Servei de Farmacologia
Clínica
®
Levosimendan (Simdax ) for the treatment of patients with severe heart failure (HF)
exacerbation
Pharmacological characteristics
Levosimendan is a positive inotrope. It increases calcium sensitivity in contractile
myofilaments during systole. It has been suggested that the effect is reduced or lost during
diastole and therefore would not alter myocardial relaxation or increase energy expenditure.
An arterial (systemic and coronary) and venous vasodilator effect is also attributed to the
drug, as it opens the ATP-dependant potassium channels and the selective inhibition of
phosphodiesterase III. It is eliminated by hepatic metabolism and has an elimination half-life
of one hour. However, one of its metabolites is active and has a more prolonged elimination
half-life (75 to 80 hours); it has been suggested that some of its haemodynamic effects
persist beyond the end of its infusion.
Efficacy
Table 1 includes information regarding four clinical trials with levosimendan. The first two,
which involved patients with acute exacerbation of chronic heart failure (HF) resulting from
ischemic or idiopathic heart disease, assessed haemodynamic effects. In the third trial, the
incidence of hypotension and/or myocardial ischemia was evaluated in patients with recent
acute myocardial infarction (five days prior) who had heart failure and needed intravenous
positive inotropic therapy. In general, the differences in haemodynamic endpoints with short
infusion durations (between 6 and 24 hours) favoured levosimendan as opposed to the
placebo. Levosimendan was again favoured over dobutamine in a comparative study. In two
of the studies, mortality was lower with levosimendan, but it was connected with a
secondary endpoint. Patients treated with levosimendan showed improvements in dyspnoea
in only one of the trials.
The SURVIVE study was recently published and is the first clinical trial designed to evaluate
mortality. It included 1,327 patients admitted for acute exacerbation of HF who required
inotropic drugs, essentially, patients in NYHA functional class IV. Levosimendan (loading
dose and infusion for up to 24 hours) was compared with dobutamine (infusion for a
minimum of 24 hours) and no significant differences in mortality were observed in the first
six months of the study (26% with levosimendan and 28% with dobutamine, RR=0.91; CI
95% 0.74-1.13). There were no differences in secondary endpoints either, such as mortality
at 31 days, cardiovascular mortality at 6 months, dyspnoea or overall clinical evaluation; only
plasma concentrations of B-type natriuretic peptide decreased more in patients treated with
levosimendan.
The results of two other clinical trials are known, but have yet to be published. The CASINO
study included patients admitted with HF in NYHA functional class IV. However, it was
interrupted before the scheduled finishing time (when 299 patients had been included
instead of the anticipated 600) because the effects on mortality were favourable to
levosimendan. At six months, mortality was significantly lower with levosimendan (15.3%)
than with both dobutamine and the placebo (39.6 and 24.7%, respectively). Although the
results were presented at a conference in 2004, the complete study has not yet been
2
published. Furthermore, it is not clear what the primary endpoint was or whether a correct
intention-to-treat analysis was carried out. The REVIVE-2 trial involving 600 patients with
similar characteristics has not been published either. The proportion of patients who
experienced an improvement in clinical symptoms during hospitalisation (combined endpoint
from the NYHA functional class and an overall evaluation) was 6% higher with levosimendan
than with placebo, and the proportion that worsened was 7% less (p=0.015, for the group).
In this study, more patients died at 90 days in the group treated with levosimendan than in
the placebo group, although the differences are not statistically significant (45 and 35
patients, respectively). The levosimendan infusion was 24 hours in both studies.
Study
No. of patients
(duration)
Treatments
Primary endpoint
Slawsky et al
(2000)
146
(6 h)
Levosimendan
(bolus of 6 μg/kg followed by
0.1-0.4 μg/kg per min)
vs
placebo
. % of patients with:
↑ 25% EVa or ↓
of the PCPb at 6 hrs
. Differences favouring
levosimendan
EV: 56% vs 4%; p<0.001
PCP: 43% vs 15%; p<0.001
LIDO
(2002)
203
(24 h)
Levosimendan
(bolus of 24 μg/kg followed
by 0.1-0.4 μg/kg per min)
vs
dobutamine
(5 μg/kg per min)
. % of patients with:
↑ 30% EVa and
↓ 25% of the PCPb
at 24 hrs
. Differences favouring
levosimendan (28% vs. 15%,
p=0.022)
. mortality at 31 and 180 daysc:
8% vs 17%; p=0.049
26% vs 38%; p=0.029
P
Results
RUSSLAN
(2002)
504
(6 h)
Levosimendan
6 μg/kg and 0.1 μg/kg /min
or 12 μg/kg and 0.2
μg/kg/min or 24 μg/kg and
0.2 μg/kg/min or 12 μg/kg
and 0.4 μg/kg/min or placebo
. % with hypotension
or ischemia at 6 hrs
. No differences
. 13.4% with grouped
levosimendan doses
Vs 10.8%; p=0.456d
. ↓ in mortality at 180 days
with levosimendanc:
22.6% vs 31.4%
SURVIVE
(2007)
1,327
(24 h)
Levosimendan
(12 μg/kg bolus followed by
0-0.1 μg/kg/min)
. Mortality due to any
cause at 180 days
. No significant differences in
mortality (26% with
levosimendan and 28% with
dobutamine)
vs
dobutamine 5 μg /kg/min
a
b
c
EV: ejection volume, PCP: pulmonary capillary pressure, refers to a retrospectively-analysed
d
secondary endpoint, a dose relationship was observed (19% with the highest levosimendan dose).
Toxicity
In the LIDO trial, a comparative study with dobutamine, the total incidence of adverse
effects was similar. Angina, thoracic pain and myocardial ischemia, as well as the proportion
of patients with arrhythmias, was more frequent with dobutamine. There was a tendency of
more hypotension and headaches with levosimendan, while there was more treatment
termination due to adverse effects with dobutamine. An increase in heart rate (average of 11
beats per min) was documented with the highest dose (24 μg/kg bolus and 0.4 μg/kg/min
infusion), but not for the lower doses. In the SURVIVE trial, the incidence of serious adverse
effects and overall incidences were similar in both groups. This was also the case in the
proportion of patients with hypotension. The presence of hypokalemia, auricular fibrillation,
headaches and extrasystoles were more frequent with levosimendan than with dobutamine,
whereas with dobutamine, there were more patients with a clinical diagnosis of HF (but not
with congestive HF, which was similar in both groups).
3
Approved indications, dose and cost
•
Approved indications: short-term treatment of severe acute exacerbation of chronic HF
and for situations in which conventional treatment is not sufficient or when inotropic
assistance is required
•
Authorisation procedure: mutual recognition
•
Recommended dose is an initial 6 to 12 μg/kg in 10 minutes, followed by 0.1
μg/kg/min for 24 hours. The infusion speed can be modified based on response,
between 0.05 and 0.2 μg/kg/min
•
Cost: the cost of one 5 ml vial with 2.5 mg/ml is € 700.64. For a 60 kg patient, the cost
of a 24-hour treatment varies between € 504 and 521 if the infusion is 0.1 μg/kg/min.
With dobutamine (5-10 μg/kg/min), the cost is around € 9-18.
Comparison of alternatives (dobutamine)
Advantages and disadvantages of levosimendan
Efficacy
Haemodynamic effects
Symptoms
Mortality
Toxicity
Convenience
Cost
Advantage (in a single comparative study with dobutamine)
Similar (no differences in the published trial)
Similar (no differences in the published trial)
Similar (different profile)
Similar
Disadvantage
Conclusion
With the currently available data, we do not believe that levosimendan, in comparison with
dobutamine, offers any advantages regarding mortality or symptoms. The incidence of
adverse effects is similar, although the profile is slightly different and the cost is higher. For
the moment, at least until all the information from the two studies pending publication is
made available, it does not appear to offer any relevant advantages.
References
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calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial
infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 2002;23:1.42232. http://eurheartj.oxfordjournals.org/cgi/reprint/23/18/1422
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