Short-Term Changes in Peak VO2 After Initiation of Dapagliflozin in Heart Failure Across Iron Status.

BACKGROUND: Some studies have indicated that sodium-glucose cotransporter-2 (SGLT2) inhibitors promote an increase in cell iron use. OBJECTIVES: The aim of this study was to examine, in patients with stable heart failure with reduced left ventricular ejection fraction (HFrEF), the effect of dapagliflozin on ferrokinetic parameters and whether short-term changes in peak oxygen consumption (Vo2) after dapagliflozin treatment are influenced by baseline and serial ferrokinetic status. METHODS: This was an exploratory analysis of a randomized, double-blind clinical trial that evaluated the effect of dapagliflozin vs placebo on peak Vo2 in patients with HFrEF (NCT04197635) and included 76 of the 90 patients initially enrolled in the trial. Changes in peak Vo2 at 1 and 3 months were explored according to baseline and longitudinal ferrokinetic parameters (natural logarithm [ln] ferritin, transferrin saturation index [TSAT], soluble transferrin receptor, and hepcidin). Linear mixed-effect regression was used for the analyses. RESULTS: Compared with placebo, dapagliflozin led to a significant decrease in 3-month ln ferritin (P = 0.040) and an increase in 1-month ln soluble transferrin receptor (P = 0.023). Between-treatment comparisons revealed a stepwise increase in peak Vo2 in the dapagliflozin group at 1 and 3 months, which was especially apparent at lower baseline values of TSAT and ferritin (P < 0.05). Lower time-varying values of TSAT (1 and 3 months) also identified patients with greater improvements in peak Vo2. CONCLUSIONS: In patients with stable HFrEF, treatment with dapagliflozin resulted in short-term increases in peak Vo2, which were most marked in patients with surrogates of greater iron deficiency at baseline and during treatment. (Short-Term Effects of Dapagliflozin on Peak Vo2 in HFrEF [DAPA-VO2]; NCT04197635).

Short-term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA-VO2 ): a randomized clinical trial.

AIMS: This study aimed to evaluate the effect of dapagliflozin on 1 and 3-month maximal functional capacity in patients with stable heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: In this multicentre, randomized, double-blind clinical trial, 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin (n = 45) or placebo (n = 45). The primary outcome was a change in peak oxygen consumption (peakVO2 ) at 1 and 3 months. Secondary endpoints were changes at 1 and 3 months in 6-min walk test (6MWT) distance, quality of life (Minnesota Living with Heart Failure Questionnaire [MLHFQ]), and echocardiographic parameters (diastolic function, left chamber volumes, and left ventricular ejection fraction). We used linear mixed regression analysis to compare endpoint changes. Estimates were adjusted for multiple comparisons. The mean age was 67.1 ± 10.7 years, 69 (76.7%) were men, 29 (32.2%) had type 2 diabetes, and 80 (88.9%) were in New York Heart Association class II. Baseline means of peakVO2 , 6MWT and MLHFQ were 13.2 ± 3.5 ml/kg/min, 363 ± 110 m, and 23.1 ± 16.2, respectively. The median (25th-75th percentile) of N-terminal pro-brain natriuretic peptide was 1221 pg/ml (889-2100). Most patients were on treatment with sacubitril/valsartan (88.9%), beta-blockers (91.1%), and mineralocorticoid receptor antagonists (74.4%). PeakVO2 significantly increased in patients on treatment with dapagliflozin (1 month: +Δ 1.09 ml/kg/min, 95% confidence interval [CI] 0.14-2.04; p = 0.021, and 3 months: +Δ 1.06 ml/kg/min, 95% CI 0.07-2.04; p = 0.032). Similar positive findings were found when evaluating changes from baseline. No significant differences were observed in secondary endpoints. CONCLUSIONS: Among patients with stable HFrEF, dapagliflozin resulted in a significant improvement in peakVO2 at 1 and 3 months. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04197635.

Noninvasive Imaging Estimation of Myocardial Iron Repletion Following Administration of Intravenous Iron: The Myocardial-IRON Trial.

Background Intravenous ferric carboxymaltose (FCM) improves symptoms, functional capacity, and quality of life in heart failure and iron deficiency. The mechanisms underlying these effects are not fully understood. The aim of this study was to examine changes in myocardial iron content after FCM administration in patients with heart failure and iron deficiency using cardiac magnetic resonance. Methods and Results Fifty-three stable heart failure and iron deficiency patients were randomly assigned 1:1 to receive intravenous FCM or placebo in a multicenter, double-blind study. T2* and T1 mapping cardiac magnetic resonance sequences, noninvasive surrogates of intramyocardial iron, were evaluated before and 7 and 30 days after randomization using linear mixed regression analysis. Results are presented as least-square means with 95% CI. The primary end point was the change in T2* and T1 mapping at 7 and 30 days. Median age was 73 (65-78) years, with N-terminal pro-B-type natriuretic peptide, ferritin, and transferrin saturation medians of 1690 pg/mL (1010-2828), 63 ng/mL (22-114), and 15.7% (11.0-19.2), respectively. Baseline T2* and T1 mapping values did not significantly differ across treatment arms. On day 7, both T2* and T1 mapping (ms) were significantly lower in the FCM arm (36.6 [34.6-38.7] versus 40 [38-42.1], P=0.025; 1061 [1051-1072] versus 1085 [1074-1095], P=0.001, respectively). A similar reduction was found at 30 days for T2* (36.3 [34.1-38.5] versus 41.1 [38.9-43.4], P=0.003), but not for T1 mapping (1075 [1065-1085] versus 1079 [1069-1089], P=0.577). Conclusions In patients with heart failure and iron deficiency, FCM administration was associated with changes in the T2* and T1 mapping cardiac magnetic resonance sequences, indicative of myocardial iron repletion. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03398681.

Iron deficiency and long-term mortality in elderly patients with acute coronary syndrome.

AIM: We evaluated the relationship between iron deficiency (ID) and long-term mortality risk in elderly patients with acute coronary syndrome (ACS). METHODS: In this prospective observational study, we included 252 patients older than 65 years with ACS. Transferrin saturation (TSAT) and ferritin were collected before discharge. RESULTS: Mean age, hemoglobin and GRACE score were 78 ± 7 years, 12.4 ± 1.8 g/dl and 138.8 ± 25.3, respectively, 112(44.4%) patients were women, and 151(59.9%) presented ID. During the follow-up, 121 (48%) patients died. Mortality rates among TSAT quartiles were: 2.38, 1.60, 0.90 and 0.95 × 10 person-years for Q1TSAT to Q4TSAT, respectively (p < 0.001) and did not differ across ferritin quartiles (p = 0.601), whereas ID definition was borderline associated (p = 0.060). Adjusted TSAT levels remained inverse, nonlinearly associated with long-term mortality risk (p < 0.001), with an exponential increased-risk from values about 20% and below. CONCLUSION: Lower TSAT levels were independently associated with increased mortality risk in these patients.

Changes in myocardial iron content following administration of intravenous iron (Myocardial-IRON): Study design.

Treatment with intravenous ferric carboxymaltose (FCM) has been shown to improve symptoms, functional capacity, and quality of life in patients with heart failure and iron deficiency. However, the underlying mechanisms for these beneficial effects remain undetermined. The aim of this study is to quantify cardiac magnetic resonance changes in myocardial iron content after administration of intravenous FCM in patients with heart failure and iron deficiency and contrast them with parameters of heart failure severity. This is a multicenter, double-blind, randomized study. Fifty patients with stable symptomatic heart failure, left ventricular ejection fraction <50%, and iron deficiency will be randomly assigned 1:1 to receive intravenous FCM or placebo. Intramyocardial iron will be evaluated by T2* and T1 mapping cardiac magnetic resonance sequences before and at 7 and 30 days after FCM. After 30 days, patients assigned to placebo will receive intravenous FCM in case of persistent iron deficiency. The main endpoint will be changes from baseline in myocardial iron content at 7 and 30 days. Secondary endpoints will include the correlation of these changes with left ventricular ejection fraction, functional capacity, quality of life, and cardiac biomarkers. The results of this study will add important knowledge about the effects of intravenous FCM on myocardial tissue and cardiac function. We hypothesize that short-term (7 and 30 days) myocardial iron content changes after intravenous FCM, evaluated by cardiac magnetic resonance, will correlate with simultaneous changes in parameters of heart failure severity. The study is registered at http://www.clinicaltrials.gov (NCT03398681).