Anemia Therapy in Patients With Infective Endocarditis

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.

In another large (n=2141), randomized study involving hemodialysis patients (PIVOTAL - Intravenous Iron in Patients Undergoing Maintenance Hemodialysis), where patients were randomized to receive either high- or low-dose IV iron sucrose, no difference in infection rates was observed between the two groups. Although infection was not a primary outcome in any of these studies and thus the studies were not pow-ered to definitively detect differences in infection rates between the intervention and control groups, the findings from these trials are of relevance when evaluating the hypothetically increased risk of infection due to IV iron treatment. In 2015, a large retrospective cohort study analyzed 22,820 American hemodialysis patients who had recently received IV iron therapy and were hospitalized for bacterial infection. The study evaluated whether continued administration of IV iron from admission to discharge was associated with adverse outcomes, including 30-day mortality, all-cause mortality within the year, length of hospital stay, and risk of readmission or death within 30 days post-discharge. Administration of IV iron during hos-pitalization was not associated with higher mortality, longer hospital stays or increased short-term risk of infection-related readmission. These findings challenge existing recommendations to routinely with-hold IV iron in this setting and highlight the need for randomized controlled trials to establish definitive clin-ical guidance.

In patients with heart failure, IV iron therapy is already included in treatment recommendations as an adjunctive treatment. Randomized trials such as AFFIRM-AHF (n=1132) found significant benefits, including reduced mortality rates, improved functional capacity, and enhanced quality of life related to IV iron therapy. The IRONMAN trial (n=1137) found that correction of iron deficiency with ferric deriso-maltose did not increase the risk of infection related hospitalization or death. The findings led to the incorporation of routine screening and treatment of anemia into current European heart failure guidelines.

In general, European guidelines for patients with heart failure specifically endorse an IV iron approach when treating anemia of inflammation, as iron absorption from oral iron preparations is generally poor in patients with ongoing inflammation. This is due to the inflammation induced upregulation of the liver-derived hormone hepcidin, which downregulates the iron-transporting protein ferroportin in cellular membranes. This leads to significantly decreased iron uptake from the gut and resulting in slow and often inefficient iron repletion.

Furthermore, gastrointestinal side effects occur in up to 60% of patients, which may limit the tolerability of oral iron therapy. The European recommendations are supported by the IRONOUT-HF trial (n=225), where oral iron supplementation did not improve functional capacity. In contrast, when comparing with IV iron therapy, IV administration can quickly reach and maintain hemoglobin levels and reduce the need for further anemia management.

ANEMIA IN PATIENTS WITH IE Patients with IE are at high risk of developing anemia, as prolonged infection periods, long-term antibiotic therapy, malnutrition, frequent blood sampling, cardiac surgery, and impaired kidney function all contribute to lower hemoglobin levels. Additionally, infection elevates hepcidin levels and thereby inflammato-ry anemia. The current literature offers limited insight into anemia in patients with IE. In a POET substudy, the investigators found anemia in 85% of patients with medically managed IE after stabilization of infection, of which 29% was moderate to severe anemia. Moderate to severe anemia was independently associated with a 5-fold increase in mortality at 6-months follow-up.

In the study ANIE (Anemia in patients with Infective Endocarditis) (unpublished), a prospective observational study of anemia in patients with IE, the investigators sought to understand the natural course of anemia in patients with IE (n=100). The aim of the study was to gain insight and to support the design of a novel approach to treatment of inflammatory anemia in this population with minimal risk to patients, while still improving outcome of the disease.

Preliminary data from the ANIE study reaffirm that at least 90% of patients with IE are affected with some degree of anemia during the course of disease. The severity of anemia appears to worsen progressively with each week of antibiotic therapy, typically peaking during the final stages of the antibiotic treatment. Notably, the data also suggest that anemia often begins to develop gradually up to 30 days before the time of diagnosis. Following the termination of antibiotic treatment, hemoglobin levels are only gradually recovering in the following months, with normalization at 3 months post-treatment.

The evidence of the use of IV iron therapy in patients with bacterial infections remains limited, and there is a critical need to evaluate the safety and efficacy of anemia treatment in patients IE. A safety-oriented approach using IV iron therapy in combination with erythropoietin (EPO) and other means to increase the hemoglobin levels may improve both short- and long-term outcomes, including functional capacity.

To minimize the risk of exacerbating infection through iron supplementation, the timing of intervention is critical. The limited literature linking adjunctive anemia therapy, such as intravenous iron, with infection risk generally reports that most infections occur within the first 30 days after iron administration. In the POET trial, specific stabilization criteria were established to define when a patient's infection was considered sufficiently controlled to allow a safe

• Difference in physical capacity three months after randomization [Time frame: Three months]
• Hemoglobin changes over time from baseline [Time frame: Four weeks and three months after randomization]
• Percentage of subjects with no anemia / normalized hemoglobin [Time frame: Four weeks and three months after randomization]
• Profiling of advanced iron metabolic markers [Time frame: Three months after randomization]
• Cardiac functional status and hemodynamic parameters [Time frame: From baseline to six and 12 weeks after randomizatoin]
• Cardiac functional status and hemodynamic parameters [Time frame: From baseline to six and 12 weeks after randomizatoin]
• Cardiac functional status and hemodynamic parameters [Time frame: From baseline to six and 12 weeks after randomizatoin]
• Patient-reported changes in Quality of Life (QOL) [Time frame: Three months after randomization]
• Patient-reported changes in Quality of Life (QOL) [Time frame: Three months after randomization]
• Recurrent infections [Time frame: Three months after randomization]
• Stroke [Time frame: Three months after randomization]
• Death [Time frame: Three months after randomization]