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Iron Deficiency in Heart Failure and Effect of Dapagliflozin: DAPA-HF Findings
Quick Takes
- Dapagliflozin improved clinical outcomes irrespective of baseline iron status, though it was shown to increase incidence of iron deficiency potentially due to enhanced erythropoiesis.
- Routine screening and treatment of iron deficiency in patients with heart failure is essential.
Study Questions:
What is the effect of dapagliflozin in patients with heart failure with reduced ejection fraction on iron status and clinical outcomes when accounting for baseline iron status?
Methods:
This post hoc analysis of the DAPA-HF (Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction) trial included 3,009 patients with New York Heart Association (NYHA) class II-IV heart failure, left ventricular ejection fraction ≤40%, elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) level, optimally treated with medications and device therapy, and baseline ferritin and transferrin saturation (TSAT) measurements available. Key exclusion criteria included symptoms of hypotension or systolic blood pressure <95 mm Hg, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, and type 1 diabetes. Iron deficiency was defined as a ferritin level <100 ng/mL or a TSAT <20% with a ferritin level of 100-299 ng/mL. The primary outcome was worsening heart failure or cardiovascular death.
Results:
Of the 3,009 patients included, 43.7% were iron deficient. Patients who were iron deficient were more likely to be female, have an eGFR <60 mL/min/1.73 m2, anemia, coronary heart disease, hypertension, diabetes, worse NYHA functional class, lower Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, higher baseline NT-proBNP and high-sensitivity troponin T, more likely to use a proton pump inhibitor, antiplatelet agent, diuretic, and less likely to be prescribed a mineralocorticoid receptor antagonist. Risk of the primary and secondary morbidity/mortality endpoints was higher for patients with iron deficiency compared to those without.
Dapagliflozin reduced the incidence of the primary endpoint compared to placebo (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85) consistently in patients with (HR, 0.74; 95% CI, 0.58-0.92) and without (HR, 0.81; 95% CI, 0.63-1.03) iron deficiency (p for interaction = 0.59). Similar results were seen for cardiovascular death, worsening heart failure, and all-cause death (p for interaction for treatment-by-iron deficiency interaction term = 0.62, 0.42, and 0.52, respectively). Dapagliflozin compared to placebo had a larger absolute risk reduction in patients with iron deficiency due to the higher event rates in these patients. Dapagliflozin had a greater effect on hematocrit, hemoglobin, reversal of anemia, and markers of iron metabolism (reductions in TSAT, ferritin, hepcidin, and increase in total iron-binding capacity and soluble transferrin receptor) compared to placebo. Development of new iron deficiency by 12 months was more likely in the dapagliflozin group compared to placebo (odds ratio, 1.74; 95% CI, 1.34-2.25; p < 0.001).
Conclusions:
Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use, but improved outcomes irrespective of iron status at baseline.
Perspective:
This study highlights the importance of screening for and treating iron deficiency as described in both the American and European heart failure guidelines. Novel findings related to dapagliflozin effects on iron indices were demonstrated by the authors, which were suggestive that sodium-glucose cotransporter 2 (SGLT2) inhibitors may stimulate erythropoiesis, which in turn may result in greater use of iron. At present, pre-existing iron deficiency is not a barrier to initiating dapagliflozin given improved outcomes were seen in patients with and without baseline iron deficiency.
Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension
Keywords: Anemia, Care Team, Coronary Disease, Diabetes Mellitus, Type 1, Erythropoiesis, Ferritins, Glomerular Filtration Rate, Heart Failure, Hematocrit, Hemoglobins, Hypertension, Iron, Natriuretic Peptide, Brain, Platelet Aggregation Inhibitors, Proton Pump Inhibitors, Receptors, Transferrin, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume, Transferrins, Troponin T, Ventricular Function, Left
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