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Scott Solomon, MD, of Brigham and Women's Hospital, discusses how baseline patient characteristics inform what cardiologists might learn from the FINEARTS-HF trial, which he presented at Heart Failure 2023.
At the Annual Congress of the Heart Failure Association of the European Society of Cardiology (Heart Failure 2023), the heart failure community were given the latest glimpse into the FINEARTS-HF trial.
A trial examining use of finerenone (Kerendia) in a cohort of patients with heart failure with mildly reduced or preserved ejection fraction, baseline data from the study cohort were presented by Scott Solomon, MD, director of the Clinical Trials Outcomes Center and Edward D. Frohlich Distinguished Chair at Harvard Medical School, which provided members of the community with context into the historic nature of the trial and the cohort.
According to data presented at the meeting, the trial has enrolled 6014 participants. For inclusion in the trial, patients were required to be 40 years go age or older, have a left ventricular ejection fraction equal to or greater than 40%, have a serum potassium level of 5.0 mmol/L or less, and have an eGFR of 25 ml/min/1.72m2 or greater. Investigators pointed out the study population for those with an ejection fraction equal to or greater than 60% was capped at 20%. Of note, patients were excluded if they reported MRA use within 30 days of randomization, had a history of MI or any event that could have reduced ejection fraction within 90 days of randomization, or if they had a systolic blood pressure equal to or exceeding 160 mmHg.
Billed as a “broadly inclusive trial”, the overall study cohort had a mean age at baseline of 72 (SD, 10) years, 45% are female, and 79% were White. Further analysis of baseline characteristics revealed 99% of patients had NYHA Class II or III heart failure, the mean KCCQ-TSS was 67 (SD, 24), the mean left ventricular ejection fraction was 53% (SD, 8), and 39% of the cohort had atrial fibrillation or flutter on enrollment.
Overall, 60% of the study population had a prior hospitalization for heart failure, 89% had a history go hypertension, and 41% had a history of diabetes. When examining baseline medication use, results indicated 98% were using diuretics, 85% were using a beta-blocker, 14% were using an SGLT2 inhibitor, 33% were using calcium channel blockers, 80% were using ACEi/ARB, and 9% were using ARNI.
According to Solomon, FINEARTS-HF will have the highest percentage of hospitalized or recently hospitalized patients of any contemporary HFmrEF/HFpEF outcomes trial and be the first outcomes trial to test the efficacy of finerenone in patients without diabetes and across a broad range of renal function. During his presentation, Solomon noted plans to pool data from FIDELIO and FIGARO with FINEARTS-HF for a prespecified pooled patient-level analysis, which should provide insight into the effects of finerenone across a wide range of Cardiometabolic disease and patients characteristics.
With an interest in learning more about the trial, data presented at Heart Failure 2023, and what we might expect to learn from the FINEARTS-HF trial in terms of clinical applicability, HCPLive Cardiology sat down with Solomon following his presentation and that conversation is the subject of the following Q&A.
HCPLive: Can you provide some context for the magnitude of this trial, both in terms of impact on care and the historic nature of the cohort?
Solomon: So, we've been working for many, many years trying to find therapies for patients with heart failure with an ejection fraction over 40%, which is this group that we now call heart failure with mildly reduced or preserved ejection fraction. The first indication in the US for these patients was sacubitril/valsartan. Then following that, we had some very impressive success with the SGLT2 inhibitors in this population. I presented the results of the DELIVER trial last year at the ESC, showing benefits across the spectrum of ejection fraction with SGLT2 inhibitors.
We've been treating patients with heart failure and reduced ejection fraction with steroidal mineralocorticoid receptor antagonists, notably spironolactone and eplerenone, for some time, with tremendous evidence that those therapies, in that population, reduce morbidity and mortality. We had conducted a trial about 15 years ago called TOPCAT with spironolactone in the heart failure with preserved ejection fraction cohort that fell somewhat short of its primary endpoint. There were some issues with that trial, including patients who were enrolled in other parts of the world who may not have had the syndrome of heart failure, but there was some suggestion that there may be benefits of MRAs in patients with heart failure with preserved ejection fraction and mildly reduced ejection fraction.
We have now undertaken to study this in FINEARTS with the nonsteroidal mineralocorticoid receptor antagonist finerenone, which differs from the drugs that we've used in the past—the steroidal MRAs like spironolactone and eplerenone. There's a different tissue distribution between the heart and the kidney that presents a more balanced distribution, which we think should lead to better overall effects on the kidney with fewer safety concerns, including hyperkalemia and renal dysfunction that we tend to see with traditional steroidal MRAs.
As you know, this therapy has already been tested in the FIDELIO and FIGARO programs. Interestingly, if you go beyond the renal outcomes in FIDELIO and FIGARO, you see a reduction in cardiovascular death and nonfatal MI, nonfatal stroke, and hospitalization for heart failure—a pretty dramatic reduction in that population, which consisted of patients with type 2 diabetes and chronic kidney disease.
The FINEARTS-HF population has patients with heart failure with mildly reduced or preserved ejection fraction who were either hospitalized, recently hospitalized, or ambulatory. This is the first trial that will look at finerenone in patients with and without diabetes. It is the first outcomes trial to examine it in patients with and without diabetes and across a very broad range of kidney function. We have already enrolled 6,014 patients across 37 countries, and it is a somewhat higher-risk population than some of the other trials like DELIVER, EMPEROR-PRESERVED, or PARAGON. This is primarily because we have enrolled people who are not just ambulatory, but there is also a fairly large subset of patients who were enrolled either in the hospital or within 7 days of a hospital admission. In total, they make up about 20% of our patients, and an additional 34% encompasses people between a week and 3 months since a heart failure hospitalization, while the remaining 46% are either beyond three months past a heart failure event or have never had a prior heart failure event. So, this will be a relatively high-risk population.
We believe that there's a lot we can learn here. First of all, it is a distinct population compared to FIGARO and FIDELIO. That was not a heart failure population; there were some people with heart failure, and there were probably people who were at risk for heart failure, but the FINEARTS-HF participants are patients who have already been diagnosed with heart failure.
We expect that a lot of these patients will be on other therapies for heart failure and hypertension, which are very, very common in this population. We expect to complement the data from FIDELIO and FIGARO. In fact, we will pull the data from those trials as well with FINEARTS-HF so that we can really examine it across the full spectrum of ejection fraction in overlapping populations with renal disease, diabetes, and heart failure.
HCPLive: When speaking with clinicians, many express concern over the risk for hyperkalemia with finerenone. With this trial provide any answers to questions surrounding this potential increase in risk?
Solomon: Of course. We are obviously looking very carefully at hyperkalemia. Any mineralocorticoid receptor antagonists will have a risk of hyperkalemia—there is no question about that. There is at least some data to suggest that, compared to spironolactone, finerenone may have the same degree of potency with a lower risk of hyperkalemia. That's something we're going to observe in this trial. One thing that we always forget is that one of the reasons MRAs may have proven useful in heart failure with reduced ejection fraction is that they raise potassium because hypokalemia is as much of a risk factor as hyperkalemia. Potassium doesn't usually cause a problem until it reaches a fairly high range of about 6 mmol. Many of our patients with heart failure, especially those who are on diuretics, end up having very low potassium, which predisposes them to sudden cardiac death. So, one of the benefits of MRAs may be to raise potassium levels slightly. However, if your potassium is already high to begin with, that could be a problem, and that's something we are watching very carefully in this trial.
HCPLive: With sacubitril/valsartan and SGLT2 inhibitors, HFpEF has undergone a revolution in recent years. Looking ahead, if this trial were to prove benefit in this population, could this be the third paradigm-shifting therapeutic advance for heart failure in a decade?
Solomon: Well, I don't like to make predictions, especially about the future. However, I can tell you that I think it is very likely that, in heart failure with mildly reduced and preserved ejection fraction, we will be using multiple therapies in the future. We now have multiple therapies available, and SGLT2 inhibitors are expected to become the standard of care in this group. I suspect that all the guidelines will soon reflect this. In the US and in around 30 other countries, sacubitril/valsartan is currently indicated for some patients in this group. It would not surprise me if, based on the results of this trial, finerenone could potentially become a third treatment option in our arsenal for these patients. We need to see which patients will benefit in the FINEARTS trial and to what extent, and how it may be distinguished from the steroidal MRAs that we are currently using in some of these patients.