The Effect of Inodilatory Agents on Mortality
The Effect of Inodilatory Agents on Mortality
Background Inodilators are commonly used in critically ill patients, but their effect on survival has not been properly studied to date. The objective of this work was to conduct a network meta-analysis on the effects of inodilators on survival in adult cardiac surgery patients, and to compare and rank drugs that have not been adequately compared in head-to-head trials.
Methods Relevant studies were independently searched in BioMedCentral, MEDLINE/PubMed, Embase, and the Cochrane Central Register of clinical trials (updated on May 1, 2014). The criteria for inclusion were: random allocation to treatment with at least one group receiving dobutamine, enoximone, levosimendan, or milrinone and at least another group receiving the above inodilators or placebo, performed in cardiac surgical patients. The endpoint was to identify differences in mortality at longest follow-up available.
Results The 46 included trials were published between 1995 and 2014 and randomised 2647 patients. The Bayesian network meta-analysis found that only the use of levosimendan was associated with a decrease in mortality when compared with placebo (posterior mean of OR=0.48, 95% CrI 0.28 to 0.80). The posterior distribution of the probability for each inodilator to be the best and the worst drug showed that levosimendan is the best agent to improve survival after cardiac surgery. The sensitivity analyses performed did not produce different interpretative result.
Conclusion Levosimendan seems to be the most efficacious inodilator to improve survival in cardiac surgery.
Cardiac surgery is frequently complicated by low cardiac output syndrome (LCOS); cardiogenic shock is associated with significant morbidity and mortality.
The combination of cardiac inotropy, peripheral vasodilation and decreased after load, gained inodilators the role of first line drugs in cardiogenic shock. This family encompasses older drugs like dobutamine, the phosphodiesterase 3 (PDE-3) inhibitors (enoximone and milrinone) and the new calcium sensitizer levosimendan. There is no doubt that inodilators can effectively improve haemodynamic parameters but they are associated with side effects and some observational trials found a significant association between inotropes administration and increased mortality in cardiac surgery.
Even if inodilators are often used in cardiac surgery and more than 1 million cardiac surgery procedures are performed worldwide every year, no large multicentre randomised trial exists to document differences in mortality when using different inodilators in cardiac surgery. Most randomised controlled trials performed on inodilators in cardiac surgery are small and, even if mortality data is often reported, it is difficult to determine which is the best agent in terms of survival. Furthermore, most published trials compare levosimendan vs placebo and milrinone vs placebo while it would be desirable to have direct comparison between inodilators. Preliminary evidence derived from meta-analyses of randomised trials, suggests that levosimendan reduces mortality in cardiac surgery but data are not updated, are not focused on inodilators and no attempt to grade the different inodilators was performed so far. The inclusion of indirect comparisons might in fact add pieces of information in a setting with scarce direct comparisons.
Our research question was to investigate which inodilator is associated with the lowest mortality after cardiac surgery. To achieve this aim we first identified and merged all randomised trials ever published on any inodilator drug (levosimendan, enoximone, milrinone and dobutamine) in adult cardiac surgery that reported mortality data. We therefore performed a Bayesian network meta-analysis of randomised trials to grade all the inodilators in order to allow physicians to optimize cost-effectiveness analyses in their centres. A network meta-analysis is a statistical technique for comparison of different treatments that were never properly studied through adequately powered randomised controlled trials, but that can be compared through a third common comparator. On the basis of statistical inference, it is possible to identify the superior treatment, reaching, through indirect comparison, reliable conclusions otherwise hard or impossible to achieve.
Abstract and Introduction
Abstract
Background Inodilators are commonly used in critically ill patients, but their effect on survival has not been properly studied to date. The objective of this work was to conduct a network meta-analysis on the effects of inodilators on survival in adult cardiac surgery patients, and to compare and rank drugs that have not been adequately compared in head-to-head trials.
Methods Relevant studies were independently searched in BioMedCentral, MEDLINE/PubMed, Embase, and the Cochrane Central Register of clinical trials (updated on May 1, 2014). The criteria for inclusion were: random allocation to treatment with at least one group receiving dobutamine, enoximone, levosimendan, or milrinone and at least another group receiving the above inodilators or placebo, performed in cardiac surgical patients. The endpoint was to identify differences in mortality at longest follow-up available.
Results The 46 included trials were published between 1995 and 2014 and randomised 2647 patients. The Bayesian network meta-analysis found that only the use of levosimendan was associated with a decrease in mortality when compared with placebo (posterior mean of OR=0.48, 95% CrI 0.28 to 0.80). The posterior distribution of the probability for each inodilator to be the best and the worst drug showed that levosimendan is the best agent to improve survival after cardiac surgery. The sensitivity analyses performed did not produce different interpretative result.
Conclusion Levosimendan seems to be the most efficacious inodilator to improve survival in cardiac surgery.
Introduction
Cardiac surgery is frequently complicated by low cardiac output syndrome (LCOS); cardiogenic shock is associated with significant morbidity and mortality.
The combination of cardiac inotropy, peripheral vasodilation and decreased after load, gained inodilators the role of first line drugs in cardiogenic shock. This family encompasses older drugs like dobutamine, the phosphodiesterase 3 (PDE-3) inhibitors (enoximone and milrinone) and the new calcium sensitizer levosimendan. There is no doubt that inodilators can effectively improve haemodynamic parameters but they are associated with side effects and some observational trials found a significant association between inotropes administration and increased mortality in cardiac surgery.
Even if inodilators are often used in cardiac surgery and more than 1 million cardiac surgery procedures are performed worldwide every year, no large multicentre randomised trial exists to document differences in mortality when using different inodilators in cardiac surgery. Most randomised controlled trials performed on inodilators in cardiac surgery are small and, even if mortality data is often reported, it is difficult to determine which is the best agent in terms of survival. Furthermore, most published trials compare levosimendan vs placebo and milrinone vs placebo while it would be desirable to have direct comparison between inodilators. Preliminary evidence derived from meta-analyses of randomised trials, suggests that levosimendan reduces mortality in cardiac surgery but data are not updated, are not focused on inodilators and no attempt to grade the different inodilators was performed so far. The inclusion of indirect comparisons might in fact add pieces of information in a setting with scarce direct comparisons.
Our research question was to investigate which inodilator is associated with the lowest mortality after cardiac surgery. To achieve this aim we first identified and merged all randomised trials ever published on any inodilator drug (levosimendan, enoximone, milrinone and dobutamine) in adult cardiac surgery that reported mortality data. We therefore performed a Bayesian network meta-analysis of randomised trials to grade all the inodilators in order to allow physicians to optimize cost-effectiveness analyses in their centres. A network meta-analysis is a statistical technique for comparison of different treatments that were never properly studied through adequately powered randomised controlled trials, but that can be compared through a third common comparator. On the basis of statistical inference, it is possible to identify the superior treatment, reaching, through indirect comparison, reliable conclusions otherwise hard or impossible to achieve.
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