Effect of Inotropes in Patients with Advanced Heart Failure: A Meta-Analysis of Randomized Trials

##plugins.themes.academic_pro.article.sidebar##

Published Nov 9, 2025
https://doi.org/10.62438/tunismed.v103i9.6513
Download
pdf
Vol. 103 No. 9 (2025): Tunis Med sept 2025

##plugins.themes.academic_pro.article.main##

Racha Ghabara
Cardiology Department, Security Forces Hospital, Faculty of Medicine of Tunis,University of Tunis EI Manar, Tunis, Tunisia
Badreddine Ben Kaab
Cardiology Department, Security Forces Hospital, Faculty of Medicine of Tunis,University of Tunis EI Manar, Tunis, Tunisia
Saoussen Antit
Cardiology Department, Security Forces Hospital, Faculty of Medicine of Tunis,University of Tunis EI Manar, Tunis, Tunisia
Chadli Dziri
Faculty of Medicine of Tunis,University of Tunis EI Manar, Tunis, Tunisia
Lilia Zakhama
Cardiology Department, Security Forces Hospital, Faculty of Medicine of Tunis,University of Tunis EI Manar, Tunis, Tunisia

Abstract

Introduction : Advanced heart failure (AHF) is associated with high morbidity and mortality. Inotropic agents such as dobutamine, levosimendan, and milrinone are commonly used to improve cardiac output, but their impact on mortality remains controversial due to limited head-to-head comparisons.


Aim : To compare the effectiveness of inotropes (dobutamine, levosimendan, milrinone) versus placebo or each other in reducing mortality in patients with AHF.


Methods : This systematic review and meta-analysis followed PRISMA guidelines and was registered with PROSPERO (CRD42024584389). We searched Scopus, CENTRAL, Google Scholar, PubMed, and clinical trial registries up to December 2024 for randomized controlled trials (RCTs) published from 2000 onward. Eligible studies included adults (≥18 years) with AHF and cardiorenal syndrome. Risk differences (RD) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed with the Cochrane Q-test, Tau², and I². Subgroup analyses and meta-regression were performed. Publication bias was evaluated using funnel plots and Duval and Tweedie's trim-and-fill method.


Results : Twenty-four RCTs involving 2,862 participants were included. The pooled RD for mortality was -0.023 (95% CI: -0.046 to 0.000; p=0.055), indicating no significant difference. Subgroup analysis by control (inotropes vs. placebo) showed similar non-significant results. Meta-regression for moderators (age, LVEF, systolic blood pressure) did not explain heterogeneity. The funnel plot suggested asymmetry, indicating potential publication bias.


Conclusions : Inotropic agents showed a non-significant trend toward reduced mortality in AHF patients. Heterogeneity limits firm conclusions. Larger RCTs are needed to identify subgroups that may benefit.

Keywords:

Advanced heart failure, inotropes, dobutamine, levosimendan, milrinone, meta-analysis, Maternal morbidity and mortality

##plugins.themes.academic_pro.article.details##

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

References

  1. Savarese G, Division of Cardiology, Department of Medicine, Karolinska Insitutet, Stockholm, Sweden, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden, Lund LH, Division of Cardiology, Department of Medicine, Karolinska Insitutet, Stockholm, Sweden, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden. Global Public Health Burden of Heart Failure. Cardiac Failure Review. 2017;03(01):7.
  2. Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. European Heart Journal. 14 oct 2023;44(39):4043‑140.
  3. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2 mai 2007;297(17):1883‑91.
  4. Bragadottir G, Redfors B, Ricksten SE. Effects of levosimendan on glomerular filtration rate, renal blood flow, and renal oxygenation after cardiac surgery with cardiopulmonary bypass: a randomized placebo-controlled study. Crit Care Med. oct 2013;41(10):2328‑35.
  5. Chen WC, Lin MH, Chen CL, Lai YC, Chen CY, Lin YC, et al. Comprehensive Comparison of the Effect of Inotropes on Cardiorenal Syndrome in Patients with Advanced Heart Failure: A Network Meta-Analysis of Randomized Controlled Trials. Journal of Clinical Medicine. janv 2021;10(18):4120.
  6. Cardio-Renal Syndrome Type 1: Epidemiology, Pathophysiology, and Treatment - Seminars in Nephrology [Internet]. [cité 13 oct 2025]. Disponible sur: https://www.seminarsinnephrology.org/article/S0270-9295(11)00182-3/abstract
  7. Cuffe MS, Califf RM, Adams KF, Benza R, Bourge R, Colucci WS, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 27 mars 2002;287(12):1541‑7.
  8. Moiseyev VS et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. Eur Heart J. 2002;23(18).
  9. Nanas JN, Tsagalou EP, Kanakakis J, Nanas SN, Terrovitis JV, Moon T, et al. Long-term Intermittent Dobutamine Infusion, Combined With Oral Amiodarone for End-Stage Heart Failure. Chest. avr 2004;125(4):1198‑204.
  10. Nieminen MS, Akkila J, Hasenfuss G, Kleber FX, Lehtonen LA, Mitrovic V, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. Journal of the American College of Cardiology. nov 2000;36(6):1903‑12.
  11. Comín‐Colet J, Manito N, Segovia‐Cubero J, Delgado J, García Pinilla JM, Almenar L, et al. Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION‐HEART multicentre randomised trial. European J of Heart Fail. juill 2018;20(7):1128‑36.
  12. Jia Z, Guo M, Zhang YQ, Liang HQ, Zhang LY, Song Y. Efficacy of Intravenous Levosimendan in Patients with Heart Failure Complicated by Acute Myocardial Infarction. Cardiology. 2014;128(2):195‑201.
  13. Jia Z, Guo M, Zhang LY, Zhang YQ, Liang HQ, Song Y. Levosimendan and Nesiritide as a Combination Therapy in Patients With Acute Heart Failure. The American Journal of the Medical Sciences. mai 2015;349(5):398‑405.
  14. Follath F, Cleland J, Just H, Papp J, Scholz H, Peuhkurinen K, 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. The Lancet. juill 2002;360(9328):196‑202.
  15. Aranda JM, Schofield RS, Pauly DF, Cleeton TS, Walker TC, Monroe VS, et al. Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: A prospective, randomized trial. American Heart Journal. févr 2003;145(2):324‑9.
  16. Llorens P, Miró Ò, Román F, Zapater P, Carbajosa-Dalmau J, Llanos L. Efficacy of early administration of levosimendan in emergency department in patients with acute heart failure: a randomized pilot clinical trial.
  17. Bonios MJ, Terrovitis JV, Drakos SG, Katsaros F, Pantsios C, Nanas SN, et al. Comparison of three different regimens of intermittent inotrope infusions for end stage heart failure. International Journal of Cardiology. sept 2012;159(3):225‑9.
  18. Giamouzis G, Butler J, Starling RC, Karayannis G, Nastas J, Parisis C, et al. Impact of Dopamine Infusion on Renal Function in Hospitalized Heart Failure Patients: Results of the Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial. Journal of Cardiac Failure. déc 2010;16(12):922‑30.
  19. Triposkiadis FK, Butler J, Karayannis G, Starling RC, Filippatos G, Wolski K, et al. Efficacy and safety of high dose versus low dose furosemide with or without dopamine infusion: The Dopamine in Acute Decompensated Heart Failure II (DAD-HF II) Trial. International Journal of Cardiology. mars 2014;172(1):115‑21.
  20. Husebye T, Eritsland J, Müller C, Sandvik L, Arnesen H, Seljeflot I, et al. Levosimendan in acute heart failure following primary percutaneous coronary intervention‐treated acute ST‐elevation myocardial infarction. Results from the LEAF trial: a randomized, placebo‐controlled study. European J of Heart Fail. mai 2013;15(5):565‑72.
  21. Kleber FX, Bollmann T, Borst MM, Costard‐Jäckle A, Ewert R, Kivikko M, et al. Repetitive Dosing of Intravenous Levosimendan Improves Pulmonary Hemodynamics in Patients With Pulmonary Hypertension: Results of a Pilot Study. The Journal of Clinical Pharma. janv 2009;49(1):109‑15.
  22. Pölzl G, Altenberger J, Comín‐Colet J, Delgado JF, Fedele F, García‐González MJ, et al. Repetitive levosimendan infusions for patients with advanced chronic heart failure in the vulnerable post‐discharge period: The multinational randomized LEODOR trial. European J of Heart Fail. nov 2023;25(11):2007‑17.
  23. Duygu H, Turk U, Ozdogan O, Akyuz S, Kirilmaz B, Alioglu E, et al. Levosimendan versus Dobutamine in Heart Failure Patients Treated Chronically with Carvedilol. Cardiovascular Therapeutics. sept 2008;26(3):182‑8.
  24. García‐González MJ, Aldea Perona A, Lara Padron A, Morales Rull JL, Martínez‐Sellés M, De Mora Martin M, et al. Efficacy and safety of intermittent repeated levosimendan infusions in advanced heart failure patients: the LAICA study. ESC Heart Failure. déc 2021;8(6):4820‑31.
  25. Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, Califf RM, et al. Heart failure etiology and response tomilrinone in decompensated heart failure. Journal of the American College of Cardiology. mars 2003;41(6):997‑1003.
  26. Altenberger J, Parissis JT, Costard‐Jaeckle A, Winter A, Ebner C, Karavidas A, et al. Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure ( LEVOREP ) study: a multicentre randomized trial. European J of Heart Fail. août 2014;16(8):898‑906.
  27. Adamopoulos S, Parissis JT, Iliodromitis EK, Paraskevaidis I, Tsiapras D, Farmakis D, et al. Effects of Levosimendan Versus Dobutamine on Inflammatory and Apoptotic Pathways in Acutely Decompensated Chronic Heart Failure. The American Journal of Cardiology. juill 2006;98(1):102‑6.
  28. Dzhaiani NA, Kositsyna IV, Gnidkina NA, Tereshchenko SN. [Efficacy of levosimendan vs dopamine in patients with resistant cardiac failure]. Ter Arkh. 2011;83(6):53‑9.
  29. Chenikala S, Nagiredi NR, Ahmed S, Banda DP. Prospective Randomized Comparative Study of Outcomes in Off-Pump CABG with Low Ejection Fraction (<40%), Priorly Optimized With Levosimendan versus Dobutamine. European Journal of Cardiovascular Medicine. 18 mars 2025;15:516‑21.
  30. Llorens P, Miró Ò, Román F, Zapater P, Carbajosa-Dalmau J, Llanos L. Efficacy of early administration of levosimendan in emergency department in patients with acute heart failure: a randomized pilot clinical trial.
  31. Belletti A, Castro ML, Silvetti S, Greco T, Biondi-Zoccai G, Pasin L, et al. The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. British Journal of Anaesthesia. nov 2015;115(5):656‑75.
  32. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, et al. A Dose-Dependent Increase in Mortality with Vesnarinone among Patients with Severe Heart Failure. N Engl J Med. 17 déc 1998;339(25):1810‑6.
  33. Metra M, Eichhorn E, Abraham WT, Linseman J, Bohm M, Corbalan R, et al. Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials. European Heart Journal. 2 déc 2009;30(24):3015‑26.
  34. Tacon CL, McCaffrey J, Delaney A. Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials. Intensive Care Med. mars 2012;38(3):359‑67.
  35. Mebazaa A, Parissis J, Porcher R, Gayat E, Nikolaou M, Boas FV, et al. Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med. 1 févr 2011;37(2):290‑301.
  36. Shahin J, DeVarennes B, Tse CW, Amarica DA, Dial S. The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery. Crit Care. 7 juill 2011;15(4):R162.
  37. Anesthesiology [Internet]. [cité 14 oct 2025]. Disponible sur: https://journals.lww.com/anesthesiology/fulltext/2014/05000/health_outcomes_with_and_without_use_of_inotropic.17.aspx
  38. Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, et al. Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction: The ROSE Acute Heart Failure Randomized Trial. JAMA. 18 déc 2013;310(23):2533‑43.
  39. Silvetti S, Greco T, Di Prima AL, Mucchetti M, De Lurdes CM, Pasin L, et al. Intermittent levosimendan improves mid-term survival in chronic heart failure patients: meta-analysis of randomised trials. Clin Res Cardiol. juill 2014;103(7):505‑13.
  40. Williams JB, Hernandez AF, Li S, Dokholyan RS, O’Brien SM, Smith PK, et al. Postoperative Inotrope and Vasopressor Use Following CABG: Outcome Data from the CAPS-Care Study. Journal of Cardiac Surgery. nov 2011;26(6):572‑8.
  41. Grossini E, Molinari C, Pollesello P, Bellomo G, Valente G, Mary D, et al. Levosimendan Protection against Kidney Ischemia/Reperfusion Injuries in Anesthetized Pigs. The Journal of Pharmacology and Experimental Therapeutics. août 2012;342(2):376‑88.
  42. Levosimendan improves renal function in acute decompensated heart failure: possible underlying mechanisms - Fedele - 2014 - European Journal of Heart Failure - Wiley Online Library [Internet]. [cité 14 oct 2025]. Disponible sur: https://onlinelibrary.wiley.com/doi/10.1002/ejhf.9
  43. Lannemyr L, Ricksten S, Rundqvist B, Andersson B, Bartfay S, Ljungman C, et al. Differential Effects of Levosimendan and Dobutamine on Glomerular Filtration Rate in Patients With Heart Failure and Renal Impairment:A Randomized Double‐Blind Controlled Trial. JAHA. 21 août 2018;7(16):e008455.