Download Levosimendan in the treatment of acute heart failure, cardiogenic

Review articles
© The Intensive Care Society 2011
Levosimendan in the treatment of acute
heart failure, cardiogenic and septic
shock: a critical review
S Mathieu, G Craig
Levosimendan is a drug which increases the sensitivity of the heart to calcium and which opens potassium channels,
resulting in inodilation. Clinical trial data from patients suffering from heart failure have demonstrated that it improves
haemodynamics without increasing intra-cellular calcium or oxygen consumption. However, there is no consistent
evidence of mortality reduction. This narrative review summarises the key trials of its use in acute heart failure, acute
coronary syndrome, cardiogenic shock and septic shock.
Keywords: levosimendan; shock; sepsis; cardiac failure; heart failure
Introduction
Heart failure is one of the most important causes of morbidity
and mortality in developed countries and causes a significant
burden on health resources. Two to three percent of the
population are affected, with prevalence rising sharply to
10-20% in those aged over seventy years. It accounts for 5% of
acute hospital admissions, with readmission rates of up to
50% at six months and a mortality of 50% within four years
of presentation.1,2
The management of acute heart failure (AHF) involves
treating the underlying cause of the acute deterioration in heart
function, alleviation of symptoms and stabilisation of
haemodynamics. The aim is to re-establish adequate perfusion
and oxygen delivery to end-organs with the use of diuretics
and vasodilators combined, if necessary, with ventilatory
support. When heart failure is severe and not responding to
first-line treatments, inotropic support may be indicated.
However, there is little evidence that agents such as
dobutamine or phosphodiesterase inhibitors improve longterm cardiac performance or patient survival3-5 and their effect
can be attenuated by concomitant use of beta-blockers.6
Levosimendan (SIMDAX® Orion Pharma, Finland) is an
inodilator with an alternative mode of action to more
traditionally used agents. It increases myocardial contractility
by enhancing the sensitivity of troponin C to calcium without
increasing intra-cellular calcium concentration. The calciumdependent binding of levosimendan means that during
diastole, it has minimal effects and therefore does not impair
relaxation of the ventricle. In addition, it decreases cardiac
work by opening ATP-dependent potassium channels in
vascular smooth muscles, resulting in systemic vasodilatation
and cardiac afterload reduction. Cardiac output is augmented
and diastolic relaxation is improved without an increase in
myocardial oxygen demand.7 Levosimendan also causes
selective phosphodiesterase-III inhibition in vitro, but the
JICS Volume 12, Number 1, January 2011
significance at therapeutic doses in vivo is not known. The long
half-life of its active metabolite results in its efficacy being
maintained for up nine days after a 24-hour infusion of
levosimendan has been stopped. This needs to be considered
when comparing it to other treatment modalities.8,9
Despite the apparent benefits of levosimendan, early trial
successes have not been consistently reproduced, leading to
uncertainty regarding its efficacy. This is reflected in the
restricted worldwide use. It is only registered for clinical use in
some European countries, South America and Asia. The
objectives of this review are to evaluate whether the use of
levosimendan compared to standard inotropic therapy or
placebo results in improved haemodynamic parameters and
more importantly, survival, in acute heart failure patients in
critical care practice. This includes use in the following:
1. Decompensated chronic heart failure
2. Left ventricular failure secondary to myocardial infarction
3. Cardiogenic shock
4. Septic shock.
Methods
A controlled vocabulary search strategy using MEDLINE (all
records to January 2010), EMBASE (all records to January
2010) and the Cochrane Central Register of Controlled
Trials, via the Health Information Resources database at
http://www.library.nhs.uk was performed and completed on
26th January 2010. Search terms included the combination of
‘levosimendan’ and ‘shock,’ ‘sepsis,’ ‘cardiac failure,’ ‘heart
failure.’ The search strategy was restricted to publications in
English, adult patients (age 18 years or older), and to human
subjects. Levosimendan use in healthy volunteers or in
chronic but stable heart failure was also excluded. The
reference lists of included citations and any potentially relevant
citations identified from electronic searches were checked for
further appropriate studies. The reference lists of any narrative
15
Review articles
reviews identified were also searched. The metaRegister for
controlled trials (http://www.controlled-trials.com/mrct/) using
the search term ‘levosimendan’ was also accessed and the
manufacturers of levosimendan were contacted to identify
unpublished studies.
All randomised controlled trials (RCTs), observational
studies and case series that included pre-specified
haemodynamic outcomes or mortality end points were
selected. The pre-specified haemodynamic outcomes were
blood pressure, ejection fraction, cardiac index or pulmonary
capillary wedge pressure changes. This article aims to
summarise the evidence from the studies identified. All RCTs
that fulfilled these inclusion criteria have also been
summarised in tabulated form for reference (Tables 1-4).
Results and discussion
1. Levosimendan use in patients with
decompensated chronic heart failure
While the evidence for improved haemodynamic effects with
levosimendan has been demonstrated repeatedly,10-24 the
evidence for survival benefit is less clear (Table 1). Four key
RCTs have failed to reach a consensus.6,25-27 In the multicentre
double-blinded RCT, ‘Levosimendan Infusion versus
Dobutamine’ (LIDO) study, 203 patients with severe lowoutput heart failure who required haemodynamic monitoring
and inotropic support, were randomised to treatment with
either levosimendan or dobutamine.6 The primary end-point of
haemodynamic benefit was demonstrated at 24 hours (≥30%
increase in cardiac output (CO) and ≥25% decrease in
pulmonary capillary wedge pressure (PCWP)) in 28% of
patients receiving levosimendan compared with 15% of
patients receiving dobutamine (p=0.002). A secondary
outcome measure, all-cause mortality at 30 days, was also
improved in the levosimendan group. A subsequent
retrospective analysis demonstrated that this survival benefit
extended to 180 days, with 12% fewer patients who received
levosimendan dying. The ‘Calcium Sensitizer or Inotrope in
Low Output Heart Failure study’ (CASINO), similarly
demonstrated a substantial mortality benefit with
levosimendan after one month and six months compared with
both dobutamine and placebo (6% mortality with
levosimendan versus 13% with dobutamine versus 8% with
placebo at one month, and 15%, 40% and 25% respectively at
six months).28 Furthermore, dobutamine was associated with
an increased mortality compared with placebo. This trial was
originally designed to recruit 600 patients. However, it was
stopped early after recruiting 299 patients, when the interim
analysis showed an apparent survival benefit with
levosimendan compared to both dobutamine and placebo. The
completed methodology and trial results have not been
published in a peer-reviewed journal.
The subsequent RCTs, REVIVE II and SURVIVE, however,
did not demonstrate mortality benefits with levosimendan and
also raised concerns over the apparent increased incidence of
deleterious side effects. In the Randomised Evaluations of
Intravenous Levosimendan Efficacy trial (REVIVE) II, 24-hour
infusions of levosimendan were compared with placebo in 600
patients.26 There was a higher incidence of hypotension (50.2%
16
vs 36.4%) and atrial fibrillation (8.5% vs 2.0%), and there was a
trend towards higher mortality at 90 days in the levosimendan
group (15.1% and 11.6%). There was a modest improvement
in patients’ symptoms based on a complex composite outcome,
but haemodynamic changes were not assessed. As with the
CASINO trial, data has been published only as a commentary
on the presentation of this trial at the American Heart
Association Meeting and has not been published in a peerreviewed journal.
The ‘Survival of Patients with Acute Heart Failure in Need
of Intravenous Inotropic Support’ (SURVIVE) study was highly
anticipated as the first prospective, double-blinded, randomised
trial that specifically looked at the effect of short-term
levosimendan on mortality as its primary end point.25 There
were 1,327 hospitalised patients recruited from 75 centres in
nine countries who required inotropic support after an
inadequate response to vasodilator and/or diuretic therapy.
While fewer patients on levosimendan died compared to those
treated with dobutamine at five days, two weeks, one month,
and six months (relative reduction in mortality of 27%, 14%,
13% and 6% respectively), these differences were not
statistically significant. A number of potential reasons may
have contributed to the lack of concordance in these findings:
• Unlike REVIVE II and SURVIVE, patients in LIDO were
excluded if they had received diuretic and vasodilator
therapy within six hours of receiving levosimendan.
• Cardiac output monitoring was not required in REVIVE II
and SURVIVE patients, despite an increased risk of
hypovolaemia with concomitant heart failure therapy. Over
a third of the placebo group in REVIVE II were rendered
hypotensive and 15% of patients in SURVIVE developed
atrial fibrillation (compared to less than two percent in
LIDO), supporting the view that fluid status and electrolyte
balance was not optimal prior to levosimendan being
commenced.
• In the SURVIVE study, where dobutamine was given
according to clinical need and not to a protocol-based
regime, no mortality benefit was found with levosimendan.
All-cause mortality at 180 days was 28% for the dobutamine
group compared with a much higher mortality in LIDO
(38%) and CASINO (40%). It is conceivable that the
differences in mortality in LIDO were due not to a decrease
in mortality with levosimendan, but rather to an increase in
mortality with the use of dobutamine. While the
extrapolation and conjecture that dobutamine may cause
harm must be viewed cautiously, it is a plausible conclusion
when considering other evidence for adverse effects of
dobutamine in patients with heart failure,3 and with
evidence that beta-blocking drugs are associated with a
beneficial effect in these patients.29 Patients randomised to
receive levosimendan in LIDO and SURVIVE, in whom
beta-blocker therapy was continued, had an independentlyassociated reduction in mortality.30 Conversely, continued
use of beta-blocker therapy appeared to attenuate the
haemodynamic effect of dobutamine.30,31
• SURVIVE included a population of patients with more
severe ischaemic heart failure (more than 85% were NYHA
class IV) and there was less attempt to control heart rates.
Volume 12, Number 1, January 2011 JICS
Review articles
Study
year (ref)
Population
N
Levosimendan dose
(length of infusion)
Comparator dose
Definition of heart
(length of infusion) failure and/or
inclusion criteria
Clinical outcome(s)
with levosimendan
Follow up
Yilmaz
2009 (20)
NYHA III- IV
with acute
systolic HF
40
Loading at discretion
of clinician +
0.1-0.2 μg/kg/min
(24 hours)
Dobutamine
minimum
5 μg/kg/min (at
least 24 hours)
LVEF <35% with
moderate to severe
right heart failure
Both levosimendan and
dobutamine improved EF
and PCWP. Only
levosimendan improved
creatinine while both
improved 24-hour
urine output
24 hours
Duygu
2008 (21)
NYHA III-IV 62
of ischaemic
origin
6-12 μg/kg +
0.1 μg/kg/min
(24 hours)
Dobutamine
5-10 μg/kg/min
(24 hours)
LVEF <40%
Both dobutamine and
24 hours
levosimendan improve LVEF
(mean change 3.5% vs 2.1%).
Levosimendan also improves
right ventricular systolic and
diastolic function
Duygu
2008 (22)
NYHA III-IV 60
of ischaemic
origin
6-12 μg/kg +
0.1 μg/kg/min
(24 hours)
Dobutamine
5-10 μg/kg/min
(24 hours)
LVEF <40%
Both levosimendan and
24 hours
dobutamine improved LVEF
(mean 3.5 mm Hg, p <0.001
vs mean 3.6 mm Hg, p <0.005
respectively). Left atrial
function responded better
to levosimendan
SURVIVE
2007 (25)
ADHF
1327 12 μg/kg +
0.1-0.2 μg/kg/min
(24 hours)
Dobutamine
minimum
5 μg/kg/min
(at least 24 hours)
LVEF <30% and
dyspnoea, oliguria,
PCWP <18 mm Hg
and/or CI <2.2
Mortality was reduced
180 days
compared with the
dobutamine group. However,
this was not statistically
significant. Greater reduction
in plasma BNP levels.
Parissis
2007 (12)
NYHA
III-IV
39
0.1 μg/kg/min
(24 hours)
Placebo
Symptomatic
LVEF ≤35%
Significant improvement in 48 hours
left ventricular ejection
fraction (26% to 30%, p<0.01),
NYHA class (p<0.01), and
plasma BNP (p<0.01). No
change with placebo.
Adamopolous NYHA
2006 (23)
III-IV
69
6 μg/kg +
0.1 μg/kg/min
(24 hours)
Dobutamine
5 -10 μg/kg/min
(24 hours) and
placebo
LVEF <30%,
CI <2.5
Improvement of
120 days
haemodynamics.
Modulation of immune
process with levosimendan.
Mean event-free survival
better but no improvement
in mortality at four months
REVIVE II
2006 (26)
ADHF
600 12 μg/kg +
0.2 μg/kg/min
(24 hours)
Placebo
LVEF ≤35% and
dyspnoea at rest
after use of diuretics
and vasodilators
Levosimendan improved
symptoms but trend
towards higher mortality
(45 deaths) compared with
placebo group (35 deaths).
Improvement in BNP levels
and hospital LOS
Parissis
2006 (13)
NYHA
III-IV
54
Placebo
LVEF ≤35%
Improvement in LVEF
72 hours
(mean 7% vs 0%), right
ventricular function, NHYA
class (3.5 to 2.4 vs unchanged)
and neurohumoral response
(reduced by 341 pg/mL
vs increased)
0.1-0.2 μg/kg/min
(24 hours)
90 days
Table 1 Summary of RCTs with levosimendan use in decompensated chronic heart failure.
JICS Volume 12, Number 1, January 2011
17
Review articles
Study
Population
year (ref)
N
Levosimendan
dose (length
of infusion)
Comparator
(length dose
of infusion)
Definition of heart
failure and/or
inclusion criteria
Clinical outcome(s)
with levosimendan
Follow up
Parissis
2006 (14)
NYHA III-IV
25
6 μg/kg +
0.1-0.4 μg/kg/min
(24 hours)
Placebo
LVEF ≤30%
Improvement of haemodynamics
and modulation of neurohumoral
and immune activation without
increasing myocardial injury
30 days
Flevari
2006 (15)
NYHA III-IV
45
0.1 μg/kg/min
(24 hours)
Placebo
LVEF ≤30%
Improvement in haemodynamics,
72 hours
NYHA class and plasma BNP levels
Tziakas
2006 (16)
NYHA III-IV
60
6 μg/kg +
0.1 μg/kg/min
(24 hours)
Placebo
LVEF ≤30%
Significant improvement on LVEF
and matrix metalloproteinase and
possible LV remodelling
24 hours
Moertl
2005 (24)
NYHA III-IV
73
12 μg/kg +
0.1 μg/kg/min
(24 hours)
PGE1 2.5ng/
kg/min (7 days)
LVEF <35%
CI<2.5
PCWP >15 mm Hg
Improved cardiac output with
levosimendan. Both drugs
reduced PCWP, pulmonary and
systemic vascular resistance, and
plasma BNP
72 days
CASINO
2004(27)
NYHA IV
199
16 μg/kg +
0.2 μg/kg/min
(24 hours)
Placebo or
dobutamine
10 μg/kg/min
(24 hours)
LVEF ≤35%
Stopped early because of
mortality benefit with
levosimendan. At six months,
mortality rates were 15% with
levosimendan, 25% for placebo
and 40% for dobutamine group
180 days
Parissis
2004(17)
NYHA III-IV
27
6 μg/kg +
0.1-0.4 μg/kg/min
(24 hours)
Placebo
LVEF ≤30%
CI ≤2.5
EF increased significantly
48 hours
(p<0.01), end systolic wall stress
decreased (p<0.05) and reduction
in IL-6 and soluble Fas and Fas ligand
Kivikko
2003(8)
NYHA III-IV
146
6 μg/kg +
0.1-0.4 μg/kg/min
(24 hours)
Placebo
LVEF ≤30%
CI ≤2.5
PCWP ≥15 mm Hg
After a 24-hour infusion, the
haemodynamic effects are
maintained for at least an
additional 24 hours
48 hours
LIDO
2002(6)
Low output
heart failure
203
24 μg/kg +
0.1-0.2 μg/kg/min
(24 hours)
Dobutamine
5-10 μg/kg/min
(24 hours)
LVEF<35%
CI <2.5
PCWP >15 mm Hg
Improved CO and PCWP. Lower
mortality at 180 days (p<0.027).
Beta blockers improve
haemodynamic effect but
attenuate it with dobutamine
180 days
Ukkonen
2000(18)
NYHA III-IV
8
18 μg/kg +
0.3 μg/kg/min
(24 hours)
Placebo
NYHA III-IV
Improvement in haemodynamics
(CO increase 32%, SV by 21%
and reduction of PCWP from
21 mm Hg to 17 mm Hg) without
increased oxygen consumption.
48 hours
Slawsky
2000(19)
NYHA III-IV
146
6 μg/kg +
0.1-0.4 μg/kg/min
(6 hours)
Placebo
LVEF ≤30%,
CI ≤.5
PCWP ≥15 mm Hg
SV increased by≥25% in 56%
6 hours
of levosimendan group vs 4%
placebo group. PCWP decreased by
≥25% in 43% vs 15%. No significant
increase in adverse effects
Follath
1999(57)
Low output
heart failure
40
6-24 μg/kg +
0.2-0.6 μg/kg/min
(12-24 hours)
Dobutamine
8-16 μg/kg/min
(12–24 hours)
(LVEF ≤35%)
CI ≤2.5
(PCWP ≥18 mm Hg)
Dose ranging and tolerability
24 hours
study preceding LIDO. Efficacy
at least comparable to dobutamine
Table 1 continued Summary of RCTs with levosimendan use in decompensated chronic heart failure.
Key ADHF = acute decompensated heart failure, N = total number of patients, NYHA = New York Heart Association classification, LVEF = left
ventricular ejection fraction, CO = cardiac output, CI = cardiac index, PCWP = pulmonary capillary wedge pressure, BP = blood pressure, SV = stroke volume, SVR = systemic vascular resistance, CS = cardiogenic shock, PCI = percutaneous coronary intervention, AMI = acute myocardial infarction, NR = not
recorded, BNP = brain natriuretic peptide, LOS = length of stay, NA = not applicable, IABP = intra-aortic balloon counter pulsation
18
Volume 12, Number 1, January 2011 JICS
Review articles
A recently published meta-analysis of 19 RCTs including
3,650 patients has shown that levosimendan improves several
haemodynamic parameters and the level of B-type natriuretic
peptide (BNP), when compared with standard therapy or
dobutamine in patients with acute severe heart failure. The
magnitudes of these changes were quantified by pooling
studies, which were adjudicated to have adequate allocation
concealment, blinding and using intention-to-treat analysis,
then calculating a weighted mean difference. Levosimendan
was associated with improvements in all of the haemodynamic
parameters evaluated. However, those reaching statistical
significance (albeit of questionable clinical significance) only
included ejection fraction (EF) (3.2% increase) and PCWP
(3.8 mm Hg decrease) compared with placebo, and cardiac
index (CI) (increase 0.33 L/min/m2), PCWP (2.9 mm Hg
decrease) and BNP (595 pg/mL decrease) compared with
dobutamine. Only three of the 19 trials in this meta-analysis
achieved all components of allocation concealment, intentionto-treat analysis and blinding (SURVIVE accounted for more
than 85% of the patients) and were included in this component
of the data analysis. Inference must therefore be interpreted
cautiously. Importantly, an overall survival benefit was not
demonstrated when levosimendan was compared with placebo
but was demonstrated when compared with dobutamine (OR
0.75, 95%CI 0.61 to 0.92, p=0.005).32
Summary
Levosimendan can produce improvements in several
haemodynamic parameters (including cardiac output, stroke
volume and heart rate, PCWP, mean arterial pressure, mean
pulmonary artery pressure, mean right atrial pressure and total
peripheral resistance). However, the magnitude of these
changes may be relatively modest. Plasma BNP levels are also
reduced and this has been identified as a predictor of an
improved outcome in patients admitted with decompensated
heart failure.
• Due to the formation of an active metabolite, the
Study,
Population
year (ref)
N
Levosimendan
dose (length
of infusion)
•
•
•
•
haemodynamic effects are maintained for several days after
stopping levosimendan infusion.
The haemodynamic effects are not attenuated with
concomitant beta-blocker therapy, unlike with the use of
dobutamine.
Mortality benefit in the earlier trials was not replicated in
SURVIVE or REVIVE II. However, in the subgroup of
patients with concomitant beta-blocker therapy, mortality
was significantly lower with the use of levosimendan.
Importantly, patients requiring ventilatory support who are
hypotensive (systolic blood pressure <85-90 mm Hg) and
have sustained a recent myocardial infarction (<8 weeks) or
have significant renal impairment, have been excluded from
the entry criteria in many of these studies.
A meta-analysis has shown that dobutamine is associated
with increased mortality compared with both levosimendan
and placebo.
2. Levosimendan use in left ventricular failure
secondary to myocardial infarction
The ‘Randomised study on Safety and effectiveness of
Levosimendan in patients with LV failure due to an Acute
Myocardial Infarct’ (RUSSLAN) was a double-blind placebocontrolled trial conducted in 504 patients with a myocardial
infarction sustained during the previous five days (Table 2).
Patients were randomised to receive either levosimendan at
four different loading dose regimens or a placebo for six hours.
Primary end points addressed the safety profile and secondary
end points included mortality up to 14 days. This was
significantly lower with levosimendan compared to placebo
(11.7% vs 19.6%; p=0.031). This reduced mortality was still
apparent at 180 days follow up, although the difference
between the two groups did not reach statistical significance
(22.6% vs 31.4%; p=0.053). It is worth noting that the
incidence of hypotension and/or ischaemia was similar in the
placebo groups and in three out of the four levosimendan
groups. However, at the highest loading dose (24 μg/kg) and
the maintenance regime (0.4 μg/kg/min) for levosimendan,
Comparator dose
(length of infusion)
Definition of
heart failure
and/or inclusion
criteria
Clinical outcome(s)
with levosimendan
Follow up
RUSSLAN LV failure
504 6-24 μg/kg +
2002(33)
following AMI
0.1-0.4 μg/kg/min
(6 hours)
Placebo
MI in last 5 days,
LV failure on CXR
and symptomatic
heart failure
Higher risk of hypotension
180 days
and/or ischaemia only in the
highest levosimendan infusion
group. Reduced risk of worsening
heart failure and death at 180 days
De Luca
2005 (34)
LV failure
following
AMI (PCI)
26
12 μg/kg
0.1-0.4 μg/kg/min
(24 hours)
Placebo
LVEF ≤40%
CI ≤2.5
PCWP ≥18 mm Hg
Improved haemodynamic
and coronary flow
reserve
Sonntag
2004(35)
LV failure
following
AMI (PCI)
24
24 μg/kg
(10 minutes)
Placebo
Large akinetic or
Levosimendan improved
hypokinetic regions the function of
stunned myocardium
1 day
<1 hour
Table 2 Summary of RCTs with levosimendan use in left ventricular failure secondary to myocardial infarction.
Key LV = left ventricular, LVEF = left ventricular ejection fraction, AMI = acute myocardial infarction, PCI = percutaneous coronary intervention,
CI = cardiac index, PCWP = pulmonary capillary wedge pressure
JICS Volume 12, Number 1, January 2011
19
Review articles
Study,
year (ref)
Population
N
Levosimendan
dose (length
of infusion)
Fuhrmann
2008(40)
AMI and PCI,
IABP,
inotropes and
vasopressor
32
Definition of
Clinical outcome(s)
cardiogenic shock with levosimendan
and/or inclusion
criteria
Follow up
12 μg/kg +
Enoximone
0.1-0.2 μg/kg/min 0.5 μg/kg
(24 hours)
+ 2-10 μg/kg/min
(NR)
SBP <90 mm Hg,
CI <2.5,
PCWP <18 mm Hg,
end organ
hypoperfusion
Significant reduction in 30-day
mortality (p= 0.023). Improved
haemodynamic parameters at
12 hours and less organ
dysfunction with levosimendan.
120 days
Samimi-Fard STEMI and PCI 22
2008(41)
24 μg/kg +
0.1 μg/kg/min
(24 hours)
Dobutamine
5 μg/kg/min
(24 hours)
NR
No improved long-term mortality
360 days
in patients with AMI revascularised
by PCI compared with dobutamine.
Mean LVEF increase greater with
levosimendan (26% vs 15%,
p=0.003)
DominguezRodriguez
2008(42)
STEMI and PCI 22
24 μg kg +
0.1 μg/kg/min
(24 hours)
Dobutamine
5 μg/kg/min
(24 hours)
NR
Improved LVEF, isovolumetric
relaxation time and E/A ratio
with levosimendan compared
with dobutamine.
24 hours
GarciaGonzales
2006(43)
AMI and PCI
24 μg kg +
0.1 μg/kg/min
(24 hours)
Dobutamine
5 μg/kg/min
(24 hours)
NR
Improved cardiac output
power at 24 hours
24 hours
22
Comparator
dose (length
of infusion)
Table 3 Summary of RCTs with levosimendan use in cardiogenic shock.
Key AMI = acute myocardial infarction, PCI = percutaneous coronary intervention, CI = cardiac index, STEMI = ST elevation myocardial infarction,
NR = not recorded, PCWP = pulmonary capillary wedge pressure, LVEF = left ventricular ejection fraction, SBP = systolic blood pressure
their incidence was almost double (19% compared with 11% in
the placebo group). Invasive haemodynamic monitoring was
not used in this study.33
Two RCTs have shown improved cardiac performance (CI,
PCWP, coronary flow reserve) following emergency
percutaneous coronary intervention in patients with acute
myocardial infarction (AMI) and left ventricle (LV)
dysfunction.34,35 These are single centre studies with only 28
patients across both studies receiving levosimendan.
Furthermore, one of the studies only administered
levosimendan for ten minutes and follow up data was
discontinued twenty minutes later.
• An early reduction in mortality compared with placebo was
not maintained at 180 days.
• No trials are currently available comparing levosimendan to
other inotropic agents.
Delle Karth and colleagues administered levosimendan to 10
patients with cardiogenic shock after myocardial infarction or
cardiac surgery that did not improve after revascularisation.39
Following intra-aortic balloon pump insertion, volume
optimisation and the use of noradrenaline to achieve a mean
arterial pressure >65 mm Hg, levosimendan was commenced at
0.1 μg/kg/min (without a bolus dose). Levosimendan resulted
in a significant increase in cardiac output, allowing four
patients to be weaned from their other therapies and all
survived to six-month follow up. Other authors have reported
comparable experiences (Table 3).
Comparative studies with other inotropes in patients with
refractory cardiogenic shock have demonstrated a mortality
benefit with levosimendan when compared with enoximone,40
but not when levosimendan is compared with dobutamine.41
With only four small RCTs with a combined number of 98
patients40-43 and only two of these trials assessing survival as
primary end points,40,41 data interpretation is limited.
3. Levosimendan in cardiogenic shock
Summary
In the initial dose-finding and therapeutic trials in patients
with decompensated heart failure, a systolic blood pressure
<90 mm Hg was an exclusion criterion (Table 3). Subsequently,
the observational BELIEF study has shown that patients with a
systolic blood pressure of <90 mm Hg are four times less likely
to respond to levosimendan.36 There are, however, several
recent clinical observations indicating that levosimendan can
improve haemodynamics even in patients with cardiogenic
shock, if it is combined with other adjunctive therapy (such as
noradrenaline and intra-aortic balloon pump counterpulsation)
to maintain adequate perfusion pressures.37,38
• Evidence is limited to a few small studies.
• There is potential benefit in the use of levosimendan as
adjunctive therapy in cardiogenic shock, but otherwise it
should be used with caution in patients with low baseline
systolic or diastolic blood pressure or those at risk for
hypotension.
Summary
20
4. Levosimendan in septic shock
It has become increasingly apparent that during sepsis,
morphological myocardial changes can occur, with resulting
biventricular dilatation and reduced ejection fraction. Left
Volume 12, Number 1, January 2011 JICS
Review articles
Study,
year (ref)
Population
N
Levosimendan
dose (length
of infusion)
Comparator
dose (length
of infusion)
Definition of septic
shock and/or inclusion
criteria
Clinical outcome(s)
with levosimendan
Follow up
Alhashemi Severe sepsis/ 42
2009(55)
septic shock
0.050.2 μg/kg/min
(24 hours)
Dobutamine
5–20 μg/kg/min
(24 hours)
Trial drugs increased
until ScvO2 ≥70%.
Rescue therapy with
noradrenaline
ICU mortality was less (48%
vs 62%). CI was less in the
levosimendan group and
both required similar
noradrenaline rescue therapy
ICU length
of stay
Morelli
2006(54)
ARDS and
septic shock
35
0.2 μg/kg/min
Placebo
Septic shock
(ACCP/SCCM)
and ARDS
The combination of
inotropic and pulmonary
vasodilating effects of
levosimendan may be
beneficial with RV failure
in patients with ARDS
and sepsis
24 hours
Morelli
2005(45)
Refractory
septic shock
28
0.2 μg/kg/min
Dobutamine
5 μg/kg/min
LVEF >45%,
PCWP ≥12mmHg
Not fluid responsive
Improved haemodynamics
and regional perfusion
under conditions where
dobutamine is no longer
efficacious
30 days
Table 4 Summary of RCTs with levosimendan use in septic shock.
Key CI = cardiac index, ARDS = acute respiratory distress syndrome, ACCP = American College of Chest Physicians, SCCM = Society of Critical Care
Medicine, RV = right ventricular, LVEF = left ventricular ejection fraction, PCWP = pulmonary capillary wedge pressure, ScvO2 = central venous oxygen
saturation
ventricular dysfunction occurs in up to half of patients with
septic shock lasting more than 48 hours and is associated with
a higher mortality (Table 4).44 The mechanism for this
reversible septic cardiomyopathy is not fully understood, but it
has been proposed that this is cytokine-mediated, with an
alteration of intracellular calcium homeostasis.45,46 This is
supported by animal models, which support the theory that
calcium desensitisation could be a potential component in
septic myocardial depression.47 Proponents of levosimendan
argue that as levosimendan acts via calcium sensitisation, this
would be a more logical choice of inotrope in septic myocardial
depression rather than dobutamine, which is generally
regarded as the agent of choice, usually in conjunction with
vasopressors.48 Also, levosimendan does not increase oxygen
demand, ameliorates the inflammatory response and may
inhibit apoptosis.12,49,50 Furthermore, alterations in sympathetic
beta-adrenergic signalling may impair the myocardial response
to endogenous and exogenous catecholamines. These
theoretical benefits have been extrapolated to show an
improved cardiac performance (unlike milrinone or
dobutamine) in sepsis-induced diastolic dysfunction in animal
models.51 While there is potential benefit in humans, published
data supporting this is restricted mostly to case reports, two
case series52,53 and three small randomised controlled trials
(two by the same lead author). The earlier RCT in 2005
included 28 patients with persisting left ventricular
dysfunction related to septic shock after 48 hours of
conventional treatment including dobutamine (5 μg/kg/min).45
Patients were randomised to receive a 24-hour infusion of
either levosimendan (0.2 μg/kg/min) or dobutamine continued
at 5 μg/kg/min. Dobutamine did not change systemic or
regional haemodynamic variables. By contrast, at the same
mean arterial pressure, levosimendan decreased pulmonary
JICS Volume 12, Number 1, January 2011
artery occlusion pressure and increased cardiac index.
Levosimendan decreased LV end-diastolic volume (EDV) and
lactate concentrations, and increased LV ejection fraction,
gastric mucosal flow, creatinine clearance, and urinary output.
A more recent RCT54 recruited 35 patients with acute
respiratory distress syndrome (ARDS) in association with
septic shock. Patients were randomly allocated to receive a
24-hour infusion of either levosimendan 0.2 μg/kg/min or
placebo. At a mean arterial pressure between 70 and 80 mm Hg
(sustained with a noradrenaline infusion), levosimendan
increased cardiac index, right ventricular ejection fraction, and
mixed venous oxygen saturation, and decreased mean
pulmonary artery pressure, pulmonary vascular resistance
index and right ventricular end-systolic volume. The most
recent RCT by Alashemi demonstrated a reduced ICU
mortality in patients who received levosimendan compared
with dobutamine when used in combination with
noradrenaline. This data has been presented as a poster at an
international meeting, but only published in abstract form.55
Summary
• There are theoretical advantages (correction of calcium
desensitisation, reduction in apoptosis and inflammatory
response) of levosimendan compared to dobutamine when
used in conjunction with vasopressor support.
• It may exacerbate hypotension with a reduction in
peripheral vascular resistance.
• Studies are limited and a large randomised controlled trial is
required to determine any potential efficacy.
Conclusion
Levosimendan has been shown to improve left ventricular
performance and to decrease left ventricular filling pressures
21
Review articles
and plasma BNP concentrations without an increase in
myocardial oxygen consumption. It does not appear to result
in tolerance and its effect is not attenuated with concomitant
beta-blocker use (both of which can occur with beta-agonists).
While these haemodynamic benefits are demonstrated
throughout the literature, they do not consistently lead to
improved survival, and the magnitude of effect in some trials is
at best modest. Possible reasons for this variability, beyond
questioning the overall efficacy of levosimendan in these
clinical situations, include:
1. Acute heart failure is a complex condition with a variety of
causes and definitions. Severity is variable and can range
from mild decompensation of chronic heart failure with
congestion at rest, to cardiogenic shock. The disease severity
between these two extremes is continuous and this severity
is not adequately captured by the clinical variables used for
the selection criteria by the clinical trials.56 The European
Society of Cardiology (ESC) and the European Society of
Intensive Care Medicine (ESICM) classification of acute
heart failure (2008) is a useful classification and hopefully
will provide more transparent comparisons between patient
study groups.1
2. There is no universally accepted management of acute heart
failure. The first European guidelines for acute heart failure
were only agreed in 2005. While these provide a more
consistent management strategy, the dose, timing, choice of
drug within classes and decision to withhold certain
therapies (eg beta blockers and vasodilators) can vary.
3. The dosing regimen of levosimendan (potentially in the face
of hypovolaemia) complicates interpretation of the data.
Administration of the loading dose of levosimendan to
patients in REVIVE II was associated with hypotension in
50% of patients and with increased propensity for
arrhythmias in SURVIVE. This may have had a negative
effect on clinical outcome.
The main lessons from previous trials are that certain prerequisites may reduce predictable negative effects of
levosimendan. It is conceivable that this would allow any
mortality benefit to be demonstrated and confirm or refute
whether levosimendan has a place in the management of acute
heart failure syndromes. These pre-requisites include:
• Correction of hypovolaemia following vasodilator and
diuretic therapy.
• Serum electrolyte correction.
• Invasive blood pressure and cardiac output monitoring.
• Individualised dosage regimen with exclusion of a loading
dose in hypotensive patients.
• Consideration of continuation of beta-blocker therapy.
• Concomitant vasopressor therapy may be required and
indeed may be essential in maintaining perfusion pressures.
With the current available evidence, it is not possible to
recommend levosimendan to all patients with acute heart
failure. However, it does have the potential to restore
haemodynamic stability either as an alternative or adjunctive
therapy. This may provide a useful option as a bridging therapy
or where other therapy has been unsuccessful. With an average
cost per patient for a 24-hour infusion approximating to 800
euros (more than twice the cost of dobutamine), there are
22
important economic implications when considering the use of
levosimendan. Appropriate patient selection and timing of
levosimendan therapy is therefore imperative.51 If it is only
used as a final measure in critically ill patients, when
traditional inotropes are ineffective, there is a danger that this
may be too late to reverse organ failure and any potential
benefit may not be demonstrated. Large prospective
randomised multicentre clinical trials are warranted to define
precise clinical indications, most appropriate timing and
mortality outcome. An important caveat to this study would be
to examine the use of dobutamine, where outcome benefit
remains to be proven and where the drug indeed may be
causing harm.
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JICS Volume 12, Number 1, January 2011
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23
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Steve Mathieu Locum Consultant in Critical Care and
Anaesthesia, The Royal Bournemouth Hospital
[email protected]
Gordon Craig Consultant in Critical Care and Anaesthesia,
Queen Alexandra Hospital, Portsmouth
THE INTENSIVE CARE SOCIETY
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JANUARY 2011
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