Pharmacologic Therapies for Chronic and Acute Decompensated Heart Failure: Specific Insights on Cardiorenal Syndromes

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Blood Purif 2014;37(suppl 2):20–33 DOI: 10.1159/000361061

Pharmacologic Therapies for Chronic and Acute Decompensated Heart Failure: Specific Insights on Cardiorenal Syndromes

Francois Roubille a, h Marion Morena b, e, f Hélène Leray-Moragues c

Bernard Canaud g, i Jean-Paul Cristol b, e, f Kada Klouche d, f

Departments of a Cardiology, b Biochemistry, c Nephrology and d Intensive Care Department, CHRU Montpellier, e Dialysis Research and Training Institute, f UMR 204, Nutripass, University of Montpellier I, and g University of Montpellier I, UFR Médecine, h Inserm U1046, University of Montpellier I, Montpellier , France; i Medical Board, Fresenius Medical Care, Bad Homburg , Germany

derlining that a multidisciplinary approach to a deeper un-derstanding of the pathophysiology of CRS is still required to improve specific treatment and clinical outcome.

© 2014 S. Karger AG, Basel

Introduction

Cardiac diseases are independently associated with a decrease in kidney function and progression of existing kidney diseases [1] . Both acute and chronic heart dys-function may induce renal dysfunction leading to cardio-renal syndrome(s) (CRS) [2–5] .

Acute or type 1 CRS is defined as acute worsening of cardiac function, in settings of acute decompensated heart failure (ADHF) or cardiogenic shock, leading to renal dysfunction (acute kidney injury). Acute kidney injury is defined as an increase in serum creatinine of ≥ 0.3 mg/dl or 26.4 μmol/l or ≥ 1.5- to 2-fold from base-line, and/or urine output <0.5 ml/kg/h for >6 h [6] . Flu-id overload and venous congestion are considered as key factors in the mechanism of renal function alteration ( fig. 1 ).

Key Words

Cardiorenal syndromes · Acute and chronic heart failure · Therapeutics · Anemia

Abstract

In the setting of cardiorenal syndrome(s) (CRS), the main pathophysiological triggers of renal disease progression in-clude increases in renal venous pressure, maladaptive acti-vation of the renin-angiotensin-aldosterone (RAAS) and the sympathetic nervous systems, and a chronic inflammatory state. In acute decompensated heart failure (HF)/type 1 CRS, diuretics remain the mainstay of first-line therapy in order to prevent congestion and renal venous hypertension. In chronic HF/type 2 CRS, RAAS multiple inhibition has been recommended in addition to diuretics. However, cotreat-ment with angiotensin-converting enzyme inhibitors/an-giotensin receptor blockers and mineralocorticoid receptor antagonists is likely to lead to more frequent occurrences of hyperkalemia and worsening renal function. In this review, the main pharmacological therapies of acute and chronic CRS are discussed regarding their indication as well as in-tended and side effects. Future therapies are suggested, un-

Published online: July 31, 2014

Prof. Kada Klouche Intensive Care Department, CHRU Montpellier 371 Avenue du Doyen Gaston Giraud FR–34295 Montpellier (France) E-Mail k-klouche @ chu-montpellier.fr

© 2014 S. Karger AG, Basel0253–5068/14/0376–0020$39.50/0

www.karger.com/bpu

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Pharmacological Management of Chronic and Acute CRS

Blood Purif 2014;37(suppl 2):20–33DOI: 10.1159/000361061

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Chronic or type 2 CRS is defined as chronic abnor-malities in cardiac function leading to renal dysfunction [3–5] . Pathophysiology is mainly a chronic activation of the renin-angiotensin-aldosterone (RAAS) and sympa-thetic nervous systems induced by arterial underfilling and/or venous congestion. In association with activation

of inflammatory pathways, it leads to progressive glomer-ulosclerosis and tubular fibrosis and atrophy [7] ( fig. 2 ).

The prevalence of CRS is likely to increase because of the common risk factors such as hypertension, diabetes, and atherosclerosis, and the improved survival of heart failure (HF) patients [8, 9] . Its occurrence is associated

AKIADHF

Chronic cardiacdysfunction

RAAS and AR blockadeAntialdosterone

Diuretics, vasodilators

Iron, ESA

Chronic worseningof renal function

• Chronic renal hypoperfusion• Tubular fibrosis• Tubular atrophy• Glomerulosclerosis

• Arterial underfilling• Decreased CO and effective circulating volume• Chronic neurohormonal activation (RAAS and sympathetic tone)• Venous congestion• Inflammatory pathways

Fig. 1. Pathophysiology and pharmacological management of acute CRS (type 1). AKI = Acute kidney injury;AR = angiotensin receptor; CO = cardiac output.

Fig. 2. Pathophysiology and pharmacological management of chronic CRS (type 2). AR = Angiotensin receptor; CO = cardiac output.

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with significantly worse outcomes [8–11] . The medical management of patients with concomitant heart and re-nal failure remains a challenge because current therapies for HF that are targeted to improve myocardial function and hemodynamic balance may have potential deleteri-ous effects on renal function. While clinical guidelines for managing HF [12] are well established, those for CRS are still lacking.

This review focuses on types 1 and 2 CRS pharmaco-logical management therapies in the light of the recent clinical advances and trials in this field.

Acute CRS (Type 1)

Fluid retention is a key feature of acute HF and acute CRS (type 1). The conventional explanation for acute CRS has revolved around hypotension with decreased cardiac output, neurohormonal activation, and renal hypoperfu-sion. Recent evidence, however, has established that renal congestion, renal venous hypertension, and raised intra-abdominal pressure – fluid overload – are more important contributors to kidney function impairment [13] . Thera-peutic strategies aim to control fluid balance and to shift fluid out of the interstitium, leading to significant relief and improved health-related quality of life. The blockade of RAAS, which may contribute to worsening renal func-tion, should be withheld or delayed in order to maintain the glomerular filtration rate (GFR) (see fig. 1 ).

Diuretics: Avoiding Congestion The treatment of fluid retention was revolutionized

with the development of thiazide diuretics in the 1950s [14] and loop diuretics in the 1960s [15] . The clinical ev-idence for the efficacy of diuretics in reducing the symp-toms of HF is based on clinical experience and relatively small randomized studies. Most clinical practice guide-lines on the management of HF have given diuretic ther-apy as a ‘class I’ recommendation (beneficial, effective or useful treatment) based on expert opinion for relief of symptoms of congestion in patients presenting with fluid retention [12, 16] . The goal of diuretic use should be to deplete the intravascular component of the extracellular fluid volume at a rate that allows for adequate refilling from the interstitial space in order to avoid precipitous intravascular volume depletion with hypotension and de-crease in tissue perfusion.

There are 4 pharmacological classes of diuretics used in HF: loop diuretics (furosemide, bumetanide, torase-mide, ethacrynic acid), thiazide diuretics (hydrochlo-

rothiazide, bendroflumethiazide, or the ‘thiazide-like’ metolazone), directly acting potassium-sparing diuretics (amiloride and triamterene), and mineralocorticoid re-ceptor antagonists (MRAs; spironolactone, canrenoate, and eplerenone).

Aldosterone receptor antagonists are mainly used at low doses as neurohormonal blockers rather than as di-uretics per se. Their diuretic effects are sometimes used in patients with right-sided HF, liver impairment, and as-cites. Potassium-sparing diuretics, such as amiloride, produce a mild or weak diuretic effect (by blocking the Na + /K + exchange pump in the distal tubule), and are therefore mainly used in combination with thiazide or loop diuretics to prevent hypokalemia. Both aldosterone receptor antagonists and potassium-sparing diuretics may induce hyperkalemia, particularly in patients with renal dysfunction [17] .

Thiazide diuretics act on the distal tubule causing a slower onset (1–2 h) and a more prolonged (12–24 h) but milder diuretic effect compared to loop diuretics. They are largely ineffective if the GFR is <30 ml/min, but they may be useful in combination with a loop diuretic in pa-tients who have refractory edema. Thiazides are more likely to result in hypokalemia and nocturia.

Loop diuretics are the most commonly used diuretics for HF, especially in CRS with acute renal dysfunction. They act on the ascending limb of the loop of Henle, blocking the reabsorption of up to 20–30% of filtered Na + . They have a rapid onset of action: only a few minutes when given intravenously or within 30 min when given orally [18] . As their action is usually of short duration, they may be given several times a day to maintain the di-uretic effect and to minimize rebound sodium reabsorp-tion. All loop diuretics are roughly equivalent in terms of efficacy, but oral bumetanide has higher bioavailability. Bumetanide is also more potent than furosemide, with a 1/40 dose equivalence. It undergoes, like torasemide, he-patic elimination as opposed to the renal elimination fu-rosemide has (likely to accumulate in case of renal func-tion impairment). All loop diuretics, particularly furose-mide, lead to a rapid increase in venous capacitance and a decline in cardiac filling pressure, coincident with a rise in plasma renin activity [19] . These systemic hemody-namic changes are unrelated to the degree and extent of the induced natriuresis. All loop diuretics possess some ototoxicity.

Placebo-Controlled Trials of Diuretics Randomized trials of diuretics in acute HF are limited

and have mostly included small numbers of patients. All

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of the trials have reported that diuretics significantly im-proved symptoms in HF, but were unable to clearly demonstrate any effect on mortality [20–22] . Nonethe-less, loop diuretics are more effective than thiazides alone in the management of HF, and international guidelines do not favor one loop diuretic over another [12, 16] .

Dose of Loop Diuretic From the ESCAPE trial database, Binanay et al. [23]

analyzed the relation between diuretic dose and outcomes in patients with severe chronic HF admitted for acute de-compensation [24] . They found that weight loss was in-dependent of the diuretic dose and that increasing the dose was associated with increases in serum creatinine and more importantly with increased risk of 6-month mortality. Previous studies of chronic HF patients have also shown an independent association between diuretic use and increased mortality [25] . However, higher diuret-ic use could have been a marker of severity and higher mortality rather than their cause. Indeed, the Diuretic Optimization Strategies Evaluation (DOSE), a large pro-spective double-blind randomized trial, evaluated diuret-ic dose and strategy in ADHF [26] . The trial randomized 308 ADHF patients to intravenous furosemide given as twice-daily boluses or continuous infusion, with either a low or high dose. No significant difference was found in global assessment of symptoms or change in serum cre-atinine over 72 h with diuretic administration by bolus or continuous infusion or with a low- versus a high-dose strategy. However, patients with a higher-dose strategy had a significantly more favorable outcome regarding re-lief of dyspnea, change in weight, and net fluid loss, but with a greater risk of serum creatinine increasing by >0.3 mg/dl within 72 h. This would suggest that the strategy of using higher doses of diuretics in ADHF on admission to hospital is likely to more rapidly control fluid retention and to relieve symptoms with a slightly higher risk of re-nal dysfunction not affecting outcome. Other recent re-ports have confirmed the safety of high-dose diuretics in ADHF [27, 28] , but data are not definitive.

Bolus versus Continuous Infusion of Loop Diuretics A Cochrane review that included only small and in-

completely blinded studies concluded that continuous loop diuretic infusion had a modest benefit in regard to urine output and safety. However, recent randomized tri-als have not shown a significant benefit with continuous infusion of furosemide as compared to twice-daily bolus injection [26, 29] .

Diuretic Resistance Patients experience diuretic resistance when higher

doses of diuretics are needed to gain a similar diuretic re-sponse or when the diuretic response is either diminished or lost before the therapeutic goal is reached. It is associ-ated with a poor prognosis and has been reported to occur in up to 1 in 3 hospitalized patients [25, 30] .

Mechanisms involved in diuretic resistance include re-duced GFR (reduced delivery and active secretion of loop diuretics), excessive Na + uptake in the proximal tubule and the loop of Henle secondary to excessive neurohor-monal activation (renin-angiotensin system), and brak-ing phenomenon (rebound excessive Na + reabsorption at both the proximal tubule and loop of Henle when there is no diuretic at action sites like the period between boluses of loop diuretics). Other mechanisms include excessive Na + intake, reduced active secretion of loop diuretic into the proximal tubule, and renal adaptation to chronic di-uretic use (tubule hypertrophy leading to more Na + and water retention than in a diuretic naive patient). Drug interaction with nonsteroidal anti-inflammatory drugs, aspirin, steroids, and pioglitazone may also lead to di-uretic resistance. However, poor compliance with diuret-ics may be misinterpreted as diuretic resistance and should be identified by a precise clinical history.

Strategies employed to overcome this resistance in a patient with ADHF include changing the administration route from oral to intravenous, continuous infusion rath-er than intermittent bolus injections, higher doses of in-travenous loop diuretics to increase the dose reaching the tubules (particularly when renal function is altered), and addition of a thiazide (hydrochlorothiazide, metolazone, etc.) to the loop diuretic [31, 32] . The evidence of a ben-eficial effect from an addition of a renal dose of dopamine (2–3 μg/kg/min), for its cardiac output increase and renal and peripheral vasodilatation [33, 34] , to intravenous fu-rosemide is weak.

The Dopamine in Acute Decompensated Heart Fail-ure (DAD-HF) trial [35] compared continuous high-dose furosemide infusion (20 mg/h) with the combination of low-dose infusion furosemide (5 mg/h) plus low-dose do-pamine (5 mg/kg/min) in 60 patients. A similar effect on total diuresis was observed in both groups, but worsening renal function and hypokalemia were significantly less common in the dopamine group. Length of stay, 60-day mortality, and rehospitalization rates were similar be-tween groups.

The Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial [36] compared the effi-cacy and safety of low-dose dopamine (2 μg/kg/min) ver-

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sus intravenous nesiritide (0.005 μg/kg/min) versus pla-cebo in 360 patients with ADHF and renal dysfunction (GFR: 15–60 ml/mn/1.73 m 2 ) treated with loop diuretics. Neither low-dose dopamine nor low-dose nesiritide en-hanced decongestion or improved renal function when added to diuretic therapy.

Other therapies have been used in addition to loop di-uretics, such as vasopressin 2 receptor antagonists [37] and adenosine antagonists [38] , but have shown mitigated results. The addition of hypertonic saline solution to furo-semide has yielded beneficial hemodynamic and diuretic effects that persist long term [39] . However, this therapeu-tic approach cannot be recommended for clinical practice until further prospective trials have evaluated it.

Finally, when ADHF patients with refractory edema become unresponsive to diuretic therapy, it may be con-sidered for ultrafiltration [12, 40, 41] . In conclusion, di-uretics remain the mainstay of first-line therapy in ADHF in spite of a weak evidence base: loop diuretics with an initial high dose as an intravenous bolus or continuous infusion remains the best strategy, with addition of a thi-azide in case of diuretic resistance and close monitoring of fluid and electrolytes balance.

Vasodilators and Nesiritide Vasodilators (nitrates and nitroprusside) decrease

preload and afterload by reducing ventricular work, in-creasing stroke volume and cardiac output [42] . Though their effects in type 1 CRS have not been studied through randomized controlled trials, they are often used in pa-tients with preserved or elevated blood pressure [43] to relieve symptoms and improve hemodynamics. In a non-randomized trial, the use of nitroprusside showed that it improves outcomes without altering renal function [44] . However, a risk of thiocyanate accumulation exists par-ticularly in patients with impaired renal function [45] .

Nesiritide is a recombinant form of human B-type na-triuretic peptide that decreases preload, afterload, and pulmonary vascular resistance and increases cardiac out-put. By inducing afferent arteriolar vasodilation and a de-crease in Na + reabsorption, it also increases diuresis [46] . However, a meta-analysis of trials in ADHF patients found that nesiritide impaired renal function and in-creased mortality in type 1 CRS [47] . In the recent AS-CEND-HF trial, O’Connor et al. [48] randomized 7,141 ADHF patients to receive either nesiritide or placebo for 24–168 h in addition to standard care, and showed that nesiritide did not affect the rate of death and rehospital-ization, had a nonsignificant effect on dyspnea, and was not associated with a worsening of renal function, but in-

stead with an increase in hypotension rates. Further anal-yses demonstrated that nesiritide did not increase urine output in these patients [49] . At this time, nesiritide can-not be recommended for routine use in ADHF patients.

Arginine Vasopressin Blockade: ‘Aquaresis’ to Potentiate ‘Natriuresis’? Both the V1a and V2 receptors could be involved in

the pathophysiology of acute HF. The V1a receptor, ex-pressed in cardiac and vascular myocytes, causes vaso-constriction [50] , produces positive inotropic effects, and induces protein synthesis [51] leading to hypertrophy. The V2 receptor, expressed in the kidney, induces de novo synthesis and insertion of the aquaporin 2 channel, and appears as a contributing factor to congestion and hyponatremia [52] . Several orally and intravenously ac-tive nonpeptide vasopressin receptor antagonists, known as vaptans, have been developed with different selectivity [53, 54] . For example, relcovaptan (OPC-21268) is a V1a selective antagonist, while nelivaptan (SSR-149415) is a V1b selective antagonist. Lixivaptan (VPA-985), tolvap-tan (OPC-41061), mozavaptan (OPC-31260), and sat-avaptan (SR-121463) are V2 selective antagonists. Final-ly, conivaptan is a V1a and V2 antagonist. It is important to note that all of these compounds are substrates and inhibitors of cytochrome P450 3A4 and should not be used with other drugs known to be metabolized by this system [55] .

Theoretically, a V2 receptor antagonist such as tolvap-tan, which induces ‘aquaresis’, could act synergistically with the diuretic-induced ‘natriuresis’ to prevent conges-tion and normalize serum sodium. From preclinical stud-ies, it was concluded that vaptan induces free water excre-tion without stimulating the RAAS, while furosemide causes sodium excretion and RAAS activation, and the effects of combination therapy might be additive and complementary.

In 2002, Udelson et al. [56] conducted the first place-bo-controlled trial of tolvaptan in congestive HF patients, showing that tolvaptan increased urinary output, nor-malized serum sodium levels, and reduced signs and symptoms of congestion. This result was confirmed by the SALT study [57] showing that 30 days of tolvaptan treatment in 445 patients (35% HF) results in an increase in serum sodium in euvolemic and hypervolemic hypo-natremia, which is not sustained following treatment ter-mination. Similar results could be obtained with another V2 receptor antagonist, lixivaptan, in patients with New York Heart Association (NYHA) class III congestive HF and normal or low serum sodium levels [58] .

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The ECLIPSE trial examined acute hemodynamics af-ter a single dose of tolvaptan in 181 HF patients with a left ventricular ejection fraction (LVEF) <40%. The results suggest that tolvaptan reduces pulmonary capillary wedge pressure and decreases filling pressure without adversely affecting blood pressure or renal function [59] .

The ACTIV trial (Acute and Chronic Therapeutic Im-pact of a Vasopressin Antagonist in Congestive Heart Failure) was designed to assess the short- and long-term effects of tolvaptan treatment on patients hospitalized for worsening HF [60] . Placebo, or 30, 60, or 90 mg of tolvap-tan were given in addition to standard therapy. Consis-tent with previous reports, urinary output increased and an improvement in signs and symptoms of HF was ob-served. No significant improvement in morbidity and mortality was observed except in the subgroup of patients with renal dysfunction and severe systemic congestion at randomization.

The EVEREST trial (Efficacy of Vasopressin Antago-nism in Heart Failure: Outcome Study with Tolvaptan) is the largest study designed to evaluate the potential effect of tolvaptan initiated during hospitalization on morbid-ity and mortality in HF patients. 4,133 patients, hospital-ized for worsening HF, with a LVEF <40% and presenting with >2 signs of fluid overload were included in the study, receiving placebo or 30 mg of tolvaptan. The results con-firm that initiating 30 mg of tolvaptan once daily during hospitalization improved short-term signs and symp-toms of HF (increased urine output, serum sodium, and decreased congestion), but had no effect on long-term HF-related morbidity or mortality. Tolvaptan does not enhance the incidence of hypotension and results in a slight increase in creatinine and decrease in blood urea nitrogen [61] .

In conclusion, vaptans, acting on total body water and not to the extracellular fluid compartment, could be con-sidered as a loop diuretic-sparing approach to acute HF syndrome management or to an attempt to overcome di-uretic resistance [62] . Assuming the deleterious side ef-fects of V1a receptor on cardiac remodeling, nonselective vasopressin inhibition, such as conivaptan, may offer an additional benefit [63, 64] .

Miscellaneous Therapies In type 1 CRS, some patients may have low blood pres-

sure and cardiogenic shock associated with poor renal perfusion. In these instances, positive inotropes such as dobutamine or phosphodiesterase inhibitors may be re-quired. They may, however, induce some harmful effects including additional ischemia and arrhythmia with no

beneficial effects on mortality [65–67] . Levosimendan, a calcium sensitizer, has shown discordant results in terms of prevention and treatment of type 1 CRS [68–70] .

More invasive therapies such as intra-aortic balloon pulsation, ventricular assist devices, or artificial hearts may be indicated as a bridge to recovery of cardiac func-tion or to transplantation.

Agents targeting vasoactive and neurohormonal effec-tor pathways like endothelin, adenosine, and vasopressin have held promise in early clinical trials in type 1 CRS, but subsequent randomized studies were disappointing [37, 71, 72] . The PROTECT trial, a placebo-controlled ran-domized study, provided evidence that rolofylline (a se-lective A1-adenosine receptor antagonist) enhances di-uresis and improves dyspnea, but definitive data did not show any benefit on renal function and outcome [38] . Rolofylline was, in addition, associated with an increased rate of adverse neurologic events like seizures and strokes [73] . Subsequent trials were all negative [74, 75] .

Relaxin is an endogenous peptide active in pregnancy that increases vasodilation, promotes renal blood flow, and increases vascular endothelial factor and angiogene-sis [76, 77] . The RELAX-AHF study [78] , designed on the basis of previous data, enrolled 1,161 ADHF patients ran-domly assigned to receive an infusion of serelaxin (30 μg/kg/day) or placebo for 48 h. Serelaxin improved dyspnea, but had no effect on mortality and readmission at 60 days, although 180-day mortality was significantly reduced. It was also associated with more significant hypotensive events and less renal impairment as compared to placebo. More data are still needed to recommend its routine use in ADHF patients.

Routinely used therapies in type 1 CRS are summa-rized in table 1 .

Chronic CRS (Type 2)

Chronic HF remains a leading cause of chronic renal function and morbidity and mortality worldwide. Recent guidelines have summarized clearly its management therapy with a significant reduction on morbidity and mortality. However, optimal management may have po-tential consequences for worsening renal function, and agreed-upon guidelines about patients with both chronic cardiac and renal dysfunctions are lacking.

Type 2 CRS is mainly due to the chronic activation of the RAAS and sympathetic nervous system secondary to arterial underfilling and venous congestion. In addition, activation of inflammatory pathways leads to glomerulo-

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sclerosis and tubular fibrosis and atrophy. Accordingly, diuretics are useful to control symptoms, but the thera-peutic cornerstone is the treatment with angiotensin-converting enzyme (ACE) or angiotensin receptor block-ers (ARBs), β-blockers (those indicated in HF), and MRA ( fig. 2 ).

RAAS Blockade, β-Blockers, and MRAs: The Therapeutic Cornerstone In HF, the beneficial effects of RAAS blockade by ACE

inhibitors and ARBs are well established and their indi-vidual impacts on renal function are well known. Multi-ple RAAS inhibition, which may represent an interesting and better alternative, has also been extensively investi-gated. In the large prospective study ONTARGET, the association of ACE inhibitors and ARBs, however, has been demonstrated as harmful [79] . The primary end-point was the evaluation of renal effects of ramipril (ACE

inhibitor), telmisartan (ARB), and the association of both of them in more than 25,000 patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes associated with end-organ damage. Al-though combination therapy reduced proteinuria to a greater extent than monotherapy, it significantly wors-ened renal outcomes (HR: 1.09, 1.01–1.18, p = 0.037). The effects on reduction of cardiovascular and renal events of the renin inhibitor aliskiren have been studied in 8,561 patients with type 2 diabetes and chronic kidney disease [80] . When added to an ACE inhibitor or ARB, it induced a decrease in blood pressure, but was unable to reduce the composite main endpoint. This association could be harmful owing to the occurrence of hyperkalemia (11.2% in the aliskiren group vs. 7.2% in the placebo group, p < 0.001) and hypotension (12.1 vs. 8.3%, p < 0.001). A sim-ilar strategy is currently being investigated in the field of chronic HF (7,000 inclusions in trial No. NCT00853658).

Table 1. Potential beneficial and adverse effects of drugs used for acute CRS (type 1)

Drugs Intended action and effects Side effects Studies

DiureticsLoop diuretics Natriuresis

Fluid overload decreaseElectrolyte imbalanceNeurohormonal activation, worsening kidney function

ESCAPE [23, 24]DOSE-HF [26]

Thiazides Overcome diuretic resistance – [32]

Vasodilators Use if congestion is present HypotensionNitroglycerin Venodilation, decreased cardiac ischemia

and afterloadHypotension, tolerance

Nitroprusside Arterial and venous dilationDecreased preload and afterload

Hypotension, thiocyanate toxicity (if decreased GFR) [44, 45]

Nesiritide Decrease in preload and afterload and PVR Increase in CO, natriuresis

Hypotension, worsening kidney function ROSE-AHF [36, 47]ASCEND HF [48, 49]

Vasopressin antagonists (vaptans)

Aquaresis and natriuresis potentiationDecrease of congestion and dyspneaOvercome diuretic resistanceHyponatremia correction

Slight increase in serum creatinineThirst

ACTIV [60]EVEREST [61]

Aldosterone antagonists Use with caution if decreased GFRHypertension control, diuresis

Hyperkalemia, worsening kidney function

RAAS and AR blockers Use with cautionAfterload and preload reduction

Worsening kidney function; hypotension, Hyperkalemia

β-Blockers Not recommended, particularly in low CO states

Cardiogenic shock and worsening kidney function

Adenosine receptor antagonists

Increased diuresis?Improved dyspnea?

Seizures and stroke PROTECT [38, 73]

Inotropes Use if very low COIncrease of CO Increase of RBF, decrease of SVR

Possible increase in myocardial injury, arrhythmiasHypotension and coronary hypoperfusionWorsened outcome

[65 – 70]

AR = Angiotensin receptor; CO = cardiac output; PVR = pulmonary vascular resistance; RBF = renal blood flow; SVR = systemic vascular resistance.

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By contrast, the association with MRAs, including spi-ronolactone and eplerenone, has led to more promising results. In patients with severe HF, the RALES trial dem-onstrated that, in addition to standard therapy, blockade of aldosterone receptors by spironolactone substantially reduces the risk of both morbidity and death (RR of death: 0.70, 95% CI: 0.60–0.82, p < 0.001) and hospitalizations [81] . Importantly, although the classical side effects were increased (gynecomastia or breast pain were 10 times more frequent, p < 0.001), the incidence of hyperkalemia was minimal in both groups (2% in the spironolactone group vs. 1% in control, p = n.s.). Similarly, in more than 3,300 patients with acute myocardial ischemia and low LVEF (EPHESUS trial), eplerenone was shown to im-prove survival and all primary endpoint parameters (RR of death: 0.85, 95% CI: 0.75–0.96, p = 0.008) [82] . Inter-estingly, the rate of serious hyperkalemia was significant-ly higher in the eplerenone group (5.5%) as compared to the placebo group (3.9%, p = 0.002), whereas the rate of hypokalemia was 8.4 versus 13.1% in the placebo group (p < 0.001). Moreover, eplerenone reduced both the risk of death and the rate of hospitalization among more than 2,700 patients with systolic HF and mild symptoms (EM-PHASIS trial; composite endpoint HR: 0.63, 95% CI: 0.54–0.74, p < 0.001). However, hyperkalemia episodes (>5.5 mol/l) occurred in 11.8% of patients in the epler-enone group versus 7.2% of those in the placebo group(p < 0.001). Nonetheless, the safety subanalysis of EM-PHASIS in chronic NYHA functional class II HF patients with an estimated GFR >30 ml/min/1.73 m 2 and potas-sium <5.0 mmol/l showed that eplerenone was both effi-cacious and safe when carefully monitored, even in sub-groups at high risk of developing hyperkalemia or wors-ening renal function [83] . Hyperkalemia variably defined as serum potassium >4.5, 5, and 5.5 mmol/l occurred in 74.7, 32.5, and 8.9% patients enrolled in EMPHASIS-HF, respectively. Worsening renal function defined as a de-crease in estimated GFR >20% or >30% from baseline oc-curred in 27 and 14% of patients, respectively [84] . Wors-ening renal function and hyperkalemia were more fre-quent when eplerenone was added, but their occurrence did not eliminate the survival benefit of eplerenone. Al-though serious hyperkalemia events were reported in ma-jor MRA clinical trials, this risk could be mitigated through appropriate patient selection, dose selection, pa-tient education, monitoring, and follow-up [85] . Indeed, in patients with acute myocardial infarct without HF, the impact of eplerenone has been recently reported as harm-less and as providing beneficial effects (REMINDER study NCT01176968). Similarly, the impact of spirono-

lactone early in patients admitted for acute coronarysyndromes is currently being investigated through the ALBATROSS study (NCT01059136).

In HF patients, with sinus rhythm and heart rate >70 bpm, and LVEF <35%, ivabradine (Procoralan ® ), a pure heart rate-lowering drug, has been recognized as an addi-tive therapy to β-blockers, ACE inhibitors, ARBs, and MRAs. β-Blockers and ivabradine exert only few effects on renal function, except through their hemodynamic (both acute and chronic) impacts. Regarding ivabradine, no specific renal concerns were raised in the SHIFT study, which reported renal deleterious effects in only 2% in the treated group versus 1% in the placebo group [86] .

In conclusion, the widespread prescription of cotreat-ments of ACE inhibitors and MRAs or ARBs and MRAs, as recently recommended [3] , is likely to lead to more frequent hyperkalemia and worsening renal function, but it also provides renoprotection (albuminuria, lower blood pressure, etc.). Nevertheless, therapeutic strategies with coprescriptions are widely used leading to the decrease of diuretic doses administered in the last 10 years (especial-ly with the introduction of ACE inhibitors). Actually, it is somewhat difficult to predict the real impact of these con-comitant prescriptions in routine practice until nation-wide registries are able to address this important ques-tion.

Diuretics Despite the improved renal hemodynamic by RAAS

blockade, sodium excretion capacity often remains poor in chronic CRS. This state justifies the use of diuretics to enhance natriuresis and reduce preload. However, renal function impairment frequently requires the increase in diuretic dose with the risk of worsening. It is therefore of paramount importance to use the right dose to achieve relief of fluid overload without adverse effects. Chronic administration of loop diuretics also leads to diuretic re-sistance and may be overcome by the therapeutic strategy used in the type 1 CRS.

Arginine Vasopressin Blockade Both V1a and V2 receptors could also be involved in

the pathophysiology of chronic HF. Plasma levels of argi-nine vasopressin were first reported elevated 30 years ago in small reports and were confirmed in large cohorts such as the Studies of Left Ventricular Dysfunction prevention and treatment trial [87] and the Survival and Ventricular Enlargement trial [88] . In addition, higher plasma argi-nine vasopressin concentration is associated with higher cardiovascular mortality at 1 year. Hyponatremia, which

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could be enhanced by loop diuretics [24] , is recognized as a marker of poor prognosis in HF [89] .

Clinical trials have demonstrated that tolvaptan causes a significant improvement in signs and symptoms of HF, partly due to rapid body weight reduction linked to ‘aqua-resis’ and an improvement of hyponatremia patients. In addition, tolvaptan was well tolerated, decreasing conges-tion without inducing clinically significant hypotension. By contrast, chronic tolvaptan therapy initiated during hospitalization had no effect on long-term morbidity or mortality and did not seem to improve cardiac remodel-ing. This lack of long-term effect was observed in the EVEREST trial [65] and confirmed in the METEOR trial (Multicenter Evaluation of Tolvaptan Effects on Left Ventricular Remodeling), including 240 patients with a LVEF <30%, based on the assumption that long-term use of vaptan could improve cardiac remodeling. After 1 year of treatment, tolvaptan does not have a discernible effect on left ventricular remodeling [90] . However, further studies are mandatory to detect subgroups of patients in whom vaptans might decrease mortality, such as patients with severe systemic congestion and hyponatremia or baseline renal dysfunction with high blood urea nitrogen levels.

Anemia Management Anemia is very common among patients with chronic

HF and seems to be linked with HF prognosis. There are several definitions of anemia; the one most frequently used is the World Health Organization criterion: hemo-globin <13 g/dl for men and 12 g/dl for women. The prev-alence of anemia varies from 15 to 70% among all chron-ic HF patients, hospitalized or not. During a 1-year course of chronic HF, 10–17% of new patients develop anemia [91] . Patients with more severe chronic HF seem to have a higher prevalence of anemia as well as female, older age, chronic kidney, and hypertensive patients [92, 93] . He-modilution may also contribute significantly to anemia in advanced chronic HF patients and must be corrected be-fore starting any anemia treatment. The diagnosis of ane-mia should search for an underlying cause using routine laboratory measurements (serum creatinine, estimated GFR, transferring saturation, ferritin, vitamin B 12 , folic acid, and thyroid-stimulating hormone).

Treatment of anemia has therefore become a thera-peutic target in this chronic HF population. Recently, large randomized controlled trials using erythropoietin-stimulating agents (ESAs) and iron supplementation therapy have been completed.

ESAs in Chronic HF The effect of erythropoietin treatment among anemic

patients with chronic HF was first reported by Silverberg et al. [94] in 2000. Erythropoietin improved cardiac and renal functions as well as functional cardiac class, and re-duced hospitalizations. A Cochrane review in 2010 in-cluded 11 studies (5 double-blinded) and showed, com-pared to controls, that ESA treatment improved exercise duration, NYHA class, ejection fraction, and quality of life indicators with a mean increase of hemoglobin of about 2 g/dl [95] . Recently, the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial, a dou-ble-blind study involving 2,278 patients assigned to re-ceive either darbepoetin alfa (target hemoglobin 13 g/dl) or placebo, showed that in the treated group (basal hemo-globin 11.2 g/dl), there was no decrease in the risk of death or hospitalization for worsening HF [96] . There was also a concern about the safety of ESA treatment in RED-HF due to a slight increase of thromboembolic events and fatal and nonfatal strokes. Therefore, routine use of ESAs for chronic HF patients with anemia is not recommended.

Correction of Iron Deficiency in Chronic HF Iron deficiency is also frequent in chronic HF and often

independent of anemia. Small studies (2006–2008) have showed interest in correcting iron deficiency, leading to a large double-blinded multicenter study published in 2009 [FAIR-HF study, 97] involving 459 chronic HF patients with iron deficiency (with or without anemia). They re-ceived weekly intravenous ferric carboxymaltose or saline for a total of 24 weeks. Patients (with or without anemia) in the intravenous iron group had improved symptoms of cardiac insufficiency, functional capacity, and quality of life indicators without significant adverse events [97] . An-other study, the IRON-HF study, compared intravenous iron, oral iron, and placebo in anemic chronic HF patients [98] . The correction of anemia was similar in the two treated groups as intravenous iron seemed to be superior in improving the functional capacity of HF patients (eval-uated on peak oxygen consumption) [98] . There have been concerns regarding the potential risk of enhanced bacterial infections [99] , iron overload [100] , and treat-ment costs for intravenous iron treatments.

In conclusion, anemia is frequent among chronic HF patients and is associated with high morbidity and mortal-ity and poor prognosis. Routine use of ESAs is not recom-mended in this population, but can be considered in se-lected patients such as kidney disease patients. Iron defi-ciency should be corrected either intravenously or orally.

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Resynchronization and Mechanical Assistance Chronic HF patients remaining symptomatic in

spite of optimal medical therapy as currently recom-mended [5, 101] could benefit from resynchronization therapy and mechanical assistance (both left ventricu-lar or right-left ventricular mechanical assistance), and even heart transplantation. The latter techniques are only for a few patients because of strict clinical inclu-sion criteria and their heaviness and cost. Resynchroni-zation therapy has been demonstrated as useful in se-lected patients [5] , especially with a large bundle branch block. Interestingly, patients can be considered as good or bad responders depending on many parameters as recently exposed in a meta-analysis exploring the sur-rogate markers of response [102] .

Therapies routinely used in type 2 CRS are summa-rized in table 2 .

Conclusion

The medical management of patients, experiencing both heart and kidney dysfunction, remains a challenge in routine practice. Indeed, potential therapies are often mutually contradictory: aggressive use of diuretics and volume depletion directly worsen renal function; ACE in-hibitors and ARBs are cardioprotective but may also tem-porary worsen renal function, and intravascular repletion and salt load preserve renal function but worsen cardiac congestion.

Though results of recent trials are neutral or negative, new insights have been gained regarding volume and neurohormonal management of HF, and promising agents such as selective cardiac myosin activators [103] and ularitide [104] are under investigation. Given the un-acceptably high rates of death in this population, one

Table 2. Potential beneficial and adverse effects of drugs used for chronic CRS (type 2)

Drugs Intended action and effects Side effects Studies

β-Blockers Control of hypertension and arrhythmias, decrease of heart ischemia, favorable renal effects (carvedilol)

Toxic effects (accumulation) if decreased GFR

RAAS or AR blockers Increase in cardiac outputDecrease in afterload

Worsening kidney functionHypotension, hyperkalemia

[79, 80]

Aldosterone antagonists Hypertension control, diuresisCardiac remodeling

Hyperkalemia, worsening kidney function RALES [81]EPHESUS [82]EMPHASIS [83–85]

Diuretics Control of hypertension, diuresis, and decrease in extracellular fluid volume

Worsening kidney function, electrolyte imbalance, diuretic resistance, hyperuricemia

ESCAPE [23 – 25]DOSE HF [26]

Iron Improvement of cardiac insufficiency and functional capacity

Toxicity FAIR-HF [97]IRON-HF [98]

ESA Correction of anemiaImprovement in cardiac and renal functions and improvement in quality of life, decreased left ventricular size

Increase in thrombosis events and fatal and nonfatal strokesRisk in patients with active malignancies

[94, 95]RED HF [96]

VasodilatorsNitroglycerinHydralazine

Decrease in preload and afterloadAlternative to RAAS blockade

Hypotension, tolerance

Inotropes Use if very low COIncrease of CO Increase of RBF, decrease of SVRBridge to cardiac transplantation

Increase in myocardial injury, arrhythmiasHypotension and coronary hypoperfusionWorsened outcome

Vasopressin antagonists (vaptans)

Correction of hyponatremiaAquaresis and natriuresis potentializaton Decrease of congestion and dyspnea

No benefit on mortality and morbidityThirst

ACTIV [60]EVEREST [61]METEOR [90]

AR = Angiotensin receptor; CO = cardiac output; RBF = renal blood flow; SVR = systemic vascular resistance.

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should agree with Fonarow [105] who stated, ‘There is a crucial need to develop new agents and effective strategies for this patient population’. Thus, the prognosis of pa-tients with CRS still needs to be improved and should encourage cardiologists, nephrologists, and internists to develop new clinical trials and therapies.

Disclosure Statement

B.C. is a full-time employee of Fresenius Medical Care.

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Pharmacologic Therapies for Chronic and Acute Decompensated Heart Failure: Specific Insights on Cardiorenal Syndromes