Iron May Reduce Heart Failure Risk in CKD, but More Trials Needed

Brendon L. Neuen, MBBS, MSc, PhD

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Iron therapy could lower the risk of hospitalization for heart failure (HF) or cardiovascular death among patients with chronic kidney disease (CKD), according to a systematic review and meta-analysis of 45 randomized clinical trials (RCTs).¹

However, while current data suggest the potential cardiovascular benefits of iron, evidence remains insufficient, particularly in non-dialysis CKD, highlighting the need for further clinical trials. Comparisons of intravenous versus oral iron, newer versus older formulations, and different oral iron doses also lacked sufficient data to determine their effects on cardiovascular outcomes.

“An important evidence gap remains – most CKD trials have focused on anemia correction rather than cardiovascular or kidney outcomes,” said Brendon L. Neuen, MBBS, MSc, PhD, director of the Kidney Trials Unit at Royal North Shore Hospital.² “Nearly all cardiovascular event data come from trials in patients with heart failure with reduced ejection fraction (HFrEF), leaving substantial uncertainty about iron’s role in heart failure with preserved ejection fraction (HFpEF). Furthermore, data on the effects of iron therapy on cardiovascular outcomes in non-dialysis CKD—particularly in patients without anemia—are limited.”

Nearly one-third of patients with CKD experience relative or absolute iron deficiency, which can reduce quality of life and lead to cardiovascular events or death, independent of anemia. Iron is frequently administered to manage anemia in CKD and reduce the need for erythropoiesis-stimulating agents (ESAs). Meanwhile, other studies have shown intravenous iron administration reduces hospitalization and improves functional status in iron-deficient patients with HFrEF.³

Clinical practice guidelines from organizations including the European Society of Cardiology (ESC) recommend intravenous iron to benefit clinical outcomes in HFrEF, independent of anemia.⁴ Kidney-focused guidelines, including those from the Kidney Disease Improving Global Outcomes (KDIGO), recommend screening for iron deficiency only in the case of anemia development, and iron only as a tool to manage anemia.⁵

Neuen and colleagues pointed to the inconsistencies in specialty care recommendations as noteworthy, given the frequent coexistence of HF and CKD, with the presence of one inherently complicating the management of the other. Iron could reduce the risk of HF and/or other cardiovascular events in patients with CKD, based on that bi-directional relationship.

Their systematic review and meta-analysis examined the Medline, Embase, and Cochrane Register databases from inception to February 2024, identifying 45 trials that matched inclusion criteria. All RCTs evaluated the effect of intravenous or oral iron to usual care or placebo on cardiovascular, kidney, and safety outcomes in eligible adults with CKD.

For the analysis, the team measured overall results and stratified by dialysis-dependent and non-dialysis-dependent CKD using random effects models. They evaluated the certainty of evidence across the Grading of Recommendations Assessments, Development, and Evaluation (GRADE) approach. A composite of HF-related hospitalizations and cardiovascular death served as the primary endpoint.

Upon analysis, iron reduced the risk of the primary composite endpoint, compared with usual care or placebo, by 16% (1658 events; risk ratio [RR], 0.84; 95% CI, 0.75–0.94) and remained consistent across dialysis- and non-dialysis-dependent CKD (P for heterogeneity = .70). These reductions owed to the components of hospitalization for HF (RR, 0.77; 95% CI, 0.61–0.96) and cardiovascular death (RR, 0.81; 95% CI, 0.65–1.02).

Neuen and colleagues identified no differences between intravenous versus oral iron, and newer versus older iron formulations, noting these data were limited in the available trials. Further safety analysis showed lower serious adverse events for iron than usual care or placebo (RR, 0.90; 95% CI, 0.82–0.98; P for heterogeneity = .09).

Based on these data, Neuen and colleagues suggested a reconsideration of current recommendations for the use of iron in CKD might allow more patients to benefit from therapy with a favorable benefit-risk profile.

“Ultimately, this divergence reflects a gap in the evidence - and it's incumbent upon us to address this through conducting a well-powered clinical outcome trial assessing both clinical and patient-reported outcomes in non-dialysis CKD to establish whether IV iron can indeed reduce heart failure and cardiovascular events in non-dialysis CKD - independent of anemia,” Neuen added.

References

1. Chan B, Varghese A, Badve SV, Neuen BL. Systematic Review of the Effects of Iron on Cardiovascular, Kidney and Safety Outcomes in Patients With Chronic Kidney Disease. Kidney International Reports. January 29, 2025. Accessed February 12, 2025. https://www.kireports.org/article/S2468-0249(25)00054-3/fulltext.

2. Neuen BL. Iron Therapy in Non-Dialysis CKD: A Call for Large-Scale Clinical Outcome Trials. LinkedIn. February 5, 2025. Accessed February 12, 2025. https://www.linkedin.com/posts/brendonneuen_iron-therapy-in-non-dialysis-ckd-a-call-activity-7290534140968407041-7zS2?utm_source=share&utm_medium=member_desktop

3. Wong MMY, Tu C, Li Y, et al. Anemia and iron deficiency among chronic kidney disease Stages 3-5ND patients in the Chronic Kidney Disease Outcomes and Practice Patterns Study: often unmeasured, variably treated. Clin Kidney J. 2019;13(4):613-624. Published 2019 Aug 3. doi:10.1093/ckj/sfz091

4. Authors/Task Force Members:, McDonagh TA, Metra M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2024;26(1):5-17. doi:10.1002/ejhf.3024

5. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease Kidney Int Suppl. 2012; 2:279-335