New non-steroidal MRA safely reduced NT-proBNP in phase IIb study
A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease
Filippatos G, Anker SD, Böhm M, et al.
Eur Heart J 2016; published online ahead of print
BackgroundGuidelines recommend the use of steroidalmineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone for symptomatic heart failure patients with reduced ejection fraction (HFrEF), which is based on data showing a reduction of mortality and morbidity in these patients [1-4]. However, prescription for patients with worsening HF is limited by the high risk of adverse events (AEs) caused by these agents, and by the particular risk of developing hyperkalaemia in patients with DM or chronic kidney disease (CKD) [5-7]. These patients need medical care that cannot be achieved with the currently available MRAs.
Finerenone, a novel non-steroidal MRA, may provide improved cardio-renal protection, particularly in high-risk patients with impaired kidney function, due to its higher potency and selectivity towards the mineralocorticoid receptor, as well as its balanced tissue distribution into heart and kidney, compared with spironolactone or eplerenone [8-10].
The phase IIa ARTS trial showed that in patients with HFrEF and mild CKD, finerenone had comparable efficacy with spironolactone, with lesser increases in serum potassium levels and smaller decreases in estimated glomerular filtration rate (eGFR), while the phase IIb ARTS-Diabetic Nephropathy study confirmed the safety of finerenone in patients with diabetic kidney disease [11,12].
In the randomised, double-blind ARTS-HF study, the 90 days efficacy and safety of five treatment regimens of finerenone (once-daily oral administration, dose uptitrated at day 30) compared with eplerenone was evaluated, in 1066 patients with worsening HFrEF and T2DM and/or CKD.
- Decreases in plasma NT-proBNP of >30% from baseline towards day 90 (responder) were similar in the finerenone and eplerenone groups, and occurred in: 37.2% of patients in the eplerenone group, 30.9% in the 2.5→5 mg finerenone group, 32.5% in the 5→10 mg finerenone group, 37.3% in the 7.5→15 mg finerenone group, 38.8% in the 10→20 mg finerenone group and 34.2% in the 15→20 mg finerenone group (P = 0.42–0.88).
- Except for the 2.5→5 mg finerenone group, the composite clinical endpoint (death from any cause, cardiovascular hospitalization, or emergency presentation for worsening chronic HF until Day 90;) occurred numerically less frequently in finerenone-treated patients compared with eplerenone. This difference reached nominal statistical significance in the 10→20 mg group (HR: 0.56; 95% CI: 0.35-0.90; nominal P = 0.02)
SafetyBased on biomarker levels for organ injury, vital signs, laboratory parameters and incidence of AEs:
- All doses of finerenone had a similar safety profile to that of eplerenone
- AEs showed a balanced distribution among all treatment groups. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients. The mean eGFR was comparable to this of eplerenone and increased slightly in the two lowest finerenone groups but decreased in the other groups.
ConclusionIn a phase IIb study in patients with worsening HFrEF requiring hospitalisation and with concomitant DM and/or CKD, finerenone, a novel non-steroidal MRA, showed a comparable safety and efficacy profile to this of eplerenone.
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Editorial comment Naegele et al encourage the translation of scientific data towards the clinic. ‘Without incorporating new science into medicine, we will be faced forever with old therapies for patients while new advances are left in the lab or worse on the shelf’. To this end, they mentioned the planned large confirmatory multicenter phase III trial of finerenone in HFrEF patients (FINESSE-HF; EUCTR2015-002168-17-SE), as the benefit of finerenone in relation to MRAs in heart failure treatment requires definitive outcome assessment. Furthermore, they highlighted the exclusion of severe CDK patients (eGFR <30 mL/min) in the ARTS-HF trial but also other studies. These patients are at an even higher risk for hyperkalaemia and AEs and this lack of information causes a gap in clinical information that is needed in the clinic. Also regarding the high activation of the renin-angiotensin-aldosterone system and the high mortality rate in these patients, there is a significant need for the validation of finerenone in these patients.
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