Lead Investigator: João Pedro Ferreira, Faculty of Medicine of Porto University
Title of Proposal Research: Anemia and the Effect of Empagliflozin in Heart Failure with Preserved Ejection Fraction (HFpEF) findings from EMPEROR-Preserved
Vivli Data Request: 9383
Funding Source: None
Potential Conflicts of Interest: I was a member of the Steering Committee for the EMPEROR studies, but I do not have any patents nor receive any payment from Boehringer-Ingelheim.
I will acknowledge/declare any potential conflicts of interest in any subsequent publication.
Summary of the Proposed Research:
Anemia is a condition that occurs when a person’s blood does not have enough healthy red blood cells (the hematocrit level) or hemoglobin to carry oxygen to the body’s tissues. Hemoglobin is a protein found in red cells that carries oxygen from the lungs to all other organs in the body. Anemia is a frequent co-morbid condition among patients with heart failure with preserved ejection fraction (HFpEF), affecting around 40% of the patients with HFpEF i.e., patients in whom the heart has problems in relaxation and filling with blood, a condition affecting more than 10% of elderly people (>75 years). Anemia may have multiple etiologies (i.e. causes), however in patients with HFpEF, anemia is usually hypoproliferative (where the bone marrow is not able to produce adequate numbers of red blood cells), caused by deficient iron utilization or low iron stores, vitamin deficiency, chronic inflammation, kidney disease, or conditions affecting the bone marrow.
Regardless of the underlying etiology, anemia is associated with low exercise capacity, impaired quality of life and a poor prognosis including a higher risk of heart failure (HF) hospitalizations and mortality.
Sodium glucose co-transporter 2 (SGLT2) inhibitors are medicines which increase hemoglobin/hematocrit and, therefore, have the potential to correct anemia.
The effect of SGLT2 inhibitors (SGLTi) on correcting anemia among patients with HFpEF has not been studied yet.
This study aims to compare the characteristics of the patients with and without anemia at baseline, study the impact of the SGLT2 inhibitor empagliflozin on hematocrit/hemoglobin and the onset of new anemia throughout the follow-up, and to assess whether the effect of empagliflozin on a broad range of outcomes was consistent irrespective of the anemia status at
baseline in patients with HFpEF enrolled in the EMPEROR-Preserved (NCT03057951) trial.
Statistical Analysis Plan:
Baseline characteristics will be compared between patients with and without anemia at baseline using chi square test for categorical variables and t-test for continuous variables. For time-to-first-event analyses, differences between the placebo and empagliflozin groups will be assessed using a Cox proportional hazards model, with prespecified baseline covariates of age, gender, geographical region, diabetes, left ventricular ejection fraction, and estimated glomerular filtration rate (eGFR). For the analysis of total (first and repeated) events, the differences between the placebo and empagliflozin groups were assessed using a joint frailty model, with cardiovascular death as competing risk. For the analysis of changes in hematocrit and hemoglobin over time, treatment effects will be assessed based on changes from baseline using a mixed model for repeated measures. For the analysis of change from baseline to last-value-on-treatment and 1-month off treatment phase will be assessed using an analysis of covariance model. The association of anemia with subsequent outcomes will be assessed in the placebo group using both the baseline and time-updated anemia status. The association of hematocrit as a continuous covariate and subsequent outcomes will also tested in the placebo group. The new initiation of iron supplements, erythropoietic therapy, and blood transfusions will be retrieved from concomitant therapies. All analyses will use the same covariates as in the Cox model and include the baseline variable as an additional covariate, where applicable. For all efficacy measures, separate analyses will be performed according to the presence or absence of anemia at baseline, and differences in the effect of empagliflozin will be assessed by interaction terms. Only complete cases will be analyzed i.e., no data imputation will be performed. All analyses will be performed using Stata(r)
Requested Studies:
A Phase III Randomised, Double-blind Trial to Evaluate Efficacy and Safety of Once Daily Empagliflozin 10 mg Compared to Placebo, in Patients With Chronic Heart Failure With Preserved Ejection Fraction (HFpEF)
Data Contributor: Boehringer Ingelheim
Study ID: NCT03057951
Sponsor ID: 1245.110
Public Disclosures:
Ferreira, J.P., Zannad, F., Vasques-Nóvoa, F., Neves, J.S., Filippatos, G., Pocock, S.J., Butler, J., Packer, M. and Anker, S.D., 2024. Anaemia, erythrocytosis, and empagliflozin in heart failure with preserved ejection fraction: the EMPEROR-Preserved trial. European Heart Journal, p.ehae864. Doi : 10.1093/eurheartj/ehae864