Abstract Body (Do not enter title and authors here): Background:
Randomized trials, including AFFIRM-AHF, show that intravenous (IV) iron improves functional status and reduces hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency. However, real-world evidence remains limited. We aimed to assess these outcomes in a large, multicenter electronic health record network.

Methods:
We conducted a retrospective, propensity score-matched cohort study using the TriNetX Global Collaborative Network. Adults with HFrEF and iron deficiency or anemia (ferritin ≤100 ng/mL or hemoglobin ≤11 g/dL) were included. Patients with prior malignancy, ESRD, erythropoietin exposure, or blood transfusion were excluded. IV iron exposure included iron sucrose, ferric carboxymaltose, ferric gluconate, ferumoxytol, iron dextran, and ferric derisomaltose. Matching was 1:1 on demographics, comorbidities, and therapies, yielding two balanced cohorts (n=62,318 each). Outcomes were assessed over two years.

Results:
IV iron therapy was associated with a modestly increased risk of supraventricular tachycardia (HR 1.15, 95% CI 1.08–1.22, p<0.001) and ventricular tachycardia (HR 1.11, 95% CI 1.05–1.17, p<0.001), but not atrial fibrillation/flutter (HR 0.98, 95% CI 0.93–1.03, p=0.985). No significant differences were observed in blood transfusion, PCI, or CABG rates. The IV iron group had significantly lower rates of elevated high-sensitivity C-reactive protein (hs-CRP ≥3 mg/L; HR 0.82, 95% CI 0.74–0.91, p<0.001), with no difference in NT-proBNP elevations. Cardiac outcomes—including cardiac arrest, acute heart failure, myocardial infarction, cardiomyopathy, and new-onset ejection fraction <20%—did not differ significantly. IV iron therapy was associated with reduced all-cause hospitalization (HR 0.74, 95% CI 0.71–0.78, p<0.001), while emergency and outpatient visit rates were similar. All-cause mortality was not significantly different (HR 1.02, 95% CI 1.00–1.04, p=0.120).

Conclusion:
In this large, real-world cohort of HFrEF patients with iron deficiency, IV iron therapy reduced hospitalizations and inflammation (hs-CRP), with no effect on mortality or most cardiac outcomes. A modest increase in SVT and VT was observed. These findings support guideline recommendations for IV iron in HFrEF and highlight the need for arrhythmia monitoring.