This meta-analysis offers a compelling signal for melatonin’s role in palliative care for Heart Failure (HF). The statistically significant and moderate-certainty finding that melatonin improves Quality of Life (QoL) is highly relevant for patients struggling with chronic symptoms. The observed reduction in fatigue and improvement in sleep quality strongly supports this benefit.

However, the enthusiasm must be tempered by the data on hard clinical endpoints. There was no improvement in Ejection Fraction (EF) and the benefit for NYHA Functional Class rests on a highly borderline pooled result (OR 4.84, p = 0.05) derived from only two non-significant studies – I never trust meta-analysis findings that are based on pooling non-significant trials. Also the certainty of evidence for both EF and NYHA FC is categorized as low due to concerns over attrition and reporting biases.

Still, with all of the clear benefits of melatonin and low risk, it’s worthwhile to include for heart failure.

💊 Clinical Bottom Line

This meta-analysis suggests that melatonin supplementation significantly improves the quality of life (QoL) in heart failure (HF) patients. The certainty of evidence for this QoL improvement is rated as moderate.

However, the evidence does not support a positive effect of melatonin on Ejection Fraction (EF) or NYHA Functional Class due to non-significant p-values (p ≥0.05) in the final analysis, and the certainty of this evidence is rated as low.

Results Summary

The meta-analysis focused on three primary outcomes: Quality of Life (QoL), Ejection Fraction (EF), and NYHA Functional Class (NYHA FC).

• Quality of Life (QoL): A significant difference was observed, favoring melatonin, with a pooled mean difference of -5.95 (95% CI: -9.54, -2.35, p = 0.001). A lower score on the MLHFQ (The Minnesota Living with Heart Failure questionnaire) indicates improvement.

  • Statistical Definition: The 95% Confidence Interval (CI) does not cross zero, and the p-value is less than 0.05, indicating a significant result.

• Ejection Fraction (EF): No statistically significant difference was found, with a pooled mean difference of 2.39 (95% CI: -1.82, 6.59, p = 0.27).

  • Statistical Definition: A Mean Difference CI that crosses zero (from -1.82 to 6.59) indicates a non-significant result.

• NYHA Functional Class (NYHA FC): A statistically approximate validity (borderline significance) was found, favoring melatonin, with a pooled odds ratio of 4.84 (95% CI: 1.00, 23.44, p = 0.05).

  • Statistical Definition: The CI is right at the threshold of significance (lower bound is 1.00).

Other Reported Effects of Melatonin

Melatonin therapy was also observed to:

• Reduce NT-Pro BNP (N-Terminal pro-B-type Natriuretic Peptide) and fatigue.

• Significantly increase sleep quality, appetite, and FMD (Flow-Mediated Dilation).

Assertive Critical Appraisal

Certainty of Evidence (GRADE Framework)

• Quality of Life (QoL): Moderate Certainty. The true effect is likely close, but could be substantially different.

• Ejection Fraction (EF): Low Certainty. The true effect may be substantially different from the estimate.

• NYHA Functional Class: Low Certainty. Due in part to studies reporting data incompletely or incorrectly, and more than 12.5% of participants missing to the outcome.

Heterogeneity

• QoL & NYHA FC: No heterogeneity was found (I² = 0%).

• EF: No significant heterogeneity was found, but I² = 69% indicates substantial heterogeneity, suggesting 69% of the variation is due to real differences rather than chance. The pooled average should be interpreted with caution.

Publication Bias

The review did not explicitly state whether an assessment for publication bias (e.g., funnel plot or Egger’s test) was performed, which is a potential omission that could lead to an overestimation of the treatment effects. However, the authors did note that one relevant study was excluded because the full-text, published in a domestic (Russian) journal, was not available.

Risk of Bias in Included Studies

• Low Risk: Selection (Random sequence generation, Allocation concealment) and performance bias (Blinding of participants and personnel) were largely deemed low risk.

• Some Concerns/High Risk: 50% of detection, reporting, and attrition biases were classified as unclear, high, and high risk, respectively. This means blinding of outcome assessment (detection bias), selective reporting (reporting bias), and incomplete outcome data (attrition bias) were major areas of concern for the primary studies, which directly downgrades the certainty of the evidence.

Special Consideration for Pooled Results (NYHA FC)

The claim for NYHA improvement rests on a borderline pooled result (OR 4.84, 95% CI: 1.00, 23.44) derived from only two studies that, by themselves, did not show a significant effect on NYHA.

• One of the included studies (Hoseini 2022) had a point estimate of 4.42 with a wide CI of [0.47, 41.31], which is non-significant on its own.

• The other study (Garakyaraghi 2012) had a point estimate of 5.29 with a wide CI of [0.57, 49.13], which is also non-significant on its own.

The overall low certainty of evidence suggests this finding should be viewed with skepticism until supported by larger trials.

Research Objective & Design

• Objective: To investigate the positive effect of melatonin on heart failure development and evaluate its efficacy on psychological (QoL), serum (NT-Pro BNP), and cardiovascular (EF, NYHA, Stroke Volume) parameters in Heart Failure (HF) patients.

• Study Design: A systematic review and meta-analysis of Randomized Controlled Trials (RCTs).

• Selection Process: Out of 8013 initially identified articles, 4 articles were selected for systematic review, and 3 articles were used for data analysis.

• Geographic Setting: All remaining studies were performed in I.R IRAN.

PICO Framework

• P (Population): Heart Failure (HF) patients classified as NYHA II and III.

• I (Intervention): Oral melatonin tablets (3, 10, or 20 mg/day).

• C (Comparison): Placebo tablets (cellulose pills or cornstarch tablets).

• O (Outcome): Psychological parameters (QoL), serum markers (NT-Pro BNP), and cardiovascular parameters (Stroke volume and NYHA).

Reporting Quality Assessment (PRISMA)

The review included a Flow Chart of study selection (Figure 1), which clearly shows the selection process from the 8013 identified articles down to the four selected for synthesis, fulfilling a key PRISMA principle. The reporting quality is high in terms of transparency and reproducibility of the selection process.

Bibliographic Data

• Title: Melatonin as a Novel Drug to Improve Cardiac Function and Quality of Life in Heart Failure Patients: A Systematic Review and Meta-Analysis

• Authors: Abolfazl Sam Daliri, Nima Goudarzi, Arshia Harati, Kourosh Kabir

• Journal: Clinical Cardiology

• Year: 2025

• DOI: https://doi.org/10.1002/clc.70107

Mandatory Disclaimer: This AI-generated analysis is for informational and research purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified health provider with any questions you may have regarding a medical condition.