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

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.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT03036124.

Keywords: anemia; erythropoiesis; ferritin; heart failure; hepcidin; iron; sodium-glucose cotransporter 2 inhibitor; transferrin.

Figure 1.

Cardiovascular outcomes according to the presence of iron deficiency. The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, or an urgent visit resulting in intravenous therapy for heart failure. The cumulative incidences of the primary outcome, worsening heart failure event, death from cardiovascular causes, and death from any cause were estimated with the use of the Kaplan-Meier method.

Figure 2.

Effect of dapagliflozin, compared with placebo, on cardiovascular outcomes according to the presence of iron deficiency. A, Primary composite outcome. B, Cardiovascular death. C, Worsening heart failure event. D, All-cause death. The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, or an urgent visit resulting in intravenous therapy for heart failure. The cumulative incidences of the primary outcome, worsening heart failure event, death from cardiovascular causes, and death from any cause were estimated with the use of the Kaplan-Meier method. The interaction P value presented represents a treatment–by–iron deficiency interaction term.

Figure 3.

Effect of dapagliflozin on the primary outcome according to baseline levels of iron metabolism biomarkers. The solid black line represents a continuous hazard ratio, and the solid red line represents a hazard ratio of 1 (ie, no difference between treatments). The shaded area represents the 95% CI around the hazard ratio. The hazard ratio represents the treatment effect of dapagliflozin compared with placebo for the primary composite outcome.

Figure 4.

Effect of dapagliflozin, compared with placebo, on hematocrit according to the presence of iron deficiency. Means and 95% CIs were derived from a mixed-effect model adjusted for baseline values, visit, randomized treatment, and interaction of treatment and visit with a random intercept and slope per patient. Least-square mean changes along with 95% CI are shown.