Milrinone or Dobutamine in Patients with Heart Failure: Evidence from Meta-Analysis

Heart failure (HF) is one of the most prevalent causes of hospital admissions, especially among the elderly. Although the therapy for HF exacerbation primarily consists of restoring euvolemia with diuretics, inotropes are still needed for treatment of patients with low cardiac output and hypotension.1 Dobutamine improves myocardial contractility via activation of β1-adrenergic receptors in cardiomyocytes, which can cause sinus tachycardia, arrhythmias and myocardial ischaemia, thus increasing mortality.2 Type-3-phosphodiesterase inhibitor milrinone improves contractility without affecting the β1-receptors and may therefore be preferred over dobutamine, especially for patients on beta-blockers. On the other hand, excessive peripheral vasodilation and hypotension can be major limitations of milrinone, especially when administered at high doses. In some studies, patients with acute HF receiving milrinone demonstrated improved survival rates compared with the patients treated with dobutamine.3, 4 In other studies, milrinone did not show a significant advantage over dobutamine with regard to either clinical outcomes or adverse effects, making the use of dobutamine more attractive due to lower cost.5, 6 Given the role that inotropes play in acute HF, the high prevalence of their use, and the discrepancies in cost between them, it is crucial to determine the differences between the efficacy and safety of these drugs to optimize HF therapy. We performed a systematic review and meta-analysis of randomized and non-randomized trials to compare the effect of milrinone and dobutamine on survival outcomes and adverse events in adult patients with HF. This systematic review and meta-analysis complied with the widely recognized Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The PubMed, Embase, and Cochrane Library electronic databases were searched for articles published from database inception until 10 August 2021 performed by two independent reviewers (L. S. and M. P.). Keywords and phrases used for search queries included ‘milrinone’, ‘dobutamine’, and ‘heart failure’. All results are presented as mean difference (MD) or odds ratio (OR) or risk ratios (RR) with their 95% confidence interval (CI). All reported P-values were two-sided, and P < 0.05 were considered statistically significant. Statistical analyses were performed using RevMan5.4 (The Cochrane Collaboration, Oxford, Copenhagen, Denmark). Nine studies including 19 045 patients were selected for meta-analysis.1-9 All studies reported the use of milrinone vs. dobutamine in HF patients (Supporting Information, Table S1). Survival to hospital discharge was reported in seven studies1-3, 6-9 and was 78.5% for the milrinone group, compared with 81.2% for dobutamine (OR = 0.98; 95% CI: 0.82 to 1.19; P = 0.86; Figure 1). The 180 day survival rate was reported in one study1 and was 11.9% for milrinone and 18.0% for dobutamine group (OR = 0.61; 95% CI: 0.36 to 1.04; P = 0.07). Pooled analysis of 1 year survival rate for milrinone and dobutamine was 62.7% vs. 43.0% (OR = 2.23; 95% CI: 1.74 to 2.85; P < 0.001), and the 2 year survival rate was 46.8% vs. 33.7%, respectively (OR = 1.06; 95% CI: 1.35 to 2.23; P < 0.001).4 Length of hospital stay was reported in five studies and was 12 (17) vs. 10.5 (10.6) days respectively for milrinone and dobutamine groups (MD = 3.12; 95% CI: 0.43 to 5.80; P = 0.02). A full overview of adverse events is presented in Supporting Information, Table S2. The use of milrinone compared with dobutamine was associated with more frequent 30 day readmission (9.5% vs. 5.0%; RR = 1.91; 95% CI: 1.31 to 2.78; P < 0.001). Conversely, in the case of hypertension, the reverse trend was observed (13.3% vs. 40.0%; RR = 0.33; 95% CI: 0.16 to 0.68; P = 0.003). In conclusion, in our analysis involving 19 045 patients, the survival to hospital discharge was comparable in HF patients receiving milrinone or dobutamine. The 180 day survival outcomes showed a trend towards better results with milrinone, compared with dobutamine, but they also did not reach statistical significance. In contrast, a pooled analysis of 1 year and 2 year survival showed a clear advantage of milrinone over dobutamine, indicating better long-term outcomes in HF patients treated with milrinone. Interestingly, patients on milrinone had less episodes of hypertension, but a higher incidence of 30 day hospital readmissions. Our analysis indicated the need to conduct further randomized clinical trials to clearly answer the question about the advantages of milrinone over dobutamine in long-term survival in HF patients. Table S1. Main characteristics of the studies comparing Milrinone and Dobutamine in heart failure patients. Table S2. Characteristics of the adverse events in Milrinone and Dobutamine groups. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.