Outpatient management of chronic heart failure.

Review

Outpatient management of chronic heart failure Elisabeth Kaldara, Despina Sanoudou, Stamatis Adamopoulos & John N Nanas†

1.

Introduction

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Treatment

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Treatment recommended in

†

University of Athens, Medical School, 3rd Cardiology Department, Athens, Greece

all HF patients

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.

4.

Treatment recommended in selected patients with systolic HF

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Other treatments

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Treatments not recommended (believed to cause harm)

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New directions in HF treatment

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Pharmacogenetics

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Conclusion

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Expert opinion

Introduction: Heart failure (HF) treatment attracts a share of intensive research because of its poor HF prognosis. In the past decades, the prognosis of HF has improved considerably, mainly as a consequence of the progress that has been made in the pharmacological management of HF. Areas covered: This article reviews the outpatient pharmacological management of chronic HF due to left ventricular systolic dysfunction and offers recommendations on the use of various drugs. In addition, the present article attempts to provide practical therapeutic algorithms based on current clinical strategies. Expert opinion: Continued research directed toward identifying factors associated with high pharmacotherapy guideline adherence and understanding of variants that influence response to drugs will hopefully halt or reverse the major pathophysiological mechanisms involved in this syndrome. Keywords: aldosterone antagonists, angiotensin-converting enzyme inhibitors, chronic heart failure, drug therapy, b-adrenergic blockers Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Chronic heart failure (CHF) has become a true epidemic that accounts for excessive morbidity and mortality and represents a true challenge for healthcare systems. HF affects at least 15 million patients in 51 European countries [1]. Its prevalence in developed countries is between 2 and 4% but increases considerably with age, reaching up to 20% in ages > 65 years [2]. This rise and true pandemic of HF is attributed mainly to the steep increase in the proportion of elderly people in the population, the effective prevention of cardiovascular mortality and improvement of post-myocardial survival. Estimated 5-year survival after the onset of HF is ~ 60% [3,4]. HF is also associated with continuously increasing annual admission rates and extremely poor survival rates after hospital admission for decompensated HF [3,4]. HF treatment attracts a share of intensive research because of poor HF prognosis. The aim of this review is to provide an update on the pharmacological interventions indicated in the outpatient management of HF due to left ventricular (LV) systolic dysfunction. Self-care management, interventions to improve adherence, diet and exercise recommendations and risk factor modification, although they are considered a part of successful HF treatment and play an important role in patient prognosis, are beyond the scope of this review. 2.

Treatment

The profound progress in unraveling the underlying mechanisms in HF enables therapeutic strategies to focus on altering the natural course of HF by inhibiting cardiovascular remodeling process and prolonging life.

10.1517/14656566.2015.978286 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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E. Kaldara et al.

Article highlights. .


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The objectives in chronic heart failure (CHF) treatment are relief of symptoms, reduction of hospital admissions, halt of disease progress, prolongation of survival and modification of endogenous pathophysiological processes. Angiotensin-converting enzyme inhibitors, b-adrenergic receptor blockers and mineralocorticoid receptor antagonists target the inhibition of renin--angiotensin--aldosterone system and adrenergic nervous system and have become a standard component of therapy for heart failure (HF). They are recommended in all patients with HF. HF optimal management requires familiarity with the treatments that have proven effective and a thorough understanding of different therapeutic modalities shown to influence patients’ prognosis and management of their adverse effects. Although recent advances have significantly improved the clinical outcomes, many of the effective treatments remain underutilized in the community, leaving much to be accomplished to derive the maximum benefit from available medication.

This box summarizes key points contained in the article.

HF is a syndrome caused by structural and/or functional abnormalities of the heart. Compensatory mechanisms such as neurohormonal systems and the adrenergic nervous system (ANS) play a key role in the pathogenesis of HF [5]. Activity and outflow of renin--angiotensin--aldosterone system (RAAS) and ANS are enormously elevated in HF in order to maintain circulatory homeostasis and cardiac output [6,7]. Inevitably, the failing heart is paying the price of significant toxicity and markedly increased morbidity and mortality [8]. The objectives in HF treatment are relief of symptoms, reduction of hospital admissions, halt of disease progress, prolongation of survival and modification of endogenous pathophysiological processes. Almost all regimens targeting the inhibition of the above mechanisms have become a standard component of therapy for HF and are recommended in all patients with HF. 3.

Treatment recommended in all HF patients

Angiotensin-converting enzyme inhibitors They are recommended (IA), in addition to a b-blocker, for all patients with an ejection fraction (EF) # 40% to improve symptoms, reduce the risk of HF hospitalization and increase survival. Angiotensin-converting enzyme inhibitors (ACEIs) are also of benefit in patients with asymptomatic LV systolic dysfunction [9]. Upregulation of the RAAS has been implicated in the pathophysiology of various cardiovascular disorders including HF. Hyperactivity of the RAAS is associated with increased peripheral resistance, sodium retention with volume expansion and increased plasma concentrations of aldosterone, 3.1

2

norepinephrine and brain natriuretic peptide (BNP) resulting in hypertrophy, fibrosis and LV remodeling [10]. The first step in the RAAS cascade is the stimulation of renin due to decreased renal blood flow and increased sympathetic activity. Renin cleaves angiotensinogen to biologically inactive angiotensin I (A-I). ACE converts A-I to angiotensin II (A-II), primarily in the lungs. A-II stimulates the release of aldosterone by the adrenal cortex [11]. A-II, which can also be produced by alternative pathways by enzymes like chymase and cathepsin G (phenomenon of ‘A-II escape’) [12], is an important mediator of cardiac remodeling. It stimulates fibroblasts to produce collagen, promotes hypertrophy of cardiac myocytes [13] and enhances cardiac fibrosis [14,15]. The role of ACE in HF therapy has been evaluated in > 30 large randomized trials which have demonstrated that ACEIs improve LV function, enhance patients’ capacity for exercise, reduce hospitalizations rates, delay disease progression, restore cardiac performance, reverse cardiac remodeling and increase survival [16-20]. These studies confirm the appropriateness of large doses of ACEIs with a therapeutic equivalent to enalapril 10 mg twice daily (b.i.d.) (Tables 1 and 2). However, the superiority of larger doses is not marked and in patients who develop intolerance of ACEIs, all efforts should be made to continue treatment, as doses equivalent to enalapril 2.5 mg b.i.d. can be of considerable benefit to patients suffering from HF [21]. In all clinical trials, the elderly, women and patients with renal failure are underrepresented. Concerns have thus been raised about safety of ACEIs in these subsets of patients. However, in population-based studies, older patients derive a similar treatment benefit, even in the presence of relative contraindications such as low blood pressure and renal dysfunction [22,23]. Glomerular filtration rate (GFR) in HF patients depends on the balance between vasodilation of the afferent and the efferent glomerular arteriole [24]. Since this tonicity is partly regulated by A-II, a small increase of creatinine and potassium is to be expected after an ACEI initiation [25]. This type of response is usually associated with preexisting renal dysfunction or severe HF. Specifically ACEIs preferentially dilate the efferent glomerular arteriole, interfering with the compensatory increase in filtrating pressures that maintain the GFR in HF patients [26]. On the other hand, this mechanism is behind the longterm renoprotective effects of ACEIs in diabetics and nondiabetics. Initiation of ACEI therapy requires adequate renal function (eGFR ‡ 30 ml/min/1.73 m2) [9]. A 10 -- 20% increase in serum creatinine is often observed within 1 week of initiation of treatment, followed, in nearly all patients, by stabilization or a return to baseline without changes in drug doses. In patients with a moderate increase in serum creatinine concentration that does not return to baseline, treatment should be individualized according to the expected benefit of therapy versus the potential risk of worsening renal function. An acute anuric response to initiation of ACE inhibition should systematically prompt a search for renovascular

Expert Opin. Pharmacother. (2014) 16(2)

Outpatient management of chronic heart failure

Table 1. Major clinical trials with angiotensin-converting enzyme inhibitors in chronic heart failure patients. Trial

Main inclusion criteria

CONSENSUS; n = 253 NYHA IV V-HeFT II; n = 806


SOLVD treatment study; n = 2569 SOLVD prevention; n = 4228 SAVE; n = 2231 TRACE; n = 1749 CHARM; n = 2028 ELITE II; n = 3512 Val-HeFT study; n = 5010 HEAAL; n = 3846

NYHA II -- III

Intervention ENAL (2.5 -- 40 mg/day) versus placebo ENAL (10 mg) versus HYDR (150 mg/day)/ + ISO-DIN 160 mg/day

Outcome 40% reduction in mortality at 6 months

Mortality 18% for ENAL versus 25% for (HYDR + ISO-DIN) At 2 years, benefit limited to white patients with high baseline renin activity NYHA II or III Enalapril versus placebo, 16% reduction in the risk of death 2.5 -- 20 mg Overall mortality 35 versus 40%, average follow up of 41 months Asymptomatic + LVEF < 35% Enalapril 20 mg versus Overall mortality was not decreased 29% placebo reduction in death and incidence of HF and 12% reduction in cardiovascular death Post-MI + LVEF < 40%/ Captopril £ 150 mg versus 19% reduction in mortality after a 42-month placebo mean follow up Patients post-MI + LVEF < 35% Trandolapril £ 4 mg versus 22% reduction in risk of death placebo Overall mortality 34.7 versus 42.3% ACEI intolerant; LVEF £ 40%/ Candesartan (4 -- 16 mg/day) 23% reduction of risk of cardiovascular versus placebo deaths or HF admission ACEI-naı¨ve, NYHA II -- IV; Losartan (50 mg) versus Losartan and captopril had similar efficacy LVEF £ 40%/ captopril (150 mg) NYHA II -- IV Valsartan (160 mg b.i.d.) Similar overall mortality in the two groups versus placebo 13.2% lower incidence of the combined end point of mortality and morbidity NYHA II -- IV, LVEF £ 40% and Losartan 150 mg versus Reduction of rate of death or admission for intolerance to ACEI losartan 50 mg/day HF with losartan 150 mg compared with 50 mg (43% patients in the 150 mg group versus 46% in the 50 mg group)

ACEI: Angiotensin-converting enzyme inhibitor; b.i.d.: Twice daily; HF: Heart failure; LVEF: Left ventricular ejection fraction; NYHA: New York Heart Association.

Table 2. Doses of pharmacological treatments indicated in patients with systolic heart failure.

ACEIs Enalapril Captopril Cilazapril Fosinopril Lisinopril Perindopril Quinapril Ramipril Trandolapril Zofenopril MRAs Spironolactone Eplerenone b-blockers Carvedilol (nonselective b1, b2 and a1 RB) Metoprolol succinate (selective b1 RB) Metoprolol tartrate Bisoprolol (selective b1 RB) ARBs Losartan Candesartan Valsartan

Starting dose

Target dose

2.5 b.i.d. 6.25 t.i.d. 0.5 q.d. 10 q.d. 2.5 q.d. 1 -- 2 q.d. 2.5 q.d. 1.25 -- 2.5 b.i.d. 1 q.d. 15 b.i.d.

10 b.i.d. > 100 2.5 q.d. 40 q.d. 40 q.d. 4 q.d. 10 q.d. 5 b.i.d. 4 q.d. 30 b.i.d.

12.5 mg/day 25 mg/day

25 -- 50-mg/day 50 mg/day

3.125 mg b.i.d. 12.5 mg q.i.d. 6.25 mg b.i.d. 1.25 mg/day

25 mg b.i.d.; 50 mg b.i.d. for patients > 80 kg 200 mg/day 50 -- 75 mg b.i.d. 10 mg/day

50 q.d. 4 or 8 q.d. 40 b.i.d.

150 q.d. 32 q.d. 160 b.i.d.

Angiotensin-converting enzyme inhibitors; ARBS: Angiotensin receptor blockers; b.i.d.: Twice daily; MRAs: Mineralocorticoid receptor antagonists; q.d.: Once daily; t.i.d.: Thrice daily.


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Table 3. Main adverse effects of angiotensin-converting enzyme inhibitors and mineralocorticoid receptor antagonists. ACEIs Contraindications: known bilateral renal artery stenosis


Spironolactone*; Eplerenone; Contraindications Addison’s disease

Side effects Hypotension, decrease in renal function, persistent dry cough, sore throat (substitution of ACEI with an ARB) hypersensitivity reactions with angioedema, urticaria and various rashes Hyperkalemia, hyperchloremic acidosis (particularly in cirrhotic) gynecomastia*, mastodynia*, menstrual disorders*, decreased libido*, impotence in men*, decrease in renal function hyponatremia

disease. This form of acute renal failure is nearly always reversible after treatment withdrawal. Hypotension is the most common adverse effect of ACEIs. All patients treated with ACEIs experience a decrease in systolic blood pressure (SBP), which usually remains asymptomatic. However, hypovolemic end-stage HF patients usually presenting with hyponatremia, a sign of profound activation of the RAAS, can become markedly hypotensive in response to the initiation of therapy, with symptoms ranging from orthostatic hypotension and light-headedness to acute renal failure and severe hypotension reversible by means of vasodilating agents. Symptoms will usually subside with the next doses of drug, and most patients will remain asymptomatic in the long term, despite a low SBP. The authors emphasize that patients in end-stage HF with profound neurohormonal activation and a low blood pressure are those deriving the largest relative benefit from ACE inhibition. Every effort should be made to keep these patients on therapy (Table 3). ACEIs cause adverse effects due to an increased production of kinin, particularly cough, and angioedema. Nonproductive cough, appearing in the first months after initiation of therapy, occurs in 15 -- 30% of patients and is the most common reason for discontinuation of therapy [27]. Angioedema is a life-threatening condition, associated with swelling of lips, tongue and mouth and, occasionally, laryngeal obstruction. Its overall incidence is < 1% and occurs more often in black and female patients, in those > 65 years, in smokers, in patients with upper airway surgery, trauma or sleep apnea syndrome and in cardiac and renal transplant recipients [28]. There is no established association between dose or type of ACEIs and the risk of developing angioedema [29]. The mechanism of angioedema in patients taking ACEIs is not immune and involves the decrease of bradykinin and substance P catabolism, as these molecules are normally metabolized by ACE. Binding of bradykinin and substance P to their vascular receptors results in vasodilation, increased vascular permeability and interstitial edema [29]. Studies also indicate that amino-terminal degradation of substance P, by aminopeptidase P (APP) and dipeptidyl 4

Drug interactions Increased risk of nephrotoxicity with NSAID, allopurinol, trimethoprim/ sulfamethoxazole Increased risk of hyperkalemia with potassium supplements and ACEIs enhancement of the action of diuretics and other antihypertensive drugs

peptidase IV, may be impaired in individuals with ACEI-associated angioedema [30]. Further, a polymorphism of XPNPEP2, a protein-coding gene, is associated with reduced APP activity and a higher incidence of ACEI-induced angioedema [31]. Unlike allergic angioedema, angioedema in patients taking ACEIs can occur without urticaria and is not typically accompanied by bronchospasm. The time between initiation of an ACEI and onset of ACEI-associated angioedema varies between the first week and months or years of treatment. Literature reports suggest that late onset of ACEI-associated angioedema is most commonly observed [32] and an average prior exposure of 12 -- 14 months has been suggested [33]. Severity varies between cases and ranges from very mild to life-threatening. In ~ 10% of cases, airway obstruction occurs and requires immediate and appropriate intervention [34]. A history of angioedema is an absolute contraindication to ACEI therapy. Hyperkalemia is another significant adverse effect of ACEIs and is more likely to develop in patients with renal dysfunction. This potassium retention is expected, as ACE inhibition lowers the concentration of aldosterone levels. In addition, the use of potassium-sparing diuretics or mineralocorticoid receptor antagonists (MRAs) can markedly increase the risk of hyperkalemia. In the SOLVD trial, there was small but statistically significant increase in serum potassium concentrations in the enalapril group (increases of 0.2 mmol/l) with serum potassium concentrations > 5.5 mmol/l observed in only 6.4% of patients. It seems that with a single RAAS inhibition the incidence of clinically significant hyperkalemia (serum potassium ‡ 6.0 mmol/l) is low (< 2%) with limited evidence to suggest that this increase in serum potassium is associated with worse outcomes [35]. Studies of dual RAAS inhibition in patients with HF have demonstrated an increased risk of hyperkalemia but with small absolute increase (0.1 -- 0.3 mmol/l), and low rates of discontinuation due to hyperkalemia (< 1%) suggesting that these changes are unlikely to have clinical significance [35].



Table 4. Major clinical trials with mineralocorticoid receptor antagonists in chronic heart failure patients. Trial RALES; n = 1663

EPHESUS; n = 6632


Emphasis --HF n = 2737

Main inclusion criteria intervention NYHA classes III -- IV, LVEF £ 35%, spironolactone 25 -- 50 mg versus placebo Recent MI LVEF < 40%, eplerenone 25 -- 50 mg versus placebo NYHA classes III -- IV, LVEF £ 35 %, eplerenone 25 -- 50 mg versus placebo

Outcome 30% reduction in the risk of death; 31% reduction in the risk of death from cardiac causes; 35% reduction of the frequency of hospitalization for worsening heart failure Reduction in all-cause mortality in the eplerenone-treated group (14.4 vs 16.7%; HR = 0.85%; 95% CI: 0.75 -- 0.96; p = 0.008). reduction in the rate of sudden death from cardiac causes Reduction of risk of death from cardiovascular causes or hospitalization for heart failure 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died, 10.8 and 13.5%, respectively, died of cardiovascular causes

ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; CI: Confidence interval; HR: Hazard ratio; LVEF: Left ventricular ejection fraction; NYHA: New York Heart Association.

3.2

Mineralocorticoid receptor antagonists

An MRA is recommended for all patients with persisting symptoms (New York Heart Association [NYHA] classes II -- IV) and an EF # 35%, despite treatment with an ACEI (or an Angiotensin receptor blockers [ARBs] if an ACEI is not tolerated) and a b-blocker, to reduce the risk of HF hospitalization and the risk of premature death [9]. Aldosterone, the downstream product of A-II in the RAAS, is mainly synthesized by the adrenal cortex and binds to mineralocorticoids receptors. Mineralocorticoid receptors are present in the kidney, colon, brain, heart and vessels and adipose tissue and bind both mineralocorticoids and glucocorticoids with equal affinity [36]. Aldosterone causes vasoconstriction, water and sodium reabsorption with concomitant potassium excretion, hypertrophy endothelial dysfunction, decreased insulin production and secretion, stimulation of sympathetic nervous system (SNS), activation of inflammatory and apoptotic pathways and fibrosis in a way similar to A-II [37]. Secondary hyperaldosteronism is often seen in patients with HF (plasma aldosterone may reach levels up to ~ 300 ng/dl, whereas in normal subjects, it reaches 5 -- 15 ng/dl) [38] despite treatment with an ACEI [39,40]. Aldosterone antagonists effectively counteract the escape of the RAAS from long-term ACE inhibition. RALES was the first large, randomized, double-blind, placebo-controlled trial to evaluate the effect of an MRA on survival in NYHA classes III -- IV patients (822 patients were assigned to spironolactone at a dose of 25 -- 50 mg/day and 841 to placebo) with LV ejection fraction (LVEF) £ 35% and on optimal medical therapy (Table 4) [41]. The trial was terminated early due to a significant mortality benefit in the spironolactone group. In the EPHESUS study, 6642 patients after acute myocardial infarction (MI) with LVEF £ 40% were randomized to receive either eplerenone or placebo [42]. Higher event rates were recorded in the placebo versus eplerenone group. EMPHASIS-HF was a randomized, double-blind, placebo-controlled trial that enrolled 2737 patients with

LVEF £ 30% and mild symptoms of HF (NYHA class II). Eplerenone was administered at a dose of 25 -- 50 mg/day in addition to standard therapy. The trial was terminated early due to significant mortality benefit in the eplerenone group [43]. In RALES, patients were not treated with standard therapy. Only 10% of patients in the placebo group and 11% in the spironolactone group received b-blockers on top of an ACEI. Tolerability and effectiveness of concomitant use of an aldosterone-receptor blocker and a b-blocker has been assessed in EMPHASIS-HF. Treatment with an ACEI, an ARB, or both and a b-blocker (unless contraindicated) at the recommended dose or maximal tolerated dose was one of the inclusion criteria of the study. Since Emphasis-HF, MRAs are considered as life-saving therapy. Eplerenone has a lower affinity to mineralocorticoid receptors than spironolactone and requires an approximately twofold higher dose [44]. Spironolactone’s half-life is 1 -- 2 h compared to eplerenone’s half-life of 4 -- 6 h. Although spironolactone half-life is shorter, its active metabolite (canrenone) has a half-life of up to 35 h, whereas eplerenone does not have an active metabolite [44,45]. The delay often observed in the normalization of serum potassium concentration after hyperkalemia caused by spironolactone is attributed to the long half-life of spironolactone metabolite [44]. Both drugs have hepatic metabolism but eplerenone is metabolized by CYP34A and all drugs that are strong inhibitors of CYP34A will result in increase of eplerenone concentration [46]. Cortisol also binds to mineralocorticoid receptors [36]. In a study of 107 stable HF patients, spironolactone increased HgAic and cortisol levels, whereas in patients treated with eplerenone, HgAic and cortisol did not change, indicating that eplerenone has a more favorable metabolic profile [47]. In large clinical trials, both diabetic and non-diabetic patients were beneficially affected by eplerenone and spironolactone in terms of mortality and hospitalization [47,48]. Spironolactone is a nonselective MRA that is


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Start

K+ ≤ 5 mmol/l or creatinine < 2.5 mg/dl

Yes Initiation of eplerenone*/spironolactone → 25/12.5 mg

3 days

Yes


K+ ≤ 5.2 mmol/l and creatinine ≤ 2.5 mg/dl

Double the dose

No 5.5 ≤ K+ ≤ 5.9 mmol/l 2.5 ≤ creatinine ≤ 3 mg/dl

5.2 ≤ K+ ≤ 5.4 mmol/l and creatinine ≤ 2.5 mg/dl K+ ≥ 5.5 mmol/l or creatinine > 3 mg/dl

Half the dose or if eplerenone is administered O.E.D temporal discontinuation for 72 h and restart if K+ < 5 mmol/l

Yes

Withdraw MRA

Maintenance of dose

Figure 1. Practical algorithm (proposed by the authors) is shown for eplerenone/spironolactone administration. MRA: Mineralocorticoid receptor antagonists.

structurally similar to progesterone and is metabolized in the liver to active metabolites. Spironolactone is also an antagonist to androgen receptors and agonist to the progesterone receptor causing endocrine adverse effects such as gynecomastia, impotence, menstrual disturbances, hirsutism and decreased libido [49]. Eplerenone is a selective MRA with limited affinity to the androgen and progesterone receptors and does not cause the sexually related adverse effects known to be associated with the use of spironolactone (Table 3) [49]. Patients at increased risk of developing severe hyperkalemia are diabetics or patients with preexisting renal dysfunction, circulating volume depletion or end-stage HF. The eGFR < 60 ml/min/1.73 m2, diabetes mellitus, elevated baseline serum potassium and prior use of antiarrhythmics have been identified as independent predictors of hyperkalemia [50]. For these patients, it is prudent to monitor the serum potassium every 2 months, even in absence of changes in drug doses or clinical status. Spironolactone or eplerenone doses of 50 mg/day should not be exceeded and, in patients with renal dysfunction, the upper limit should probably be limited to 25 mg once daily (q.d.). It should be stated that eGFR 6

30 -- 49 ml/min/1.732 does not prohibit an attempted increase of the administered dose if serum potassium is < 5.5 mmol/l (Figure 1, Table 2). We must note that no hyperkalemia-related deaths were reported in RALES, EPHESUS or EMPHASIS-HF trials [44]. In the EPHESUS study, a 4.4 and 1.6% absolute increase in the incidence of K+ > 5.5 mmol/l and ‡ 6.0 mmol/l, respectively, was observed. About < 1% of patients who were randomized to eplerenone had to discontinue therapy because of hyperkalemia. The favorable effect of eplerenone on allcause mortality was not affected by hyperkalemia, with no significant relationship between the change in serum K+ from baseline and the effectiveness of eplerenone in reducing total mortality [50]. In the RALES study, the risk of hyperkalemia was higher in those with impaired baseline renal function but the benefit of spironolactone therapy on total mortality was present regardless of potassium change [51]. In the EMPHASIS-HF, age ‡ 75 years, hypertension, diabetes mellitus, non-white race, EF < 30% and treatment with an antiarrhythmics drug or loop diuretic were associated with a higher incidence of worsening renal function and




hyperkalemia. Eplerenone retained its survival benefits and none of these independent baseline risk factors compromised the cardiovascular benefit of eplerenone in reducing all-cause mortality [52]. In conclusion, results from the major MRA clinical studies demonstrate a beneficial effect of MRAs on all-cause mortality. Baseline risk factors for the development of hyperkalemia do not have a significant impact on the cardiovascular benefits of MRAs as long as periodic monitoring of serum potassium in patients with risk factors of hyperkalemia is implemented and a prudent use of these agents is promoted. b-blockers HF is characterized by elevated adrenergic tone mediated by increased norepinephrine and epinephrine plasma levels leading to stimulation of cardiac b adrenergic receptors (b1-ARheart, b2-AR-smooth muscle cells, b3-AR-adipose tissue and b4, a novel functional state of b1 receptor) [53]. The heart expresses mainly b1, b2 in a ratio of 8:2 and, to a lesser extent, b3 receptors. Overexpression of b1-AR as a compensatory mechanism results in increased myocardial contractility and cardiac output. That is why initiation of b-blocker in HF patients might cause a temporary symptomatic deterioration. In the long term, activation of ANS mediates remodeling via vasoconstriction and increased afterload, increased sodium and fluid retention, increased oxygen demands, increased muscle stress, promotion of apoptosis and necrosis of the cardiomyocytes. Therefore, the most feared and limiting adverse effect, which prevents b-blocker administration to the best candidates for such therapy, is worsening of HF. Although the survival benefit begins early after treatment initiation, the symptomatic benefit of b-adrenergic blockade may take months to appear and, initially, patients might suffer from exacerbation of HF-related symptoms [54]. In the meantime, the downregulation of b1 receptors that occurs during the course of HF leads to desensitization of the cardiac muscle to circulating catecholamines [55]. The b-blockers induce upregulation of adrenergic receptor (AR) [56], decrease the elevated adrenal outflow by restoring the negative feedback on catecholamine release [57] and improve myocardial perfusion by enhancing neoangiogenesis [58], resulting in reverse remodeling. That is the reason why the onset of improvement after starting treatment may occur after 3 -- 6 months. In the COPERNICUS study, the rates of assigned treatment withdrawal over 1 year were 14.8 and 18.5% for carvedilol and placebo, respectively, thus confirming that by: i) avoiding the treatment of volume-overloaded patients or patients with recent cardiac decompensation; ii) slow up-titration of drug doses; and iii) regular clinical monitoring, b-adrenergic blockade is well tolerated and highly effective in patients with advanced HF [59]. After complete resolution of an episode of acute deterioration, weaning from inotropic support and return of euvolemia, an attempt at reintroducing a b-adrenergic blocker can be made, starting with very low doses under close monitoring. 3.3

These salutary effects have been confirmed in several randomized, controlled clinical trials (Table 5). Four large-scale, placebo-controlled b-blocker studies in systolic HF demonstrated that treatment with b-blockers is associated with significantly lower risk of death from all causes [60]. A comparison between stratified subsets of CIBIS-II, COPERNICUS and SENIORS-SHF versus subsets of MERIT-HF [61] showed that the effects of bisoprolol, metoprolol controlled release/ extended release and carvedilol on patient prognosis were similar. Nebivolol, a vasodilating b1 receptor antagonist, seems to be less effective and not better tolerated. In SENIORS [62], nebivolol in elderly (age ‡ 70 years) patients with HF showed a beneficial effect on prognosis. In another meta-analysis of 21 trials that included 23,122 HF patients [63], no significant differences in mortality outcome among atenolol, bisoprolol, bucindolol, carvedilol, metoprolol and nebivolol were found, suggesting that there is a class effect benefit of all b-blockers. Nevertheless, we must emphasize that, in contrast to ACEIs, for which class effects predominate, only bisoprolol, carvedilol, sustained-release metoprolol and nebivolol have so far been recommended by the ESC guidelines [9]. In the same meta-analysis, carvedilol was associated with lipid and glucose lowering, a trend toward lower rates of cardiac mortality, and was proposed by the authors as preferred treatment in patients with cardiovascular comorbidities. Theoretically, the a1-adrenergic blocking activity of carvedilol offers an advantage when initiating treatment in severely ill patients, as its vasodilating properties can reduce afterload, counterbalancing its negative inotropic effects and preserving cardiac output. Nevertheless, these effects do not seem to play a significant role in the long term. However, these same properties are responsible for its stronger hypotensive effects compared with metoprolol or bisoprolol. Therefore, in patients with SBP approaching 85 mmHg, or who are intolerant to carvedilol because of symptomatic hypotension, metoprolol or bisoprolol are alternative choices. In all the trials reviewed in this paper so far, b-adrenergic blockers were administered to patients already treated with ACEIs, as well as with diuretics and digoxin as needed. The benefit conferred by b-adrenergic blockade is additive to that conferred by ACE inhibition. Therefore, candidates for treatment with b-adrenergic blockers should be placed on therapy while they are being treated with ACEIs. In addition, symptomatic patients should be treated with diuretics before being placed on b-adrenergic blockade to prevent acute cardiac decompensation. Unless specific properties are in demand for example, b1-AR-selectivity, the use of one particular b-blocker over the others is not indicated. In summary, b-adrenergic blockers are now recommended for all patients presenting with HF or asymptomatic LV dysfunction, unless contraindicated (Figure 2, Tables 2 and 6). Subgroup analyses of large trials demonstrated that they have favorable effects on survival, morbidity and symptoms


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Table 5. Major clinical trials with b-blockers in chronic heart failure patients.


Trial

Main inclusion criteria intervention

Outcome

MDC; n = 338

Dilated cardiomyopathy METO up to 150 mg/ day* versus placebo

MERIT-HF; n = 3991

NYHA class II or III METO up to 200 mg/day versus placebo

US CARV-HF Program; n = 1094 CIBIS; n = 641 CIBIS II; n = 2647

NYHA class II or class III CARV up to 50 mg/day versus placebo

BEST; n = 2708

NYHA class III or class IV BUCIND up to 100 mg b.i.d. versus placebo

COPERNICUS; n = 2289

NYHA class III or class IV without volume overload, LVEF < 25% CARV up to 50 mg/day* versus placebo Post-MI, LVEF < 40% CARV up to 50 mg/day* versus placebo NYHA class II or class IV, LVEF < 35% CARV up to 50 mg/day versus METO 100 mg Aged ‡ 70 years LVEF £ 35% nebivolol (titrated from 1.25 to 10 mg o.d.)

CAPRICORN; n = 1959 COMET; n = 3029 SENIORS; n = 2128

NYHA class III or IV, LVEF < 40% BISO up to 10 mg/day versus placebo NYHA class III or class IV, LVEF < 35% BISO up to 10 mg/day versus placebo

Reduced likelihood for cardiac transplantation and greater increase in LVEF and exercise tolerance with METO, no difference in mortality 34% relative risk reduction of death at 12 months and of overall mortality from 11 to 7.2% with METO, reduction in deaths due to worsening of HF, sudden deaths and hospitalizations. Symptomatic improvement with METO CARV, 3.2 versus 7.8% decrease in hospitalizations; 14.1 versus 19.6% decrease in deaths due to HF progression and sudden deaths Reduction of relative risk of death with BISO All-cause mortality was reduced in the BISO group (from 17.3 -- 11.8%) together with hospitalizations (15% reduction) Nonsignificant mortality reduction (30% for BUCIND versus 33% for placebo, p = 0.16). Only non-black patients experienced significant survival benefit. Analyses from other trials confirmed that black patients derive similar benefits as white patients from treatment with metoprolol and carvedilol Decrease in all-cause mortality with CARV (11.4 versus 18.5% for placebo) Significant reduction in overall mortality with CARV, 12 versus 15% Mortality of 34% with CARV versus 40% with METO (p = 0.0017) Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (p = 0.21)

b.i.d.: Twice daily; BISO: Bisoprolol; CARV: Carvedilol; HF: Heart failure; LVEF: Left ventricular ejection fraction; METO: Metoprolol; NYHA: New York Heart Association; o.d.: Once daily.

regardless of age, gender, initial heart rate or SBP or the presence of diabetes mellitus [64,65]. Initiation of carvedilol in patients with signs and symptoms of congestion or low cardiac output is not recommended unless combined with administration of large doses of diuretics and inotropes. Phosphodiesterase inhibitors, such as milrinone, or the new calcium sensitizer levosimendan are preferred over the sympathomimetic dobutamine, which has significantly reduced efficacy in the setting of b-blockade. By nonselectively blocking both b1- and b2-receptors, carvedilol nearly abolishes any cardiac response to dobutamine, thereby rendering this agent practically ineffective during episodes of HF decompensation. Metoprolol, due to its selectivity for b1 receptors, is less inhibitory and will allow an inotropic response through a b2-mediated effect [66]. The benefit conferred by b-adrenergic blockade is additive to that conferred by ACE inhibition. Therefore, candidates for treatment with b-adrenergic blockers should be placed on therapy while they are being treated with ACEIs. In patients with borderline systolic pressure, it is recommended to start treatment with a b-adrenergic blocker and postpone the up-titration of the ACEI (if 8

tolerated) until subsequent follow-up visits, rather than to optimize the dose of ACEI first [67,68]. After stabilization of b-blocker dose, ACEI dose is increased, unless there is specific indication to warrant exclusive administration and maximization of b-blocker (e.g., angina, hypertension/inappropriate sinus tachycardia and tachyarrhythmia)

Treatment recommended in selected patients with systolic HF

4.

Diuretics Diuretics alleviate symptoms and signs of circulatory congestion by inhibiting the reabsorption of sodium or chloride, either in the loop of Henle (loop diuretics, such as furosemide, bumetanide and torsemide) or in the distal tubule (thiazides, potassium-sparing diuretics), and by promoting renal secretion of sodium [9]. Diuretics were introduced for the treatment of HF nearly 50 years ago [69,70]. Diuretics promote the renal excretion of salt and water, which decreases ventricular filling pressures -- a major determinant of these patients’ functional status and clinical outcome [71,72]. 4.1



Start

Initiation of β-blockers

1 week

Yes

Reduction of morning dose

BP < 90 mmHg

No

Yes


HR < 60 beats/min and symptoms of dizziness or weakness

Reduction of dose

No

HR < 50 beats/min

Yes

Reduction of dose even without symptoms

Increase of dose weeklly until target dose is achieved Total daily dose should be considered optimal when resting BP and HR is estimated between 90 – 100 mmHg and 55 – 60 beats/min respectively.

Figure 2. Practical algorithm (proposed by the authors) is shown for b-blockers administration. BP: Blood pressure; HR: Hazard ratio.

Table 6. Main adverse effects of b-blockers. b-blockers Contraindications asthma (COPD is not a contraindication) Second- or third-degree AV block (in the absence of a permanent pacemaker)

Side effects

Drug interactions

Hypotension, bradycardia impotence, fatigue, leukopenia, thrombocytopenia

Risk of prolongation of atrioventricular conduction, bradycardia with calcium channel blockers with negative inotropic effects

AV: Atrioventricular; COPD: Chronic obstructive pulmonary disease.

In addition, the administration of diuretics alleviate systemic venous congestion, which is reported to contribute to the development of several complications during the evolution of HF, such as chronic renal [73-75] or hepatic [76,77] dysfunction and anemia [78]. Loop diuretics are considered agents of choice because they are more effective in promoting renal excretion of salt and water than all other classes of diuretics [79]. Thiazide diuretics (chlorthalidone, hydrochlorothiazide) have a moderate effect and can be combined with loop diuretics [80]. Thiazide diuretics have long half-life and their action lasts longer and when added to the shorter-acting loop diuretics maintain diuresis after loop diuretic has worn off [80]. Potassium-sparing diuretics (amiloride hydrochloride) are weak diuretics and are most often administered in combination with thiazides or loop diuretics to prevent hypokalemia [81]. Although loop diuretics have the same mechanism of action, they possess different pharmacological properties [81]. Bumetanide and torsemide have a greater bioavailability compared to furosemide. Torsemide has a longer

half-life that in renal and hepatic failure it is further prolonged [82]. The average duration of effect is 6 -- 8 and 4 -- 6 h for furosemide and torsemide and bumetanide, respectively [82]. In small-scale clinical trials, the pharmacokinetic profiles of torsemide and bumetanide compared with furosemide were proven more favorable [83]. In two randomized trials comparing furosemide with torsemide, torsemide significantly reduced HF and cardiovascular-related hospital readmissions and was associated with a trend in reducing all-cause mortality [84]. Large clinical studies designed to compare the effects of different types of loop diuretics in chronic HF are in demand in order to document on the superiority of a certain loop diuretic and establish it as first-line therapy in HF. Numerous adverse effects have been attributed to the use of diuretics, especially when administered in high doses (Table 7). They have been implicated, in particular, in the depletion of electrolytes, especially potassium and magnesium, which might explain the increased incidence, in the studies of LV


9

E. Kaldara et al.

Table 7. Main adverse effects of furosemide, digoxin and amiodarone. Side effects

Interactions

Hypokalemia; hypochloremic alkalosis; hypocalcemia increase of glucose, lipids, uric acid serum levels urticaria

ACTH and corticosteroids increase the risk of hypokalemia

Anorexia, nausea, vomiting, confusion, tremors, hallucinations, abnormal vision arrhythmias of all types and usually nodal escape rhythm, atrioventricular conduction disturbances

Amiodarone, certain antibiotics (macrolides, gentamicin) and NSAIDs increase the level of digoxin

Bradycardia, lipofuscin deposition in the cornea which resolves after discontinuation of the drug, photosensitivity, rash, skin staining hyperthyroidism, hypothyroidism, pulmonary fibrosis, hepatotoxicity

Exacerbation of the negative dromotropy action with b-blockers, calcium antagonists or inhibitors of MAO Increased likelihood of torsade de pointes due to QT prolongation with class I antiarrhythmics enhances the action of digoxin and warfarin

Furosemide


Digoxin Contraindications: AV block Wolff--Parkinson--White syndrome, hypertrophic obstructive cardiomyopathy Amiodarone Contraindications: Sick sinus syndrome, sinus bradycardia, atrioventricular block

ACTH: Adrenocorticotropic hormone; AV: Atrioventricular; MAO: Monoamine oxidase.

dysfunction, of arrhythmic deaths of patients treated with a potassium non-sparing diuretic [85]. Patients should be closely monitored and electrolyte depletions should be promptly corrected. Concurrent treatment with an ACEI or mineralocorticoid receptor blocker lowers the incidence of profound hypokalemia induced by diuretics. There is no evidence that diuretics change the course of the disease or long-term prognosis. Loop diuretics, in particular, which possess the most potent natriuretic properties, have been assigned a class I recommendation for the relief of symptoms in patients presenting with signs of congestion [81]. However, this recommendation is supported by a level of evidence C and no systematic algorithm to optimize the dosing regimen. The administration of high doses of diuretics for HF has been associated with an increased morbidity and mortality. High doses of diuretics may cause depletion of the circulating blood volume, a mechanism held responsible for the stimulation of the RAAS and SNS [86,87]. The inappropriate activation of these neurohormonal systems has serious adverse consequences on the progression and prognosis of HF [88,89]. Volume depletion and the activation of the SNS causes vasoconstriction, which, alone or combined with hypotension, causes hypoperfusion of the kidneys and eventually leads to the deterioration of renal function observed with the administration of diuretics (Figure 3) [90]. Because of the activation of the RAAS caused by diuretics, they should always be used in combination with an ACEI aldosterone antagonist. Inappropriate use of diuretics can cause serious adverse events with no survival benefit (Table 7). Congestion refractory to conventional treatment often complicates chronic HF. Diuretic resistance results in insufficient diuresis. Several factors contribute to diuretic resistance. Increased delivery of diuretic activates a tubuloglomerular feedback mechanism, which causes diuretic resistance, stimulation of the renin--angiotensin--aldosterone axis and activation of 10

the sympathetic nervous system [91]. Proximal (post-diuretic effect) and distal (rebound sodium retention) tubule hyperfunction, loop of Henle (braking phenomenon) hyperfunction as well as hypertrophy and hyperfunction of distal tubule cells results in increased sodium retention and aldosterone secretion, which markedly limits the efficacy of loop diuretics [92]. In addition, renal dysfunction, often seen in chronic HF, reduces the tubular diuretic delivery. Increase of dose of diuretic and administration in two or three divided doses, dose limitation of sodium intake, and coadministration of ACEIs and MRAs may be considered [92]. Combination with thiazides, may be considered for cases of refractory congestion but the electrolyte abnormalities (hyponatremia or hypokalemia) and the deterioration of renal function that can rapidly caused [93] impose a significant restriction on routine clinical use. Loop diuretics are most commonly administered intermittently by intravenous bolus injections [94]. This mode of administration may lead to marked fluctuations in intravascular volume, high plasma furosemide concentrations and a parallel to the plasma concentration, rate of furosemide excretion in the urine [95]. It is reasonable to assume that continuous infusion does not result in fluctuations in intravascular volume and allows a constant diuresis. Moreover, this mode of administration would prevent accumulation of high levels of furosemide that could increase furosemide toxicity. Continuous infusion could also be rapidly terminated in case of an inappropriately increased diuresis. In patients with HF refractory to conventional doses of furosemide, continuous intravenous administration may overcome diuretics resistance and theoretically improve diuresis. In the DOSE study, a prospective, double-blind, randomized trial [96], there was no significant difference in patients’



*Patients already on diuretics double the administened dose

Start*

No

Yes Edema, orthopnea

Stable patients

No

Initiation of 80 mg

Signs of low flow

Yes

1 week

Yes

Initiation of furosemide with 40 mg o.d. 1 week Estimated J.V.P < 6 cmH 20

Yes


No Estimated 6< J.V.P > 10 cmH 20

No Estimated J.V.P > 10 cmH 20

Evaluation of patient’s status consider discontinuation or decrease of furosemide

Yes

Persistence of symptoms

Hospitalisation, iv diuretics, inotropes

Yes Double the daily administered dose

Evaluation of patient’s status consider decrease or maintenance of furosemide

Yes

Yes

Persistence of symptoms

Maintain dose

No

Consider UF

Maintain dose, attempt to reduce the dose after clinical stabilization

Figure 3. Practical algorithm (proposed by the authors) is shown for furosemide administration. UF: Ultrafiltration.

global assessment of symptoms or change in serum creatinine over 72 h with diuretics continuous infusion or intermittent bolus strategies or with a high dose compared with a low dose. The high-dose strategy was associated with greater diuresis and more favorable outcomes in relief of dyspnea, change in net weight and net fluid loss, at a cost of transient worsening of renal function. A subanalysis of DOSE showed that in patients with higher outpatient oral diuretic doses (‡ 120 mg/day of furosemide equivalent), an intermittent bolus intravenous diuretic strategy may result in greater diuresis [97]. It has been demonstrated that continuous infusion of furosemide will provide gentle and sustained diuresis that may reach a peak only several hours after the initiation of infusion [98]. In our clinical setting, the applied strategy is continuous administration of two times the oral dose preceded by a loading dose equivalent to the numerical value of the oral outpatient dose. Whether high doses of diuretics represent a marker of disease severity and clinical instability or an independent marker of prognosis is still under investigation [99-104]. 4.1.1

Practical recommendations

4.1.2

Caution in

. Coadministration of cardiac glycosides (close monitor-

ing of electrolytes). . The elderly, especially during summer months (close

monitoring for dehydration). . Patients with lupus (lupus may exacerbate). . Patients presenting with hypotension. . Asymptomatic ! reduction of dose if no symptoms or signs

of congestion are present.Symptomatic ! reduction of dose if no symptoms or signs of congestion are present and downtitrate or discontinue blood pressure-lowering agents.

. Patients

presenting with hyponatremiaHypervolemic hypotonic hyponatremia ! Restriction of water.Hypovolemic hypotonic hyponatremia ! Intravenous hypertonic saline [105,106].Euvolemic hypotonic hyponatremia ! Restriction of dietary water, hypertonic saline with or without loop diuretics.

. Renal impairment (rising creatinine/BUN--urea) !

. Laboratory measurements (urea/BUN, creatinine, K+),

1 week after initiation of furosemide and after each increase in the administered dose. . Substitution of K+, if K +< 4 mmol/l (increase of ACEI dose, addition of an MRA, if tolerated, potassium supplements, magnesium supplements).

hypovolemia/dehydration, discontinuation of other nephrotoxic agents, reduction dose of ACEI /ARB; consider ultrafiltration. It must be noted that most patients require the continuation of long-term administration of diuretics. In a study of


11

E. Kaldara et al.

attempted diuretic withdrawal in 41 patients in stable HF, treatment had to be reintroduced in > 70% of patients at a median of 15 days because of a return of symptoms [107]. An initial requirement of > 40 mg furosemide predicted an increased risk of clinical deterioration after diuretic withdrawal.

Angiotensin receptor blockers ARBs are currently recommended as an alternative in patients intolerant of an ACEI and not as add-on therapy in patients already treated with an ACEI and a mineralocorticoid antagonist [9]. The role of ARBs in HF has been evaluated as primary therapy compared to placebo and ACEI, and as add-on therapy in patients already treated with an ACEI (Table 1). In several small studies, ARBs have tended to lower mortality and morbidity in comparison with placebo. In direct comparisons with ACEIs, the effects of ARBs on symptoms and hemodynamic function were similar, as well as similar or slightly less prominent on mortality. The HEAAL study suggested that increased doses of an ARB would be needed to achieve the maximal benefit of an ACEI but it did not provide a definite conclusion about [108,109] whether a high-dose ARB is better than ACEI monotherapy or whether the use of combination therapy in smaller doses is better than the maximum tolerated dose of RAAS blockers. Nevertheless, the results of HEAAL that a higher dose of losartan is more effective compared with the currently recommended dose cannot be extended to other ARBS. After the publication o f several large clinical trials, combination therapy of ACEI and ARB is not a recommended routine treatment. The rationale of giving ACEI/ARB combination was to limit ‘A-II escape’ [110,111]. The CHARM-Added trial showed an added benefit on mortality and morbidity by combining an ARB with an ACEI in the treatment of patients with chronic HF. In one meta-analysis (17,337 patients in total), ACEI/ARB combination was associated with significantly higher rates of worsening renal function, hyperkalemia and symptomatic hypotension [112]. In the ONTARGET study, although patients with HF were excluded, the combination of telmisartan with ramipril was associated with an increased risk of cardiovascular and renal diseases [113]. ARBs are currently recommended as an alternative treatment when ACEIs are not tolerated, particularly when ACEIs have to be discontinued because of kinin-mediated adverse effects such as cough or angioedema. It should be pointed out that angioedema caused by ACEIs can also rarely be caused by ARBs. In patients treated with adequate doses of ACEI and b-adrenergic blocker but intolerant of MRAs, a cautious attempt can be made to add an ARB, provided that there are no contraindications, such as renal dysfunction, hyperkalemia or hypotension. ARBs are not recommended


4.2

12

as add-on therapy in patients already treated with an ACEI and a MRA [9]. Vaptans Vaptans are vasopressin receptor antagonists (VRAs). Arginine vasopressin (AVP) plays a central role in water and sodium homeostasis and exerts its action via three receptor subtypes V1a in vascular smooth muscle cells, V1b and V2 in the renal collecting duct [114]. In HF, AVP is upregulated and induces vasoconstriction and cardiac cell hypertrophy via V1a receptor activation and enhances water retention via V2 receptor, as compensatory mechanisms to increase the effective arterial volume [115]. As a result of AVP-mediated retention of water, blood sodium is diluted and hyponatremia occurs. Conivaptan is a V1a/V2 nonselective VRA and tolvaptan is the first oral VRA. These novel drugs restrict fluid retention without causing any electrolyte abnormalities or renal impairment. Vaptans can help in decreasing the dose of diuretics in HF [116]. Short-term trials like EVEREST [117,118] demonstrated a rapid increase in urine output and serum sodium but failed to improve clinical outcome. Similarly, long-term trials have failed to demonstrate a favorable effect on patients’ prognosis. [119]. It should be emphasized that EVEREST did not solely include patients with HF and hyponatremia. In an analysis of 457 patients with hyponatremia from the EVEREST trial, tolvaptan compared to placebo exerted more beneficial effects (greater increase of serum sodium, greater weight reduction and greater relief of dyspnea at discharge) [120]. It should also be noted that a significant reduction in cardiovascular morbidity and mortality after discharge (p = 0.04) was observed in patients with profound hyponatremia (< 130 mmol/l; n = 92) [121]. Large randomized clinical trials in patients with hyponatremia and HF are still missing [121]. Vasopressin antagonists may be considered for short-term treatment of profound and persistent hyponatremia refractory to other treatments in patients with AHF. 4.3

Ivabradine Heart rate lowering in HF is associated with improved prognosis. Ivabradine is a heart-rate-lowering agent that selectively blocks I(f) current of cardiac pacemaker cells, resulting in heart rate reduction, prolongation of diastole, increase in coronary flow and myocardial perfusion with reduction in myocardial oxygen demand and increase in oxygen supply [122]. Ivabradine lowers heart rate without negative inotropic effect. In the SHiFT study, 10,917 patients with coronary artery disease and LVEF £ 40% were randomized to receive ivabradine or placebo in addition to standard medical therapy [123]. In the SHIFT study, the addition of ivabradine 5 to 7.5 mg b.i.d. on top of the maximum tolerated optimal therapy significantly reduced cardiovascular mortality or HF hospitalizations by 18%. This effect was driven mainly by a significant reduction in HF hospitalizations and HF deaths. First hospitalization 4.4




for worsening HF was reduced by 26% (p < 0.0001), as was HF death, which was reduced by 26%. In another post-hoc analysis of SHIFT [124], in 272 patients with severe HF (LVEF £ 20% and/or NYHA class IV) and baseline heart rate ‡ 75 bpm, ivabradine reduced the rate of cardiovascular death or HF hospitalization. In another analysis of SHIFT [125], ivabradine significantly reduced cardiovascular death or HF hospitalization only in the subgroups of patients receiving £ 50% of target b-blocker dose, suggesting that ivabradine effect on outcome is determined by the degree of heart rate reduction and not by the b-blocker dose. The b-blocker therapy should be initiated and up-titrated to target dose. Addition of ivabradine should be considered after failure to reduce heart rate by conventional medical therapy. In June, Therapeutic Goods Administration, Australia’s regulatory agency for medical drugs and devices, has reported that in a prespecified subgroup of patients with symptomatic angina, a small but statistically significant increase in the combined risk of cardiovascular death and nonfatal MI with ivabradine compared to placebo was observed. Patients in the study received up to 10 mg b.i.d., which is higher than the currently authorized maximum daily dose (7.5 mg b.i.d.) Although the main results of SIGNIFY are scheduled to be presented on 31 August at the European Society of Cardiology meeting in Barcelona., on 8 May, the European Medicines Agency announced that it had initiated a review of ivabradine based on preliminary results.

Combination of hydralazine and isosorbide dinitrate

4.5

Vasodilator therapy has been utilized for the treatment of HF in the past 20 years. These drugs confer hemodynamic benefits such as increase of cardiac output, lowering of peripheral vascular resistance and venous dilatation [126]. The combination of isosorbide dinitrate (ISDN) and hydralazine (HYD) was studied in three large randomized controlled trials, V- HeFT I [127], V-HeFT II (27% black men) [128] and finally the A-HeFT, which included 100% self-identified black patients of both sexes [129]. In V-Heft I, in patients with mild-to-severe HF (NYHA classes II -- III), the combination of ISDN and HYD when compared with prazosin, an a1-adrenergic blocker, or placebo was associated with a 34% reduction in mortality risk. In V-Heft II trial, which compared ISDN and HYD with enalapril, patients receiving enalapril had a 28% reduction in mortality risk compared with those receiving ISDN and HYD. The VHeft II trial showed that although nitrates and HYD exerted a slightly better benefit on exercise tolerance and LVEF, patients who were treated with ACEIs had a significantly reduced mortality. A subanalysis of V-HeFT I and V-HeFT II demonstrated that black patients receiving ISDN and HYD had a 47% reduction in relative mortality risk compared with non-black patients.

In A-Heft (The African-American Heart Failure Trial) [130], treatment of African-American NYHA class III/IV HF patients with fixed-dose of ISDN/HYD combination reduced mortality and morbidity and improved patient reported functional status compared with standard therapy alone, with or without b-blockers or ACEI. Adverse events that occur with a greater incidence in the ISDN/HYD group than in the placebo group were headache, dizziness, nausea and vomiting, hypotension, congestion and tachycardia. At present, the combination of ISDN/HYD can be considered in addition to optimal therapy for black patients with HF. This treatment can also be considered for Caucasian patients who remain symptomatic despite maximal treatment or as a pharmacogenetic therapeutic approach in order to identify ‘responders’ to ISDN/HYD based on their genetic characteristics [131]. Digoxin It is recommended in patients with atrial fibrillation and HF or in patients with sinus rhythm and severely symptomatic HF despite standard medical treatment that includes ACEIs and b-blockers [9]. Digoxin’s primary mechanism of action is inhibition of the Na+ Ka+-ATPase, which increases the intracellular concentration of Na. This results in enhancement of the sodium--calcium exchange and increase of intracellular calcium concentration. Elevated intracellular calcium concentration causes significant improvement of the myocardial contraction and an increase of the cardiac output [132]. Digoxin has a direct sympatholytic effect. It amplifies baroreflex mechanisms by attenuating baroreceptor sensitivity and causes vasodilatation in patients with HF while causing vasoconstriction in normal subjects. Digoxin increases parasympathetic activity and acts by slowing atrioventricular conduction and prolonging the atrioventricular node refractory period. Digoxin intoxication may trigger arrhythmias but therapeutic doses do not increase arrhythmias in the absence of ischemia [133-135]. Digoxin also decreases serum norepinephrine, aldosterone concentrations and plasma renin. By improving the neurohormonal profile, digoxin increases urine output and restores hemodynamics by reducing pulmonary capillary wedge pressure in volume-overloaded HF patients [136]. However, when euvolemia is achieved by diuretics or vasodilators, no further reduction in pulmonary capillary wedge pressure or increase in cardiac output is achieved, suggesting that hemodynamic improvement is sustained during chronic therapy with digoxin [137]. Small clinical trials have demonstrated a beneficial effect on exercise capacity and alleviation of symptoms but no effect on survival. In the DIG trial [138], 6800 ambulatory patients with HF (LVEF £ 45%) were randomly assigned to digoxin or placebo, in addition to diuretics and ACEIs. Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization overall and for worsening HF. Females with hypertension, patients with higher EF and higher SBP did not benefit from digoxin administration. It is 4.6


13


E. Kaldara et al.

reasonable to consider avoiding the use of digoxin in patients with this profile [139,140]. In a post hoc analysis of the DIG trial, which examined survival according to digoxin serum concentrations in men, overall mortality was decreased in the group whose concentrations were between 0.5 and 0.8 ng/ml, was unchanged with concentrations 0.9 and 1.1 ng/ml and was increased with concentrations > 1.2 ng/ml [141]. Another post hoc analyses of the DIG trial [142] demonstrated that digoxin improved outcomes in NYHA classes III -- IV patients with LVEF < 25%, or cardiothoracic ratio > 55%, and should therefore be considered in these patients. A post hoc analyses indicated that low (0.5 -- 0.9 ng/ml) compared to higher (‡ 1 ng/ml) serum digoxin concentration reduces mortality and that low-dose digoxin (£ 0.125 mg/ day) predicts low serum digoxin concentration [143]. In the DIG trial, the median dose of digoxin (0.25 mg/day) and the target serum digoxin concentration (0.8 -- 2.5 ng/ml) were higher, which may account for the lack of long-term mortality benefit of digoxin. In the elderly, in patients with myocardial ischemia, hypoxemia, hypothyroidism or hyperthyroidism, electrolyte or acid--base balance disorders, administration of digoxin should be made judiciously (Table 7). In all these situations, treatment should be initiated in smaller doses and, if possible, the level of digoxin in plasma should be determined (6 h after oral administration). About < 20% of the absorbed digoxin is metabolized and the rest is excreted unchanged in the urine. The half-life of digoxin is 36 -- 48 h in patients with normal renal function and 3.5 -- 5 days in end-stage renal failure patients. Treatment usually begins with 0.25 mg/day for 5 days and serum concentration is measured at that time [137,141]. If serum concentration is £1 ng/ml, a maintenance dose of 0.25/day is preferred, with the exception of the elderly, women, patients with low body weight and patients with reduced renal function or receiving amiodarone. In these patients, a dose of 0.125 mg/day is preferred [36]. Oral anticoagulants There is no evidence that an anticoagulant in patients with HF, sinus rhythm and no risk factors for thromboembolism will reduce mortality/morbidity compared to placebo [9]. HF is associated with increased risk of thromboembolic complications. Impaired hemodynamics, reduced peripheral blood flow, increased risk of LV thrombus formation, endothelial dysfunction, neurohormonal activation, chronic oxidative stress and increase of proinflammatory cytokines account for the predisposition to thromboembolism. Apart from established indications, for example, atrial fibrillation, LV thrombi and previous embolic events, there is no robust evidence to support administration of vitamin K antagonists to patients with CHF in sinus rhythm [144]. The Warfarin/Aspirin Study in Heart failure (WASH), a randomized controlled trial comparing no antithrombotic therapy, aspirin (300 mg/day) and warfarin (international normalized ratio = 2.5) in 279 patients with HF and LV 4.7

14

systolic dysfunction, provided no evidence that antithrombotic therapy is effective or safe in patients with HF [145]. In the HELAS study [146], a multicenter, randomized, double-blind, placebo-controlled trial, 197 HF patients (EF < 35%) were enrolled. Patients with ischemic heart disease were randomized to receive either aspirin 325 mg or warfarin. Patients with dilated cardiomyopathy were randomized to receive either warfarin or placebo. No significant difference in the incidence of embolic events between groups was observed. As previously mentioned, oral anticoagulation is indicated in certain groups of HF patients and its use in patients with HF and sinus rhythm is not supported in the clinical practice [147]. Thromboembolism prophylaxis in patients with HF and AF should be based on CHA2DS2-VAS score: cardiac failure, hypertension, age ‡ 75 years (doubled), diabetes, stroke (doubled), vascular disease, age 65 -- 74 years and sex category (female). Antiarrhythmic therapy Annually, > 300,000 cases of sudden cardiac death (SCD) occur in the USA, representing a major public health concern [148]. SCD mainly results from severe ventricular arrhythmias, ventricular fibrillation and in < 30% from bradyarrhythmias [149]. These arrhythmias can be the result of structural changes in the myocardium or electrical remodeling, for example, ion channel dysfunction. Classes IA and IC and the class III agent d-sotalol are contraindicated in HF. In contrast, amiodarone has a low proarrhythmic potential and when administered orally has a minimal negatively inotropic effect [150,151]. In all patients with HF presenting with ventricular arrhythmias, the first step of treatment should be the identification and correction of precipitating factors (e.g., electrolyte disorders, use of proarrhythmic drugs, myocardial ischemia), as well as the optimization of standard medical treatment. Routine use of amiodarone is not recommended in patients for primary prevention of life-threatening arrhythmias or SCD, because of lack of benefit and potential drug toxicity (Table 7). Amiodarone is recommended in patients with an implantable cardioverter-defibrillator who continue to have symptomatic ventricular arrhythmias or recurrent shocks despite optimal treatment and device reprogramming and in optimally treated patients in whom an implantable cardioverter-defibrillator is not considered an option [152]. Amiodarone is also the drug of choice to maintain sinus rhythm in patients with HF and prior to atrial fibrillation [9]. Oral amiodarone pharmacological activity requires about 2 weeks and lasts 30 -- 45 days after discontinuation. A typical maintenance dose of amiodarone in stable patients is £ 200 mg/day after a loading dose of 600 -- 800 mg/day in divided doses for 2 to 4 weeks [153,154]. 4.8

. Oral: initiation200 mg thrice daily for 1 week;200 mg b.

i.d. for another week; andmaintenance dose of 200 mg/day or the minimum necessary for control of arrhythmias



. Intravenously (emergency presentation of arrhythmias):

loading dose 300 over a period of 2 h; and maintenance dose 10 -- 20 mg/kg/24 h (up to 1200 mg/24 maximum) for a few days.

These agents cause hepatotoxicity. ERAs also interact with CYP450 activities. Currently there are no indications for their introduction to HF treatment [9].

Neutral endopeptidase inhibitors and vasopeptidase inhibitors

5.2


4.9

Calcium channel antagonists

Nifedipine, diltiazem and verapamil are not recommended for patients suffering from HF because they worsened HF and increased mortality in patients with LV dysfunction after MI and conferred no benefit [154-157]. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial [158], patients in NYHA class III or class IV and LVEF < 30% were randomly assigned to a treatment with amlodipine (second-generation calcium antagonists) or placebo, in addition to optimal treatment. A nonsignificant decrease in overall mortality was observed in the amlodipine group. In patients with non-ischemic heart disease, overall mortality was significantly reduced by amlodipine. The PRAISE II trial [159] did not confirm these results. In the V-HeFT III trial [160], 450 men suffering from chronic HF were randomly assigned to felodipine or placebo. Exercise capacity, quality of life, hospitalization rates and overall mortality remained similar in both groups. Despite the absence of symptomatic improvement or survival prolongation by calcium antagonism in chronic HF, both amlodipine and felodipine are safe and well tolerated and can be used in patients treated with ACEIs and b-adrenergic blockers who need additional therapy for hypertension or angina. 5.

Other treatments

Endothelin receptor antagonists Endothelin-1 (ET-1) is a peptide that via ETA (vascular smooth cells) and ETB (vascular smooth cells and endothelium) receptors induces coronary, renal, portal and intestinal vasoconstriction [161]. In HF, ET-1 levels are increased. Initially, ET-1 acts as an early compensatory mechanism. It increases the contractility of cardiac muscle and reduces renal blood flow and GFR, leading to fluid and sodium retention. ET-1 activates RAAS and vice versa [162]. This synergistic action causes elevation of vascular resistance, increase in cardiac work load and ventricle wall tension and impairment of cardiac contractility resulting in cardiac remodeling. Additionally, the proarrhythmic properties attributed to endothelin also favor further progression of HF. ET-1 blockage has been proposed as a possible therapeutic target. Endothelin antagonists (ERAs) lead not only to vasodilatation but also to a decrease of the endothelial-derived relaxing factor, prostacyclin and nitric oxide with potential harmful effects [162,163]. ERAs may cause headache, nausea, rhinitis, sinusitis, dyspnea, chest pain and dose-related anemia, mostly due to a nonspecific vasodilatory effect. 5.1

In HF, an increase in levels of natriuretic peptides (NPs) is documented. Atrial NP (ANP) and BNP are synthesized mainly in response to increased LV end-diastolic pressure and their release is enhanced by endothelin, A-III and cytokines. They exert their action via NP receptors A and B, causing systemic vasodilatation and dilatation of the afferent glomerular arterioles, together with constriction of the efferent glomerular arterioles, decrease of sodium reabsorption in renal tubules causing natriuresis and inhibition of RAAS and sympathetic nervous system activation [164]. Because of the salutary effects of NPs to both preload and afterload, many studies suggested a relationship between NP level and HF severity. At present, ANP/BNP measurements represent an established diagnostic tool and a marker of disease progress and provide an evaluation of the efficacy of treatment applied. Agents that influence NPs favorably are inhibitors of ANP/ BNP degradation. Two classes of them are distinguished: neutral endopeptidase inhibitors (NEPIs) and vasopeptidase inhibitors (VPIs) [165]. NEPI (neprilysin) leads to plasma level increase of both NPs and vasoconstrictory factors, resulting also in a lack of afterload decrease. NEPIs are reported to be beneficial in HF treatment, especially because of lowering the preload, secondary to natriuresis with no direct impact on RAAS and sympathetic activity [166]. VPIs cause simultaneous NEP and ACE inhibition resulting in an increase of NPs with no accompanying increase of A-II and aldosterone and no decrease on bradykinin level which is broken down by both NEPI and ACEI and is associated with an antiplatelet effect and improvement of endothelium function [167]. Side effects of administration of the VPI omapatrilat (dizziness, headache, nausea dry cough, angioedema about three times more often than ACE) have restricted their use. It is not known if other VPIs have this harmful effect with such frequency [168]. Novel angiotensin-receptor/neprilysin inhibitors seek to investigate clinical efficacy and safety of combined RAAS blockade and NEPI-mediated NP increase [169].

Anti-cytokine therapy Proinflammatory cytokines, such as TNF-a, IL-6 as well as soluble TNF receptors (s-TNF-R1, s-TNF-R2) are implicated in the pathogenesis of HF. TNF-a is not only a key factor of inflammatory process [170,171] but it also has been associated with cardiac cachexia and extracellular matrix remodeling, 5.3


15

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resulting in progressive stiffening of the ventricular walls and loss of contractility [172,173]. TNF-a blockade in HF has been investigated as a possible therapeutic target. The b-adrenergic agonists, phosphodiesterase inhibitors, pentoxifylline, adenosine, mAbs against TNF-a (e.g., infliximab), recombinant TNF-a soluble receptor (etanercept) have been investigated but with no favorable results in patients with HF [174].

Treatments not recommended (believed to cause harm) Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.

6.

Glitazones, most calcium channels blockers (with the exception of amlodipine and felodipine), NSAIDs and COX-2 inhibitors are not recommended. Addition of an ARB or renin inhibitor to the combination of an ACEI and a MRA should be avoided [9]. 7.

New directions in HF treatment

16

BAY 94-8862 Hyperkalemia and renal dysfunction are common side effects of MRAs and impose a significant restriction to up-titration of administered doses resulting in undertreatment. The rates of hyperkalemia and renal dysfunction are even higher in patients with HF and either type 2 diabetes mellitus or moderate chronic kidney disease (CKD) [181]. These high-risk patients usually tolerate only low doses of an MRA (e.g., average dose of 25 mg/day eplerenone in EMPHASIS-HF trial). In ARTS [182], BAY 94-8862 was investigated in subjects with stable and mild or moderate HF and compared to placebo, as well as to 25/50 mg q.d. spironolactone. All doses of BAY 94-8862 (2.5, 5 and 10 mg q.d. as well as 5 mg b.i.d.) showed less potassium increase and renal disorders than spironolactone. Only 50% of all subjects in the spironolactone treatment group could be up-titrated from 25 to 50 mg after 14 days of treatment. All investigated doses of BAY 94-8862, with the exception of 2.5 mg q.d., showed comparable effects on NPs and albuminuria. In ARTS HF Study (Phase IIb Safety and Efficacy Study of Different Oral Doses of BAY94-8862 in Subjects with Worsening Chronic HF and Left Ventricular Systolic Dysfunction and Either Type 2 Diabetes Mellitus with or without Chronic Kidney Disease or Chronic Kidney Disease Alone), different oral doses of BAY 94-8862 will be investigated in subjects with either type 2 diabetes mellitus with or without CKD or moderate CKD and will be compared with eplerenone in terms of hyperkalemia and worsening of renal function [183]. 7.3

Aliskiren An alternative approach to blockade of the RAAS is inhibition of renin, the enzyme for the formation of A-II [175]. The renin inhibitor aliskiren blocks the first and rate-limiting step of RAAS and therefore prevents the formation of all breakdown products of both A-I and A-II, including bradykinin. In the ALOFT study, addition of aliskiren to an ACEI (or ARB) and b-blocker was well tolerated and exhibited beneficial neurohormonal effects [176]. In the ASTRONAUT trial, 1639 patients were randomized to receive either aliskiren or placebo [177] on top of standard therapy. Addition of aliskiren did not reduce cardiovascular death or HF rehospitalizations. It should be pointed out that diabetic patients receiving aliskiren experienced worse post-discharge outcomes. In ATMOSPHERE [178], ~ 7000 patients with systolic HF were randomized to receive either enalapril 10 mg b.i.d., aliskiren 300 mg q.d. or the combination of both drugs. ATMOSPHERE will assess whether aliskiren/enalapril combination is superior to enalapril monotherapy and whether aliskiren monotherapy is superior or at least noninferior to enalapril monotherapy in terms of mortality and hospitalization rates and will definitively determine the role of aliskiren to RAAS blockade in patients with chronic systolic HF. It should be highlighted that the ALTITUDE study (aliskiren or placebo was given on top of ACEI or ARB in diabetic patients) was discontinued because patients treated with aliskiren had an increased risk of nonfatal stroke, renal dysfunction, hyperkalemia and symptomatic hypotension [179]. Since then, the European Medicines Agency has issued a directive that for the current aliskiren indication (treatment of hypertension) the combination of aliskiren with an ACEI or ARB is prohibited in patients with diabetes mellitus or an eGFR of < 60 ml/min/1.73 m2. h. 7.1

LCZ696 PARADIGM-HF [180] is assessing whether simultaneously blocking the RAAS and increasing NPs levels with a metallopeptidase neprilysin inhibitor LCZ696, 200 mg b.i.d., is superior to blocking the RAAS with enalapril 10 mg b.i.d. in improving prognosis of patients with HF. The trial was due to conclude around October 2014 but the data monitoring comittee recommended stopping it in March because of a benefit to patients that was overwhelmingly statistically significant. LCZ696 improved the primary composite end point of cardiovascular death or HF hospitalization and reduced cardiovascular mortality alone. The data monitoring comittee rules were that the trial could only be stopped if there was a strongly statistically significant benefit on both the primary composite end point and on the cardiovascular mortality end point. The trial is currently closing out and the final data will then be analyzed. The investigators have applied to present their results at ESC Congress 2014 in Barcelona, Spain. 7.2

SERCA2a gene therapy The CUPID 2 trial will determine whether enhancement of calcium upregulation in 250 patients with advanced HF by percutaneous intracoronary administration of gene therapy will improve clinical outcome. A recombinant adenoassociated virus serotype 1/SERCA2a will be administered 7.4



intracoronary and will increase SERCA2a protein levels and enhance intracellular Ca release. The trial is currently recruiting patients and is estimated to release results events by mid-2015 [184]. Serelaxin Serelaxin is a recombinant form of relaxin, a natural human peptide with systemic and renal vasodilating effects. In the preliminary study of relaxin in acute HF (PreRELAX-AHF) [185] was designed to assess the effect of different doses of intravenous relaxin compared with placebo on dyspnea relief, resolution of signs of congestion, decrease in body weight and in diuretic use in patients with acute HF and normal or increased blood pressure and to assess the safety of relaxin in these patients. Relaxin was associated with favorable clinical outcomes, including signs of HF, in-hospital worsening of HF, length of stay, cardiovascular death or readmission at 60 days and 180-day cardiovascular mortality, with acceptable safety. In RELAX-AHF, 1161 patients were randomly assigned to serelaxin or placebo. Serelaxin improved dyspnea in the visual analog scale AUC but not when measured by Likert scale, and there were no improvements in the composite endpoints that included readmission to hospital at day 30 or day 60. Serelaxin reduced cardiovascular death all-cause mortality at 180 days [186]. It must be emphasized that RELAX-AHF was not prospectively designed or powered as a mortality trial and had a moderate number of death events, and the patients enrolled in this study represented a specific AHF group of patients. In this setting of patients, serelaxin exerted beneficial effects on clinical outcomes.


7.5

Other currently recruiting HF clinical trials The U.S. National Institutes of Health clinical trial site was searched for currently recruiting HF clinical trials. Trial characteristics and study objectives were extracted from the registry website and are described briefly. Functional impact of GLP-1 for HF treatment with primary objective to test the hypothesis that, compared with placebo, therapy with subcutaneous GLP-1 agonist in the post-acute HF syndrome discharge period will be associated with greater clinical stability at 6 months. Effects of pentoxifylline on LV systolic function indices and circulating biomarkers in patients with chronic congestive HF with primary objective to test the hypothesis that, compared with placebo, therapy with pentoxifylline will increase LVEF by > 5%. Resveratrol: a potential anti-remodeling agent in HF, from bench to bedside with primary objective to test the hypothesis that, compared with placebo, therapy with resveratrol will improve quality of life and cardiac function assessed by echocardiography. Effects of thalidomide on LV morphology and function in patients with congestive HF -- the THUNDER trial with 7.6

primary objective to test the hypothesis that, compared with placebo, therapy with oral thalidomide will favorably affect LV morphology and improve function in patients with CHF. Randomized, multicenter study comparing the effect of two regimens of combined immunosuppressive therapy in the treatment of inflammatory cardiomyopathy czech-icit (czech inflammatory cardiomyopathy immunosuppression trial) with primary objective to test the hypothesis that, compared with standard therapy, combined therapy with prednisone and azathioprine will increase LVEF. Phase III, multicenter, randomized, double-blind, placebocontrolled trial to evaluate the efficacy and safety of ularitide (urodilatin) intravenous infusion in patients suffering from acute decompensated HF (TRUE-AHF) with primary objective to test the hypothesis that, compared with placebo, urodilatin will improve patients’ clinical status comprising elements associated with patient global assessment (improvement, lack of improvement, or worsening; persistent or worsening HF requiring an intervention [initiation or intensification of intravenous therapy, circulatory or ventilatory mechanical support, surgical intervention, ultrafiltration, hemofiltration or dialysis]) and all-cause mortality. b-3 agonist treatment in HF with primary objective to test the hypothesis that mirabegron on top of optimized evidence-based pharmacological HF treatment, compared with placebo, will increase LVEF (measured by MRI or CT). A randomized, double-blind, placebo-controlled study of the effect of liraglutide on LV function in chronic HF patients with and without type 2 diabetes (The LIVE-study) with primary objective to test the hypothesis that liraglutide will improve LV function, measured by echo in chronic HF patients with and without type 2 diabetes after 24 weeks of treatment. 8.

Pharmacogenetics

ACEIs The potential role of genetic variability in interindividual difference in ACEI response has been extensively explored over the past two decades, often with contradictory results. Significant associations have been reported for specific variants in AGT (rs7079), AT1 (haplotypes H2, H3), REN and ACE2, although further validation is pending. Variants in the genes ACE, AGT, AT1 (A1166C) and AT2 do not appear to play a significant role in patients’ response to ACEI. Genetic variants in the genes B1AR (e.g., Arg389Gly, Ser49Gly) and B2AR (e.g., Glu27Gln, Arg16Gly) have been extensively investigated for their potential role in determining patient response to b-blockers. However, the results remain largely contradictory to date [187]. 8.1

b-blockers Of particular interest, a variant in the gene GRK5 (Q41L) acts to attenuate b1AR signaling in a manner similar to partial b1AR antagonism with b-blockers, favoring protection 8.2


17

E. Kaldara et al.

against remodeling and improving survival [188]. Overall, limited consistent data is delaying the incorporation of pharmacogenetics in routine b-blocker prescription. Nevertheless, several genetically guided HF drug trials are ongoing, such as the safety and efficacy trial of bucindolol versus metoprolol CR/XL in 3200 patients homozygous for B1AR Arg38 [189] and the study evaluating the impact of genetic variations on candesartan response in patients already on an ACEI [190].


9.

Conclusion

HF is a clinical syndrome associated with significant morbidity and mortality. However, in contrast to its increasing prevalence, better management in the earlier stages has been successful in slowing the rates of disease progression. Its optimal management requires: primary prevention; early detection of HF; implementation of therapeutic algorithms; individually tailored medical treatment; and utilization of specialist services. 10.

Expert opinion

HF treatment attracts a share of intensive research because of poor HF prognosis. Undoubtedly, there has been a decrease in both short- and long-term mortality over the past two decades, which probably reflects increasing utilization of evidence-based therapies, implementation of therapeutic strategies for comorbidities and modification of cardiovascular risk factors. Nevertheless, standard medical therapy still yields an unsatisfactorily low rate of complete response and has limited effect on modifying disease trajectory and successfully preventing remodeling of the myocardium. Continued research Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

18

Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2008;10(10):933-89 Frigola-Capell E, Comin-Colet J, Davins-Miralles J, et al. Survival in Mediterranean ambulatory patients with chronic heart failure. A population-based study. Rev Esp Cardiol 2013;66(7):539-44 Mcmurray JJ, Stewart S. Heart failure epidemiology, aetiology, and prognosis of heart failure. Heart 2000;83:596-602

4.

.

directed toward identifying more effective treatments that produce fewer long-term sequels is critical for addressing these remaining challenges. Looking ahead, an evolving approach for tailoring HF therapy involves the evaluation of patients’ genetic makeup. Pharmacogenetics is specifically investigating genetic variants that influence response to drugs either in terms of therapeutic benefit or adverse effects. In oncology clinics, pharmacogenetic testing is already a reality, and for certain treatments, it is a FDA-recommended or even required procedure. In HF clinics, however, the incorporation of pharmacogenetics has been hindered by a pronounced inconsistency of findings across studies. This could be attributed to a variety of reasons such as the size of patient cohorts, cross-study differences in patient categorization, the involvement of a broad range of other external and internal environmental factors, the potential interaction of coexisting genetic variants, differences in pharmacokinetics/pharmacodynamics and many others. Such studies are setting the foundations for a deeper understanding of the poly-parametric system regulating patient response to HF drugs and will open the way to the development of more comprehensive algorithms to guide HF treatment.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.

Ho KKL, Anderson KM, Karmel WB, et al. Survival after the onset of congestive heart failure in the Framingham heart study subjects. Circulation 1993;88:107-15 Another follow-up report of the Framingham study describing extremely poor survival rates in those individuals diagnosed with chronic heart failure.

5.

Skeggs LT, Dorer FE, Kahn JR, et al. The biochemistry of the renin--angiotensin system and its role in hypertension. Am J Med 1976;60:737-48

6.

Spinarova L, Vitovec J. Neurohumoral changes in chronic heart failure. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2007;151(2):201-7


7.

Ma TK, Kam KK, Yan BP, Lam YY. Renin--angiotensin--aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 2010;160(6):1273-92

8.

Benedict CR, Johnstone DE, Weiner DH, et al. Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the Registry of Studies of Left Ventricular Dysfunction. SOLVD investigators Am Coll Cardiol 1994;23:1410-20

9.

Mcmurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task force for the diagnosis and treatment of acute


and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803-69 10.


11.

12.

13.

Dostal DE, Baker KM. The cardiac renin--angiotensin system: conceptual, or a regulator of cardiac function? Circ Res 1999;85:643-50 Otani H, Otsuka F, Inagaki K, et al. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions. Endocrinology 2008;149(6):2816-25 Schunkert H, Ingelfinger JR, Hirsch AT, et al. Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest 1992;90:1523-9 Lijnen P, Petrov V. Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol 2000;32:865-79

15.

Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. CircRes 1993;73:413-23

17.

18.

19.

20.

Raman VK, Lee YA, Lindpaintner K. The cardiac renin--angiotensin--aldosterone system and hypertensive cardiac hypertrophy. Am J Cardiol 1995;76:18D-23D

14.

16.

Results of the survival and ventricular enlargement trial. The SAVEInvestigators. N Engl J Med 1992;327(10):669-77

21.

Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. The NETWORK Investigators. Eur Heart J 1998;19:481-9

22.

Havranek EP, Abrams F, Stevens E, Parker K. Determinants of mortality in elderly patients with heart failure: the role of angiotensin-converting enzyme inhibitors. Arch Intern Med 1998;158:2024-8

23.

Shlipak MG. Pharmacotherapy for heart failure in patients with renal insufficiency. Ann Intern Med 2003;138:917-24

25.

Pedrino GR, Rosa DA, Lopes OU, Cravo SL. Neurobiology of body fluid homeostasis: transduction and integration. Chapter 8. De Luca LA Jr, Menani JV, Johnson AK, editors. Catecholaminergic medullary pathways and cardiovascular responses to expanded circulating volume and increased osmolarity; Boca Raton, FL: CRC Press; 2014

26.

Jong P, Yusuf S, Rousseau MF, et al. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a followup study. Lancet 2003;361(9372):1843-8 Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction.

Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a metaanalysis of major clinical trials. J Am Coll Cardiol 2003;41:1529-38

24.

Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-35 Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med 1992;327:685-91

Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333(25):1670-6

27.

Schoolwerth AC, Sica DA, Ballermann BJ, Wilcox CS. Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation 2001;104:1985-91 Sa´nchez-Borges M, Gonza´lez-Aveledo LA. Angiotensin-converting enzyme inhibitors


and angioedema. Allergy Asthma Immunol Res 2010;2(3):195-8 28.

Hoover T, Lippmann M, Grouzmann E, et al. Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors. Clin Exp Allergy 2010;40:50-61

29.

Andrew N, Gabb G, Del Fante M. ACEI associated angioedema - a case study and review. Aust Fam Physician 2011;40(12):985-8

30.

Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV, ACE inhibition, and angioedema. Hypertension 2008;51:141-7

31.

Duan QL, Nikpoor B, Dube M, et al. A variant in XPNPEP2 is associated with angioedema induced by angiotensin converting enzyme inhibitors. Am J Hum Genet 2005;77:617-26

32.

Hedner T, Samuelsson O, Lunde H, et al. Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors. BM J 1992;304:941

33.

Jones RL, Gabb GM. Angioedema and ACE inhibitors or angiotensin II receptor blockers, revisited. Pharmacoepidemiol Drug Saf 2010;19:S145

34.

Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme inhibitorinduced angioedema. Otolaryngol Head Neck Surg 2007;137:931-5

35.

Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol 2010;5:531-48

36.

Guichard JL, Clark D III, Calhoun DA, Ahmed MI. Aldosterone receptor antagonists: current perspectives and therapies. Vasc Health Risk Manag 2013;9:321-31

37.

Kawano H, Do YS, Kawano Y, et al. Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts. Circulation 2000;101:1130-7

38.

Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2001;345(23):1689-97

39.

Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995;9(1):145-9

19

E. Kaldara et al.

40.

41.


42.

Jorde UP, Vittorio T, Katz SD, et al. Elevated plasma aldosterone levels despite complete inhibition of the vascular angiotensin-converting enzyme in chronic heart failure. Circulation 2002;106(9):1055-7 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341(10):709-17

51.

52.

Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348(14):1309-21

43.

Zannad F, Mcmurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364(1):11-21

44.

Zannad F, Gattis Stough W, Rossignol P, et al. Mineralocorticoid receptor antagonists for heartfailure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J 2012;33:2782-95

45.

Survival Study (EPHESUS). Circulation 2008;118:1643-50

53.

54.

Struthers A, Krum H, Williams GH. A comparison of the aldosteroneblockingagents eplerenone and spironolactone. Clin Cardiol 2008;31:153-8

Vardeny O, Wu DH, Desai A, et al. Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). Am Coll Cardiol 2012;60(20):2082-9 Rossignol P, Dobre D, McMurray JJ, et al. Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail 2014;7(1):51-8 Granneman JG. The putative beta4adrenergic receptor is a novel state of the beta1-adrenergic receptor. Am J Physiol Endocrinol Metab 2001;280(2):E199-202 Macdonald PS, Keogh AM, Aboyoun CL, et al. Tolerability and efficacy of carvedilol in patients withNew York Heart Association class IV heart failure. J Am Coll Cardiol 1999;33:924-31

46.

Guglin M, Kristof-Kuteyeva O, Novotorova I, Pratap P. Aldosterone antagonistsin heart failure. J Cardiovasc Pharmacol Ther 2011;16:150-9

55.

Rengo G, Lymperopoulos A, Leosco D, Koch WJ. GRK2 as a novel gene therapy target in heart failure. J Mol Cell Cardiol 2011;50(5):785-92

47.

Yamaji M, Tsutamoto T, Kawahara C, et al. Effect of eplerenone versus spironolactone on cortisol and hemoglobinA(c) levels in patients with chronic heart failure. Am Heart J 2010;160:915-21

56.

Iaccarino G, Tomhave ED, Lefkowitz RJ, Koch WJ. Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade. Circulation 1998;98(17):1783-9

48.

O’Keefe JH, Abuissa H, Pitt B. Eplerenone improves prognosis in postmyocardial infarction diabetic patients with heart failure: results from EPHESUS. Diabetes Obes Metab 2008;10:492-7

49.

Maron BA, Leopold JA. Aldosterone receptor antagonists: effective but often forgotten. Circulation 2010;121:934-9

50.

Pitt B, Bakris G, Ruilope LM, EPHESUS Investigators. Serum potassium and Clinical Outcomes in the Eplerenone Post--Acute Myocardial Infarction Heart Failure Efficacy and

20

57.

58.

Rengo G, Perrone-Filardi P, Femminella GD, et al. Targeting the beta-adrenergic receptor system through G-protein-coupled receptor kinase 2: a new paradigm for therapy and prognostic evaluation in heart failure: from bench to bedside. Circ Heart Fail 2012;5(3):385-91 Dedkov EI, Christensen LP, Weiss RM, Tomanek RJ. Reduction of heart rate by chronic beta1-adrenoceptor blockade promotes growth of arterioles and preserves coronary perfusion reserve in postinfarcted heart. Am J Physiol Heart Circ Physiol 2005;288(6):H2684-93


59.

Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8

60.

Klapholz M. beta-blocker use for the stages of heart failure. Mayo Clin Proc 2009;84(8):718-29

61.

Wikstrand J, Wedel H, Castagno D, McMurray JJ. The large-scale placebocontrolled beta-blocker studies in systolic heart failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF. Intern Med 2014;275(2):134-43

62.

Dobre D, van Veldhuisen DJ, Mordenti G, et al. Tolerability and doserelated effects of nebivolol in elderly patients with heart failure: data from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial. Am Heart J 2007;154(1):109-15

63.

Chatterjee S, Biondi-Zoccai G, Abbate A, et al. Benefits of b blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ 2013;346:f55

64.

Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensinconverting enzyme inhibitors and betablockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta analysis of major clinical trials. J Am Coll Cardiol 2003;41:1529-38

65.

Rouleau JL, Roecker EB, Tendera M, et al. Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure: the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. J Am Coll Cardiol 2004;43:1423-9

66.

Metra M, Nodari S, D’aloia A, et al. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol 2002;40:1248-58

67.

Remme WJ, Riegger G, Hildebrandt P, et al. The benefits of early combination treatment of carvedilol and an ACE-


inhibitor in mild heart failure and left ventricular systolic dysfunction. The carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN). Cardiovasc Drugs Ther 2004;18:57-66 68.


69.

70.

71.

72.

Sliwa K, Norton GR, Kone N, et al. Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure. J Am Coll Cardiol 2004;44:1825-30 Routier G. Acute pulmonary edema in carbon monoxide poisoning. Value of intravenous acetazolamide. J Sci Med Lille 1962;80:352-4 Ledingham JG. Ethacrynic acid parenterally in the treatment and prevention of pulmonary edema. Lancet 1964;1:952-4 Stevenson LW. Are hemodynamic goals viable in tailoring heart failure therapy? Hemodynamic goals are relevant. Circulation 2006;113:1020-7 Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660-7

73.

Damman K, Voors AA, Hillege HL, et al. CIBIS-2 Investigators and Committees. Congestion in chronic systolic heart failure is related to renal dysfunction and increased mortality. Eur J Heart Fail 2010;12:974-82

74.

Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589-96

75.

Damman K, Ng Kam Chuen MJ, MacFadyen RJ, et al. Volume status and diuretic therapy in systolic heart failure and the detection of early abnormalities in renal and tubular function. J Am Coll Cardiol 2011;57:2233-41

76.

Gaillourakis CC, Rosenberg PM, Friedman LS. The liver in heart failure. Clin Liver Dis 2002;6:947-67

77.

Meyers RP, Cerini R, Sayegh R, et al. Cardiac hepatopathy: clinical, hemodynamic and histologic characteristics and correlations. Hepatology 2003;37:393-400

78.

Westenbrink BD, Visser FW, Voors AA, et al. Anaemia in chronic heart failure is

not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well. Eur Heart J 2007;28:166-71 79.

Gupta S, Neyses L. Diuretic usage in heart failure: a continuing conundrum in 2005. Eur Heart J 2005;26(7):644-9

80.

Sica DA, Carter B, Cushman W, Hamm L. Thiazide and loop diuretics. J Clin Hypertens (Greenwich) 2011;13(9):639-43

81.

Michael Felker G. Diuretic management in heart failure. Congest Heart Fail 2010;16(Suppl 1):S68-72

82.

83.

84.

Felker GM, Mentz RJ. Diuretics and ultrafiltration in acute decompensated heart failure. J Am Coll Cardiol 2011;59:24 Wargo KA, Banta WM. A comprehensive review of the loop diuretics: should furosemide be first line? Ann Pharmacother 2009;43(11):1836-47 Dinicolantonio JJ. Should torsemide be the loop diuretic of choice in systolic heart failure? Future Cardiol 2012;8(5):707-28

85.

Cooper HA, Dries DL, Davis CE, et al. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999;100:1311-15

86.

Francis GS, Siegel RM, Goldsmith SR, et al. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart-failure activation of the neurohumoral axis. Ann Intern Med 1985;103:1-6

87.

Bayliss J, Norell M, Canepa-Anson R, et al. Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J 1987;57:17-22

88.

Tomaschitz A, Pilz S, Ritz E, et al. Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure. Eur Heart J 2011;32:2642-9

89.

Triposkiadis F, Karayannis G, Giamouzis G, et al. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol 2009;54:1747-62

90.

Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004;147:331-8


91.

Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology 2001;96:132-43

92.

Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol 2010;36:19

93.

Oster JR, Epstein M, Smoller S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med 1983;99:405-6

94.

Selby VN, Teerlink JR. What’s new in the treatment of acute heart failure? Curr Cardiol Rep 2013;15:393

95.

Branch RA, Roberts CJ, Homeida M, Levine D. Determinants of response to frusemide in normal subjects. Br J Clin Pharmacol 1977;4(2):121-7

96.

Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364(9):797-805

97.

Shah RV, Mcnulty S, O’connor CM, et al. Effect of admission oral diuretic dose on response to continuous versus bolus intravenous diuretics in acute heart failure: an analysis from diuretic optimization strategies in acute heart failure. Am Heart J 2012;164(6):862-8

98.

Copeland JG, Campbell DW, Plachetka JR, et al. Diuresis with continuous infusion of furosemide after cardiac surgery. Am J Surg 1983;146(6):796-9

99.

van Wart SA, Shoaf SE, Mallikaarjun S, Mager DE. Population-based metaanalysis of furosemide pharmacokinetics. Biopharm Drug Dispos 2014;35:119-33

100. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 2013;128:e240-327 101. Neuberg GW, Miller AB, O’Connor CM, et al. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J 2002;144:31-8 102. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol 2006;97:1759-64 103. Abdel-Qadir HM, Tu JV, Yun L, et al. Diuretic dose and long-term outcomes in

21

E. Kaldara et al.

elderly patients with heart failure after hospitalization. Am Heart J 2010;160:264-71 104. Mielniczuk LM, Tsang SW, Desai AS, et al. The association between high-dose diuretics and clinical stability in ambulatory chronic heart failure patients. J Card Fail 2008;14:388-93


105. Agrawal V, Agrawal M, Joshi SR, Ghosh AK. Hyponatremia and hypernatremia: disorders of water balance. J Assoc Physicians India 2008;50:956-64 106. Singer GG, Brenner BM. Fluid and electrolyte disturbances. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. 16th edition. Volume 1 Mc Graw Hill; New York: 2005. p. 252-62 107. Grinstead WC, Francis MJ, Marks GF, et al. Discontinuation of chronic diuretic therapy in stable congestiveheart failure secondary to coronary artery disease or to idiopathic dilatedcardiomyopathy. Am J Cardiol 1994;73:881-6 108. Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009;374(9704):1840-8 109. Konstam MA, Neaton JD, Poole-Wilson PA, et al. Comparison of losartan and captopril on heart failurerelatedoutcomes and symptoms from the losartan heart failure survival study (ELITE II). Am Heart J 2005;150:123-31 110. Ennezat PV, Berlowitz M, Sonnenblick EH, Le Jemtel TH. Therapeutic implications of escape from angiotensin-converting enzyme inhibition in patients with chronic heart failure. Curr Cardiol Rep 2000;2(3):258-62 111. Balcells E, Meng QC, Johnson WH J, et al. Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations. Am J Physiol 1997;273:1769-74 112. Phillips CO, Kashani A, Ko DK, et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials.

22

Arch Intern Med 2007;167(18):1930-6. Review 113. Mann JF, Schmieder RE, Mcqueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGETstudy): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372(9638):547-53 114. Manning M, Stoev S, Chini B, et al. Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog Brain Res 2008;170:473-512 115. Decaux G, Soupart A, Vassart G. Non-peptide arginine vasopressin antagonists: the vaptans. Lancet 2008;371:1624-32 116. Aditya S, Rattan A. Vaptans: a new option in the management of hyponatremia. J Appl Basic Med Res 2012;2(2):77-83 117. Gheorghiade M, Konstam MA, Burnett JC, 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(12):1332-43 118. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) Investigators. JAMA 2007;297(12):1319-31 119. Ali F, Guglin M, Vaitkevicius P, Ghali JK. Therapeutic potential of vasopressin receptor antagonists. Drugs 2007;67(6):847-58; Review 120. Hauptman PJ, Burnett J, Gheorghiade M, et al. Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan. J Card Fail 2013;19:390-7 121. Filippatos TD, Elisaf MS. Hyponatremia in patients with heart failure. World J Cardiol 2013;5(9):317-28

heart failure (SHIFT): a randomized placebo-controlled study. Lancet 2010;376(9744):875-85 124. Borer JS, B€ohm M, Ford I, et al. Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study). Am J Cardiol 2014;113(3):497-503 125. Swedberg K, Komajda M, B€ohm M, et al. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitorivabradine Trial) study. J Am Coll Cardiol 2012;59(22):1938-45 126. Corbala´n R, Kunstmann S, Jalil J. Vasodilator agents in chronic heart failure: which is the best option? Rev Med Chil 1993;121(1):81-8 127. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314(24):1547-52 128. TAylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57 129. Ghali JK, Tam SW, Ferdinand KC, et al. Effects of ACE inhibitors or betablockers in patients treated with the fixed-dose combination of isosorbide dinitrate/hydralazine in the AfricanAmerican Heart Failure Trial. Am J Cardiovasc Drugs 2007;7(5):373-80 130. CHENG JW. A review of isosorbide dinitrate and hydralazine in the management of heart failure in black patients, with a focus on a new fixeddose combination. Clin Ther 2006;28(5):666-78 131. Ferdinand KC, Elkayam U, Mancini D, et al. Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the AfricanAmerican heart failure trial. Am J Cardiol 2014;114(1):151-9

122. Ferrari R. Ivabradine: heart rate and left ventricular function. Cardiology 2014;128(2):226-30

132. Zarowitz BJ, Gheorghiade M. Optimal heart rate control for patients with chronic atrial fibrillation: are pharmacologic choices truly changing? Am Heart J 1992;123:1401-3

123. Swedberg K, Komajda M, B€ohm M, et al. Ivabradine and outcomes in chronic

133. Krum H, Bigger JT, Goldsmith RL, et al. Effect of long-term digoxin therapy



onautonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995;25:289-94


134.

Ferguson DW, Berg WJ, Sanders JS, et al. Sympathoinhibitory responses to digitalisglycosides in heart failure patients: direct evidence from sympathetic neural recordings. Circulation 1989;80:65-77

135.

Newton GE, Tong JH, Schofield AM, et al. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol 1996;28:155-61

136.

Gheorghiade M, Hall VB, Jacobsen G, et al. Effects of increasing maintenance dose ofdigoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin- converting enzyme inhibitors. Circulation 1995;92(7):1801-7

137.

Gheorghiade M, Adams KF, et al. Digoxin in the management of cardiovascular disorders. Circulation 2004;109:2959-64

138.

The effect ofdigoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-33

139.

140.

Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-11 Ather S, Peterson LE, Divakaran VG, et al. Digoxin treatment in heart failure--unveiling risk by cluster analysis of DIG data. Int J Cardiol 2011;150(3):264-9

141.

Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871-8

142.

Gheorghiade M, Patel K, Filippatos G, et al. Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial. Eur J Heart Fail 2013;15:551-9

143.

144.

Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post-hoc analysis of the DIG trial. Eur Heart J 2006;27(2):178-86 Dotsenko O, Kakkar VV. Antithrombotic therapy in patients with chronic heart failure: rationale, clinical

evidence and practical implications. J Thromb Haemost 2007;5(2):224-31 145.

146.

Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004;148(1):157-64 Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK; HELAS investigators. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail 2006;8(4):42832

147.

Lip Gy, Shantsila E. Anticoagulation versus placebo for heart failure in sinus rhythm. Cochrane Database Syst Rev 2014;3:CD003336 doi: 10.1002/ 14651858.

148.

Narang R, Cleland JG, Erhardt L, et al. Mode of death in chronic heart failure. A request and proposition for more accurate classification. EurHeartJ 1996;17(9):1390-403

149.

150.

Hallstrom A, Pratt CM, Greene HL, et al. Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial. J Am Coll Cardiol 1995;25(6):1250-7 Waldo AL, Camm AJ, Deruyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996;348(9019):7-12

151.

Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995;333(2):77-82

152.

Bardy GH, Lee KL, Mark DB, et al. A miodarone or an implantable cardioverter-defibrillator for congestive heart failure. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. N Engl J Med 2005;352(3):225-37. Erratum in N Engl J Med 2005;352(20):2146

153.

Roy D, Talajic M, Dorian P, Connolly S. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342(13):913-20


154. Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007;4(9):1250-9 155. Elkayam U, Amin J, Mehra A, et al. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990;82:1954-61 156. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S. Diltiazem increases late-onset congestive heart failurein postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation 1991;83:52-60 157. Effect ofverapamil on mortality and major events after acute myocardial infarction (theDanish Verapamil Infarction Trial IIDAVIT II). Am J Cardiol 1990;66:779-85 158. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronicheart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335:1107-14 159. Thackray S, Witte K, Clark AL, Cleland JG. Clinical trials update: optime-CHF, Praise-2, All-Hat. Eur J Heart Fail 2000;2:209-12 160. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy inpatients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997;96:856-63 161. Motte S, Mcentee K, Naeije R. Endothelin receptor antagonists. Pharmacol Ther 2006;110:386 162. Tostes RCA, Muscara MN. Endothelin receptor antagonists: another potential alternative for cardiovascular diseases. Curr Drug Targets Cardiovasc Haematol Disord 2005;5:287 163. Ertl G, Bauersachs J. Endothelin receptor antagonists in heart failure: current status and future directions. Drugs 2004;64(10):1029-40

23

E. Kaldara et al.

164. Han B, Hasin Y. Cardiovascular effects of natriuretic peptides and their interrelation with endothelin-1. Cardiovasc Drugs Ther 2003;17(1):41-52 165. Sharp A, Mayet J. The utility of BNP in clinical practice. J Renin Angiotensin Aldosterone Syst 2004;5:53


166. Dawson A, Struthers AD. Vasopeptidase inhibitors in heart failure. J Renin Angiotensin Aldosterone Syst 2002;3(3):156-9 167. Tabrizchi R. Dual ACE and neutral endopeptidase inhibitors: novel therapy for patients with cardiovascular disorders. Drugs 2003;63(20):2185-202 168. Aronson D, Krum H. Novel therapies in acute and chronic heart failure Pharmacology and Therapeutics. 2012;135:1-17 169. Mcmurray JJ, Packer M, Desai As, et al. Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail 2014;16(7):817-25 170. Feldman AM, Combes A, Wagner DC, et al. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol 2000;35:537 171. Parissis JT, Venetsanou KF, Mentzikof DG, et al. Tumor necrosis factor-alpha serum activity during treatment of acute decompensation of cachectic and non-cachectic patients with advanced congestive heart failure. Cardiovasc J 1999;33:344 172. Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201 173. Bozkurt B, Kribbs SB, Clubb FJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factoralpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382 174. Mann DJ, Mcmurray JJV, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the randomized etanercept worldwide evaluation (RENEWAL). Circulation 2004;109:76

24

175. Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension 2002;39(1):E1-8 176. Sidik NP, Solomon SD, Latini R, et al. Effect of aliskiren in patients with heart failure according to background dose of ACE inhibitor: a retrospective analysis of the Aliskiren Observation of Heart Failure Treatment (ALOFT). Cardiovasc Drugs Ther 2011;25(4):315-21 177. Gheorghiade M, B€ohm M, Greene SJ, et al. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. ASTRONAUT Investigators and Coordinators. JAMA 2013;309(11):1125-35 178. Krum H, Massie B, Abraham WT, et al. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the aliskiren trial to minimize outcomes in patients with heart failure (ATMOSPHERE) study. Eur J Heart Fail 2011;13(1):107-14 179. Parving HH, Brenner BM, Mcmurray JJ, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): rationale and studydesign. Nephrol Dial Transplant 2009;24(5):1663-7 180. Mcmurray JJ, Packer M, Desai As, et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail 2014;16(7):817-25 181. Ezekowitz JA, Mcalister FA. Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials. Eur Heart J 2009;30(4):469-77 182. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel nonsteroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease:


a randomized, double-blind trial. Eur Heart J 2013;34(31):2453-63 183. Pitt B, Filippatos G, Gheorghiade M, et al. Rationale and design of ARTS :a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease. Eur J Heart Fail 2012;14(6):668-75 184. Greenberg B, Yaroshinsky A, Zsebo Km, et al. JACC Heart Fail 2014;2(1):84-92 185. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebocontrolled, parallel-group, dose-finding phase IIb study. Lancet 2009;373:1429-39 186. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:29-39 187. Konoshita T. Do genetic variants of the Renin-Angiotensin system predict blood pressure response to Renin-Angiotensin system-blocking drugs? A systematic review of pharmacogenomics in the Renin-Angiotensin system. CurrHypertens Rep 2011;13(5):356-61 188. Liggett SB, Cresci S, Kelly RJ, et al. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med 2008;14(5):510-17 189. Genetically targeted therapy for the prevention of symptomatic atrial fibrillation in patients with heart failure. GENETICAF. Available from: http:// clinicaltrials.gov/ct2/show/NCT01970501 190. A pharmacogenomic study of candesartan in heart failure. J Clin Hypertens (Greenwich) 2011.13(9):639-43. Available from: http://clinicaltrials.gov/ct2/show/ NCT00400582)



Affiliation Elisabeth Kaldara1, Despina Sanoudou2, Stamatis Adamopoulos3 & John N Nanas†1 † Author for correspondence 1 University of Athens, Medical School, 3rd Cardiology Department, Mikras Asias 67, 11527 Attiki, Athens, Greece Tel: +30 2108236877; Fax: +30 2107789901; E-mail: [email protected] 2 University of Athens, Medical School, Department of Pharmacology, Athens, Greece 3 Onassis Cardiac Surgery Centre, 2nd Department of Cardiology, Athens, Greece


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Korean Guidelines for Diagnosis and Management of Chronic Heart Failure.

Management of Noncardiac Comorbidities in Chronic Heart Failure.

Chronic Heart Failure Follow-up Management Based on Agent Technology.

Fluid Management in Patients with Chronic Heart Failure.

Outpatient management of heart failure in the United States, 2006-2008.

Biomarkers in outpatient heart failure management; Are they correlated to and do they influence clinical judgment?

Chronic heart failure.

Heart failure: chapter 6. Pharmacological treatment of chronic heart failure.

Chronic heart failure.

Management of perioperative heart failure.

Treatment of chronic heart failure.

Pathophysiology of chronic heart failure.

Treatment of chronic heart failure.

Management of chronic heart failure: biomarkers, monitors, and disease management programs.

Chronic renal failure: management.

Management of Chronic Heart Failure in Primary Care: What Evidence do we have for Heart Failure with Preserved Systolic Function?

Characterization and prediction of adverse events from intensive chronic heart failure management and effect on quality of life: results from the pro-B-type natriuretic peptide outpatient-tailored chronic heart failure therapy (PROTECT) study.

Management of chronic renal failure.

Management of chronic renal failure.

Periodontitis in Chronic Heart Failure.

[Resilience in chronic heart failure].

Drugs for chronic heart failure.

Quinapril in chronic heart failure.

Differences in exercise capacity in patients with chronic left heart failure and chronic right heart failure.