Hello, this is BKM Boskert, Professor of Medicine from Baylor College of Medicine. Today I will be presenting Treatment of Iron Deficiency, the Clinical Trials and Evidence. Prior attempts of targeting anemia with erythropoietin-stimulating agents have proven to be unsuccessful, as shown on this slide, with results from the RED-HF trial, which demonstrated association with increased embolic and thrombotic adverse events in patients with heart failure. With recognition of iron deficiency as a major comorbidity and prognosticator in heart failure, subsequent studies focused on treatment of iron deficiency. It's very important to recognize that oral iron supplementation is ineffective in patients with heart failure. This is attributed to hepcidin, the main hormone that is responsible for control of the iron reserves in the body, and is increased in inflammation and advanced heart failure state, and is implicated for increased degradation of theroportin and decreased dietary iron absorption. In the Iron Out study, shown on this slide, carried out in patients with heart failure with reduced EF, NYHA class 2-3 heart failure with iron deficiency, a 16-week course of oral iron given at 300 mg daily dose was ineffective. There were no differences in exercise capacity measured as a change in peak VO2. And more importantly, despite a total dose of 33 grams throughout the study of oral iron, TSAT and ferritin changes were very minimal over 16 weeks, not reaching normalization. In comparison, in studies with IV iron, as shown on the right panel, with IV ferric carboxymaltose in the FAIR-HF trial, the total iron supplementation dose was 2 grams and resulted in a significant increase in ferritin level as well as TSAT levels, which normalized at 16 weeks compared to placebo. This is further supported by findings from the Iron Out study demonstrating that high hepcidin levels predicted poor responsiveness to oral iron and higher quartiles of hepcidin levels were associated with lower delta changes in TSAT and a blunted fall in the soluble transferrin receptor levels. With recognition of poor absorption and bioavailability of oral iron in heart failure patients, studies with IV iron were designed. One of the largest earlier studies was the FAIR-HF trial, which enrolled approximately 450 patients with symptomatic heart failure with reduced EF and iron deficiency anemia, which was defined as a serum ferritin level of less than 100 or transferrin saturation less than 20% in the setting of ferritin level 300. This definition will be used consistently across the future trials and is now currently used in our guidelines for definition of iron deficiency. This study examined the efficacy of IV ferric carboxymaltose randomized against placebo in a blinded fashion and followed up for six months. The study demonstrated significant improvements in global assessment, NYHA class, six-minute walk distance, and quality of life as early as four weeks, and the results were sustained and significant at six months. Furthermore, these benefits were seen regardless of anemia among patients with iron deficiency with or without anemia. These results were confirmed by a longer term trial called the CONFIRM trial, which again enrolled patients with symptomatic heart failure with reduced EF and iron deficiency defined as serum ferritin less than 100 or less than 300 combined with TSAT level less than 20%, which demonstrated significant improvement in six-minute walk distance at six months. An improvement in six-minute walk distance and symptoms were significant also at one year after randomization. These two major trials, FAIR-HF and CONFIRM heart failure demonstrated that IV iron repletion in ambulatory patients with heart failure reduced EF and iron deficiency, improved functional status, quality of life, and reduced heart failure symptoms. Interestingly, the CONFIRM-HF trial demonstrated significant reduction in heart failure hospitalizations, which was a secondary endpoint with IV carboxymaltose at one year. Subsequent meta-analyses supported the finding of reduction in heart failure hospitalizations as well as combined endpoints with cardiovascular hospitalizations and cardiovascular mortality with meta-analyses at the individual patient level data. Concordant across all trials was the findings of improvement in quality of life, functional capacity, and NYHA classification. A more recent trial, the AFIRM-AHF trial evaluated the effect of IV ferricarboxymaltose on outcomes of patients who were stabilized after an episode of acute heart failure. Inclusion criteria included iron deficiency defined as serum ferritin less than 100 or 100 to 300 range accompanied with a TSAT less than 20% and EF less than 50%. Patients were randomized to ferricarboxymaltose or placebo after stabilization of acute heart failure hospitalization and the first dose of IV iron was given pre-discharge. This study demonstrated a trend for reduction in the total endpoint of cardiovascular death and heart failure hospitalization which did not reach the significance by a very small margin of a p-value of 0.059. But importantly, by a pre-specified sensitivity analysis looking at patients enrolled before the COVID pandemic, the COVID sensor analysis demonstrated the primary endpoint achieving significance. So those individuals who were enrolled in the pre-COVID era, there was evidence for reduction in heart failure hospitalizations and cardiovascular death. The AFIRM trial demonstrated that the hospitalization provides a key opportunity for treatment with IV iron and that it is safe and that it is effective and treatment to target approach is practical and can help individualize therapy. A more recent study called the IRONMAN trial was carried out again in patients with heart failure with reduced EF and iron deficiency and in this study iron deficiency was defined as either ferritin less than 100 or TSAT level less than 20%. Examining the efficacy and safety of IV ferric derisomaltose compared against standard of care demonstrated again a significant trend or a trend for reduction in cardiovascular death and heart failure hospitalization which didn't reach statistical significance at the end of the study. But again very similar to AFIRM AHF trial in a pre-specified COVID-19 sensitivity analysis when the patients were excluded for those who were recruited after the COVID pandemic the results reached significance statistical significance nominally. So this study also supported the concept of benefits with IV iron treatment in patients with heart failure reduced EF. There are ongoing large-scale trials with IV iron replacement that will inform its efficacy and safety in large scale in terms of heart endpoints including cardiovascular mortality and heart failure hospitalizations. And these include the HEART-FID study and FAIR-HF2 study with IV ferric carboxymaltose in patients with heart failure with reduced EF and also ferric carboxymaltose in patients with heart failure with preserved EF in hospitalized patients in the FAIR-HF preserved EF trials. The 2022 ACC AHA HFSA heart failure guidelines specify measurement of iron or iron studies as part of the baseline evaluation in all patients with heart failure as a class one indication. So iron studies should be performed for all heart failure patients. And there is a class 2a recommendation for treatment with IV iron in patients with heart failure with reduced EF with iron deficiency with or without anemia to improve functional status and quality of life. In the guidelines there is a class 3 recommendation against use of erythropoietin stimulating agents in patients with heart failure and anemia. So overall in summary treatment of iron deficiency is beneficial in patients with heart failure with significant improvements in quality of life exercise performance and functional status. Recent studies such as AFIRM acute heart failure study as well as IRONMAN imply benefit in reduction heart failure hospitalizations which await further larger scale studies to confirm its efficacy. Treatment of iron deficiency is effective only with IV iron not with oral iron in patients with heart failure. Treatment is safe to be initiated pre-discharge for hospitalized patients with heart failure and heart heart failure guidelines suggest that in patients with heart failure with reduced EF and iron deficiency with or without anemia intravenous iron replacement is reasonable to improve quality of life and functional status. And further ongoing studies will answer the question of efficacy of iron replacement therapy in reducing heart failure hospitalizations and cardiovascular mortality in patients with heart failure with reduced EF as well as heart failure with preserved EF. Thank you for your attention.

iron deficiency

heart failure

erythropoietin-stimulating agents

intravenous iron supplementation

ferric carboxymaltose