Abstract Body (Do not enter title and authors here): Background: Iron deficiency is a common comorbidity in patients with pulmonary hypertension (PH), affecting approximately 43–60% of this population. Iron plays a crucial role in oxygen transport and cellular energy metabolism, and its deficiency has been associated with impaired exercise tolerance and worse clinical outcomes. While intravenous iron supplementation, has shown promise in improving functional parameters in heart failure, its role in PH remains less well defined. A systematic synthesis of the evidence is warranted to better understand the potential therapeutic value of iron supplementation in this high-risk population.
Hypothesis: Our hypothesis proposes that iron supplementation may significantly improve functional outcomes in PH patients with documented iron deficiency.
Methods: We conducted a systematic review and meta-analysis to evaluate the effect of iron supplementation on the functional capacity in adults with PH. We used PubMed, MEDLINE and EMBASE for our systematic search of relevant studies published between 2014-2024. The studies reported a change in functional capacity with a 6-minute walk test (6MWT) distance. To assess study quality, we used the Newcastle- Ottawa Scale for observational studies and Jadad score for randomized controlled trials (RCTs). Using random-effects models, we calculated the mean differences with a 95% confidence interval.
Results: From the collected studies, nine studies met the inclusion criteria (Figure 1). The pooled effect showed a significant improvement in 6MWT distance following iron supplementation (28.64 meters; 95% CI: 16.64 to 40.64; p < 0.01) with a substantial heterogeneity (78.5%) (Figure 2) . Of the studies considered, high-quality RCTs displayed smaller, non-significant changes (10.65 meters; 95% CI: -10.81 to 32.11) and non-randomized studies showed larger effects on functional capacity (31.68 meters; 95% CI: 21.90 to 41.45) (Figure 3). Improvements were more evident in patients with anemia at baseline.
Conclusions: Iron supplementation may improve functional capacity in patients with pulmonary hypertension, particularly those with anemia. However, heterogeneity, potential bias, and differences between randomized and non-randomized studies limit the strength of current evidence. Well-designed, adequately powered trials are needed to clarify the clinical benefits and underlying mechanisms. Until then, iron therapy should be considered on a case-by-case basis.