1. 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

2. 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.Braunwald, et al. A textbook of Cardiovascular Medicine. Elsevier Saunders, 7th Ed, 509-539 2.Felker G et al. The problem of decompensated heart failure: nomenclature, classification and risk stratification. Am Heart L 2003; 145: S18-25 3.Swedberg K et al. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2005; 45: 123-200

3. 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

4. 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

5. 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 Class 7 – 1st year 2005/2006 7.Nieminen M et al. Guidelines on the diagnosis and treatment of acute heart failure. Eur Heart J 2005; 44: 567-610

6. Class 7 – 1st year 2005/2006 Levosimendan (8-10) It is a new calcium-sensitizer, which is able to enhance celular responsiveness to Ca 2+ 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 Ca 2+ 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.Kivikko M et al. Sustained haemodynamic effects of intravenous levosimendan. Circulation 2003; 107: 81-86 9.Innes C et al. Levosimendan: a review of its use in the management of acute decompensated heart failure: Drugs 2003; 63: 2651-2671 10.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

7. 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;

8. 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

9. Methods Bibliographic research in medical databases: PubMed’s Cochrane’s online database. Searching criteria: from the earliest achievable date until the present day.

10. 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

11. 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.

12. 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

13. Number of articles throughout selection: Systematic review phaseResults Pubmed’s Query 115 articles 25 not excluded 8 included Cochrane’s Query Total included articles 39 articles 18 not excluded 10 included 8 repeated 10 articles Class 7 – 1st year 2005/2006

14. Gantt Diagram and Flowchart Work project and Gantt Chart FlowchartDatabase SPSS DatabaseWebsite Link

15. 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. Class 7 – 1st year 2005/2006