Finerenone Fills a Therapeutic Gap in Heart Failure

One of the most eagerly awaited trials presented at the European Society of Cardiology’s 2024 congress in London was FINEARTS-HF, which investigated the efficacy of finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), in patients with heart failure (HF). No previous trial had robustly demonstrated the efficacy of MRAs in HF with preserved ejection fraction (HFpEF), so this was potentially a practice-changing trial that would elevate MRAs as a new therapeutic pillar.
HFpEF is a complex clinical syndrome in which patients have signs and symptoms similar to those associated with HF with reduced ejection fraction (HFrEF). But patients with the latter syndrome have normal or near-normal left ventricular ejection fraction (LVEF), which usually is defined as ≥ 50%. The underlying pathophysiology of HFpEF is increased left ventricular hypertrophy and stiffness that leads to increased left ventricular filling pressure and left ventricular diastolic dysfunction. Many of us in primary care previously called this syndrome “diastolic HF.”
HFpEF is more prevalent with increasing age and is driven by a range of comorbidities, including type 2 diabetes (T2D), obesity, hypertension, and obstructive sleep apnea. HFpEF is also more common in women.
Much of HFpEF is managed in primary care; indeed, many areas in the United Kingdom (including my own) do not have defined HFpEF secondary care referral pathways, which leaves primary care doctors to manage symptoms and comorbidities. This task is challenging because of the associated workload implications, burden on healthcare resources, and longstanding lack of evidence-based therapies. Furthermore, diagnostic coding of HFpEF is heterogeneous in primary care, thus leading to inconsistent follow-up and reduced opportunity for research to improve outcomes for patients with HFpEF. Ongoing education is required to support primary care physicians in the diagnosis and management of HFpEF.
The management of HFrEF is well established. Evidence-based foundational therapy includes renin-angiotensin-aldosterone system inhibitors (RAASi), beta-blockers, MRAs, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are all associated with significant reductions in morbidity and mortality. Until recently, however, there have been no compelling evidence-based interventions to reduce the morbidity associated with HFpEF, and management was largely focused on symptom control and optimization of comorbidities.
The TOPCAT trial demonstrated the potential benefits of spironolactone in HFpEF. This trial did not achieve its primary endpoint (a composite of cardiovascular death, hospitalization for HF, and aborted cardiac arrest). Yet, a post hoc analysis that explored the benefits of spironolactone by geographical region found that patients recruited outside Georgia and Russia (which were deemed problematic study sites) had better outcomes. The exclusion of these sites from the TOPCAT data was controversial. Nonetheless, the US Food and Drug Administration granted an indication for spironolactone for patients with mildly reduced ejection fraction (HFmrEF).
More recently, the EMPEROR-Preserved and DELIVER trials, which studied empagliflozin and dapagliflozin, respectively, robustly established SGLT2 inhibitors as a new standard of care for HFpEF, irrespective of diabetes status. The drugs were associated with statistically and clinically significant reductions in HF outcomes but notably no corresponding reduction in cardiovascular (CV) mortality.
FINEARTS-HF investigated the efficacy of finerenone in addition to usual therapy in HFmrEF and HFpEF (which was defined as LVEF ≥ 40%). The primary endpoint was a composite of total worsening HF events and death from CV causes. 
Finerenone is a nonsteroidal MRA (nsMRA) and, as such, has quite different pharmacokinetics and clinical effects from those of spironolactone and eplerenone, which are steroidal MRAs. Specifically, finerenone does not significantly lower blood pressure and has fewer steroid-induced adverse effects, such as gynecomastia, impotence, and low libido. But like steroidal MRAs, finerenone can also lead to hyperkalemia. 
Previous studies of finerenone (such as FIDELIO-DKD, FIGARO-DKD, and the FIDELITY meta-analysis) have demonstrated robust kidney and CV benefits (including a reduction in hospitalization for HF) across a broad range of estimated glomerular filtration rates and albuminuria in patients with T2D and chronic kidney disease (CKD). FINEARTS-HF, however, is unique in exploring the effects of finerenone in patients without diabetes.
After a median follow-up of 32 months, the rate of the primary endpoint in FINEARTS-HF was significantly reduced by 16% with finerenone compared with placebo. This reduction resulted from a decrease in worsening HF events. This effect is similar in magnitude to the effect seen with SGLT2 inhibitors in EMPEROR-Preserved (21% relative risk reduction with empagliflozin) and DELIVER (18% relative risk reduction with dapagliflozin). 
Importantly, the beneficial effects of finerenone were seen independently of baseline SGLT2 inhibitor use. Only around 13% of participants used SGLT2 inhibitors because study recruitment took place just before SGLT2 inhibitors were approved. Notably, symptoms improved with finerenone, as evidenced by a significant change in Kansas City Cardiomyopathy Questionnaire patient-reported total symptom score.
Again, as with SGLT2 inhibitors, there was no corresponding reduction in CV death with finerenone. This result is likely related to the fact that patients with HFpEF have a higher incidence of death from non-CV causes (related to their comorbidities) than do patients with HFrEF, among whom most deaths have CV origin. The trial may thus have been underpowered to detect a difference in CV death.
Despite significantly affecting kidney outcomes in patients with T2D and CKD, finerenone had no effect on a prespecified kidney outcome, compared with placebo, in FINEARTS-HF. One reason might be that the trial participants were at low risk for progressive kidney disease and had low levels of albuminuria.
With respect to adverse effects, finerenone was generally well tolerated. As expected, more hyperkalemia and less hypokalemia were observed with finerenone than with placebo.
Hyperkalemia is the elephant in the room for primary care; it is the source of much concern. The risk for hyperkalemia is often the main barrier to the wider use of spironolactone for resistant hypertension, as well as a common cause for the premature cessation of RAASi for various indications, including CKD.
But primary care physicians can be reassured that finerenone, compared with placebo, was associated with only a small increase in potassium. Potassium levels > 6.0 mmol/L were recorded in 86 patients in the finerenone group and 41 patients in the placebo group. No episodes of hyperkalemia led to death. Hospitalization occurred in 16 patients in the finerenone group and seven individuals in the placebo group. Nevertheless, primary care physicians will require education and support to encourage the wider use of finerenone among patients with HFpEF, which will address their unmet therapeutic need.
Overall, FINEARTS-HF cements the position of finerenone as a new pillar of therapy for HFmrEF and HFpEF, alongside SGLT2 inhibitors. After lacking effective therapies for many years, we now have two robust evidence-based treatments to help improve quality of life, if not quantity of life, in patients with HFpEF.