Download Use of levosimendan in the treatment of acute heart failure

FACULTY
OF
M EDIC INE – U NIVERSITY
OF
P ORTO
Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
Use of levosimendan in the treatment of acute heart failure
Cristina Mendes,
David Mota,
Débora Monteiro,
Diana Gomes
[email protected]
[email protected]
[email protected]
[email protected]
Diana Martins
Diana Rodrigues
Diogo Garrido
Diva Oliveira
[email protected]
[email protected]
[email protected]
[email protected]
Ricardo Correia
[email protected]
Adviser: Dra. Filipa Almeida, [email protected], Class: 7
Abstract
Introduction: Acute heart failure (AHF) is a condition that can result from any structural or functional
cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood
throughout the body.
Usual treatments for AHF are inotropic agents. A new inotropic agent, levosimendan, was developed for
the treatment of this disease. It has been shown to bring better haemodynamic function in patients with
decompensated heart failure while maintaining arterial blood pressure.
Aim: Estudar o efeito do levosimendan no tratamento da insufiência cardíaca aguda comparando-o com
os tratamentos usuais (dobutamina e dopamina).
Methods: A literature search covering PubMed and Cochrane medical databases was conducted to
identify randomised controlled trials (RCT’s) about the effects of Levosimendan in the treatment of acute
heart failure. The articles obtained in this search were submitted to an exclusion phase, followed by an
inclusion phase. A total amount of 10 articles meeting the inclusion criteria were accepted and were
statistically analyzed by a group of three reviewers.
Results: Levosimendan was effective in the treatment of acute heart failure. From the total analyzed
articles, 5 were found to report statistically significant results, from which 4 revealed a favorable effect of
levosimendan in the treatment of AHF.
Discussion: based on the available studies, levosimendan showed to be more advantageous than placebo
concerning the number of survivors after 6 months of treatment, the variation of SV after 24 hours of
infusion, a SV increase of 25% or more and favourable variation of BNP levels after 48 hours of
treatment.
Key-words: Heart Failure, Congestive; Cardiotonic Agents; Shock, Cardiogenic
Introduction
Acute Heart Failure (AHF) is a physiopathologic state, defined as the rapid onset of
symptoms and signs secondary to abnormal cardiac function [12], in which the heart is
prevented from pumping the required amount of blood to suppress the tissues’ metabolic
needs [11]. It is usually a consequence of a severe anatomic or functional change, such
as an acute myocardial infarction, a hypertensive crisis or an acute arrhythmia or even a
decompensation of pre-existing chronic heart failure [13], commonly accompanied by a
FACULTY
OF
M EDIC INE – U NIVERSITY
OF
P ORTO
Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
sudden appearance of symptoms, such as fatigue, orthopnea, weakness, chest pain,
increased BNP levels, among others, hence the “Acute” designation.
Brain Natriuretic Peptides (BNP) are cardiac neurohormones that appear as a sistemic
response to increases in ventricular wall tension, pressure overload and also ventricular
volume expansion. Therefore, it is easy to understand that increased levels of serum
BNP indicate overworking of ventricular muscle and/or some sort of cardiac
disfunction, often associated with AHF.
Patients with AHF have a very poor prognosis, being that in the largest randomized trial
to date in patients hospitalized with decompensated heart failure, the 60-day mortality
rate was 9.6% and the combined rate for mortality and re-hospitalization within 60 days
was 35,2% [14]. Estimates of the risk of death or re-hospitalizations within 60 days of
admission vary from 30 to 60% depending on the population studied. [15, 16]
The goals of common treatments are to improve symptoms and to stabilize the
hemodynamic condition, turning to several drugs that can be used for such purpose, as
for instance: diuretics, vasodilators, inotropic agents (such as dobutamine or dopamine,
who mimic the actions of the nervous sympathetic system), vasopressor agents (such as
epinephrine or norepinephrine) or phosphodiesterase inhibitors [17]. Levosimendan,
that is an inotropic agent, is on the top of the list of the leading drugs in the treatment of
this pathology. It appears to be an alternative treatment to AHF [18] because it works as
a calcium-sensitizer, which is able to enhance cellular responsiveness to Ca2+ without
increasing calcium’s intracellular concentration, improving myocardial contractility
(inotropic agent) without altering the heart muscle cells’ natural physiologic conditions.
It does so by increasing Troponin C’s affinity to Ca2+ and helping to maintain its
original conformation. It is also a vasodilator, by activating ATP-dependent potassium
channels that cause an increased diameter of blood vessels throughout the body.
The other inotropic therapies appear to be associated with higher mid/long term
mortality rate and conditions such as arrhythmias and disturbed oxygen balance on the
heart. Recently some studies have been published about the efficacy and safety of
levosimendan in the treatment of AHF.
FACULTY
OF
M EDIC INE – U NIVERSITY
OF
P ORTO
Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
Methods
The bibliographic research was performed in PubMed and Cochrane’s databases, from
the earliest achievable date until that day. The query to search Pubmed was defined as:
(("Heart Failure, Congestive"[MeSH] OR "Shock, Cardiogenic"[MeSH] OR heart
failure OR cardiac insufficiency) AND (levosimendan OR calcium sensitizer) AND
(placebo
OR
“Dopamine”[MeSH]
OR
Dopamine
OR
Dobutamine
OR
"Dobutamine"[MeSH] OR inotropic OR "Epinephrine"[MeSH] OR Epinephrine OR
norepinephrine OR adrenaline OR noradrenaline OR "Norepinephrine"[MeSH] OR
"Cardiotonic
Agents"[MeSH]
OR
"Phosphodiesterase
Inhibitors"[MeSH]
OR
"Natriuretic Peptide, Brain"[MeSH] OR “Atrial Natriuretic Factor”[MeSH])) NOT
Review.
Another query was also defined to search Cochrane’s database: ("Heart Failure" OR
"Cardiogenic Shock" OR “acute heart failure” OR “acute cardiac insufficiency”) AND
(levosimendan OR “calcium sensitizer”) AND (placebo OR Dopamine OR Dobutamine
OR
inotropic
OR
Epinephrine
OR
Norepinephrine
OR
Cardiotonic
OR
“Phosphodiesterase Inhibitors”).
As much as 115 articles in Pubmed and 39 articles in Cochrane were found.
After searching, the exclusion criteria were established. In the exclusion process, done
by three reviewers, articles were considered relevant when presented in English,
Portuguese, Spanish and French and mentioned levosimendan, directly or indirectly
(through other designation such as calcium sensitizer) and did not approach its effects
on the heart and/or cardiac tissue. The searched articles should also be either a
randomized clinical trial or an observational longitudinal study. Upon tracing, 84
articles from PubMed and 21 articles from Cochrane were excluded.
In the following stage another group of three reviewers defined the inclusion criteria
which highlighted the articles that were directly related to the reviews’ main subject and
compared the therapeutical effects of levosimendan with those of other standard
treatments, tested on a minimum of 5 human individuals. With the approval of the
majority of the reviewers, 8 articles were included from PubMed and 10 articles from
Cochrane, of which 8 were repeated when crossed with PubMed’s results.
FACULTY
OF
M EDIC INE – U NIVERSITY
OF
P ORTO
Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
In the end, a pool of 10 different articles was available for data extraction, having
selected and obtained the most relevant results from each individual article, bearing in
mind the project’s objective, and registering them with the help of SPSS.
Results
Article
number
Measured parameter
Compares
Levosimendan
to:
Difference
of
survivors after 6 Dobutamine
months of treatment.
Difference
of
2
survivors after 6
Placebo
months of treatment.
Comparative increase
3
Placebo
in HR.
Difference of SV
4a
variation after 24
Placebo
hours of infusion.
Difference of SV
4b
variation after 24 Dobutamine
hours of infusion.
Difference
of
subjects
whose
5
stroke
volume
Placebo
increased 25% or
more after treatment.
Difference of disease
progression (death or
6
rehospitalization) 5
Placebo
months
after
treatment.
Difference of BNP
levels variation after
7
Dobutamine
48
hours
of
treatment.
Difference of SV
8
variation after 6
Placebo
hours of infusion.
Difference of HR
9
variation after 24
Placebo
hours of treatment.
Difference of HR
10
variation after 12 Dobutamine
hours of treatment.
Table 1. Results extracted from analyzed articles.
1
n
(comparison)
Result
Favorable to
Statistically
Significant
(p<0,05)
103
100
11%
Levosimendan
n/a
103
102
5,2%
Levosimendan
Yes
4
4
7%
Placebo
Yes
23
20
21,47
%
Levosimendan
Yes
23
20
5,96%
Levosimendan
No
98
48
52%
Levosimendan
Yes
17
17
18%
Levosimendan
n/a
15
14
25,41
%
Levosimendan
Yes
98
48
30,95
%
Levosimendan
n/a
15
15
1,05%
Levosimendan
No
7
8
2,52%
Levosimendan
No
n
(levosimendan)
FACULTY
OF
M EDIC INE – U NIVERSITY
OF
P ORTO
Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
Discussion
This study shows that levosimendan presents a favorable effect on patients with acute
heart failure (AHF) in mosto f the evaluated paramenters.
Acording to article [2], 6 months after treatment, levosimendan leads to a larger number
of survivors when compared to placebo, demonstrating an improved treatment
efficiency.
In article 3, however, placebo was found to have an advantage in the heart’s rate
variation, being that it’s reported increase by the use of levosimendan is not adequate
for AHF patients who need to stabilize heart rate at lower values.
In article [4], levosimendan is compared to placebo and dobutamine, although only the
first comparison (levosimendan vs placebo) is statistically significant. A larger variation
of SV after 24 hours of infusion was verified in levosimendan’s results. This
haemodynamic effect is a favourable consequence of this new drug’s administration in
the treatment of AHF, as it reveals an improvement in cardiac function.
Article [5] also evaluates SV variation, detailing a percentage of patients that showed an
increase of 25% or more in SV, where once again levosimendan was found to be more
effective than placebo.
Finally, article [7] shows a comparison of levosimendan to dobutamine, where
levosimendan was found to cause a larger decrease of BNP levels, which is also
considered a positive result seeing that BNP is secreted by the heart’s ventricles in
response to excessive stretching of myocytes (heart muscle cells), and therefore elevated
BNP levels in the blood can be used to diagnose AHF.
Other articles focused on this study (1, 4b, 6, 8, 9, 10) are not discussed here, given the
fact that they do not provide statistically significant results.
It is also important to point out that the results from this study might not be strictly
rigorous, given some methodologic limitations inherent to either its design or execution,
such as the limited number of participants in some clinical trials, the unavailability of
some articles found on the searched databases, inclusion and exclusion criteria that
might not be the most appropriate and the possibility of human error during the
inclusion, exclusion and/or article analysis.
FACULTY
OF
M EDIC INE – U NIVERSITY
OF
P ORTO
Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
Conclusion:
The studies show levosimendan to be an effective drug in the treatment of acute heart
failure (AHF). The parameters evidenced in table 1 and discussed above demonstrate its
advantageous effect compared to dobutamine, in one of the cases, and to placebo, in
other three. Levosimendan is therefore an innovating inotropic agent that can become a
promising, if not leading treatment to AHF.
A possible exception to this statement is the heart rate increase upon use of
levosimendan verified in the article [3], which is not recommended in such cases, as
AHF patients tend to require stabilization at lower heart rates, but, as discussed above,
further research in this matter might be of interest as the study that indicated this had a
somewhat small participant number.
Acknowledgments
We would like to thank Dr. Filipa Almeida, our teacher for Medical Informatics on the
subject of “Introduction to Medicine – IM” and our project orientor, for all her help and
guidance throughout the entire project.
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Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
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Department of Biostatistics and Medical Informatics
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