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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The evolution of heart failure management over recent decades: from CONSENSUS to CIBIS

Philippe Lechat*

Pharmacology Department, Pitié-Salpêtrière Hospital, AP-HP, 47 Boulevard de l'Hôpital, 75013 Paris, France

* Corresponding author. Tel: +33 1 42 16 16 82; fax: +33 1 42 16 16 88. E-mail address: philippe.lechat{at}psl.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
The treatment of chronic heart failure (CHF) has changed greatly during the last two decades, moving from therapy based on a haemodynamic model to treatments targeting the neuroendocrine systems and the remodelling process. The use of inotropic agents to compensate for the loss of contractile force resulted only in neutral or deleterious effects on long-term prognosis. Vasodilator therapy was then introduced with the objective of improving haemodynamics and reducing cardiac load. The first vasodilator studied, hydralazine/isosorbide dinitrate, was rapidly superseded by the ACE-inhibitors, the first neurohormonal antagonists to demonstrate mortality reduction in CHF, and to inhibit left ventricular (LV) remodelling. During the 1980s, ACE-inhibitors were shown to benefit patients in all NYHA classes including patients with asymptomatic LV dysfunction. The concept of neurohormonal blockade was then extended to the sympathetic nervous system. Although the first evidence of a beneficial effect of beta-blockade dates back as early as 1975, it was not until the 1990s that major randomized controlled trials showed a mortality reduction of approximately one-third when beta-blockers were given in addition to standard therapy with ACE-inhibitors and diuretics. In recent years, the aldosterone antagonists have also emerged as beneficial treatments for severe CHF. However, other neurohormonal antagonists have proved disappointing. Most recently, cardiac resynchronization therapy, with or without an implantable cardioverter defibrillator, has also been shown to reduce morbidity and mortality in selected patients. With the range of drugs and devices now available, the challenge now is to find the optimal combination for each patient.

Key Words: Chronic heart failure • ACE-inhibitor • Beta-blocker • Inotropic agents • Diuretics • Digitalis • Cardiac resynchronization therapy • Randomized controlled trials


   Introduction
Top
 Abstract
 Introduction
Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
Chronic heart failure (CHF) is a complex condition, and the history of its management reflects our evolving understanding of its pathophysiology. In the past, pharmacological treatment was aimed only at relieving oedema and improving haemodynamics. In recent years, however, attention has shifted to target neuroendocrine activation and the remodelling process. Currently, the major pharmacological treatments for CHF are diuretics, ACE-inhibitors, beta-blockers, and (in NYHA classes III and IV) aldosterone antagonists.1,2 Device therapy is also beginning to play an important role in selected patients with CHF, and many other new treatments continue to be evaluated. This review outlines the recent history of treatment for CHF and the evidence underlying current treatment recommendations.1,2


   Diuretics
Top
 Abstract
 Introduction
 Diuretics
Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
The first models of CHF, developed in the 1940–60, focused on haemodynamics and on oedema as the key feature of CHF, leading to the widespread use of diuretics. Today, diuretics are still used in most CHF patients for the symptomatic treatment of heart failure when there is evidence of fluid overload (pulmonary congestion or peripheral oedema),1,2 but there is no evidence that they improve survival.


   Inotropic agents
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
Initially, it was believed that inotropic support was required to compensate for the loss of contractile force in CHF. Inotropes have an established place in acute decompensated heart failure, but the long-term use of most inotropic agents appears to have neutral or even deleterious effects on prognosis, despite transient beneficial effects on functional symptoms. Xamoterol, milrinone, enoximone, flosequinan, vesnarinone, pimobendan, and ibopamine have all been shown to increase mortality in CHF. For example, a study of the beta1 partial agonist, xamoterol, in severe CHF found that mortality was significantly increased over a 100-day follow-up when compared with placebo.3

In contrast to other inotropes, cardiac glycosides (digitalis:digoxin, digitoxin) have no detrimental effect on survival when used long-term in CHF; this may be because they act primarily by attenuating neurohormonal activation rather than as inotropic agents.4 Cardiac glycosides are clearly indicated in patients with heart failure complicated by atrial fibrillation,1 but their role in patients with sinus rhythm is more controversial.4 The DIG trial found that digoxin did not reduce overall mortality, although it reduced the rate of hospitalization, both overall and for worsening heart failure.5 ESC guidelines1 state that there is an indication for cardiac glycosides for symptom control in patients with worsening (NYHA III and IV) and end-stage (NYHA IV) heart failure, and in those with NHYA II who are recovering from more severe heart failure.

Calcium sensitizers, of which levosimendan is the most important, are a new class of inotropic agents that improve haemodynamics without increasing cAMP and intracellular calcium concentrations. Levosimendan has been investigated in long-term use as well as in acute decompensated heart failure. Recently, the intravenous levosimendan compared with dobutamine in severe low-output heart failure trial (LIDO)6 indicated a beneficial effect of levosimendan on 6-month mortality. However, the longer-term (survival of patients with acute heart failure in need of intravenous inotropic support) trial (SURVIVE), presented at the American Heart Association meeting in November 2005, did not show a statistically significant reduction in the primary endpoint of 180-day all-cause mortality.

Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP. The Prospective Randomized Milrinone Survival Evaluation (PROMISE) showed that despite its beneficial haemodynamic actions, long-term therapy with oral milrinone increased morbidity and mortality in patients with severe CHF (NYHA Class III or IV).7 More recently, Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-HF) showed that milrinone was deleterious in exacerbations of ischaemic CHF, with a neutral or beneficial effect in non-ischaemic CHF.8


   Vasodilators
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
As inotropic agents proved to be unsuitable for long-term use, attention quickly switched to vasodilator therapies, aiming to improve haemodynamics and reduce cardiac load.

Hydralazine/isosorbide dinitrate
The first vasodilator to be studied in a large randomized controlled trial was hydralazine/isosorbide dinitrate. The first Vasodilator-Heart Failure Trial Study Group trial (V-HeFT I)9 showed that the addition of hydralazine/isosorbide dinitrate to digoxin and diuretics improved left ventricular (LV) function and reduced mortality. However, a second trial, V-HeFT II,10 showed the ACE-inhibitor enalapril to have more effect on mortality than hydralazine/isosorbide dinitrate, suggesting that ACE-inhibitors are the vasodilators of choice.

However, there may be a specific place for hydralazine/isosorbide dinitrate in black patients. Retrospective analysis of the V-HeFT I and II data suggested that, in black patients, hydralazine/isosorbide dinitrate was as effective as an ACE-inhibitor.11 Recently, the combination of isosorbide dinitrate plus hydralazine added to standard therapy including an ACE-inhibitor has been found to increase survival among black patients with advanced CHF (NYHA III or IV) (Figure 1).12


Figure 0081
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  		Figure 1 Kaplan–Meier estimates of overall survival for 1050 black patients with CHF (NYHA Class III or IV) receiving either hydralazine hydrochloride 225 mg/isosorbide dinitrate 120 mg daily, or placebo. This study suggests a specific role for this hydralazine/isosorbide dinitrate in black patients. Reproduced with permission from Taylor AL et al.12 Copyright © 2004 Massachusetts Medical Society. All rights reserved.

 
ACE-inhibitors
The renin–angiotensin–aldosterone system (RAAS) has an important role in the regulation of blood volume, blood pressure, and electrolytes and is activated in CHF. ACE-inhibitors reduce the conversion of angiotensin-I to the vasoconstrictor angiotensin-II. They thereby indirectly cause vasodilatation and decreased aldosterone secretion. ACE-inhibitors act as vasodilators to increase cardiac output by reducing afterload, but it is now clear that much of their long-term benefit comes from a direct effect on the heart; prevention of progressive LV dysfunction by inhibiting ventricular remodelling.1

Numerous studies (see below) have shown that ACE-inhibitors reduce long-term mortality and improve ejection fraction. They are therefore recommended by ESC guidelines for all patients with a subnormal LV ejection fraction (LVEF) (<40–45%), with or without symptoms.1

The first major ACE-inhibitor study to show mortality benefit in CHF was the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)13 in patients in NYHA class IV. This was confirmed in patients with less severe disease by the SOLVD treatment arm.14 ACE-inhibitors have also been shown to reduce morbidity and mortality in asymptomatic patients with LV dysfunction, as shown by the prevention arm of the SOLVD study,15 the Survival and Ventricular Enlargement (SAVE) study,16 and the Trandolapril Cardiac Evaluation (TRACE) study.17 In addition, the Heart Outcomes Prevention Evaluation (HOPE) study has demonstrated a benefit of ACE-inhibition in patients with normal LV function but a high risk of cardiovascular disease.18

A 1995 meta-analysis of ACE-inhibitor trials including over 7000 patients found a 23% mortality reduction and a 35% reduction in the combined endpoint of mortality and hospitalizations for heart failure worsening.19 Similar benefits were observed with different ACE-inhibitors (enalapril, captopril, ramipril, quinapril, and lisinopril). Reductions for total mortality and the combined endpoint were similar for various subgroups examined (age, sex, aetiology, and NYHA class) (Figure 2). The reduction in mortality was primarily because of fewer deaths from progressive heart failure.


Figure 0082
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  		Figure 2 Total mortality by various subgroups in ACE-inhibitor trials including more than 7000 patients. Benefit was demonstrated in all subgroups. Overall mortality reduction was 23% (P<0.001). Data from Garg R, Yusuf S.19

 
AT-II receptor blockers
Angiotensin-II (AT-II) receptor blockers (ARBs) inhibit the RAAS by blocking the actions of AT-II at the AT1 receptor. They produce more complete blockade of the actions of AT-II than ACE-inhibitors, and mostly avoid the bradykinin-mediated side effects of ACE-inhibitors, such as cough. ESC guidelines1 state that ARBs can be used as an alternative to ACE-inhibitors in symptomatic patients intolerant of ACE-inhibitors. This recommendation is based on the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative20 and CHARM-Overall21 trials with candesartan, and the Valsartan Heart Failure Trial (Val-HeFT) with valsartan.22,23 ACE-inhibitors and ARBs seem to have similar effects on mortality and morbidity in CHF. The combination may also confer additional benefits in terms of mortality and hospitalizations (as evidenced by the CHARM-Added study24). ESC guidelines state that ARBs can be considered in combination with ACE-inhibitors in patients who remain symptomatic.21,24–26

Concern was raised about a possible negative interaction of ARBs and beta-blockers by a subgroup analysis of Val-HeFT,23 and by the Losartan Heart Failure Survival Study (ELITE II).27 However, later studies suggest that this concern is unfounded; no negative interaction was observed in CHARM-Added,24 or in a study of patients with acute MI complicated by heart failure or LV dysfunction.28

A recent analysis presented at the ESC Congress in Stockholm in 2005 (unpublished data) showed that annual mortality in Val-HeFT and CHARM-Added was much lower in beta-blocker treated groups in both trials (P<0.01), regardless of whether patients were also receiving placebo or an ARB. This analysis suggested that the overall benefit of the ARB vs. placebo was similar in CHARM and Val-HeFT but was less important in the beta-blocker treated patients where annual mortality was low.


   Calcium antagonists
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
In general, calcium antagonists (especially diltiazem and verapamil) are not recommended for the treatment of CHF, and must not be used in combination with beta-blockers.1 Newer calcium antagonists (felodipine, amlodipine) do not increase survival when added to standard therapy with diuretics and ACE-inhibitors, but may be considered as additional therapy for hypertension or angina. The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) found that, although amlodipine reduced the combined risk of fatal and non-fatal events in non-ischaemic cardiomyopathy by 31% and the risk of death by 46%, it had no benefit in patients with ischaemic cardiomyopathy.29


   Aldosterone antagonists
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
Aldosterone has an important role in the pathophysiology of heart failure, promoting vascular and myocardial fibrosis, neurohormonal activation, arrhythmogenesis, and potassium and magnesium depletion.1,30 Aldosterone release is dependent on AT-II, and can be partially prevented by ACE-inhibitors. However, some activation of the RAAS escapes during ACE-inhibition. Aldosterone antagonists offer an additional means of inhibiting aldosterone activity.

European Society of Cardiology (ESC) guidelines now recommend aldosterone antagonists in addition to standard treatment in patients with advanced CHF (NYHA classes III and IV), in addition to ACE-inhibition.1 This recommendation is based on the outcome of the Randomized Aldactone Evaluation Study (RALES), in which low-dose spironolactone (12.5–50 mg/day) reduced mortality and morbidity in patients with advanced CHF and volume overload (Figure 3).31 More recently, the Eplerenone Post-AMI Heart Failure Efficacy and Survival (EPHESUS) trial also showed that eplerenone reduces mortality and morbidity in post-MI patients with LV dysfunction and CHF.32 As a result, the 2005 ESC guidelines also recommend the use of aldosterone antagonists in addition to ACE-inhibitors and beta-blockers to reduce mortality and morbidity in post-MI patients with LV systolic dysfunction and signs of heart failure or diabetes.1


Figure 0083
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  		Figure 3 Probability of survival among patients with severe CHF receiving spironolactone 25 mg daily (n=822) or placebo (n=841) in the RALES study. The risk of death was 30% lower among patients in the spironolactone group than among patients in the placebo group (P<0.001). Reproduced with permission from Pitt B et al.31 Copyright © 1999 Massachusetts Medical Society. All rights reserved.

 

   Beta-blockers
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
Beta-blockers were traditionally considered contraindicated in CHF because of their acute negative inotropic effect. However, in the last decade, the concept of neurohormonal inhibition has been extended from the RAAS to the sympathetic nervous system (SNS), based on the observed deleterious effects of chronic beta-adrenergic stimulation. The exact mode of action of beta-blockers in CHF is uncertain, but probably includes anti-arrhythmic effects, beneficial haemodynamic effects (especially on heart rate and heart rate variability), prevention of catecholamine toxicity at the cellular level and reverse remodelling.33

The belief that beta-blockers should be avoided in CHF was first challenged in 1975 by a small study in which seven Swedish patients with advanced congestive cardiomyopathy were shown to benefit from beta-blockade.34 Over the years, it was shown that long-term use of beta-blockers in CHF reduced symptoms, improved exercise capacity, and ventricular function.35 These findings raised the question of whether beta-blockade could reduce mortality in CHF and add to the benefits already demonstrated with ACE-inhibitors.

The first trial of a beta-blocker in CHF with mortality as the main endpoint was the Cardiac Insufficiency Bisoprolol Study (CIBIS) with bisoprolol.36 This showed a non-significant 20% reduction in all-cause mortality in the bisoprolol group (P=0.22) and significant improvements in survival in some subgroups, and led to the larger CIBIS II trial.37,38

CIBIS II was the first randomized controlled trial to show a significant reduction in all-cause mortality with a beta-blocker in CHF. It was followed by two more landmark trials—the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) with metoprolol succinate CR/XL,39 and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS)40 with carvedilol. All three trials showed a remarkably consistent effect, with a reduction in all-cause mortality of 34–35% when the beta-blocker was added to standard therapy (diuretics, ACE-inhibitors, and optional digitalis glycosides) (Figure 4). In these trials, beta-blockers also achieved significant long-term reductions in cardiovascular mortality, sudden death, and death due to progression of heart failure. In addition, they reduced hospitalizations (all-cause, cardiovascular, and worsening heart failure), improved functional class (NYHA) and reduced heart failure worsening. More recently, a significant effect on a combined mortality and morbidity endpoint has been demonstrated in elderly patients in SENIORS with nebivolol.41 As described by Willenheimer in this Proceedings, the CIBIS III trial has recently shown that starting treatment of mild-to-moderate CHF with a beta-blocker (bisoprolol), followed by the addition of an ACE-inhibitor (enalapril), is as effective and well tolerated as starting with an ACE-inhibitor.42,43


Figure 0084
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  		Figure 4 Mortality reduction in major randomized controlled trials of beta-blockade. In trials on bisoprolol, metoprolol, and carvedilol there was a remarkably consistent mortality reduction of 34–35%,38–40 but no significant mortality reduction was seen in BEST.44

 
Only one large placebo-controlled beta-blocker trial failed to show a mortality benefit: the Beta-blocker Evaluation of Survival (BEST)44 with the non-selective agent bucindolol. This was stopped early because of lack of significant difference in mortality between the two groups (33% under placebo, 30% under bucindolol, P=0.13). Various explanations have been proposed for the discrepancy between BEST and other beta-blocker trials. Although bucindolol has sympatholytic activity because of its strong beta2-adrenergic blockade, and only weak alpha1-blocking vasodilatory properties, it also has intrinsic sympathomimetic activity, which may be harmful in CHF.45

As a result of the pivotal clinical trials, today beta-blockers may now be considered central to the treatment of CHF. It should be remembered that the mortality reduction of approximately one-third achieved in randomized controlled trials was in addition to standard treatment with ACE-inhibitors and diuretics. The recently published ESC guidelines therefore recommend:1 that beta-blockers should be considered for all patients with stable, mild, moderate, or severe CHF (NYHA Classes II and IV) and reduced LVEF on standard treatment with ACE-inhibitors and diuretics, unless there is a contra-indication. They also state that beta-blockers should also be used in patients with LV systolic dysfunction following MI, regardless of whether symptomatic CHF is present, in addition to ACE-inhibitors. (The ACC/AHA guidelines also recommend that patients with LV dysfunction and a reduced LVEF should receive beta-blockers, but do not stipulate that it should be after MI).2 The expanding role of beta-blockers in the treatment of CHF has also been recognized in the recent publication of an Expert Consensus on beta-adrenergic receptor blockers by the European Society of Cardiology (ESC).46

European guidelines state that the beta-blockers selected for use in CHF should be those with proven efficacy in randomized controlled trials—bisoprolol, metoprolol succinate, carvedilol, and nebivolol. Whether there are any clinically relevant differences between the beta-blockers shown to be effective in CHF remains open to debate. Only one randomized head-to-head trial, the Carvedilol or Metoprolol European Trial (COMET) has been carried out to compare the effects of beta-blockers in heart failure.47 COMET compared the non-selective agent carvedilol with the beta1-selective agent metoprolol tartrate in 3029 patients with mild, moderate, or severe CHF. The findings of COMET have been criticized on the grounds that the dose of metoprolol tartrate used was too low to achieve equivalent beta1-blockade in the two groups, and the formulation used was not that used in the MERIT-HF study (on which the indication for metoprolol in CHF is based).48 COMET used immediate-release metoprolol tartrate at a mean dose of 85 mg/day, whereas MERIT-HF used extended-release metoprolol succinate at a mean dose of 149 mg/day. However, differences between beta-blockers cannot be ruled out—for example, a recent study showed that carvedilol shows persistent binding to cardiac beta-receptors after it has been eliminated from the plasma, whereas metoprolol does not.49


   Other neurohormonal antagonists
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
New neurohormonal receptor antagonists have so far proved somewhat disappointing in CHF. Omapatrilat is a dual ACE and neutral-endopeptidase (NEP) inhibitor that inhibits endogenous vasoconstrictor systems (ACE) and the breakdown of the vasodilator factor NEP. However, the Omapatrilat Vs. Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) showed no evidence of superiority to standard treatments in CHF (Figure 5).50 Endothelin receptor antagonists (ERAs) act to combat the effects of endothelin, which is a potent vasoconstrictor, and also has chronic effects such as fibrosis, neurohormonal stimulation, and cell proliferation. The ERA bosentan produces favourable short-term haemodynamic effects in heart failure. However, a recent long-term study was terminated early owing to safety concerns and no convincing long-term benefit has therefore been demonstrated.51 The MOXCON study with moxonidine, an imidazoline receptor agonist, was also stopped early because of excess mortality and morbidity in the treatment group, suggesting that central generalized sympathetic inhibition may be undesirable in CHF.52


Figure 0085
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  		Figure 5 In the OVERTURE study, the ACE–NEP inhibitor omapatrilat (40 mg once daily, n=2886) reduced mortality in patients with CHF (NYHA Class II–IV) but was not more effective than enalapril alone (10 mg bid, n=2884). Reproduced with permission from Packer M et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure, the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920–926.

 

   Anti-cytokine treatments
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 
Tumour necrosis factor alpha (TNF-alpha) has deleterious cardiovascular effects. Etanercept, a protein directed against TNF, was tested in CHF in the RENAISSANCE and RECOVER trials,53 but a combined analysis of both trials (RENEWAL) showed no difference between etanercept and placebo for either the primary endpoint (all-cause death or hospitalization for HF) or the secondary endpoint, all-cause mortality.54


   Statins
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
Device therapy
 Other new therapies
 Conclusions
 References
 
It has been hypothesized that statins may also offer benefits in CHF, independent of their cholesterol-lowering action. The Losartan Heart Failure Survival Study II (ELITE II),27 compared the effects of losartan vs. captopril on survival; of 3127 patients, 12.7% received statin therapy. Patients receiving statins had a reduced risk of death, independent of other parameters. The potential benefit of ancillary properties of statins is currently being investigated in the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) in 4950 patients with symptomatic CHF (NYHA III–IV with LVEF ≤40% or NYHA II with LVEF ≤35%).55 Patients have been randomized to rosuvastatin (10 mg daily) or placebo for 52 months. The primary endpoint is cardiovascular death, MI, or non-fatal stroke. A beneficial interaction has also been proposed between beta-blockers and statins. Recent analysis of data from the CIBIS II trial indicates a strong beneficial interaction between bisoprolol and statin therapy (Krum et al., personal communication).


   Device therapy
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
Other new therapies
 Conclusions
 References
 
The place of implantable devices in therapy for CHF is increasing. Several trials have demonstrated that cardiac resynchronization therapy (CRT) (also known as biventricular pacing) can reduce symptoms and hospitalization in CHF.56–59 Effects on mortality have also been demonstrated with CRT alone59 or in combination with an implantable cardioverter defibrillator (ICD).58 The 2005 ESC guidelines1 therefore state that CRT can be considered in NYHA Class III and IV patients with reduced ejection fraction and QRS width ≥120 ms, who remain symptomatic despite optimal pharmacological therapy.

ICD therapy is recommended for secondary prevention in those who have already survived cardiac arrest or sustained ventricular tachycardia (poorly tolerated or associated with reduced systolic LV function).60 ICD implantation is also considered reasonable as primary prevention in selected patients considered to be at high risk for ventricular arrhythmias—those with LVEF <30–35%, not within 40 days of MI, who are already on optimal pharmacological therapy.61–63 On the basis of the recent Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) study,58 implantation of a combined CRT–ICD device can be considered with the aim of reducing mortality and morbidity in patients who remain symptomatic with severe CHF (NYHA III or IV) with LVEF ≤35% and QRS duration ≥120 ms.


   Other new therapies
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
Conclusions
 References
 
Additional approaches under investigation are aimed at increasing angiogenesis or repairing the failing heart via gene therapy64 or cell transplantation.65


   Conclusions
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
References
 
The past two decades have seen remarkable advances in the treatment of CHF. However, there is no room for complacency. The prevalence of this devastating disease is increasing, and many patients do not yet receive recommended evidence-based treatments. Under-prescription of beta-blockers is a particular concern.66,67 Polytherapy in heart failure appears to be necessary and beneficial, but poses many challenges to clinicians and healthcare systems. With all the different therapies now available, the current challenge for physicians is to determine the optimal drug and dose combination for individual patients.

Conflict of interest: P.L. has served as chairman and/or co-chairman of CIBIS I, II, and III trials.


   References
Top
 Abstract
 Introduction
 Diuretics
 Inotropic agents
 Vasodilators
 Calcium antagonists
 Aldosterone antagonists
 Beta-blockers
 Other neurohormonal antagonists
 Anti-cytokine treatments
 Statins
 Device therapy
 Other new therapies
 Conclusions
 References
 

  1. Swedberg K, Cleland J, Dargie H . Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26: 1115–1140.[Free Full Text]
  2. Hunt SA, Abraham WT, Chin MH . ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). Circulation 2005; 112: 1825–1852.[Free Full Text]
  3. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1–6.[CrossRef][ISI][Medline]
  4. Riaz K, Forker AD. Digoxin use in congestive heart failure. Current status. Drugs 1998; 55: 747–758.[CrossRef][ISI][Medline]
  5. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–533.[Abstract/Free Full Text]
  6. Follath F, Cleland JG, Just H . Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002; 360: 196–202.[CrossRef][ISI][Medline]
  7. Packer M, Carver JR, Rodeheffer RJ . Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991; 325: 1468–1475.[Abstract]
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