Presence of Anemia Negatively Impacts Long-Term Prognosis in HFmrEF

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Anemia and iron deficiency are prevalent in heart failure with mildly reduced ejection fraction and may worsen mortality and rehospitalization outcomes.

A retrospective study evaluated the prognostic impact of anemia and iron deficiency in patients hospitalized with heart failure with mildly reduced ejection fraction (HFmrEF) in a single-center registry over 30 months.

More than half of patients with HFmrEF in the analysis were affected by anemia and its presence was independently associated with an increased risk of all-cause mortality and HF-related rehospitalization, which remained after multivariable adjustment.

“The present study further underlines the recent upgrade of the assessment and treatment of iron deficiency in patients with HFmrEF,” wrote the investigative team, led by Michael Behnes, First Department of Medicine, University Medical Center Mannheim.

Given ongoing, global changes in demographics, risk stratification for HF remains complex, with increases reported in the number of patients with HF and related comorbidities.2 Anemia is particularly prevalent in HF, with approximately every other patient hospitalized for HF exhibiting the hematologic condition.3

Anemia has been linked with poorer long-term outcomes in patients with HFrEFand heart failure with preserved ejection fraction. On the other hand, conclusions on the prognostic impact of anemia in HFmrEF are limited in current literature.1 The potential value of intravenous iron supplementation in HF has been reported in numerous trials, but there are limited studies in HFmrEF.

For this study, Behnes and colleagues sought to clarify the association of anemia and iron deficiency in a retrospective registry of consecutive patients hospitalized with HFmrEF at their academic institution from January 2016 to December 2022.

Diagnosis of HFmrEF was determined based on 2021 European Society of Cardiology guidelines for acute and chronic HF.4 The definition of anemia was based on World Health Organization (WHO) guidance, with hemoglobin levels <13 g/dL in men and <12 g/dL in women. Iron deficiency was measured as a ferritin level < 100 μg/L or 100–299 μg/L if the transferrin saturation was <20%.

The rates of all-cause mortality during a median follow-up of 30 months comprised the primary end point, with secondary end points including all HF-related rehospitalizations during the follow-up period.1 An HF-related hospitalization was deemed to be rehospitalization due to worsening HF requiring intravenous diuretic therapy.

After identifying 2228 patients hospitalized with HFmrEF during the study period, exclusions left the final cohort of 2154 patients with MFmrEF. With a median hemoglobin level of 12.2 g/dL, the prevalence of anemia was 51.7%. Individuals with anemia were older (median, 78 vs. 72 years; P = .001), had higher proportions of hospitalizations for decompensated HF < 12 months (13.7% vs. 7.5%; p =.001), and exhibited greater rates of chronic kidney disease (44.5% vs. 17.2%; P = .002), than those without the condition.

Upon analysis, during the median follow-up of 30 months, the presence of anemia was associated with a higher risk of all-cause mortality (44% vs. 18%; hazard ratio [HR], 3.021; 95% CI, 2.552–3.576; P = .001), meeting the primary endpoint. Anemia was also associated with the risk of rehospitalization for worsening HF (18% vs. 8%; HR, 2.351; 95% CI, 1.819 - 3.040; P = .001) at 30 months, meeting the secondary endpoint.

After multivariable adjustment, Behnes and colleagues indicated the presence of anemia remained independently associated with an increased risk of both the primary and secondary end points at 30 months (all P = .001).

Among 1113 patients identified with anemia, iron status was measured in only 296 patients (27%). The corresponding prevalence of iron deficiency was 50%. More patients with iron deficiency experienced prior congestive HF (51.7% vs. 36.2%; P = .007) and were admitted with decompensated HF <12 months (23.8% vs. 12.1%; P = .008).

At the 30-month mark, the risk of all-cause mortality did not differ in patients with or without iron deficiency (44% vs. 48%; 95% CI, 0.831–1.162; P .279). However, individuals with iron deficiency experienced an increased risk of HF-related rehospitalization at 30 months (25% vs. 15%; HR, 1.746; 95% CI, 1.024 - 2.976; P = .038).

As iron status was measured in approximately one-quarter of patients with HF and concomitant anemia only, Behnes and colleagues suggested a gap persists between guideline recommendations and routine clinical care.

“Therefore, the present study warrants the need for a better implementation of the measurement of iron status in patients with HFmrEF,” they wrote.


  1. Schupp T, Weidner K, Reinhardt M, et al. Effect of anemia and iron deficiency in heart failure with mildly reduced ejection fraction. Eur J Clin Invest. Published online April 10, 2024. doi:10.1111/eci.14205
  2. Khan MS, Samman Tahhan A, Vaduganathan M, et al. Trends in prevalence of comorbidities in heart failure clinical trials. Eur J Heart Fail. 2020;22(6):1032-1042. doi:10.1002/ejhf.1818
  3. Pintér A, Behon A, Veres B, et al. The Prognostic Value of Anemia in Patients with Preserved, Mildly Reduced and Recovered Ejection Fraction. Diagnostics (Basel). 2022;12(2):517. Published 2022 Feb 17. doi:10.3390/diagnostics12020517
  4. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. 2021 Oct 14;:]. Eur Heart J. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368