Finerenone Cuts Intensification of Oral Diuretics in Outpatient Setting: FINEARTS-HF

The need to intensify oral diuretic therapy in patients who have heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) is significantly decreased with finerenone (Kerendia; Bayer), a new analysis of the FINEARTS-HF study shows.  

The intensification of oral diuretic therapy in the outpatient setting was not part of the study’s primary endpoint of worsening HF or cardiovascular mortality, but it happened frequently within the randomized trial and was associated with worse prognosis, report investigators. 

“We’ve always focused on heart failure hospitalization or death as the outcome in clinical trials, but we know that many patients experience what we call worsening heart failure without hospitalization,” said lead investigator Jonathan Cunningham, MD, MPH (Brigham and Women’s Hospital, Boston, MA). “Patients may be treated in the outpatient setting, rarely with intravenous diuretics in a specialty clinic, but far more commonly with just an increase in their oral diuretic medication.”

The study, which was published last week in JAMA Cardiology, showed that subsequent mortality following oral diuretic intensification was roughly 2.5 times higher than in patients without any worsening HF.

“In clinical practice and clinical trials, we would do well to recognize patients with worsening heart failure agnostic to the setting,” said Cunningham.

In the FINEARTS-HF trial, published in 2024, treatment with finerenone reduced the study’s primary endpoint of first worsening HF events or cardiovascular mortality by 16% when compared with placebo in 6,001 patients with HFmrEF/HFpEF. Worsening HF events, defined as either a hospitalization or urgent HF visit requiring intravenous diuretics, were reduced by 18%, but there was no significant difference in the risk of cardiovascular mortality.

Tariq Ahmad, MD (Yale School of Medicine, New Haven, CT), who wasn’t involved in FINEARTS-HF, said the intensification of oral diuretic therapy, as an endpoint, isn’t clinically meaningful to most practicing clinicians. Moreover, the effect of finerenone on reducing the event—finerenone cut the need for intensification by 11%—was very small.

Ahmad, who is the chief of the Yale HF program, said the number needed-to-treat to prevent a single patient from requiring intensified oral diuretic therapy would be quite high, and that’s a tough ask from an expensive medication when spironolactone is available as a cheaper option. Moreover, he questioned the need for intensified oral diuretic therapy as an additional outcome to study when it is not that dissimilar to what has been previously published.

“Obviously, there’s a role for pharmaceutical studies in medicine, but there needs to be a little bit of a balance between helpful publications and lots of similar studies about an agent with a modest overall benefit,” he told TCTMD. “I don't know how you would tell this story to frontline clinicians.”

Even in the main trial, the reduction in the primary endpoint was driven by fewer HF hospitalizations, which is already a softer endpoint in cardiovascular medicine. This new analysis is simply a “different way of looking at the same thing” but adds little helpful information for doctors in clinical practice, said Ahmad.  

To TCTMD, Cunningham said the analysis should be viewed as exploratory, though he pointed out that while outpatient oral diuretic intensification can be seen as a milder or earlier form of worsening HF, “it’s still a lot worse than not having any” type of worsening morbidity. Some of these patients may progress to require hospitalization while others will recover from this milder stage and not move into worsening states of progression, he noted. 

Exploratory Expanded Endpoint

In FINEARTS-HF, there were 1,250 patients who required oral diuretic intensification in an outpatient clinic, 664 who experienced a first HF hospitalization, and 87 who needed an urgent HF visit for intravenous loop diuretics.  

The median time from randomization to requiring intensified oral diuretic therapy was 146 days, which was less than the median times from randomization to an urgent HF visit or HF hospitalization (221 and 309 days, respectively). Intensified oral diuretic therapy included patients started on a loop diuretic, had an increase in the loop diuretic dosage, and those started on a thiazide diuretic.

In clinical practice and clinical trials, we would do well to recognize patients with worsening heart failure agnostic to the setting. Jonathan Cunningham

Subsequent mortality was higher in those who had a worsening HF event than in those who did not, but mortality was highest for patients hospitalized for HF (27.7 deaths per 100 patient-years). Subsequent mortality for patients treated as an outpatient for oral diuretic intensification and those who required an urgent HF visit was 11.6 and 13.6 deaths per 100 patient-years, respectively. For those who did experience a worsening HF event, the subsequent mortality rate was 4.5 events per 100 patient-years.

In the trial, finerenone cut the risk of outpatient oral diuretic intensification by 11% compared with placebo (HR 0.89; 95% CI 0.80-0.98).

When investigators looked at an expanded primary endpoint that included the need for upped intensity of oral diuretics as part of worsening HF events, the number of patients experiencing an event increased from 1,343 to 2,238. Here, finerenone cut the risk of the expanded composite endpoint by 15% compared with placebo (HR 0.85; 95% CI 0.78-0.92).

Cunningham was encouraged that finerenone cut the risk of oral diuretic intensification. “It provides additional evidence for clinicians and supports the use of finerenone in this [HFmrEF/HFpEF] population,” he said.

Outpatient vs Inpatients HF Events

Gregg Fonarow, MD (University of California, Los Angeles), and colleagues, in an editorial, point out that intravenous diuretics and escalated HF care are frequently handled in the outpatient setting. Like Ahmad, the editorialists weigh the utility and practicality of tracking the need for oral diuretic intensification, which they say is a “more accessible initial treatment for worsening heart failure.”

They point to the DELIVER trial with dapagliflozin (Farxiga; AstraZeneca) where patients with HFmrEF/HFpEF requiring outpatient oral diuretic intensification were at a higher risk of subsequent hospitalization and mortality. Along with the new FINEARTS-HF analysis, the data suggest it could be a clinically meaningful part of a primary composite endpoint in HF trials, but there are caveats.     

“A therapy that impacts outpatient diuretic intensification episodes alone without any effect on HF hospitalization or cardiovascular mortality is not likely to be considered clinically relevant, without compelling data, enough to support the long-term use of an expensive new therapy,” write Fonarow et al.

In clinical research, this would be a softer endpoint relative to HF hospitalization, and that might create a “false perception of HF disease progression,” they write.

Am I going to [reach] for expensive medication with a not very low number needed to treat, especially when another cheaper therapy is available? Tariq Ahmad

The SUMMIT trial defined worsening HF event as intravenous therapy in an urgent care setting or intensification of oral diuretic therapy. For SUMMIT, though, oral diuretic intensification had to be accompanied by signs and symptoms of HF, something the FINEARTS-HF investigators didn’t require for their analysis.

To TCTMD, Ahmad said the new analysis might be academically interesting for trialists, but he worried about an increasing gap between clinical trials in HF and patient care.

“You end up viewing the patient as a clinical trial [as opposed to] an individual basis,” he said. “Many of the patients I have with heart failure are elderly, on a fixed income. Am I going to [reach] for expensive medication with a not very low number needed to treat, especially when another cheaper therapy is available? Is this truly patient centered care?”