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

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 microg/kg was infused over 10 min, followed by a continuous infusion of 0.1 microg kg(-1) min(-1) for 24 h. Dobutamine was infused for 24 h at an initial dose of 5 microg kg(-1) min(-1) without a loading dose. The infusion rate was doubled if the response was inadequate at 2h. 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.

Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril.

OBJECTIVE: Levosimendan in a new inodilator drug that sensitizes troponin C in heart muscle cells to calcium, thus improving contractility. In previous studies, a single 2 mg intravenous dose of levosimendan increased cardiac output (CO) in healthy volunteers by about 40% and decreased pulmonary capillary wedge pressure in heart failure patients by 40-50%. The aim of the present, double-blind study was to evaluate the safety of concomitant use of levosimendan and an ACE-inhibiting drug. METHODS: The haemodynamic effects of levosimendan, given with or without captopril, were evaluated by using 2-dimensional echocardiography, repeated blood pressure measurements and by ambulatory ECG recordings. Twenty-four male patients with stable NYHA II-III heart failure (EF < 40%) after a previous myocardial infarct were given, in randomised order, a single i.v. infusion of levosimendan or placebo. The infusions were repeated after 2 weeks treatment with upto 50 mg b.i.d. of captopril. Twelve patients received levosimendan 1 mg and twelve received 2 mg. RESULTS: Mean CO was increased from 6.0 to 6.8 1 . min-1 in patients receiving 1 mg levosimendan compared to placebo, but only from 6.3 to 6.5 1 . min-1 in patients receiving 2 mg. The increase in CO was statistically significant when all levosimendan patients were compared to placebo. Heart rate did not change after either dose. Mean stroke volume increased significantly after 1 mg but not after 2 mg of levosimendan. The addition of captopril did not change the effects of levosimendan. No additional decrease in systolic or diastolic blood pressure was observed when levosimendan and captopril were given concomitantly. CONCLUSION: It seems that concomitant treatment with captopril does not change the haemodynamic effects of levosimendan. No adverse haemodynamic interactions were seen.

Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure.

Levosimendan is a new inodilatory agent that sensitizes troponin-C in heart muscle cells to calcium, thus improving contractility. The pharmacokinetics of levosimendan were evaluated using a double-isotope technique in eight healthy volunteers and in eight patients with mild congestive heart failure (CHF). A single i.v. dose of 0.50 mg 14C-labeled levosimendan and a single oral dose of 0.50 mg 13C15N-labeled levosimendan were administered concomitantly. The elimination half-lives (mean +/- SD) of levosimendan were 0.96 +/- 0.16 h in healthy volunteers and 1.03 +/- 0.11 h in patients. The respective figures for total drug were 5.73 +/- 1.53 h and 5.23 +/- 0.99 h. Clearances of levosimendan averaged 359 +/- 69 ml/min in healthy volunteers and 296 +/- 61 ml/min in patients and of total drug 104 +/- 15 and 85 +/- 20 ml/min, respectively. Volumes of distribution at steady state were for levosimendan 21.9 +/- 5.9 L in healthy volunteers and 19.5 +/- 4.5 L in patients and for 14C-drug 27.9 +/- 5.3 L and 23.8 +/- 2.8 L, respectively. The bioavailability of oral levosimendan was 85 +/- 6% in healthy volunteers and 84 +/- 4% in patients.