INFUSE HFPEF - PROJECT SUMMARY/ ABSTRACT Iron deficiency is the most common micronutrient deficiency worldwide, affecting 25% of the population. In older adults with heart failure (HF), its prevalence ranges from 40–50% and is associated with worse health status, functional limitations, and increased risks of hospitalizations and death. Once considered only a reversible cause of anemia, iron deficiency is now recognized as an independent comorbidity in HF, even without anemia. Intravenous (IV) iron has proven effective in improving health status and functional capacity in HF with reduced ejection fraction (HFrEF), and guidelines now recommend IV iron for iron-deficient HFrEF patients. However, patients with HF with preserved ejection fraction (HFpEF)—the fastest-growing HF phenotype, with a higher prevalence of iron deficiency—remain largely excluded from these studies. HFpEF affects over 3 million older adults in the U.S., contributing to poor health status, functional impairment, and hospitalizations. To address this critical knowledge gap, we propose the Iron Needed for Function and Undesirable Symptoms in Elderly with HFpEF (INFUSE-HFpEF) study, a double-blind, placebo-controlled randomized clinical trial of IV iron in 300 ambulatory older patients with HFpEF and iron deficiency. This collaboration among Duke University/Duke Clinical Research Institute (DCRI), Kaiser Permanente Northern California (KPNC), Mount Sinai Health System (MSHS), and St. Luke’s Mid America Heart Institute (MAHI) will evaluate the net clinical benefit of IV iron on patient-centered outcomes, including a composite of death, all- cause hospitalization, and health-related quality of life (QoL), as well as its impact on physical function. The INFUSE-HFpEF study incorporates three innovative approaches. First, it employs a patient-centered strategy by prioritizing patient-reported outcomes such as QoL alongside traditional endpoints, reflecting their growing importance in HFpEF trials and FDA endorsement for regulatory approval. Second, it adopts a pragmatic design with broad eligibility criteria and diverse representation, embedding the trial within routine care and leveraging electronic health records to address gaps in inclusion of older adults, women, and ethnically diverse populations. Third, it incorporates novel physical activity measures as secondary endpoints, using wearable- derived metrics such as step count and gait speed. These measures will be validated against established gold standards, including the 6-minute walk test (6-MWT) and cardiopulmonary exercise testing (CPET) parameters like peak VO₂, aligning with the FDA’s Digital Health Innovation Action Plan. INFUSE-HFpEF will advance understanding of iron deficiency in HFpEF, addressing NIA’s Strategic Goal C-3 to “develop interventions for treating…or mitigating the impact of age-related diseases and conditions.” This trial has the potential to transform care for iron-deficient HFpEF patients, bridging evidence gaps and improving patient-centered and clinical outcomes, while serving as a model for research in aging populations with complex multimorbidity.
