Pharmacological options for acute heart failure syndromes: current treatments and unmet needs
Division of Cardiology, University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
* Corresponding author. Tel: +358 94717 2200; fax: +358 94717 4015. E-mail address: markku.nieminen{at}hus.fi
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Abstract |
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 Top Abstract IntroductionAcute heart failurePathophysiological mechanisms...Clinical management of acute...ConclusionsAcknowledgementReferences |
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Although acute heart failure represents a major burden on public health worldwide, there has been little research in this field and many treatment strategies are based on clinical experience rather than on evidence from randomized trials. Goals of acute treatment include stabilization of haemodynamics and symptomatic relief. Therapeutic options include digoxin, diuretics, nitrovasodilators, and positive inotropic agents, each of which is associated with clinical limitations. Although digoxin appears to be beneficial in some patients, its role in management of acute heart failure remains uncertain. Diuretics are well established as a mainstay of therapy and provide rapid symptomatic relief, but recent evidence links high-dose diuretic use with adverse outcomes. Nitrovasodilators can improve haemodynamics, but problems with this drug class include tachyphylaxis and dose-related side effects. Positive inotropic agents are useful for increasing cardiac index in patients with low-output heart failure, but there are concerns that inotrope use is associated with a worsened prognosis. It is hoped that the novel therapies that are currently emerging, including the natriuretic peptide nesiritide and the calcium sensitizer levosimendan, will address some of the currently unmet treatment needs without the limitations of current treatments.
Key Words: Acute disease • Congestive heart failure, classification/pathophysiology/therapy • Pharmacotherapy
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Introduction |
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TopAbstractIntroductionAcute heart failurePathophysiological mechanisms...Clinical management of acute...ConclusionsAcknowledgementReferences |
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Acute decompensated heart failure represents a major and growing health problem for society. However, relatively little research has been performed in this field to provide a basis for rational treatment strategies. Although treatment guidelines abound for chronic heart failure (CHF), they remain absent for acute heart failure. This current lack of formal clinical guidance for the management of acute heart failure in Europe will, however, soon be addressed by guidelines currently to be published by the European Society of Cardiology (ESC). These guidelines are being developed by the Acute Heart Failure Task Force, comprising members from the working groups on heart failure and acute cardiac care of the ESC and representatives from the European Society of Intensive Care Medicine.
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Acute heart failure |
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TopAbstractIntroductionAcute heart failurePathophysiological mechanisms...Clinical management of acute...ConclusionsAcknowledgementReferences |
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Acute heart failure is defined as the rapid onset of symptoms secondary to abnormal cardiac function and, as it is often life threatening, requires urgent treatment. The cardiac dysfunction in acute heart failure can be related to systolic or diastolic dysfunction, abnormalities of cardiac rhythm or pre-load/after-load mismatch. The term acute heart failure covers a number of distinct clinical conditions. Acute decompensated heart failure is used to describe an episode of acute worsening of underlying chronic congestive heart failure that requires hospitalization or a first episode in patients with no history of heart failure (e.g. precipitated by acute myocardial infarction or cardiac/non-cardiac surgery).
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Pathophysiological mechanisms underlying heart failure |
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TopAbstractIntroductionAcute heart failurePathophysiological mechanisms...Clinical management of acute...ConclusionsAcknowledgementReferences |
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Our increasing understanding of the pathophysiological mechanisms underlying heart failure may be expected to translate into the development of novel effective approaches by which to treat this challenging syndrome. For example, two important pathophysiological mechanisms are neuroendocrine activation and disturbance of calcium regulation, both of which have been the focus of drug development in recent years.
Neuroendocrine activation stimulates the sympathetic nervous system and renin–aldosterone–angiotensin system, with the release of antidiuretic hormone, cytokines, endothelin, and natriuretic peptides; these directly contribute to the underlying pathophysiology of acute heart failure and subsequent compensatory response of the heart.1 Vasoconstriction and an increase in systemic vascular resistance are produced via stimulation of 
-adrenergic receptors and AT1-receptors. Angiotensin II and adrenaline may produce myocardial hypertrophy, and apoptosis and necrosis of cardiac cells. The ß-adrenergic system is desensitized via the down-regulation and uncoupling of ß1-adrenoceptors and via an increase of inhibitory G-protein -subunits. The disturbance of catecholaminergic effects in patients with acute heart failure leads to a deterioration of cardiac function, an increase in filling pressure, and an increase in wall tension, which culminates in critical left ventricular deterioration. Other unknown mediators may also be involved.
The disturbance of calcium regulation in both acute and chronic congestive heart failure leads to the attenuation of contractile function in the cardiac myocytes.2 All levels of the calcium mechanism are affected, which ultimately leads to a reduction of calcium regulation in the myocyte and attenuation of contractility. The energy systems of the myocyte are likewise affected in acute heart failure.
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Clinical management of acute heart failure |
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The objectives of clinical management for patients with acute heart failure are multiple; they encompass the treatment of both overt and underlying heart disease. The immediate clinical goal is to stabilize patients' haemodynamics (notably, decrease pulmonary capillary wedge pressure and increase cardiac output; Table 1) and provide symptom relief. A comprehensive clinical assessment and echocardiography should be advocated as routine procedure for all patients. Before considering treatment options for patients with acute heart failure, it is important to reiterate that this patient group comprises very sick individuals with low cardiac outputs. Thus, the therapeutic goals need to be realistic and defined accordingly. Long-term management goals for acute heart failure should aim to reduce progression of the disease, thereby reducing hospital readmission and mortality.
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Most patients presenting with acute heart failure will be treated with oxygen and possibly morphine to assist with pulmonary venous dilation and symptom relief. A variety of therapeutic options exist for acute heart failure, including digoxin, diuretics, nitrovasodilators (e.g. nitroglycerin, nitroprusside), and positive inotropic agents (e.g. dobutamine, milrinone). However, each drug class is associated with clinical limitations. Newer therapies (e.g. the natriuretic peptide nesiritide and the calcium sensitizer levosimendan) are emerging, along with the hope that these agents may address some of the currently unmet treatment needs.
Digoxin
Digoxin appears to be beneficial in patients with a high heart rate, atrial fibrillation, and possibly in patients with enlarged ventricles and systolic dysfunction. The safety of digoxin in standard doses was demonstrated in the DIG trial, though it is questionable whether standard doses achieve plasma concentrations that fall within the generally accepted therapeutic range.3 Although digoxin does not reduce overall mortality, it does appear to reduce the rate of hospitalization both overall and for worsening heart failure. However, the importance of the role of digoxin in the management of acute heart failure based on the results of the DIG trial remains equivocal.
Diuretics
The use of diuretics in the treatment of heart failure is well established. Patients without signs of cardiogenic shock or symptomatic hypotension who have evidence of volume overload generally receive diuretics, most commonly intravenous furosemide.4 The reliance on intravenous diuretics is reflective of the fact that most patients present with evidence of volume overload and diuretics provide rapid relief of breathlessness and oedema. However, a diuretic-based approach has significant limitations. Diuretic requirements in patients with CHF increase with disease progression, and thus intensity of diuretic treatment may have prognostic implications in these patients.5 Indeed, attenuated diuretic response has been shown to be associated with a poor prognosis and increased risk of death during the subacute period of hospitalization of patients with decompensated CHF, though a direct or indirect relationship remains to be confirmed.5 Moreover, high-dose diuretic use is increasingly recognized to be associated with adverse outcomes.6–8 Although a proportion of this association may be related to the degree of severity of illness in patients with heart failure, intensive diuretic treatment can cause deleterious activation of neurohormones and precipitate cardiac arrhythmias.6
Vasodilators
Vasodilators are the most commonly used therapy for acute heart failure across Europe. Nitrovasodilators (e.g. nitroglycerin, nitrates, and nitroprusside) act by increasing levels of cyclic GMP in the vascular smooth muscle cell with resultant peripheral arteriolar (and to a lesser extent, venous) vasodilatation providing decreased filling pressures and systemic vascular resistance. Nitrovasodilators may also increase cardiac output and decrease heart rate and cardiac work,9 but induce tachyphylaxis. Nitroglycerin appears to be an effective treatment for acute heart failure but its use is characterized by the need to up-titrate the dose as a result of the rapid development of tolerance and the occurrence of dose-related side effects, notably hypotension.10 Nitrates, such as isosorbide dinitrate, appear to have a favourable haemodynamic profile compared with furosemide, although such findings are based on small studies. Notably, a high-dose isosorbide dinitrate plus low-dose furosemide regimen has been shown to be superior to a low-dose isosorbide dinitrate plus high-dose furosemide regimen with respect to the need for mechanical ventilation and frequency of myocardial infarction in patients with severe pulmonary oedema and oxygen saturation <90%.11 In this study, high-dose isosorbide dinitrate was found to have a good safety and efficacy profile in controlling severe pulmonary oedema when given as repeated intravenous boluses after low-dose intravenous furosemide. Nitroprusside is effective in reducing left ventricular filling pressures and systemic vascular resistance.12 In addition, there is evidence that short-term tailored therapy with nitroprusside and diuretics resulted in a marked decrease in neurohumoral activation with improvements in haemodynamics.13 However, the need for invasive monitoring with the administration of nitroprusside and the absence of any outcome data will most likely preclude its more widespread use.
Nesiritide: a recombinant natriuretic peptide
Nesiritide is a balanced arterio-venous vasodilator that was introduced into clinical practice in the USA in 2001 where it has already gained acceptance and widespread use, and more recently in Switzerland and Israel. Endogenous human B-type natriuretic peptide (hBNP) is secreted by the myocardium in response to heart failure.14 Nesiritide is recombinant hBNP and therefore chemically and structurally identical to the endogenous hormone. Nesiritide increases cGMP levels and has venous and arterial vasodilatory effects that reduce pre-load and after-load, and induces coronary vasodilation.15,16 Nesiritide has demonstrated efficacy in decreasing pulmonary capillary wedge pressure—an important outcome predictor in acute heart failure17—and improving other haemodynamic parameters in a number of clinical trials.18–21 Dyspnoea was also improved compared with nitroglycerin or placebo at 3 h. Nesiritide treatment is associated with a reduced use of concomitant diuretics,19 which may be beneficial as excessive diuretic use is associated with deleterious effects.6 Administration of nesiritide is associated with a decrease in the deleteriously high levels of neurohormones (such as aldosterone and endothelin-1) that occur in acute heart failure.19,22
Nesiritide is generally well tolerated, with headache and hypotension being the most commonly reported side effects. Nesiritide has been shown to be associated with fewer adverse events than nitroglycerin, and, in contrast to dobutamine, is not associated with an increased proarrhythmic risk.20,21,23
Inotropic agents
Positive inotropic agents, such as dobutamine and milrinone, have been used in the treatment of patients with low-output heart failure for a number of years. These agents exert a positive inotropic action primarily by increasing levels of cAMP and calcium handling in cardiac myocytes. However, there remains insufficient data on the efficacy or safety of these agents in the management of acute heart failure. For example, although a large number of studies with dobutamine have been performed over the last three decades, none have been controlled and most were small in size, thus limiting any clinical conclusions that can be drawn.
Inotropic agents have been shown to be associated with a greater proarrhythmic risk than other acute heart failure therapies. Dobutamine is associated with a significant increase in ventricular tachycardia, repetitive ventricular beats, premature ventricular beats, and heart rate compared with nesiritide.21 Milrinone is also associated with an increased risk of arrhythmias.24 Moreover, despite conferring short-term haemodynamic improvement in a proportion of acute heart failure patients, there is increasing recognition that agents with positive inotropic activity can increase mortality.20,23 Dobutamine may also worsen splanchnic tissue perfusion.25
The overall therapeutic benefits of this drug class appear limited when compared with other agents; with neither dobutamine nor milrinone reducing the length of hospital stay.21,24 Although increased cardiac output with dobutamine has been shown to be similar to that with nitroprusside in patients with acute heart failure, nitroprusside also provided improvements in pulmonary capillary wedge pressure, left atrial pump volume, and diastolic filling pattern.26 In contrast, dobutamine was associated with a variable pulmonary capillary wedge pressure response and no improvement in diastolic filling pattern.
Calcium sensitization: levosimendan
Levosimendan, a calcium sensitizing inotropic agent, is another agent that has been introduced for the management of acute decompensated heart failure in a number of countries. Levosimendan increases contractility of the heart by increasing the sensitivity of the contractile proteins to intracellular ionized calcium in the cardiac myocytes.27 As it has a neutral effect on cAMP levels, levosimendan may be expected to avoid the limitations of the aforementioned cAMP-dependent inotropic agents. Levosimendan also stimulates peripheral vasodilation through ATP-dependent potassium channels,28 though the relative contribution of these effects to its clinical profile remains to be determined.
Levosimendan has been shown to improve haemodynamic parameters in patients with chronic congestive heart failure.29,30 Unlike the cAMP-dependent positive inotropes, levosimendan does not appear to predispose to calcium-induced arrhythmias or increase oxygen consumption.31 Retrospective analysis of 6 month follow-up data from the LIDO study suggests a mortality advantage compared with dobutamine.29 These observations are supported by preliminary data from the CASINO study that suggest a potential mortality benefit for levosimendan compared with dobutamine and placebo.32 Further studies are ongoing to establish whether these results can be verified.
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Conclusions |
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TopAbstractIntroductionAcute heart failurePathophysiological mechanisms...Clinical management of acute...ConclusionsAcknowledgementReferences |
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Acute heart failure is a severe condition that is associated with a complex and varied pathophysiology. Initial therapy in patients with acute heart failure should be directed at improving oxygenation and patient haemodynamics as well as providing symptom relief. The evidence base for many traditional therapies is weak, and, in some cases, short-term benefits are gained at the expense of long-term outcomes. Diuretics provide rapid and significant symptomatic relief in a proportion of patients, but questions remain as to their appropriate clinical use. Nitrovasodilators are commonly used but may be limited by their side effect profile and the development of tolerance. Nesiritide, recombinant hBNP, is the most recent addition to the vasodilator drug class and appears to offer several advantages over other agents in this class. The use of positive inotropic agents in patients requiring cardiac support must be balanced against the possibility of worsened prognosis. Levosimendan may prove to be a useful alternative in acute heart failure patients requiring inotropic support. Other avenues of research are also ongoing, with endothelin receptor antagonism emerging as a promising new approach that remains to be validated.
In conclusion, the evidence base for emergent treatments is stronger than that for ‘traditional’ agents for acute heart failure. Increasing clinical data from future well-designed studies will confirm the spectrum of appropriate clinical use of each of these therapies.
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Acknowledgement |
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TopAbstractIntroductionAcute heart failurePathophysiological mechanisms...Clinical management of acute...ConclusionsAcknowledgementReferences |
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Meeting session and publication supported by an unrestricted educational grant from GlaxoSmithKline Ltd.
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References |
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