A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease

Abstract

Aims: To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.

Methods and results: Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7-10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42-0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups.

Conclusion: Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.

Keywords: Finerenone; Mineralocorticoid receptor antagonists; Worsening heart failure.

© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1

Patient disposition. All patients from the safety-analysis set were considered for the full-analysis set if they had baseline and at least one post baseline plasma N-terminal pro-B-type natriuretic peptide level value or who died, experienced permanent (≥5 consecutive days) withdrawal of study drug after cardiovascular hospitalization, or after emergency presentation for worsening chronic heart failure. The per-protocol set comprised all patients from the full-analysis set with valid plasma NT-proBNP data at visit 7 (Day 60 ± 2) or later and no major protocol deviations.

Figure 2

Proportion of patients with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide concentration from baseline at Day 90 (full-analysis set). Patients who died prior to Day 90 or who experienced permanent (≥5 consecutive days) withdrawal of study drug after a cardiovascular hospitalization or emergency presentation for worsening chronic heart failure were counted as nonresponders for the primary efficacy analysis.

Figure 3

Mortality/morbidity outcomes in patients with worsening chronic heart failure with reduced ejection fraction receiving eplerenone or different doses of finerenone. Cumulative event rates of the composite endpoint of death from any cause, cardiovascular hospitalization, or emergency presentation for worsening chronic heart failure in the full-analysis set.

Figure 4

Mean change in serum potassium concentration from baseline to Day 90 in patients with worsening chronic heart failure with reduced ejection fraction receiving eplerenone or different doses of finerenone. Changes were assessed by analysis of covariance with the factors treatment group, comorbidities, mineralocorticoid receptor antagonist use at emergency presentation to hospital, region, and the baseline value as covariates.