Affirming the Role of IV Iron in Acute Heart Failure: The AFFIRM-HF Trial

Iron homeostasis is essential for cell energy, effective hematopoiesis, and organ metabolism.¹  Approximately 1.24 billion people worldwide are affected by iron deficiency (ID) anemia, and it is considered a significant contributor to disability globally.^2,3  In the past few decades, tremendous research has improved our understanding of how inflammation of chronic disease modulates hepcidin regulation and contributes to ID.⁴  In patients with heart failure (HF), the prevalence of ID with or without anemia reaches estimates as high as 40 to 80 percent.^4,5  ID in patients with HF, irrespective of hemoglobin, contributes to cardiac and peripheral muscle dysfunction, resulting in decreased exercise capacity, poor quality of life, increased hospitalization, and patient mortality. Furthermore, recurrent hospitalization of patients with HF poses ongoing health care burden and economic challenges.^6,7 

Current guidelines from the Canadian Cardiovascular Society recommend that intravenous (IV) iron be considered for patients with HF with reduced ejection fraction (HFrEF) and ID to improve exercise tolerance and quality of life, and reduce HF hospitalizations (strong recommendation, moderate quality of evidence).⁸  IV iron rapidly repletes iron stores and is recommended over oral administration. Numerous clinical trials and meta-analyses have improved the quality of evidence on the above outcomes including FAIR-HF, CONFIRM-HF, and EFFECT-HF (Table), but these studies have not demonstrated a mortality benefit. Of note, these studies evaluated the use of IV iron in chronic ambulatory patients with HF.

In AFFIRM-AHF, investigators aimed to prospectively evaluate the use of ferric carboxymaltose (FCM) compared to placebo in stabilized patients following an acute HF episode, when the risks of rehospitalization and mortality are anticipated to be the highest. This was a multicenter double-blind randomized control trial examining the effect of FCM versus placebo (1:1) with a primary composite outcome of total hospitalizations for HF and cardiovascular (CV) death up to one year following hospitalization and stabilization after an episode of acute HF. The study involved 121 sites in Europe, South America, and Singapore, and enrolled 1,108 eligible patients who had been hospitalized with acute HF and concomitant ID (ferritin < 100 µg/L, or 100-299 µg/L with transferrin saturation < 20%) and had a left ventricular ejection fraction lower than 50 percent. In the FCM group, 293 primary events occurred, compared to 372 events in the placebo arm (rate ratio, 0.79; 95% CI, 0.62-1.01; p=0.059). There was no difference in CV death between the two groups (p=0.81).

Although the study fell just shy of its composite primary outcome of total HF hospitalizations and cardiovascular death, the investigators concluded that in patients with ID and HF with an EF lower than 50 percent, FCM could be safely used around the time of discharge following an acute episode of HF, leading to a reduced risk of HF hospitalizations without an apparent impact on CV mortality. While the COVID-19 pandemic affected patient management and follow-up during this study, a pre-COVID sensitivity analysis did demonstrate a statistically significant reduction in the primary outcome. Interestingly, a subgroup analysis in nonischemic patients with HF did not favor FCM over placebo, which speaks to the variability and heterogeneity in the pathophysiology of heart disease in this patient population. Further studies are needed.

Following this trial, a meta-analysis that included 2,166 patients across seven trials, including data from AFFIRM-AHF, confirmed that IV iron reduced the composite outcome of HF hospitalizations or CV death (odds ratio, 0.73; p=0.0003), but the impact on CV death alone was uncertain (p=0.47).⁹  There are four other ongoing clinical trials evaluating the use of FCM in HRrEF (NCT03036462, NCT03037931, NCT01978028, NCT03218384).