Anemia Therapy in Patients With Infective Endocarditis (POET-IRON)

BACKGROUND Infective endocarditis (IE) is a life-threatening condition with an almost 100% fatality rate if untreated and a one-year mortality of approximately 30% in treated patients. There are 600-700 annual cases in Denmark and there is a rising global incidence. Due to aging populations and increased use of invasive devices, IE remains a critical healthcare challenge. Beyond its direct complications such as heart failure, need for acute cardiac surgery, serious septic embolisms, and persistent systemic inflammation, IE is strongly associated with varying degrees of anemia, which is associated with a significant worsening of long-term outcomes. The Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis study (POET) found that 85% of stable patients with IE had anemia, with 29% experiencing moderate to severe anemia, which was associated with a 5-fold higher mortality rate at 6-months follow-up

. Anemia of inflammation, often accompanied by iron deficiency anemia, results from disrupted iron distri-bution rather than depleted iron stores. Traditionally, infection related anemia has been attributed to a part of the innate immune response in relation to infection/inflammation. In this process, hepcidin, a hormone upregulated by inflammatory cytokines like interleukin-6 (IL-6), plays a pivotal role as it causes intracellular iron sequestration, primarily in macrophages, markedly reducing circulating levels of iron in the blood, and inhibits iron absorption from the gut. This protective mechanism is thought to be an evolutionary defense mechanism against bacteremia, as it restricts bacterial access to iron and thereby limits bacterial growth, with animal studies showing a higher risk of uncontrolled infection when intravenous (IV) iron was administered at time of infection. On this basis, iron treatment has been considered contraindicated in bacterial infections. Acute infection also triggers systemic inflammation, which increases metabolic turnover, redistributes trace elements, and accelerates urinary and gastrointestinal losses, which often results in in functional or absolute micronutrient deficits. The oft-cited "two-to threefold increase" in micronutrient requirements originates from critical care guidelines and is well-documented in severe infection, but remains less clearly defined in milder cases. Treatment of these patients support normalization, rather than high-dose supplementation, of vitamin C, vitamin D, zinc, and selenium. These vitamins and minerals support neutrophil and epithelial integrity, enhances antimicrobial peptide production, and maintains oxidative balance. For example, zinc supplementation has been shown to modestly reduce the incidence and shorten the duration of acute respiratory infections in adults, particularly among those who are deficient. Selenium is essential for selenoproteins that regulate redox balance and immune cell activity; supplementation in deficient patients may improve inflammatory control, though high-dose regimens in critical illness have shown inconsistent benefits.

In summary, targeted repletion of specific micronutrients such as vitamin C, vitamin D, zinc, and selenium can help restore immune competence and redox balance in deficient patients, though high-dose strategies in acute illness often yield inconsistent results. By contrast, the role of iron supplementation in the setting of infection related anemia remains more controversial. Yet, IV iron therapy (e.g., ferric derisomaltose) has been shown to reduce readmissions and improve physical capacity and quality of life in other cardiac patients and patients with chronic kidney failure, without increasing the risk of infection. In patients with pure inflammatory anemia i.e. rheumatic disease, IV iron therapy is a well-established treatment. Nevertheless, clinical studies investigating iron supplementation in patients with infective inflammation and anemia have shown mixed results with regard to infection risk.

A systematic review and meta-analysis of 154 randomized clinical trials (RCTs) found that IV iron therapy was associated with a modestly increased risk of bacterial infections (RR 1.16; 95% CI, 1.03-1.29). Notably, none of the RCTs reported data on positive microbiology cultures and only one study reported information on antibiotic treatment of infections. No association was found between IV iron therapy and mortality, or length of hospital stay. Thus, the authors highlighted considerable heterogeneity in the definitions and reporting of infections and concluded that there remains a critical need for well-designed studies using standardized infection endpoints to determine the clinical relevance of this association. In studies of iron supplementation in children with a high prevalence of anemia, an increased incidence of diarrhea and overgrowth of particularly gram-negative bacteria in the gastrointestinal tract was observed. However, no increase in hospital-requiring diarrhea was found and in a systematic review by the Cochrane Institute, which examined RCTs in this area, found no increased risk of death with oral iron supplementation.

Anemia in hemodialysis patients is a well-known issue, and these patients are treated with both erythro-poiesis-stimulating agents (ESA) and iron supplementation. As hemodialysis patients have a high risk of bacterial infections due to the nature of the dialysis procedure itself, the potentially increased risk of infec-tion associated with IV iron supplementation in these patients has been studied in several trials. Observational studies have found a weak association between iron supplementation and bacterial infec-tions. However, in the DRIVE study (Dialysis Patients' Response to IV Iron with Elevated Ferritin) (n=134), a randomized trial of IV iron gluconate supplementation in hemodialysis patients, no difference in infection incidence was found between the iron-treated and placebo groups during the 6-week study period. In an additional 6-week follow-up (DRIVE-II), a higher frequency of serious adverse events (SAEs) was observed in the control group, including 10 cases of infection compared to 4 cases in the IV iron group.