Topline results from the FINEARTS-HF trial of finerenone showed a significant reduction in cardiovascular death and recurrent heart failure in patients with midrange and preserved left ventricular ejection fraction (LVEF).
The new topline results suggest treatment with finerenone leads to a meaningful reduction in major adverse cardiovascular events. And if the final results hold up at the late-breaker trial presentation at the European Society of Cardiology (ESC) Congress 2024 in London, it could be practice-changing.
Anticipation is high for new level 1 evidence for a drug with which there are already years of experience. And there is speculation that surprises about the safety of the mineralocorticoid receptor antagonist (MRA) are unlikely given that it has already been available in the United States and elsewhere for several years for other uses.
The FINEARTS-HF trial is important because options are limited for the treatment of patients with heart failure with midrange (HFmrEF) or preserved (HFpEF) ejection fraction. Treatment advances over the last 30 years have already helped people with heart failure with reduced ejection fraction (HFrEF). But for patients with midrange or preserved disease — typically defined as LVEF ≥ 40% to 50% and LVEF ≥ 50%, respectively — there hasn’t been much help.
A New Option
“This is a population for which there is still a huge unmet need,” said principal investigator Scott D. Solomon, MD, director of the Clinical Trials Outcomes Center at Brigham and Women’s Hospital in Boston, Massachusetts. “Currently, the only definitive therapies are sodium-glucose cotransporter 2 inhibitors,” he said, pointing out that the US Food and Drug Administration has also allowed sacubitril plus valsartan treatment for some patients.
Although researchers have watched a signal of benefit in HFmEF and HFpEF with MRAs, the FINEARTS-HF trial is the first phase 3 double-blind multinational trial to confirm improved outcomes in this population, said Solomon.
In the FINEARTS-HF trial, about 6000 patients with symptomatic heart failure but LVEF ≥ 40% were randomized to the nonsteroidal selective MRA finerenone or placebo and then followed for up to 42 months. Finerenone is approved worldwide for the treatment of chronic kidney disease associated with type 2 diabetes.
The primary outcome was a composite of cardiovascular death and heart failure events, whether first or recurrent, defined as hospitalization or urgent healthcare visits for heart failure.
In TOPCAT, conducted by the National Institutes of Health and published 10 years ago, investigators compared spironolactone with placebo but the trial “missed the primary endpoint,” said Solomon.
A Look Back at TOPCAT
In terms of the primary composite endpoint of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure, the rates in TOPCAT were lower among those randomized to the MRA spironolactone than placebo (18.6% vs 20.4%; P=.14) but it was only a trend. Hospitalization for heart failure was the only outcome of the composite endpoint that reached significance (P=.04).
“After the trial was unblinded, it was discovered that patients enrolled in Russia and the Republic of Georgia had very low event rates most likely because they did not have heart failure. In the patients enrolled in the Americas, there was a post-hoc suggestion of benefit,” Solomon said.
The new study in patients with heart failure with LVEF ≥ 40% is one of several in a program of investigations called MOONRAKER that was created to evaluate the effect of finerenone across the spectrum of heart failure severity as defined by heart function and symptoms.
The trial design of FINEARTS, published earlier this year, had numerous entry criteria, such as use of a diuretic for ≥ 30 days and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (≥ 300 pg/mL), to ensure a population with symptomatic and physiologic heart failure were enrolled.
In chronic kidney disease for which finerenone is now indicated, it is postulated that the relative selectivity of this MRA might be relevant to its inhibition of mineralocorticoid receptor overactivation, a purported mechanism of benefit.
Although many clinicians considered the signal of benefit in TOPCAT with MRA therapy in heart failure to be sufficient to consider it an option, according to Solomon, FINEARTS is now expected to provide level 1 evidence.
A ‘Major Advance’ on the Way
“We will have to see the final results, but FINEARTS-HF appears to be a major advance in the field of heart failure,” said Deepak L. Bhatt, MD, director, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai in New York City.
“I was hoping and expecting that this trial would be positive, so I was happy to see the press release,” he added. Like Solomon, he was already inclined to expect a benefit from MRA in heart failure patients with relative preserved ejection fraction based on the TOPCAT post-hoc analyses. Bhatt said FINEARTS-HF topline results now “prospectively validates the hypothesis, albeit with finerenone.”
Bertram Pitt, MD, professor emeritus, University of Michigan at Ann Arbor, and a principal investigator of many of the MRA trials in heart failure, including TOPCAT, said that the positive topline results of the FINEARTS-HF trial “validates our efforts over several years evaluating the role of MRAs in patients with heart failure across the spectrum of LVEF.”
Also a coauthor of FINEARTS-HF, Pitt was the first author of the 2023 EPHESUS trial that established the steroidal MRA eplerenone as a standard of care in patients with HFrEF.
While FINEARTS appears to establish MRA therapy in any degree of left ventricular dysfunction, Pitt says new studies will be needed to assess the differences in efficacy and safety, if any, between the nonsteroidal finerenone and the steroidal MRAs eplerenone and spironolactone.
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