Finerenone improves outcomes in patients with mildly reduced, preserved ejection fraction
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Key takeaways:
- Finerenone reduced risk for CV death and worsening heart failure vs. placebo in this patient population.
- Pooled analyses demonstrated the benefits of finerenone and other MRAs in high-risk patients.
In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone reduced risk for CV death and worsening HF by 16% compared with placebo, researchers reported at the European Society of Cardiology Congress.
The results of the double-blind, randomized FINEARTS-HF trial, simultaneously published in The New England Journal of Medicine, mean that finerenone (Kerendia, Bayer), a nonsteroidal selective mineralocorticoid receptor antagonist, represents the second class of drugs to have a positive CV outcomes trial in patients with HFmrEF or HFpEF, following SGLT2 inhibitors, Scott D. Solomon, MD, the Edward D. Frohlich Distinguished Chair and professor of medicine at Harvard Medical School and senior physician and director of the Clinical Trials Outcomes Center at Brigham and Women’s Hospital, told Healio.
“We currently have one clear winner in patients with heart failure and mildly reduced or preserved ejection fraction, which are SGLT2 inhibitors ... and in the U.S. we have the availability of sacubitril/valsartan (Entresto, Novartis), and the FDA has given it an expanded indication for mildly reduced or preserved ejection fraction, but they have qualified that by saying it is most effective in patients with ejection fraction below normal,” Solomon told Healio. “With these data, we are now potentially able to add at least a second pillar ... to SGLT2 inhibitors in treating patients with heart failure with mildly reduced or preserved ejection fraction.”
In related Hot Line session presentations at the ESC Congress, a meta-analysis of trials of MRAs in patients with HF, simultaneously published in The Lancet, showed that the drug class lowers risk for CV death or HF hospitalization by 34% in patients with HF with reduced EF and by 13% in patients with HFmrEF or HFpEF. In addition, the FINE-HEART pooled analysis of the FINEARTS-HF, FIDELIO-DKD and FIGARO-DKD trials, simultaneously published in Nature Medicine, showed finerenone lowered risk for various heart- and kidney-related outcomes in patients with a variety of cardio-kidney-metabolic disorders including HF, diabetes and chronic kidney disease.
FINEARTS-HF
Solomon and colleagues randomly assigned 6,001 patients with symptomatic HF and EF of 40% or more (mean age, 72 years; 45% women; mean EF, 53%) to receive once-daily finerenone (maximum dose, 20 mg for patients with estimated glomerular filtration rate < 60 mL/min/1.73 m2 and 40 mg for patients with eGFR 60 mL/min/1.73 m2) or placebo on top of usual therapy. Median follow-up was 32 months.
“We knew that finerenone was beneficial in patients with chronic kidney disease and diabetes, because there had been two large outcome trials, FIDELIO-DKD and FIGARO-DKD, in that population,” Solomon told Healio. “The efficacy of MRAs at all in patients with mildly reduced or preserved ejection fraction has not been established. The TOPCAT trial tested the steroidal MRA spironolactone in patients with HFpEF. TOPCAT did not meet its primary endpoint, but post hoc analyses suggested there were patients enrolled in that trial, primarily in Russia and the Republic of Georgia, who didn’t actually have heart failure and probably were not taking [the study] medication. A lot of people have said that had we done that trial in the right patients, then there may have been a benefit [for MRAs in HFpEF]. But the data have not been definitive. In the U.S. guidelines, spironolactone has a Class IIb indication. In the European guidelines, it does not have a guideline-recommended indication for this patient population. Therefore, we intended to determine whether finerenone — which is more selective for the MR receptor than steroidal MRAs, has a shorter half-life and has more balanced distribution between the heart and the kidneys — could benefit patients with heart failure with mildly reduced or preserved ejection fraction.”
During the study period, the primary outcome of total worsening HF events (defined as first or recurrent unplanned hospitalization or urgent visit for HF) and CV death occurred 1,083 times in the finerenone group and 1,283 times in the placebo group (rate ratio = 0.84; 95% CI, 0.74-0.95; P = .007; absolute risk reduction, 3.3 per 100 patient-years), Solomon told Healio.
The results were driven by worsening HF events (finerenone, 842; placebo, 1,024; rate ratio = 0.82; 95% CI, 0.71-0.94; P = .006) as opposed to CV death (finerenone, 8.1%; placebo, 8.7%; HR = 0.93; 95% CI, 0.78-1.11), the researchers found. All-cause mortality was not different between the groups (HR = 0.93; 95% CI, 0.83-1.06), Solomon said.
The finerenone group had greater improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score (+ 8 vs. + 6.4; between-arm difference, + 1.6; 95% CI, 0.8-2.3; P < .001), Solomon told Healio.
Serious adverse events occurred in approximately 40% of both groups, he said.
“We saw more hyperkalemia, as expected with a mineralocorticoid receptor antagonist,” Solomon told Healio. “But the incidence of severe hyperkalemia — for example, hyperkalemia leading to hospitalization — was very small, 0.5% in the finerenone group and 0.2% in the placebo group, and there were no cases of hyperkalemia leading to death. We saw considerably less hypokalemia in the finerenone group than in the placebo group.”
Approximately one-fifth of patients in both groups discontinued the study medication before the end of the trial, he told Healio.
The primary endpoint results were consistent across all specified subgroups, and did not vary by sex, EF or whether a patient was taking an SGLT2 inhibitor — “the only current guideline-recommended therapy in this population” — at baseline, he told Healio.
“There is still considerable residual risk in this population despite the use of drugs like SGLT2 inhibitors,” Solomon told Healio. “Here, we have the ability to further reduce morbidity and mortality in these patients. This was a win for finerenone.”
MRA meta-analysis
Pardeep S. Jhund, MBChB, PhD, professor of cardiology and epidemiology at the University of Glasgow and honorary consultant cardiologist at Queen Elizabeth University Hospital, Glasgow, U.K., and colleagues conducted an individual patient-level meta-analysis of four trials of MRAs in patients with HF:
- FINEARTS-HF, which analyzed finerenone in patients with HFmrEF or HFpEF;
- TOPCAT, which analyzed spironolactone in patients with HFmrEF or HFpEF;
- RALES, which analyzed spironolactone in patients with HFrEF; and
- EMPHASIS-HF, which analyzed eplerenone in patients with HFrEF.
In the entire cohort of 13,846 patients, MRAs were associated with reduced risk for CV death or HF hospitalization (HR = 0.77; 95% CI, 0.72-0.83), but the effect size was greater in HFrEF (HR = 0.66; 95% CI, 0.59-0.73) than in HFmrEF/HFpEF (HR = 0.87; 95% CI, 0.79-0.95; P for interaction = .012), Jhund said at a press conference.
MRAs reduced HF hospitalization in all trials, and they reduced CV death and all-cause death in the HFrEF trials but not the HFmrEF/HFpEF trials, according to the researchers.
MRAs doubled the risk for hyperkalemia and halved the risk for hypokalemia, but the incidence of serious hyperkalemia was low, at 2.9%, he said.
“This meta-analysis ... confirms the benefits of MRAs in heart failure,” Jhund said at the press conference. “We should use MRAs in patients with heart failure without a contraindication.”
FINE-HEART pooled analysis
Muthiah Vaduganathan, MD, MPH, cardiologist and co-director of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital and on faculty at Harvard Medical School, and colleagues conducted the FINE-HEART pooled analysis of three trials of finerenone:
- FINEARTS-HF in patients with HFmrEF or HFpEF;
- FIDELIO-DKD; and
- FIGARO-DKD.
“Despite advances in medical therapy, the burden of [cardio-kidney-metabolic syndrome] has remained very high at the population level,” Vaduganathan said at the press conference. “Each of these trials had individual endpoints, but none were individually powered for mortality, so that was of particular importance to this analysis.”
The primary endpoint of CV death did not significantly favor finerenone vs. placebo (HR = 0.89; 95% CI, 0.78-1.01; P = .076), he said.
“We found that a large number of deaths could not specifically be adjudicated as cardiovascular vs. non-cardiovascular etiology, so in a prespecified sensitivity analysis considering undetermined deaths as cardiovascular deaths, that improved the certainty of evidence,” he said. In that analysis, finerenone reduced risk for CV death by 12% (HR = 0.88; 95% CI, 0.79-0.98; P = .025), Vaduganathan said.
In addition, compared with placebo, finerenone reduced risk for all-cause mortality (HR = 0.91; 95% CI, 0.84-0.99; P = .027), HF hospitalization (HR = 0.83; 95% CI, 0.75-0.92; P < .001) and the composite kidney endpoint of sustained eGFR decline of 50% or more, kidney failure or death due to kidney failure (HR = 0.8; 95% CI, 0.72-0.9; P < .001), he said.
The pooled analysis did not reveal any new or unexpected safety signals, and the results were consistent across all subgroups, including whether a patient was taking an SGLT2 inhibitor or a GLP-1 receptor agonist at baseline, he said.
“The totality of evidence supports the disease-modifying potential of finerenone in broad, high-risk populations with overlapping cardiovascular, kidney and metabolic conditions,” Vaduganathan said.
References:
- Jhund PS, et al. Hot line 7.
- Vaduganathan M, et al. Hot line 7. Both presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
- Jhund PS, et al. Lancet. 2024;doi:10.1016/ S0140-6736(24)01733-1.
- Solomon SD, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2407107.
- Vaduganathan M, et al. Nat Med. 2024;doi:10.1038/s41591-024-03264-4.
For more information:
Scott D. Solomon, MD, can be reached at ssolomon@bwh.harvard.edu.
Perspective
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HF with EF of 40% or more is a key population and, for many years, we did not have an effective treatment. Recently, we got positive results from the SGLT2 inhibitors in this population, and some positive results from semaglutide 2.4 mg (Wegovy, Novo Nordisk) in patients with HFpEF and obesity. We also have the very controversial TOPCAT trial, with a famous geographical imbalance. The trial was positive if patients from Russia and the Republic of Georgia were excluded, so many doctors in the Americas have prescribed spironolactone for patients with HFpEF.
However, a problem with spironolactone is that the rates of hyperkalemia are very high, and there is concern that the increased potassium levels may be negative for the patient. Now, we have a nonsteroidal MRA that causes less risk for hyperkalemia than spironolactone. In FINEARTS-HF, we learned that finerenone improves hard endpoints in patients with moderately reduced EF (40%-50%) and HFpEF (over 50%). But the effect size was moderate, 16%, compared with SGLT2 inhibitors, which reduce CV death and HF worsening by 30% to 35%. A reduction in CV death with finerenone was not expected, because there was no reduction in CV death with SGLT2 inhibitors; the results for all have been driven by HF events.
While finerenone is a nonsteroidal MRA and induces less hyperkalemia than steroidal MRAs, the rates of hyperkalemia were higher, almost double, in the finerenone group than in the control group. The rates of hospitalization for hyperkalemia were very low, which is reassuring. Of note, we are starting to become more comfortable with hyperkalemia. In the past, as soon as potassium reached 5 mmol/L, many doctors would stop the MRA for fear of a ventricular arrhythmia. There was a lingering fear about it. But right now, we are starting to realize two things. No. 1, on some occasions, allowing a potassium level up to 5.5 mmol/L does not increase mortality and still gives the patient the benefit of taking the medication. No. 2, SGLT2 inhibitors reduce the rate of hyperkalemia. Almost every patient with HFpEF should be on an SGLT2 inhibitor, so this will reduce the risk for hyperkalemia posed by spironolactone or finerenone.
So far, finerenone is approved for nephology indications, but in my practice, the rate of prescription is very low. When finerenone gets approved by the FDA for HFmrEF and HFpEF, it will definitely be used for that population.
The question will be the price. Finerenone is an expensive medication. Maybe some doctors will continue to prescribe spironolactone, which is much cheaper. The rate of uptake will depend on the approval of insurance companies. Polypharmacy will also be a consideration. Patients with HFpEF are already on many medications, and finerenone would be another. And will insurance companies approve two or all of an SGLT2 inhibitor, a GLP-1 receptor agonist and finerenone for the same patient? None of them are cheap. If cost is an issue, the cardiologist will have to decide which one to focus on. It’s hard to say, but I think some cardiologists will go for semaglutide, because it has additional benefits on the kidneys, as the FLOW trial demonstrated, and on reducing obesity. If there is no problem with insurance approval, then cardiologists will prescribe finerenone to our patients.
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Solomon SD, et al. Hot line 7. Presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
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