Intravenous Iron Reduces CV Death, Hospitalizations in Iron-Deficient Heart Failure

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A meta-analysis of 14 randomized trials suggests a beneficial effect of intravenous iron on cardiovascular mortality and heart failure readmissions.

A new meta-analysis and metaregression explored the potential beneficial treatment effect of intravenous (IV) iron treatment among patients with iron-deficient heart failure (HF).1

Results from the meta-analysis of 14 randomized controlled trials (RCT) investigating IV iron compounds revealed a reduction in both cardiovascular (CV) mortality and HF-related events with IV iron supplementation. Baseline transferrin saturation (TSAT) levels <20% were suggested to play a notable role in the overall benefit of intravenous iron treatment on HF-related events.

“This meta-analysis provides important novel information about the cumulative benefit of IV iron on hard clinical endpoints in patients with HF, allowing practicing physicians and other entities (drug approval agencies, guideline committees, and governments) to get an appropriate treatment effect estimation of the benefit of IV iron based on the totality of all data generated in HF,” wrote the investigative team, led by Pieter Martens, MD, PhD, MSc, of the department of cardiology at Ziekenhuis Oost Limburg.

Iron deficiency is common among patients with HF, affecting around 40% to 50% of patients with chronic stable HF and up to 80% of patients with acute HF.2 Evidence from RCTs have reported a causal effect between iron deficiency and worse functional status and clinical outcomes. However, the overall benefit of IV iron on clinical outcomes, including CV mortality or HF hospitalizations, in those with HF has not been established.1

The current meta-analysis examined the overall effect of IV iron on CV death and HF admissions, as well as the impact of TSAT on the benefit of IV iron usage. Investigators noted concern has been raised with the current definition of iron deficiency, as patients with baseline TSAT >20% often exhibit a more benign disease trajectory and a potentially limited response to IV iron.

Martens and colleagues performed a systematic review of all published randomized controlled trials assessing the effect of IV iron versus placebo in patients with iron deficiency and HF between January 2000 and August 2023. No restrictions were made regarding the type of IV iron formulation, the definition used to define iron deficiency, or the type of HF.

For the analysis, the overall treatment effect of IV iron was estimated using a fixed-effects model for CV death, CV death, HF admission, first HF admission, and total HF admissions. Mixed-effects metaregression was utilized to assess the effect of baseline TSAT on the treatment effect of IV iron across trials.

The study team identified 14 randomized controlled trials in the systematic review and included them in the meta-analysis. Across the trials, the meta-analysis included aggregate-level data on 6,624 patients with HF, of which 3,407 were randomized to IV iron and 3,217 to placebo. Overall, the meta-analysis included data on a total of 979 CV deaths, 1,903 combined CV deaths with HF admission events, 937 first HF admissions, and 1,902 total HF admissions.

Upon analysis, treatment with IV iron showed a borderline significant effect on CV mortality (odds ratio [OR], 0.867 [95% CI, 0.755 - 0.955]; P = .0427) without any heterogeneity. Meanwhile, treatment with IV iron showed a significant effect on the combined endpoint of CV death and HF admission (OR, 0.838 [95% CI, 0.751 - 0.936]; P = .0015), first HF admission (OR, 0.855 [95% CI, 0.744 - 0.983]; P = .0281), and total HF admissions (rate ratio [RR], 0.739 [95% CI, 0.661 - 0.827; P <.0001).

Martens and colleagues observed significant heterogeneity among trial results for first and total HF admissions. Mixed-effect metaregression revealed some of the heterogeneity in the overall treatment effect linked to baseline TSAT. The study team found trials with baseline TSAT ≤20% had larger treatment effects suggesting a reduction in HF admissions, while a higher TSAT did not.

In a recent interview with HCPLive, Muthiah Vaduganathan, MD, MPH, the co-director of Cardiometabolic Implementation Science at Brigham and Women’s Hospital, shared his perspective on newly available IV iron guidelines and the renewed interest in iron supplementation for HF among cardiologists.2

“We've had early evidence that was fairly compelling around functional capacity, and perhaps even quality of life, but never really would single studies have we seen any shifts in terms of hospitalizations for HF or mortality,” Vaduganathan told HCPLive.2 “That is until recently and I think that's why we've seen this resurgence in focus because clinicians are seeing that a real potential that this therapeutic option can actually improve patient wellbeing.”


  1. Martens P, Augusto SN Jr, Mullens W, Tang WHW. Meta-Analysis and Metaregression of the Treatment Effect of Intravenous Iron in Iron-Deficient Heart Failure. JACC Heart Fail. Published online December 1, 2023. doi:10.1016/j.jchf.2023.11.006
  2. Martens P, Nijst P, Verbrugge FH, Smeets K, Dupont M, Mullens W. Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection frac- tion. Acta Cardiol. 2018;73(2):115–123.
  3. Campbell P. Interpreting new IV iron guidelines, with Muthiah Vaduganathan, MD, MPH. HCP Live. October 9, 2023. Accessed January 9, 2024.