Can a meta-analysis that mixes apples with oranges be used to demonstrate that levosimendan reduces mortality after coronary revascularization?

We read with a great deal of interest the recently published meta-analysis of Maharaj and Metaxa [1] describ ing the eff ects of levosimendan on mortality after coronary revascularization. Th e authors concluded that levosimendan is able to reduce mortality in patients undergoing myocardial revascularization. Th eir conclu sion, however, is unreliable and misleading for several reasons. Th e basic reason is that their meta-analysis did not include comparable studies, thus violating the basic principle of meta-analysis. We believe that the inclusion in meta-analyses of studies so radically diff erent is a methodological bias: characteristics of patients, doses used and timing of drug administration were discordant enough to make a true meta-analysis impossible. What is missing is a critical analysis of individual studies: the authors have only tried to give a pooled estimate of eff ectiveness of levosimendan administration. As Green [2] points out about meta-analyses: ‘Metaanalysis should only be performed when the studies are similar with respect to population, outcome and intervention.’ Th e article of Moharaj and Metaxa does not follow these simple principles. We believe it is not correct to include in the same analysis studies where levosimendan is used for the treatment of postoperative cardiogenic shock and studies where it is used as ischemic preconditioning before cardiopulmonary bypass [3,4]. For example, the study of Tritapepe and colleagues [5] included in this meta-analysis describes the eff ects of a single low dose (24 mcg/kg) of levosimendan infused before cardiopulmonary bypass in patients under going surgical myocardial revascularization only for the assess ment of the possible preconditioning eff ect of the drug. Although we believe that levosimendan is an eff ective drug for the treatment of cardiogenic shock, we also believe this meta-analysis does not provide enough evidence that levosimendan can decrease mortality after myocardial revascularization.

similar with respect to population, outcome and intervention. ' Th e article of Moharaj and Metaxa does not follow these simple principles. We believe it is not correct to include in the same analysis studies where levosimendan is used for the treatment of postoperative cardiogenic shock and studies where it is used as ischemic preconditioning before cardiopulmonary bypass [3,4]. For example, the study of Tritapepe and colleagues [5] included in this meta-analysis describes the eff ects of a single low dose (24 mcg/kg) of levosimendan infused before cardiopulmonary bypass in patients under going surgical myocardial revascularization only for the assess ment of the possible preconditioning eff ect of the drug.
Although we believe that levosimendan is an eff ective drug for the treatment of cardiogenic shock, we also believe this meta-analysis does not provide enough evidence that levosimendan can decrease mortality after myocardial revascularization.

© 2010 BioMed Central Ltd
Can a meta-analysis that mixes apples with oranges be used to demonstrate that levosimendan reduces mortality after coronary revascularization?

Ritesh Maharaj and Victoria Metaxa
We would like to thank Dr Meco and colleagues for their interest in our recently published meta-analysis [1]. Th e main goal of meta-analyses is to obtain a summary estimate across data sets and is substantially diff erent to the aims of an individual trial [6,7]. Accounting for trial level diff erences remains a signifi cant analytical challenge when pooling results, and we report how these diff erences may infl uence conclusions [8]. In our report we off er a qualitative assessment of the combinability or clinical heterogeneity by way of the study descriptors [1]. A small amount of between-trial heterogeneity can be accounted for by using the random eff ects model as opposed to the fi xed eff ects model. In our report the eff ect of levosimendan versus control using the random eff ects model remained consistent (odds ratio 0.43 (95% confi dence interval 0.21 to 0.89)).
Subgroup meta-analysis attempts to examine the eff ects of potential confounding, though we appreciate that such analyses should be interpreted with some *Correspondence: massimo.meco@virgilio.it 1 Istituto Clinico Sant' Ambrogio, Cardiac Surgery, Intensive Care and Anesthesia Departement, Via Faravelli, 16 20171 Milan, Italy Full list of author information is available at the end of the article consideration. We have conducted subgroup analyses comparing levosimendan in the elective versus emergent setting, as well as comparisons between levosimendan with other vasoactive agents and placebo. Th e fi ndings of these analyses are explained in the manuscript and are aimed at improving the clinical relevance of the conclusions drawn. Th ese methods aim to address the obvious heterogeneity that does exist and show a consistent clinical and biological signal in favor of levosimendan compared with control. A meta-analysis published ahead of print evaluating the role of levosimendan in mortality reduction and hospitalization included 45 studies that ranged from cardiology to sepsis and vascular and cardiac surgery settings [9]. Subgroup analysis of patients receiving a bolus, no bolus and dose >0.1 mcg/kg/minute all showed statistical signifi cance in favor of levosimendan.