Finerenone in heart failure: walking a fine line

This editorial refers to ‘A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes and/or chronic kidney disease’†, by G. Filippatos et al., on page 2105. More than half a century ago, Hans Selye, one of the grandfathers of stress and steroid hormone research, observed in a small 1960 study that spironolactone substantially protects salt- and fludrocortisone-treated rats from cardiac necrosis and renal calcification, and reduces their mortality.1 Back then, spironolactone was simply known as a synthetic mineralocorticoid receptor antagonist (MRA) for the medical control of oedema and ascites, without any concept of the benefits for clinical outcomes. Four decades later, after the ascendency of angiotensin-converting enzyme (ACE) inhibitors and beta-blockers had passed, mineralocorticoid receptor (MR) antagonism found its way as a major step towards improving survival of patients with heart failure with publication of the RALES trial in 1999.2 Today, the two MRAs, spironolactone and eplerenone, have a grade 1A recommendation for patients with heart failure with reduced ejection fraction (HFrEF) who have persisting symptoms despite therapy with an ACE inhibitor (or angiotensin receptor blocker) and a beta-blocker.3 Based on their pivotal trials, they are known to reduce both all-cause mortality and heart failure hospitalizations.2,4,5 Despite this evidence, the use of MRAs is still suboptimal in clinical practice, in contrast to ACE inhibitors or beta-blockers, partly because of physician inertia and poor recognition of the benefits vs. risks, with notable concerns for hyperkalaemia.6 This sparked the development of a third-generation of MRAs that would more selectively target benefits and minimize risks with altered receptor affinity and tissue tropism using non-steroidal molecules. Finerenone is the most clinically advanced non-steroidal MRA in development. The dihydropyridine-based compound has a high affinity for the MR, similar to spironolactone, while maintaining a very low affinity for androgen, glucocorticoid, and progesterone receptors, similar to eplerenone.7 Pre-clinical studies indicate that finerenone concentrates equally in cardiac and renal tissues, an important difference from spironolactone and eplerenone which have a higher tendency to concentrate in the kidney (Figure 1).8 This suggests a more favourable balance between cardioprotection and renal side effects, especially in populations prone to hyperkalaemia such as patients with chronic kidney disease or diabetes. Overview on the cardiovascular and renal effects of mineralocorticoid receptor antagonists (MRAs) in heart failure and comparison of the three MRA generations (spironolactone, eplerenone, and finerenone). Finerenone is characterized by a high affinity for the mineralocorticoid receptor (MR) while having a low affinity for other steroid hormone receptors (SHRs) such as glucocorticoid, progesterone, and androgen receptors.7 Because of its more equal tissue distribution in heart and kidney (based on rat studies8), it is presumed that finerenone has a more favourable drug profile than the two previous MRA generations. In the first phase II safety and tolerability trial (ARTS), finerenone led to a smaller increase in serum potassium and a lower frequency of hyperkalaemia than spironolactone in HFrEF patients with mild to moderate chronic kidney disease.9 The highest dose of finerenone tested, 10 mg per day, reduced N-terminal pro brain natriuretic pepide (NT-proBNP) and albuminuria to a similar degree as spironolactone while leading to a lower rate of hyperkalaemia, blood pressure decrease, and worsening renal function. Filippatos et al. now report the results of the larger ARTS-HF trial, a multicentre phase IIb dose-finding study in patients with worsening HFrEF and co-existing moderate chronic kidney disease and/or type 2 diabetes mellitus.10 In total, 1066 patients were randomized within 7 days of an emergency hospitalization for worsening heart failure to one of five different dose groups of finerenone or eplerenone. The drugs were titrated to target doses after 30 and 60 days as tolerated by potassium levels. The primary endpoint was the percentage of individuals with a decrease in the cardiac biomarker NT-proBNP of >30% after 3 months of treatment relative to baseline. The trial showed a comparable efficacy between all dose groups of finerenone and eplerenone in the primary endpoint of NT-proBNP reduction of >30%. Finerenone appeared to be well tolerated, and no significant differences in treatment-emergent adverse events were noted between the groups. An exploratory composite endpoint comprising death from any cause, cardiovascular hospitalizations, and emergency presentation for worsening HF showed a significant reduction in the 10–20 mg finerenone group compared with eplerenone. Except for the lowest dose group, a trend of reduction in the composite endpoint was also seen in the other finerenone groups. There was a numerically higher increase in mean serum potassium levels with eplerenone compared with finerenone, and a numerically lower incidence of hyperkalaemia was noted in all finerenone dose groups (3.6–3.8%) compared with eplerenone (4.7%), apart from the highest finerenone dose group (15–20 mg; 6.3%). No significant differences in blood pressure reduction and decrease in estimated glomerular filtration rate (eGFR) were noted. A somewhat inconsistent dose response notwithstanding, these results show a promising safety and efficacy profile of the drug, corroborating evidence from the previous ARTS trial.9 Pre-clinical studies in rats suggested that finerenone leads to an even greater reduction in proBNP than equivalent natriuretic doses of eplerenone.8 The lack of differences in NT-proBNP reduction between both agents in ARTS-HF is unclear but may be explained by differences in drug metabolism and action in humans. It is worth noting that some imbalances in baseline characteristics existed in the trial, particularly higher baseline NT-proBNP in the eplerenone group and the lowest dose finerenone group. It is also possible that putative beneficial effects of finerenone are independent of NT-proBNP levels, and other cellular mechanisms are involved. In this regard, the results of the exploratory composite endpoint of cardiovascular mortality and hospitalizations in the 10–20 mg group are encouraging, showing the importance of considering the totality of data for drug development at this early stage. Given the low number of events, the high number of comparisons, and the lack of significant differences in the highest dose group, they have to be interpreted with great caution, and confirmation is needed in a larger, sufficiently powered trial. The rate of potassium increase and significant hyperkalaemia was low in the trial, and differences between finerenone and eplerenone were less pronounced than with spironolactone in the ARTS trial.9 This is to be expected given the higher mineralocorticoid receptor binding affinity of spironolactone compared with eplerenone on a mg/mg basis and the higher target doses of finerenone in the ARTS-HF study.11 How would finerenone act in populations with an even higher risk of hyperkalaemia and adverse events, such as patients with severe chronic kidney disease (eGFR <30 mL/min)? This population was excluded in ARTS-HF but also in prior MRA trials, leaving a gap in evidence on a population commonly encountered in clinical practice. In light of the high activation of the renin–angiotensin–aldosterone system and high mortality in this patient subset, a significant clinical need for a designated trial exists. Whether and to what extent finerenone holds its promise to walk the fine line of greater selectivity, greater potency, and fewer side effects, and ultimately provides a net clinical benefit vs. established MRAs in heart failure requires definitive outcome assessment. To this end, a large confirmatory multicentre phase III trial of finerenone in HFrEF patients was recently announced (FINESSE-HF; EUCTR2015-002168-17-SE). It is critical to conduct such trials when there is a potential for a better, safer drug than what is currently available as standard of care to treat such a large, high-risk population as HFrEF. Some may consider it a social contract to those who have volunteered in the past for the clinical development as well as a societal obligation to continuously advance therapies that hold such promise. 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. Conflict of interest: F.R. has nothing to disclose related to the submitted work. Outside the submitted work, F.