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

Kieran F. Docherty, Paul Welsh, the DAPA-HF Investigators and Committees, 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. SolomonNaveed Sattar, Pardeep S. Jhund, John J.V. McMurray

Research output: Contribution to journalArticleAcademicpeer-review

62 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)980-994
Number of pages15
JournalCirculation
Volume146
Issue number13
DOIs
Publication statusPublished - 27 Sept 2022
Externally publishedYes

Bibliographical note

Funding Information:
The DAPA-HF trial was funded by AstraZeneca. Dr McMurray is supported by a British Heart Foundation Center of Research Excellence grant (RE/18/6/34217).

Publisher Copyright:
© 2022 The Authors.

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