Iron Deficiency in Heart Failure and Effect of Dapagliflozin: Findings From DAPA-HF

• DOI: 10.1161/circulationaha.122.060511
• Publication Date: 2022-09-26T18:00:31Z
• Authors: Kieran F. Docherty; Paul Welsh; Subodh Verma; Rudolf A. De Boer; Eileen O’Meara; Olof Bengtsson; Lars Køber; Mikhail N. Kosiborod; Ann Hammarstedt; Anna Maria Langkilde; Daniel Lindholm; Dustin J. Little; Mikaela Sjöstrand; Felipe A. Martinez; Piotr Ponikowski; Marc S. Sabatine; David A. Morrow; Morten Schou; Scott D. Solomon; Naveed Sattar; Pardeep S. Jhund; John J.V. McMurray
• Keywords: Iron; heart failure; 03 medical and health sciences; iron; 0302 clinical medicine; Glucosides; Hepcidins; Original Research Articles; Receptors, Transferrin; Receptors, Erythropoietin; Humans; transferrin; Benzhydryl Compounds; Heart Failure; ferritin; Stroke Volume; Iron Deficiencies; sodium-glucose cotransporter 2 inhibitor; anemia; Ferritins; Transferrins; hepcidin; erythropoiesis; Biomarkers

Background: Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline.

Methods: Iron deficiency was defined as a ferritin level <100 ng/mL or a transferrin saturation <20% and a ferritin level 100 to 299 ng/mL. Additional biomarkers of iron metabolism, including soluble transferrin receptor, erythropoietin, and hepcidin were measured at baseline and 12 months after randomization. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.

Results:

Of the 4744 patients randomized in DAPA-HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P <0.0001). The effect of dapagliflozin on the primary outcome was consistent in iron-deficient compared with iron-replete patients (hazard ratio, 0.74 [95% CI, 0.58–0.92] versus 0.81 [95% CI, 0.63–1.03]; P -interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo.

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.

Registration:

URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.