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Class 7 – 1st year 2005/2006
Systematic Review
Use of Levosimendan on the treatment
of Acute Heart Failure
Cristina Mendes, David Mota, Débora Monteiro, Diana Rodrigues, Diana Martins, Diana
Gomes, Diogo Garrido, Diva Oliveira e Ricardo Correia
Introduction to Medicine
21st of March of 2006
Oporto Medical Faculty
Class 7 – 1st year 2005/2006
Introduction
 Acute Heart Failure (AHF) is a fisiopathologic state in which
the heart is prevented from pumping the required amount of
blood to suppress the tissues’ metabolic needs. (1)
 Is defined as the rapid onset of symptoms and signs secondary
to abnormal cardiac function (2)
 AHF is usually a consequence of a severe anatomic or
functional change, such as an acute myocardial infarction, an
hypertensive crisis or an acute arrhythmia or even a
decompensation of pre-existing chronic heart failure (3)
1.
2.
3.
Braunwald, et al . A textbook of Cardiovascular Medicine. Elsevier Saunders, 7th Ed,
509-539
Felker G et al. The problem of decompensated heart failure: nomenclature, classification
and risk stratification. Am Heart L 2003; 145: S18-25
Swedberg K et al. Guidelines for the diagnosis and treatment of chronic heart failure.
Eur Heart J 2005; 45: 123-200
Class 7 – 1st year 2005/2006
 Sudden appearance of symptoms, such as fatigue, orthopnea,
weakness, chest pain, among others, hence the “Acute”
designation.
 Patients with AHF have a very poor prognosis. 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 an rehospitalization
within 60 days was 35,2% (4)
 Estimates of the risk of death or rehospitalizations within 60
days of admission vary from 30 to 60% depending on the
population studied (5, 6)
4.
Cleland J el al. The Euroheart failure survey program. Eur Heart J 2003; 24: 442-463
5.
McAlister f et al. A systematic review of randomized trials of disease management
programs in heart failure. Am J Med 2001; 110: 378-384
6.
Rich M et al. A multidisciplinary intervention to prevent the readmission of elderly
patients with congestive heart failure. N Engl J Med 1995; 333:1190-1195
Class 7 – 1st year 2005/2006
 The goals of this treatment are to improve symptoms
and to stabilize the haemodinamic condition.
 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.
Class 7 – 1st year 2005/2006
 There are a lot of drugs that can be used in
the treatment of AHF, such as (7)
• diuretics
• vasodilators
• inotropic agents: such as dobutamine
or dopamine, who mimic the actions of
the nervous sympathetic system,
phosphodiesterases inhibitors
• vasopressor agents in the cardiogenic
shock such as epinephrine or
norepinephrine
7.
Nieminen M et al. Guidelines on the diagnosis and treatment of acute heart failure.
Eur Heart J 2005; 44: 567-610
Class 7 – 1st year 2005/2006
Levosimendan (8-10)
• It is a new calcium-sensitizer, which is able to enhance
celular responsiveness to Ca2+ without increasing it’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 it’s original conformation.
• It is also a vasodilator, by activating ATP-dependent
potassium channels that cause an increased diameter of
blood vessels throughout the body.
8.
9.
10.
Kivikko M et al. Sustained haemodynamic effects of intravenous levosimendan. Circulation 2003;
107: 81-86
Innes C et al. Levosimendan: a review of its use in the management of acute decompensated
heart failure: Drugs 2003; 63: 2651-2671
Peter Tassani et. Al. Effect of the Calcium Sensitizer Levosimendan on the Performance of
Ischaemic Myocardium in Anaesthetised Pigs. Cardiov drugs therapy 2002; 16; 435-441
Class 7 – 1st year 2005/2006
 Levosimendan appears to be an alternative
treatment to AHF (11)
 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
11 - F Follath, et al . Efficacy and safety of intravenous levosimendan compared with dobutamine
in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet
2002;
Class 7 – 1st year 2005/2006
Aim of the Study
to perform a systematic review
concerning
the
effects
of
levosimendan in the treatment of
AHF when compared to the
conventional therapy
Class 7 – 1st year 2005/2006
Methods
 Bibliographic research in medical
databases:
• PubMed’s
• Cochrane’s online database.
 Searching criteria:
from the earliest achievable date
until the present day.
Class 7 – 1st year 2005/2006
 Query used to search PubMed:
(("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
 Query used to search Cochrane:
("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”)
Class 7 – 1st year 2005/2006
 Initial tracing (exclusion): performed by one
group, composed of three reviewers, according
to the exclusion criteria mentioned below:
1. Not being presented in English, Portuguese,
Spanish and French.
2. Not mentioning levosimendan, directly or
indirectly (through other designation such as
calcium sensitizer).
3. Not to be a randomized clinical trial or an
observational longitudinal study.
4. Not to approach the effects of levosimendan
on the heart and/or cardiac tissue.
Class 7 – 1st year 2005/2006
 Inclusion criteria:
• performed by one group, composed of three reviewers.
• inclusion of the article was dependent on the overall
approval between the three reviewers, bearing in mind
the inclusion criteria set below:
1. Being directly related to the review’s main subject.
2. Compare the therapeutical effects of levosimendan with
those of other standard treatments such as dobutamine,
dopamine, other inotropic agents or even placebo.
3. Should have a minimum “n” (sample size) of five
individuals.
4. Test subjects should be human.
Included articles were registered with the use of SPSS
Class 7 – 1st year 2005/2006
Number of articles throughout selection:
Systematic review phase
Pubmed’s Query
Cochrane’s Query
Total included articles
Results
115 articles
25 not excluded
8 included
39 articles
18 not excluded
10 included
8 repeated
10 articles
Class 7 – 1st year 2005/2006
Gantt Diagram
and Flowchart
Work project and Gantt Chart
Flowchart
Database
SPSS Database
Website
Link
Class 7 – 1st year 2005/2006
Conclusion
 The studies show levosimendan to be an effective drug in the
treatment of acute heart failure (AHF). Analyzed results
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. Further
research in this matter might be of interest as the study that
indicated this had a somewhat small participant number.