–1540.

52. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011; 365: 32–43.

53. Teichman S, Unemori E, Teerlink J, et al. Relaxin: Review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010; 7: 75–82.

54. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recom-binant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): A randomised, placebo-controlled trial. Lancet 2013; 381: 29–39.

55. Cotter G, Kaluski E, Stangl K, et al. The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure. Eur J Heart Fail 2004; 6: 601–609.

56. McMurray JJ, Teerlink JR, Cotter G, et al. Effects of tezos-entan on symptoms and clinical outcomes in patients with acute heart failure: The VERITAS randomized controlled tri-als. JAMA 2007; 298: 2009–2019.

57. Gheorghiade M, Konstam MA, Burnett JC, et al. Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clini-cal effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007; 297: 1332–1343.

58. Goldsmith SR and Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005; 46: 1785–1791.

59. Gheorghiade M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA 2004; 291: 1963–1971.

60. Goldsmith SR, Elkayam U, Haught WH, et al. Efficacy and safety of the vasopressin V1A/V2-receptor antagonist conivaptan in acute decompensated heart failure: A dose-ranging pilot study. J Cardiac Fail 2008; 14: 641–647.

61. Dittrich HC, Gupta DK, Hack TC, 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 Cardiac Fail 2007; 13: 609–617.

62. Gottlieb SS, Brater DC, 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.

63. Lüss H, Mitrovic V, Seferovic PM, et al. Renal effects of ula-ritide in patients with decompensated heart failure. Am Heart J 2008, 155: 1012.e1–8.

64. Erdmann E, Semigran MJ, Nieminen MS, et al. Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart fail-ure. Eur Heart J 2013; 34: 57–67.

65. McKie PM, Sangaralingham SJ and Burnett JC Jr. CD-NP: An innovative designer natriuretic peptide activator of par-ticulate guanylyl cyclase receptors for cardiorenal disease. Curr Heart Fail Rep 2010; 7: 93–99.

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8 European Heart Journal: Acute Cardiovascular Care

App

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01)

by guest on November 21, 2014acc.sagepub.comDownloaded from

Ennezat et al. 9

Des

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out

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Ren

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chan

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ded

to

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24 h

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PCW

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m H

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ca

thet

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mm

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add

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need

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ntro

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in

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at 6

an

d 24

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posi

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App

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x 1.

(C

ontin

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(Con

tinue

d)

by guest on November 21, 2014acc.sagepub.comDownloaded from

10 European Heart Journal: Acute Cardiovascular Care

Des

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nIn

clus

ion

crite

ria

Mea

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e♀

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1161

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125

mm

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M

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n=20

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a m

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f 60

days

4133

LV E

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m

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with

hy

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and

gr

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r w

eigh

t lo

ss in

pa

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s as

sign

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lvap

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PR

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trav

enou

s ro

lofy

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to

3 d

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2033

Estim

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cre

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clea

ranc

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20–8

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min

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use

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7033

32%

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succ

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trea

tmen

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ath

or wor

seni

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failu

re

or r

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func

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or

no

chan

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the

pat

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cond

ition

.

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0.8%

pat

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s in

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ro

lofy

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grou

p ha

d se

izur

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CI:

card

iac

inde

x; G

FR: g

lom

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ltrat

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rate

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hea

rt fa

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; HD

F: h

igh

dose

furo

sem

ide;

LD

F: lo

w d

ose

furo

sem

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LD

FD: l

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furo

sem

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and

low

-dos

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pam

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LV

EF: l

eft

vent

ricu

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ejec

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frac

tion;

MD

RD

: Mod

ifica

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dis

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; NS:

non

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ant;

PCW

P: p

ulm

onar

y ca

pilla

ry w

edge

pre

ssur

e; S

BP: s

ysto

lic b

lood

pre

ssur

e; U

F: u

ltraf

iltra

tion.

App

endi

x 1.

(C

ontin

ued)

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