The Optimal Dosage and Duration of ω-3 PUFA Supplementation in Heart Failure Management: Evidence from a Network Meta-Analysis

Abstract

Heart failure is a progressive condition associated with a high mortality rate. Despite advancements in treatment, many patients continue to experience less-than-ideal outcomes. ω-3 (n-3) polyunsaturated fatty acids (PUFAs) have been studied as a potential supplementary therapy for heart failure, but the optimal dosage and duration of supplementation remain unclear. This network meta-analysis (NMA) aimed to assess the efficacy of various n-3 PUFA supplementation regimens in patients with heart failure, focusing on dose-dependent and time-dependent effects. We conducted a systematic search for randomized controlled trials (RCTs) on n-3 PUFA supplementation in heart failure till 13 September, 2024. The primary outcome was the change in heart function, specifically left ventricular ejection fraction. Secondary outcomes included changes in peak oxygen consumption (VO₂), blood B-type natriuretic peptide concentrations, and quality of life. The safety analysis focused on dropout rates (i.e., patients leaving the study for any reason before completion) and all-cause mortality. A frequentist-based NMA was performed. This NMA, which included 14 RCTs with 9075 participants (mean age, 66.0 y; 23.3% female), found that high-dose n-3 PUFA supplementation (2000-4000 mg/d) over a duration of ≥1 y significantly improved left ventricular ejection fraction and peak VO₂ compared with those of control groups. Lower doses and shorter treatment periods did not produce the same benefits. No significant differences were found in dropout rates or all-cause mortality between the n-3 PUFAs and control groups. Long-term, high-dose n-3 PUFA supplementation, particularly with a predominance of docosahexaenoic acid or eicosapentaenoic acid, enhances cardiac function in patients with heart failure without increasing risk of adverse events. Further well-designed RCTs with long treatment durations (i.e., >1 y) and stringent heart failure inclusion criteria are necessary to confirm these findings and reduce potential biases. This trial was registered at PROSPERO as CRD42024590476.

Keywords: DHA; EPA; LVEF; PUFA; cardiovascular disease; heart failure; network meta-analysis; ω-3 polyunsaturated fatty acid.

FIGURE 1

PRISMA2020 flowchart of current network meta-analysis.

FIGURE 2

Network structure of the primary outcome: changes of left ventricular ejection fraction (LVEF). The overall structure of the network meta-analysis. The lines between nodes represent direct comparisons from various trials, with the numbers over the lines indicating the number of trials providing these comparisons for each specific treatment. The thickness of the lines corresponds to the number of trials linked to the network. Extreme_High_Equal, extreme high dosage (≥4000 mg/d) n–3PUFA treatment with composition of EPA/DHA ratio equal to 1; Extreme_High_n3PUFA_EPA_dominant, extreme high dosage (≥4000 mg/d) n–3PUFA treatment with composition of EPA predominant; Extreme_High_pure_EPA, extreme high dosage (≥4000 mg/d) n–3PUFA treatment with composition of pure EPA; High_n3PUFA_DHA_dominant, high dosage (≥2000 mg/d but <4000 mg/d) n–3PUFA treatment with composition of DHA predominant; High_n3PUFA_EPA_dominant, high dosage (≥2000 mg/d but <4000 mg/d) n–3PUFA treatment with composition of EPA predominant; High_pure_EPA, high dosage (≥2000 mg/d but <4000 mg/d) n–3PUFA treatment with composition of pure EPA; Medium_n3PUFA_DHA_dominant, medium dosage (≥1000 mg/d but <2000 mg/d) n–3PUFA treatment with composition of DHA predominant; Medium_n3PUFA_EPA_dominant, medium dosage (≥1000 mg/d but <2000 mg/d) n–3PUFA treatment with composition of EPA predominant; NMA, network meta-analysis; OR, odds ratio.

FIGURE 3

Forest plot of primary outcome: changes of left ventricular ejection fraction (LVEF). When the effect size (expressed as SMDs) was >0, the specified treatment was associated with greater improvement in LVEF in patients with heart failure than in patients receiving controls. Further, we marked the ranking of superiority of each experimental arm. Extreme_High_Equal, extreme high dosage (≥4000 mg/d) n–3PUFA treatment with composition of EPA/DHA ratio equal to 1; Extreme_High_n3PUFA_EPA_dominant, extreme high dosage (≥4000 mg/d) n–3PUFA treatment with composition of EPA predominant; Extreme_High_pure_EPA, extreme high dosage (≥4000 mg/d) n–3PUFA treatment with composition of pure EPA; High_n3PUFA_DHA_dominant, high dosage (≥2000 mg/d but <4000 mg/d) n–3PUFA treatment with composition of DHA predominant; High_n3PUFA_EPA_dominant, high dosage (≥2000 mg/d but <4000 mg/d) n–3PUFA treatment with composition of EPA predominant; High_pure_EPA, high dosage (≥2000 mg/d but <4000 mg/d) n–3PUFA treatment with composition of pure EPA; Medium_n3PUFA_DHA_dominant, medium dosage (≥1000 mg/d but <2000 mg/d) n–3PUFA treatment with composition of DHA predominant; Medium_n3PUFA_EPA_dominant, medium dosage (≥1000 mg/d but <2000 mg/d) n–3PUFA treatment with composition of EPA predominant; NMA, network meta-analysis; OR, odds ratio.