Elsevier

The Lancet

Volume 360, Issue 9328, 20 July 2002, Pages 196-202
The Lancet

Articles
Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial*

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Summary

Background

Levosimendan, a novel calcium sensitiser, improves myocardial contractility without causing an increase in myocardial oxygen demand. We compared the effects of levosimendan and dobutamine on haemodynamic performance and clinical outcome in patients with low-output heart failure.

Methods

Patients were recruited into a multicentre, randomised, double-blind, double-dummy, parallel-group trial. Under continuous haemodynamic monitoring, an initial loading dose of levosimendan of 24 μg/kg was infused over 10 min, followed by a continuous infusion of 0·1 μg kg−1 min−1 for 24 h. Dobutamine was infused for 24 h at an initial dose of 5 μg kg−1 min−1 without a loading dose. The infusion rate was doubled if the response was inadequate at 2 h. The primary endpoint was the proportion of patients with haemodynamic improvement (defined as an increase of 30% or more in cardiac output and a decrease of 25% or more in pulmonary-capillary wedge pressure) at 24 h. Analyses were by intention to treat.

Findings

103 patients were assigned levosimendan and 100 dobutamine. The primary haemodynamic endpoint was achieved in 29 (28%) levosimendan-group patients and 15 (15%) in the dobutamine group (hazard ratio 1·9 [95% CI 1·1–3·3]; p=0·022). At 180 days, 27 (26%) levosimendan-group patients had died, compared with 38 (38%) in the dobutamine group (0·57 [0·34–0·95]; p=0·029).

Interpretation

In patients with severe, low-output heart failure, levosimendan improved haemodynamic performance more effectively than dobutamine. This benefit was accompanied by lower mortality in the levosimendan group than in the dobutamine group for up to 180 days.

Introduction

Heart failure is a common and growing problem associated with frequent admissions to hospital and a poor prognosis. It is the one most frequent reason for hospital admissions in people aged over 65 years,1 and about 5000 hospital admissions per million population per year are attributable to or complicated by heart failure.2 Many of these hospital stays are long; 5% or more of medical beds could be occupied by patients with heart failure, accounting for more than 50 000 hospital bed-days per million population per year.2, 3 About 40% of patients die within a year of an acute exacerbation of severe heart failure.4

Management of an exacerbation of heart failure varies according to its cause and presentation. Recognition and treatment of precipitating factors such as rapid atrial fibrillation, myocardial ischaemia, and infection are of key importance. Acute cardiogenic pulmonary oedema is frequently treated with intravenous diuretics and oxygen alone, but opioids and nitrates probably have a valuable role,5 although no substantial studies have been done. When exacerbation of heart failure is accompanied by hypotension, oliguria, or other evidence of a low cardiac output, inotropic agents may be considered. However, there is little evidence that intravenous inotropic therapy with ß-agonists or phosphodiesterase inhibitors improves outcome.6, 7 A meta-analysis of trials of intravenous inotropic agents suggested a non-significant trend towards increased mortality,8 and studies of oral compounds have consistently shown excess mortality.9, 10

Levosimendan is a novel agent with a dual mechanism of action developed for the treatment of decompensated heart failure. This agent sensitises troponin C to calcium in a manner dependent on calcium concentration, thereby increasing the effects of calcium on cardiac myofilaments during systole and improving contraction at low energy cost.11, 12, 13, 14, 15 Calcium concentration, and therefore sensitisation, declines or is lost during diastole, allowing normal or improved diastolic relaxation. Unlike agents that act through adrenergic pathways, levosimendan does not cause diastolic calcium overload, which can impair myocardial relaxation, increase energy expenditure, or both,12, 16 effects that could result in the adverse effects of the latter classes of inotropic agents. Levosimendan also leads to vasodilatation through the opening of ATP-sensitive potassium channels.17 By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand.12, 13, 17, 18, 19

Dose-ranging studies, with infusion times from 6 h to 24 h, have already shown that levosimendan improves cardiac haemodynamics and offers symptomatic benefit in patients with severe heart failure.20, 21 Although placebocontrolled studies of dobutamine have shown that this drug improves haemodynamic variables, outcome data are few.8, 22 We compared the effects of dobutamine and levosimendan on haemodynamics over 24 h and then prospectively followed up clinical outcome over the next 31 days. Furthermore, at the request of the regulatory authorities, data were gathered retrospectively to assess whether differences in outcome noted at 31 days were sustained at 180 days.

Section snippets

Patients

This multicentre, randomised, double-blind, double-dummy, parallel-group trial was done at 26 centres in 11 European countries (Austria, Denmark, Finland, France, Germany, Hungary, Italy, Switzerland, the Netherlands, Sweden, and the UK). The primary objective was to compare the proportions of patients with haemodynamic improvement at the end of the 24-h infusion period in the groups assigned dobutamine or levosimendan.

Eligible patients were those admitted to hospital with low-output heart

Characteristics of study groups

203 patients were enrolled between Jan 2, 1997, and Nov 3, 1998: 103 were assigned treatment with levosimendan and 100 dobutamine (figure 1). Baseline characteristics of the two groups are summarised in table 1. Four patients (one assigned levosimendan, three dobutamine) did not receive an infusion of the study drug (catheter insertion failed or consent was withdrawn during catheter insertion) and did not undergo any haemodynamic measurements. These patients were included in all efficacy and

Discussion

In this study, there was greater haemodynamic improvement in patients with severe low-output heart failure with a 24 h infusion of levosimendan than with dobutamine. At the doses studied, levosimendan was associated with a slightly greater increase in cardiac output, and more pronounced decreases in pulmonary-capillary wedge pressure and systemic vascular resistance than dobutamine. These findings are consistent with those of other studies20 and with the known positive inotropic and peripheral

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