Introduction

Jill Frost (DCE): Hello, and welcome to the CCO Medical Specialties podcast. I am your host, Jill Frost. Today's episode features a deep dive into the Pivotal Phase III FINEARTS-HF trial with Dr. Ty J. Gluckman, Medical Director, Center for Cardiovascular Analytics, Research, and Data Science at Providence Health Institute, Providence Health System. Understand how the treatment landscape is evolving for patients with heart failure and mildly reduced or preserved ejection fraction with the emerging role of mineralocorticoid receptor antagonist.

This episode is part of a larger educational program titled Advancing Heart Failure Care: The Expanding Role of MRAs in HFmrEF and HFpEF.

For more information on Dr. Gluckman, along with a link to the larger educational program, please visit the show notes for this episode. Now let us get started and hear what the experts have to say about this important topic.

Dr. Ty Gluckman (Providence Health Institute): Hi, my name is Ty Gluckman. I am a clinical cardiologist in Portland, Oregon, within the Providence Health System, and it is a real pleasure to be chatting today about heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction, and in particular, the opportunity to highlight the role of mineralocorticoid receptor antagonists in this patient population and insights that we have gotten most recently from the FINEARTS Heart Failure Trial.

Before diving into that trial, I think it is important to appreciate the fact that heart failure with mildly reduced ejection fraction, and in particular, heart failure with preserved ejection fraction, represents a sizable portion of the overall heart failure population. In fact, heart failure with preserved ejection fraction constitutes about 50% of all heart failure cases, and in particular, is rising in prevalence as we have an aging population with comorbidities that are increasing in prevalence, namely obesity, hypertension, and diabetes mellitus and the population that has heart failure with mildly reduced ejection fraction and preserved ejection fraction faces substantial increased morbidity and mortality.

It is also important to appreciate the fact that for the last 35 years, we have had tremendous advances in the treatment and management of heart failure with reduced ejection fraction, but we have lagged and had less in terms of available therapies to address these other populations that are growing in prevalence.

Now, when we talk about these populations that have heart failure with mildly reduced ejection fraction and preserved ejection fraction, it is really a key underpinning to realize that overactivation of mineralocorticoid receptors may drive some of the pathophysiologic changes with these conditions, namely myocardial remodeling and fibrosis can be a big driver of these conditions and thus has been a historical rationale for targeting this through the use of mineralocorticoid receptor antagonists.

It makes sense because aldosterone contributes to salt and fluid retention, potassium loss, fibrosis, and inflammation, and in fact works within the kidney, the heart, and the vasculature, and thus it seems rather intuitive that by targeting the mineralocorticoid receptors, you can potentially produce favorable effects by decreasing sodium and fluid retention that can lead to lower preload and congestion. You can decrease myocardial and vascular fibrosis that produces favorable remodeling, and you can decrease inflammatory cytokines and oxidative stress. And ultimately, the hope would be that this translates into improvement in heart outcomes in this population.

When we talk about mineralocorticoid receptor antagonism, it is important to appreciate the fact that historically we have had access to so-called steroidal MRAs, namely drugs like spironolactone and eplerenone, and these are drugs that have less specific selectivity and have the potential of having off-target effects, namely in terms of androgen and progesterone receptors, that may produce other effects, hormonal effects, within the body. They do have established benefits that I will touch on in a moment in terms of the heart failure with reduced ejection fraction population, and their use in patients with chronic kidney disease, particularly in those individuals that may have type 2 diabetes, may be limited by an increased risk of hyperkalemia. And more recently, we have had access to so-called non-steroidal MRAs, drugs like finerenone that have higher selectivity with regard to the mineralocorticoid receptors and therefore an anticipated lower risk of hormonal disturbances overall.

Historically, we have had a range of different trials that have highlighted the benefits of MRAs in heart failure. This began with the RALES trial, introducing spironolactone's use in heart failure with reduced ejection fraction. The EPHESUS trial, introducing the use of eplerenone in heart failure with reduced ejection fraction after a myocardial infarction. This was followed up by the EMPHASIS heart failure trial, using eplerenone in patients with mild heart failure with reduced ejection fraction, mainly defined by those who had myocardial association Class II functional status. And all of these have substantiated the value of using MRAs, specifically the steroidal MRAs, in patients with heart failure with reduced ejection fraction.

Almost a decade ago, we saw data supporting the use of spironolactone in heart failure with preserved ejection fraction in the TOPCAT trial, but really it produced mixed results with no significant reduction in primary outcomes and differences based on whether the study was evaluating patients in the Americas versus non-American sites. And it has raised questions about the role of using MRAs, mineralocorticoid receptor antagonists, in this heart failure with preserved ejection fraction population. The most recent guidelines have introduced this as a Class IIb recommendation, noting that a drug like spironolactone, a steroidal MRA, could be used or may be considered in this patient population.

So, as of today, we have underutilization of MRAs in patients across the heart failure continuum based on ejection fraction, but in particular, this may be driven by less available data for their use in patients with heart failure with mildly reduced and/or preserved ejection fraction. Obviously, this needs to be balanced with the potential for hyperkalemia in patients in particular with chronic kidney disease.

And so, it is a good pivot point at this point to sort of talk about the FINEARTS heart failure trial that was intended to better understand whether we could impart new knowledge and have improved understanding of the role of MRAs in patients with mildly reduced ejection fraction or preserved ejection fraction heart failure to understand the benefits in this patient population.

This was a large trial that looked at individuals with symptomatic heart failure, New York Heart Association Class II-IV, with a left ventricular ejection fraction greater or equal to 40%. They could have ambulatory heart failure or been hospitalized for heart failure. They had to be on diuretic therapy for greater or equal to 30 days before randomization and then have structural heart abnormalities per local imaging along with elevated natriuretic peptide levels.

Just over 6,000 individuals in this randomized-controlled trial were randomized either to finerenone, the non-steroidal MRA, or a placebo with a follow-up over a duration of approximately 36 months. The primary endpoint of this trial was looking at total cardiovascular deaths and heart failure events, and there were a number of key secondary endpoints that were evaluated, including the individual components of the primary endpoint. There was also a look at renal outcomes, all-cause mortality, and change in functional status.

Importantly in this trial, and to be celebrated, nearly half of the individuals enrolled in this trial were female. There was a distribution across the New York Heart Association class continuum of those individuals enrolled in the trial, but it is important to call out that about 70% of individuals were Class II and around 30% were Class III. Approximately 60% of patients had been previously hospitalized for heart failure, and in terms of the ejection fraction, these individuals had an ejection fraction just over 50%. These patients were being treated with standard-of-care therapy, although incorporation of an SGLT2 inhibitor, which was amongst the newest therapies for this patient population, was under 15%.

When one looks at the primary endpoint of this trial, which again was a composite of cardiovascular death and total worsening heart failure events, patients that were treated with finerenone saw a significant reduction in the rate of this primary composite endpoint, with an overall 16% relative risk reduction in that primary efficacy endpoint that was highly statistically significant. The curve separated very early on with consistency of separation over the duration of the 36 months of follow-up in this trial.

When one looks at the other composite endpoints and individual endpoints that were looked at in this trial, it is important to realize that the primary endpoint in this trial was driven disproportionately and overwhelmingly by total worsening heart failure events, such that there was an approximate 18% relative risk reduction that was statistically significant that drove that endpoint over the 36-month duration. In short, when one looks at the composite of cardiovascular death and total heart failure events, it was total worsening heart failure events that drove that primary composite outcome.

There was a statistically significant reduction or change in the Kansas City Cardiomyopathy Questionnaire score, the total summary score, supporting the notion that the benefits conveyed by the use of finerenone not only reduced total events in terms of worsening heart failure events, the composite of cardiovascular deaths and heart failure events, but there was also an improvement in functional status in this patient population.

I think it is always important when we think about digesting a trial like this to ask the question, would the benefits that were observed in this trial be conveyed to the patient sitting in front of me, and in particular, specific subgroups of patients that may be looked at in this trial? So, in an analysis that looked at individual subgroups, whether stratified by their systolic blood pressure being less than or equal to 130 mmHg or greater than 130 mmHg, whether they were previously being treated with an SGLT2 inhibitor or not, whether their estimated glomerular filtration rate was less than 60 mmHg, so-called stage 3 or greater chronic kidney disease, or greater than or equal to 60 mmHg, and whether their index heart failure events was recent, within the last week, was within the last week to 3 months, or whether it was greater than 3 months out, or they had no prior heart failure events, we saw a largely consistent effect favoring finerenone in this patient population.

In short, there was consistency across multiple different groups across this patient population.

Now, although there was a strong favorable benefit to the use of the non-steroidal MRA finerenone in this trial, when one looks at the safety component, most often one thinks about the risk for hyperkalemia, in particular because this patient population is enriched with a group of patients that are more likely to have chronic kidney disease. We know that in individuals with chronic kidney disease who are exposed to MRAs, there is an increased risk of hyperkalemia in this patient population.

In terms of overall serious adverse events of any type, there was no difference between those individuals receiving finerenone versus those receiving placebo. When one also looks at a serum creatinine greater than or equal to 3 mg/dL, that was a prespecified safety endpoint that was evaluated, there was a lower rate of that occurring in those exposed to finerenone compared to placebo. Although it invites questions given the fact that MRA or mineralocorticoid receptor antagonism can have favorable effects in the kidney, this may be evidence of some of the favorable effects that can occur in organ systems outside the heart.

When one looks at the rates of hyperkalemia, we know that individuals who had potassium levels of 5.5 mmol/L or greater, there was an approximate doubling of the rate of that in those individuals exposed to finerenone compared to placebo, and one saw a similar pattern if you used a cut point of greater than 6 mmol/L as a cut point for this analysis as well. Not surprisingly, given the trend towards pushing potassium levels up, rates of hypokalemia, defined as a potassium less than 3.5 mmol/L, were less prevalent, about half as frequent, in those receiving finerenone compared to placebo. And one did see a higher rate of a systolic blood pressure less than 100 mmHg, not surprising given the fact that MRAs are in fact used for treatment of hypertension in other populations as well.

Overall, FINEARTS heart failure represents a pivotal and important trial that adds to our understanding of the role of using a mineralocorticoid receptor antagonist, and in this case in particular, a non-steroidal MRA in patients with mildly reduced and preserved ejection fraction heart failure.

Finerenone in this trial was associated with a significant reduction in the composite of cardiovascular death and worsening heart failure events, a key composite outcome that is looked at consistently in the heart failure population. It was also associated with an improvement in quality of life for this patient population, and represents a tremendous advance insofar as the fact that we have a paucity by comparison to heart failure with reduced ejection fraction in terms of trials that are available to understand the impact on hard cardiovascular events.

The benefits conveyed by finerenone in this trial were consistent across some groups, and we saw this based upon left ventricular ejection fraction range, prior use of an SGLT2 inhibitor across different ranges of renal function. Now, while there was efficacy that was demonstrated by the reduction in this hard composite endpoint, we did see hyperkalemia more frequently in those receiving finerenone, and it strongly reinforces the need to closely monitor and follow individuals exposed to any MRA in cases of heart failure, but in other populations as well, particularly if they have chronic kidney disease as a comorbid condition.

So, as we think about the role going forward of a population that is increasing in prevalence, particularly those with preserved ejection fraction heart failure, defined as a left ventricular ejection fraction greater or equal to 50%, it is really important to realize that other than a loop diuretic being used in patients with symptoms or signs of volume overload, which has received a Class I recommendation in this patient population, and the SGLT2 inhibitor class, which has received a Class IIa recommendation in patients with heart failure with preserved ejection fraction, we really have far fewer therapies available to us, and the mainstay of guideline-directed medical therapy is much less robust, despite being the largest segment of the heart failure population that is growing in prevalence.

The FINEARTS heart failure trial represents a particularly important clinical trial that helps to add to our improved understanding of how best to address this patient population. The role of this non-steroidal MRA, finerenone, showing promise in this patient population of mildly reduced ejection fraction heart failure and preserved ejection fraction heart failure, holds hope that with further guidance that comes out in the future, we will be able to have a broader armamentarium of therapies available to address this patient population, notwithstanding the recognition that finerenone and the role of a mineralocorticoid receptor antagonist can have effects that are favorable in individuals with chronic kidney disease and other patient populations.

In light of the data that I have shared related to the FINEARTS heart failure trial, I am particularly excited by the fact that we have another clinical trial that expands the armamentarium of therapies that we have at our disposal for patients with heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction.

Now, this is important in part because heart failure with preserved ejection fraction constitutes at least 50% of cases of heart failure. It is also the largest growing segment of patients with heart failure. And as we compare and contrast patients who are managed today for heart failure with reduced ejection fraction, where we have a wide array of therapies at our disposal, we have relatively fewer therapies available for those with mildly reduced and preserved ejection fraction heart failure.

Today, our guidelines let us know, as the only Class I recommended intervention or pharmacotherapy, that loop diuretics be used in those individuals with symptoms or signs of volume overload. And as a Class IIa recommendation, we have available or at our disposal the use of SGLT2 inhibitors to help this patient population. Beyond that, we move quickly to the Class IIb recommendations of drugs that may be considered, including an ARNI, or an angiotensin receptor blocker, and the steroidal MRAs like spironolactone and eplerenone.

The data that is available from the FINEARTS heart failure trial substantiates the value of the non-steroidal MRA finerenone in being able to significantly reduce the composite of cardiovascular death and worsening heart failure events driven by a reduction in heart failure hospitalizations. This really holds promise that we have a greater array of therapies, namely the use of finerenone, to be incorporated into our treatment armamentarium, and I hope that we see future guidance and guidelines that incorporates it as a stronger recommendation in this patient population. We will see in the future whether that holds true.

From a safety perspective, MRAs do, whether steroidal or non-steroidal, increase the risk for hyperkalemia. Fortunately, severe forms of hyperkalemia are still rare, but nonetheless, this strongly reinforces the vigilance in monitoring patients for hyperkalemia, particularly if they have chronic kidney disease. And perhaps it comes as no surprise that as we talk about the mechanisms by which MRAs work, that they would have effects that extend beyond the heart into the vasculature and kidneys and hold promise in an ever-growing population with chronic kidney disease with cardiometabolic abnormalities, that we may see an expanded role of MRAs in this patient population overall.

So, as we think about managing, and you think about managing your next patient with mildly reduced ejection fraction heart failure, preserved ejection fraction heart failure, I think it is exciting to think about how we may incorporate finerenone as a non-steroidal MRA into your treatment paradigm going forward.

I hope the information shared here today is helpful. It is been a great opportunity to be able to share new insights from a pivotally important trial, and I thank you for the opportunity.

Jill Frost: Thank you, Dr. Gluckman, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program, Advancing Heart Failure Care: The Expanding Role of MRAs, and HFmrEF and HFpEF, please click the link in the show notes. And be sure to check back regularly for more episodes on important medical specialties topics.