Mineralocorticoid Receptor Antagonists in Heart Failure: The Evolving Treatment Landscape

Announcer:
Welcome to CME on ReachMD. This activity, titled "Mineralocorticoid Receptor Antagonists in Heart Failure: The Evolving Treatment Landscape,” is provided by Voxmedia.

Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements as well as the learning objectives.

Dr. Butler:
Let's start with the aldosterone pathophysiology, MRAs, and outcomes in heart failure with reduced ejection fraction.

Now, obviously, aldosterone, we know about it from a physiologic perspective for sodium and water balance, and it is critical for the normal functioning of the body, for normal functioning of aldosterone as well. However, the problem is the aldosterone dysregulation and dysfunction. And when I say aldosterone dysregulation or dysfunction, we have all been sort of thinking about Conn’s syndrome and primary hyperaldosteronism, adrenal adenomas, and that is sort of one extreme. The issue is inappropriate aldosterone levels which may be normal for any given PRA that may be suppressed as well. So, what we are talking about chronic exposure to aldosterone dysregulation that has been associated with various different pathophysiologic abnormalities that are shown in this slide. These are either secondary activation of the neurohormonal system or primary effects on the various different organ system that leads to dysfunction over time.

The primary driver of the aldosterone physiologically is angiotensin II. So at one point we did feel that giving somebody an ACE inhibitor would be great not only for the angiotensin II-related adverse effect but also aldosterone-related adverse effect because suppressing the angiotensin II production will decrease aldosterone levels as well. And indeed if you look at the top panel that is the case that when you give somebody an ACE inhibitor, their ACE activity goes down, and if you look at the bottom panel, their initial aldosterone level goes down pretty substantially. The problem is this phenomenon called aldosterone breakthrough, whereby after a few days of therapy with ACE inhibitors, aldosterone level through alternate pathway, chymases, and other pathway starts being produced by the body, and the aldosterone level goes up. And therefore, we have now established that you need dual therapy to have adequate aldosterone modulation.

Initially, most of the data for aldosterone came with hypertension. The higher the aldosterone level, more the hypertension, and hence aldosterone antagonism as a drug of choice for patients with resistant hypertension. But soon it became evident that not only is it important in terms of sodium and fluid regulation and hypertension, but actually the end organ damage and associated cardio, kidney, and other outcomes as well. The higher the aldosterone level, the worse the outcomes in patients with heart failure, and that is true both for heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.

So now the story builds. There is pathophysiology. There is end organ damage from a pathophysiologic perspective, and now there is correlation of worse outcomes with aldosterone levels and outcomes in both heart failure with reduced and preserved ejection fraction.

Similarly, there are a couple of studies that also show that patients, when they come in with myocardial infarction, the higher their aldosterone level, the worse the outcomes for these patients. Again, a couple of different cohorts have shown that as well.

So naturally, the next step was to use aldosterone antagonist in patients with heart failure, and the highest need in the beginning was heart failure with reduced ejection fraction. Remember that the RALES trial was done in an era where the heart failure therapy was largely digoxin and diuretics, and ACE inhibitors were being established at that time- maybe it's me actually, so let me just take this out. Okay - was being developed at this time. So remarkable results in the RALES trial. These were really sick patients with heart failure. Smaller study, even in 6 months, you saw pretty remarkable benefit, and then the benefit continues to accrue. This was the steroidal MRA spironolactone that was assessed. Significant improvement in patients with severe symptomatic heart failure.

That led to the door to look at in more expanded population. One problem with steroidal MRA was the progestational side effects. The one was obviously hyperkalemia, which is a pervasive problem across all aldosterone antagonists. Whether it is steroidal MRA, nonsteroidal MRA, or aldosterone synthase inhibitor. But then with steroidal MRA there are specific progestational side effects because they are non-selective, so gynecomastia and menstrual abnormalities. So that did become a little bit of a problem.

So now that we have data with severe heart failure, what about just more run-of-the-mill, milder forms of heart failure with reduced ejection fraction that was assessed in the EMPHASIS trial. And again, a large outcomes trial showing consistency of benefit, cardiovascular death, heart failure, hospitalization, with now not spironolactone but with eplerenone, another MRA, showing benefit. If you look at the secondary endpoint of mortality itself, that was also statistically significantly reduced, with a pretty significant reduction in the hazard ratio, about a 24% relative risk reduction. Heart failure hospitalization even more impressive result over 40% relative risk reduction.

So at this point we had the data for patients across the spectrum of severity of heart failure, both with mild, moderate, and severe heart failure. So the natural extension is post myocardial infarction risk of heart failure, and whether that could be mitigated, that was assessed again with eplerenone in the EPHESUS trial post MI patients, acute MI with evidence of congestion or diabetes or EF less than 40%, and again very consistent with the other trials benefit, significant relative risk reduction in total mortality and new onset heart failure as well in this trial.

So now we sort of have check, check, check across the spectrum of post MI heart failure, chronic heart failure, mild to moderate symptoms, and severe symptoms across the entire spectrum with MRAs. One thing that we did realize that in the setting of acute MI, it does matter that we need to be initiating these therapies earlier rather than later. So the sooner we start the therapy, the better it is. And therefore, this became the Class I recommended therapy for patients with heart failure, barring any contraindication. The two things to worry about that, all of this data was generated in patients with GFR less than 30. This is a little bit of a problem, and the reason why it is a little bit of a problem is because as heart failure progresses, invariably the renal function gets worse, and a lot of our sickest patient in highest need for therapy do not get the therapy because either they have never been tested. There is contraindication for MRA use less than GFR of 30 and hyperkalemia. But the bigger problem is the is the perceptual problem that even—or not necessarily perceptual but a real problem, that even if the GFR is greater than 30, there is no absolute contraindication that clinicians are worried about hyperkalemia, and the rates start going down with the GFR below 60, and especially GFR below 45.

Now, because of this issue of either real risk or perceptual risk, the problem is that that clinician makes decision based on a whole lot of conscious and subconscious input. But this also includes discussing it with the patients, and sometimes there are patient preferences. But also importantly, when there are older patients, patients with multimorbidity, lower GFR, diabetes, all of this sort of mixture that puts them at higher risk of hyperkalemia, that even if they don't have any history of hyperkalemia, it is one thing to have either contraindication, GFR less than 30, serum potassium more than 5.2-5.5. So that's one category. The second category is you don't have contraindication, but you tried it, you fail. Hyperkalemia occurred. You stop the drug, you reinitiate it. Hyperkalemia reoccurred. Okay, so you're not giving it.

But then there is a third category, and we are learning more and more about this category. That many patients who don't have an absolute contraindication, who have never been tried on an MRA, but they simply don't get started on MRA for the fear of hyperkalemia. And while it is easy for us to say that, oh, the clinicians are being too cautious, maybe that there are some real concerns. I mean, older patients, patients who live far away, patients who don't have home health, we don't have functional approved home testing for serum potassium yet. So if you cannot closely monitor somebody and somebody have multimorbidity that puts them at a higher risk of hyperkalemia, I can at least empathize with the clinician's perspective that a lot of the time the therapy is not given. The bottom line here is again going back to the same conundrum we have: our sickest patients who need the therapy the most, who are at the highest risk, are the least likely to get therapy.

So I'm going to quote a whole lot of papers that all of them are written by Dr. Steve Greene, and he has done tremendous work in this field overall. So these are some data from cardiology and primary care practices, which were audited, again, significant lack of GDMT use. But as you can see, the highest gap was seen with mineralocorticoid receptor antagonists. Less than 1/3 of the patients were on MRA.

This is Get With The Guidelines, again, highlighting post discharge use of the patients, and again ample opportunities across disease states. But you can see that it is one thing. You know, you would have hoped that the patients in the outpatient were getting appropriate therapy so that they don't get hospitalized in the first place. But once they get hospitalized, the risk is really accentuated. So you would think that that would really alarm folks to go ahead and start the medication. But you can see what a few percentage of patients post discharge shown here in the pink bars get started on MRA therapy overall.

This is another database from US Optum database again showing different studies. Maybe the numerical differences are there. Here, about 40%, 60% of the patients not getting MRA. Again, the consistent message is that majority of the patients are not getting MRA for heart failure.

Once you initiate the therapy for whatever reason, for complications, for intolerance, for whatever reason, the discontinuation rate of all the RAAS inhibitors is the highest for MRA. Again, even if you start the therapy. One big issue is the therapy never gets started. But the other issue is if the therapy does get started, it gets discontinued frequently for intolerance. And this discontinuation is not benign. When you discontinue the therapy, these patients are at a higher risk for worse outcome for cardio-kidney outcomes overall, which begs the question that our sickest patient who need the therapy the most, you cannot give them the therapy. You stop the therapy, and their outcome gets worse. All of this makes sense, and all of this is well documented. Then we need solutions. We either need therapies that have aldosterone modulation properties, and they don't have as much risk of hyperkalemia, or we need alternate ways with potassium binders or something like to facilitate the use of MRA. But the bottom line is that aldosterone discontinuation is not a good idea. The previous slide I showed you was from US cohort Optum database, and this is from European cohort. Again, showing the same consistent message overall.

So now we do have two different kinds of MRAs: nonsteroidal MRA and steroidal MRA, and they are fundamentally different MRAs. One, spironolactone gets converted to canrenone, which has a very, very long half-life, whereas finerenone, nonsteroidal MRA, has a shorter half-life. The way they bind to the receptor and the receptor conformational change, that also makes some difference in terms of the competitive agonism with aldosterone. Downstream genomic effects and the gene regulation, again, basic sciences study tell us that there are differences in terms of regulation of the gene that causes fibrosis and inflammation. In terms of the body distribution, finerenone is more distributed equally between the heart and the kidneys, whereas the spironolactone is more targeted towards the kidney function overall, whether that has something to do with higher risk of hyperkalemia, I don't know.

So there are all of these differences, but then these differences get translated into differences in clinical outcome behavior that we see also. Now again, we would love to have head-to-head studies, which we don't. So now we are sort of looking at the effect of various things like diabetes and atrial fibrillation and all of those across various different trials. And I think Dr. Vaduganathan is going to expand on that as well. But to suffice it to say that these drugs are not all the same.

So with that said, aldosterone dysregulation is associated with worse cardiovascular outcomes, aldosterone modulation improve outcomes in patients with heart failure, with reduced ejection fraction. However, the steroidal MRAs are significantly underprescribed because of either actual or feared complications resulted to that, and that steroid and nonsteroidal MRAs have distinct pharmacokinetic and pharmacodynamic profiles.

And with that, I will turn it over to the next speaker. Thank you very much.

Dr. Vaduganathan:
Alright. Thank you, Javed, and thank you all. I will continue this with discussion of some of the clinical data in heart failure with mildly reduced or preserved ejection fraction. And I'd like to continue this theme of why would an MRA with slightly different maybe molecular structure or chemical structure actually have a different downstream effect on patient outcomes. And part of that relates to how aldosterone actually affects clinical risk. And so you see aldosterone here, unlike typical cell surface receptors, aldosterone actually doesn't bind predominantly to cell surface receptors. Instead, it actually needs to get into the nucleus, bind to, and ultimately affect downstream gene transcription. And as such, the actual chemical confirmation of any agonist or antagonist of aldosterone can have profound effects on downstream protein regulation.

And we heard that there is now a very large wave, and we've all had- spironolactone, eplerenone have been household names for decades in cardiovascular practices, but in the last just years, we've seen a tremendous growth in drug discovery with more specific inhibitors of the mineralocorticoid, trying to achieve that holy grail that Javed set up of antagonizing the mineralocorticoid receptor without attendant risks of hyperkalemia.

So, in terms of heart failure with preserved ejection fraction, the first major trial was the TOPCAT trial. This was now a decade ago of spironolactone across six countries globally in about 3,400 individuals. This was an NIH sponsored trial, and unfortunately, the trial missed its primary endpoint of cardiovascular death, reported cardiac arrest, and hospitalization for heart failure, and did have some increased risk of hyperkalemia and worsening kidney function. But importantly, there was marked regional heterogeneity in this trial, such that it appeared that some countries—patients in some countries—appeared to benefit, whereas in other countries they didn't benefit, and notably in certain countries, especially the Russia and Georgia, there was concerns around protocol deviation, study conduct issues that patients may not actually have been receiving the study drugs. And even when measuring that metabolite that Javed mentioned, canrenone, in patients' urine, she found that disproportionately in Russia and Georgia there was limited drug adherence and study protocol deviations. And as such, this introduced significant complexity in the interpretation of the TOPCAT trial, and so we look forward to subsequent trials with spironolactone in HFpEF.

So, just at the American College of Cardiology meeting, a second spironolactone trial was announced, and this was a German national trial, initially anticipated to have about 1,300 individuals enrolled. Unfortunately, it was stopped early due to loss of funding, and ultimately enrolled 730 patients, and as such was largely underpowered to assess its primary outcome. And for what it's worth, these are the results. And as you can see, there was still no difference observed with spironolactone compared with placebo in this population. Furthermore, this was a lengthy trial and was confounded and affected by COVID-19. And there was very, very high rates of drug discontinuation. Even approaching 50 to 60% of patients were not on the assigned study drug by the end of the trial.

And so these are two shots on goal. And unfortunately, we don't yet have evidence that spironolactone is actually effective in this population at higher ejection fractions. And this is much different from the very strong data from heart failure with reduced ejection fraction with RALES and EMPHASIS-HF.

So now enter more specific inhibitors of the mineralocorticoid receptor, including nonsteroidal MRAs such as finerenone. And so I'll discuss finerenone quite a bit because it's the nonsteroidal MRA with the greatest body of evidence at present. But there are others that are being studied and underway.

So FINEARTS-HF was the definitive trial that studied finerenone in heart failure with preserved ejection fraction. This was a large-scale global trial conducted across 6,001 participants. Patients were randomized to finerenone, targeting either 20 or 40 mg, depending on the patient's GFR and compared with against placebo, and patients were followed for on average about 2 to 3 years for outcome assessment. And the trial actually met its primary endpoint with a 16% reduction in the primary outcome of cardiovascular death and total worsening heart failure events. This was largely driven by a reduction in total worsening heart failure events. There was also concomitant improvements in health-related quality of life.

And so I thought that it would be helpful, and especially since we are in the World Cup season, that we could do some head-to-head comparisons here, and these are unfortunately indirect comparisons. The key limitation to all this discussion is that we don't have direct randomized evidence of a nonsteroidal MRA versus a steroidal MRA, and so we're left with indirect comparisons between the largest trials we have available, and that's TOPCAT and the FINEARTS-HF trial. And for comparison's sake, we've limited the TOPCAT trial to the Americas cohort. Those are the four countries where we felt that there weren't substantial protocol deviations.

And so here are some notable differences, at least in this indirect comparison context. So first of all, there's no major attenuation of benefit with the nonsteroidal MRA finerenone as you get up to very high ejection fractions. We've seen this with many renin angiotensin aldosterone system inhibitors that as EF progressively marches up to especially ejection fractions above 60%, when the RAS system may not be as active, you see attenuation of benefit, and we saw that in the TOPCAT trial, including in the Americas cohort, whereas no such attenuation was seen in FINEARTS-HF.

The second potential difference is that FINEARTS-HF was very notably enriched with patients who were either hospitalized or recently hospitalized, and so had a very large population of patients above over 1,000 patients who were in this sort of high-risk early worsening heart failure category, and those patients appeared to benefit just as much, if not perhaps even greater degree than patients who are stable in ambulatory care. TOPCAT was not actually designed to be enriched for this hospitalized cohort, so we have less information about the use of the drug in the hospital and the safety of initiation implementation in the hospital.

We know that finerenone is a much more specific inhibitor of the mineralocorticoid receptor, whereas steroidal MRA, based on its chemical structure, may have actually metabolic consequences and metabolic effects that are off target. And in fact, in FINEARTS-HF, there was actually a signal towards reduction in new onset diabetes with finerenone, and this is on the magnitude, and you could see here of 20 to 30%. So it's not a small reduction, and some of the positive effects might be reductions in systemic inflammation, fibrosis that all influence insulin sensitivity, but also patients are feeling better; they're moving more, and that might also influence insulin sensitivity

In contrast, spironolactone had neutral or a modestly adverse glycemic profile in the TOPCAT trial, but also in previous preclinical studies. And again, that might be because of that steroidal backbone.

Another potential effect is on other cardiovascular events, and so in FINEARTS and in broader sort of set of finerenone-related trials, those signal towards reduction in new onset atrial fibrillation. Again, the mineralocorticoid receptor is broadly expressed, including in the atria, and so it's posited that a drug that specifically inhibits MR activity might reduce atrial fibrosis, atrial remodeling, and in FINEARTS-HF and in the broader program, there's a reduction in new onset atrial fibrillation. And again, that signal wasn't able to be seen in the TOPCAT trial, including in the Americas cohort, based on these data.

So the final aspect is related to the broader picture and our high-risk patients that Javed introduced of those who sit at the intersections of cardiovascular and kidney disease, those are often the patients that we’re least sort of excited about treating with an MRA because of concerns around hyperkalemia. But importantly, finerenone was initially indicated for exactly that population of type 2 diabetes and chronic kidney disease. And two large-scale trials preceded FINEARTS-HF, and so when we take the totality of evidence across this sort of CKM spectrum, we see that finerenone has effects on not only cardiovascular endpoints but also kidney outcomes, and even at the bottom, all-cause mortality, all-cause hospitalization, returning to the hospital for any reason.

So, these are the updated now FDA approvals for finerenone, initially approved for CKD associated with type 2 diabetes but also approved now for heart failure with an LVEF above 40% to reduce cardiovascular death for heart failure events. And importantly, while spironolactone hasn't been well studied in chronic kidney disease, the available data don't suggest a discernible benefit. This was the largest study called BARACK-D. This studied low-dose spironolactone on cardiovascular outcomes in a stage 3b CKD population. Most of these patients were older with low levels of albuminuria, so it's a bit difficult to kind of compare it with the previous finerenone trials. But again, no discernible benefit as of yet.

So while we don't have large-scale outcome trials that compare these two drugs, we do have head-to-head trials that are earlier phased to evaluate safety. So the more recent trial was the CONPASS trial. This was a primary aldosteronism trial that actually compared head-to-head in a small context spironolactone versus finerenone, and again expectantly there was less increases in potassium levels with finerenone compared with spironolactone.

In the ARTS trial, which was an older trial, large trial of chronic heart failure and kidney disease, this was about 389 patients, and again, finerenone had lower risks of renal impairment, kidney failure, and hyperkalemia compared head-to-head against spironolactone.

Javed already mentioned that spironolactone has this risk of gynecomastia. This was not seen with more specific inhibitors of the mineralocorticoid receptor, and those off-target effects weren't seen in FINEARTS-HF.

So speaking about potassium in terms of quantitative assessment, in FINEARTS the average potassium increase was about 0.2 mEq/L, and in TOPCAT Americas it was about 0.3. So on average, you might say these are small differences in average increases in potassium, but at the margins, those individuals who run into problems cross boundaries of let's say 5.5 or 6, where we start to get concerned about safety, that risk increased by about twofold in FINEARTS-HF compared with about threefold in TOPCAT America. So that gives you about a relative context about safety.

So this is a really, really exciting space. There's a lot of new evidence that's emerging. There are several additional trials planned with finerenone that are underway, including in heart failure with preserved ejection fraction. There is another nonsteroidal MRA called balcinrenone, which that study will report next year. That's studying a higher risk population with an eGFR that's going down to 20. And then there's upstream inhibition of aldosterone to produce the very synthesis of aldosterone, and so might have even further upstream effects. And those two are being studied in heart failure with preserved ejection fraction.

So this is an exciting space not only in the treatment of heart failure but also prevention of heart failure, recognizing that aldosterone has important inputs not only in the progression of disease but also incipient or incident heart failure risk, and we've seen this with finerenone in the treatment of chronic kidney disease. We see actually reductions in heart failure risk as the predominant finding in the first years of treatment with downstream effects of prevention of kidney disease progression. So, heart failure might be an initial event that is actually prevented with therapies like finerenone.

And excitingly, now I’d shared that finerenone was studied in patients with CKD and type 2 diabetes; that was the initial labeling. Just in the last months, just last month, this trial FINE-CKD was announced and published that evaluated finerenone in patients with CKD without diabetes. So think other forms of CKD glomerulonephritides. Many of these individuals had IgA nephropathy. They're conditions in which we used to use sort of very specific steroid or immune modulating therapies. Now we can use general sort of CKM therapies that target broad risk. And when we put this together, we again see that finerenone has important effects on many outcomes, including mortality across a broad spectrum of CKD.

So, until very recently, we've had very limited evidence of how to treat those patients with non-diabetic forms of CKD, RAS inhibitors, SGLT2 inhibitors were all that were available. Now we're adding finerenone as an additional pillar, and it's an exciting space. There's more that's being studied in this population.

So to close here, type 1 diabetes is something we don't talk enough about, unfortunately. It's a relatively smaller group of individuals in the United States and worldwide, but there are tremendous long-term risks because they live with this condition for their lifetime, and as such, they're at very high risks of cardiovascular and kidney disease progression. And until recently, we've had very, very limited evidence-based approaches about how to attenuate those risks. Finerenone was studied actually in type 1 diabetes and CKD in the FINE-ONE study, and this is undergoing regulatory evaluation. Actually, showed benefits similar to its benefits in type 2 diabetes.

So, quick comparison here. A lot of this comparison is because of a lack of evidence, rather than necessarily neutral or negative evidence with spironolactone and steroidal MRAs. But that said, the available evidence with multiple now heart failure and CKD trials are just simply lacking with spironolactone. So, the first issue is related to the metabolic axis. Steroidal MRAs have potentially a neutral or maybe even adverse risk of glycemia. Finerenone reduces the risk of new onset diabetes. In terms of cardiovascular protection in CKD, this is perhaps the strongest level of evidence with finerenone, again, no matching evidence with spironolactone. For heart failure with reduced ejection fraction, that was the data that Javed shared very clearly. Spironolactone and eplerenone should continue to be favored. Finerenone is being studied in ongoing trials, but that remains to be seen. And in heart failure with mildly reduced or preserved ejection fraction, at the present time, the only available evidence of benefit is with finerenone. The two trials that we reviewed with spironolactone were neutral.

And so in 2026, we really do think that combination therapy, now with established standards of care like SGLT2 inhibitors, MRA should now be added as a second pillar of care in this population. In general, our preference, based on the available evidence and the strength of evidence, is preferring a nonsteroidal MRA. However, when cost, affordability, access presents issues, I think a steroidal MRA is a reasonable alternative, based on just common sense and ability to improve outcomes here.

So, I will turn it over to now Steve, who will take us through a case to bring this home.

Dr. Greene:
Alright, thanks very much, and we're going to wrap things up here with a case to hopefully tie everything together.

So this case is a 58-year-old woman who is referred to heart failure clinic following a recent diagnosis of HFpEF. So her heart failure journey started in January of 2025. She presented to the local emergency department with dyspnea, edema, swelling. They quickly recognized that she had congestive heart failure. They diagnosed her with HFpEF with an ejection fraction of 60%. They also diagnosed her with a nonischemic cardiomyopathy based on cardiac MRI. They did some fine-tuning of her medicines. They noted that she was hypertensive, so started on her antihypertensive medicines, and they also started her on a loop diuretic and thought, well, now that she's tuned up with these medications, surely she'll get back to normal and stay out of the hospital. But unfortunately, just 2 months later, she's right back in that same emergency department, getting hospitalized again with very similar symptoms. Again, the shortness of breath, the orthopnea, the edema. They treat her with IV diuretics. They send her home from the hospital, but this time they refer her to your heart failure clinic.

And when you're reviewing her chart in the lead-up for her visit with you, you look at her comorbidities and you see many of the usual suspects that track with a diagnosis of HFpEF. You see type 2 diabetes. You see stage 3b CKD. You see hypertension, and you see obesity. And her BMI is 35. You also look at her concurrent medications, and you see that she's on furosemide 40 mg daily. She's on some medicines for her blood pressure, amlodipine 5 mg daily, lisinopril 10 mg daily. She's on a statin, and she's on some medications for her type 2 diabetes. She's on metformin, and she's on semaglutide 2 mg once weekly.

So when you're thinking through a patient like this in heart failure clinic, the guidelines clearly say that we need to have a sense of urgency with how we treat our patients. When you look specifically at the European Society of Cardiology guidelines, they say for patients who have been recently hospitalized for heart failure, we need to embrace a strategy of simultaneous or rapid sequence initiation of GDMT, either pre-discharge or early post-discharge. GDMT should be initiated over days to weeks and optimized, not over months and years or never, as is unfortunately the reality oftentimes in clinical practice. And this recommendation is based on the STRONG-HF trial, which told us that simultaneous or rapid sequence initiation of GDMT and optimization of GDMT, if you compare that with the usual status quo, one at a time, serial, slow, selective approach, that status quo, one-at-a-time approach leads the patients either, A, never getting on medications at all, or at best only after substantial delay, and two, needlessly exposes patients to excess clinical risk of death and hospitalization. These are the real risks of omission when we do that slow and steady approach with GDMT.

So, with that being said, I want to turn to our expert panel. You know, we're seeing this patient in our HFpEF clinic, and you know, as Muthu showed on the last slide of his presentation, we're missing two of the key pillars of HFpEF therapy: an SGLT2 inhibitor and nonsteroidal MRA. Now, when a patient like this, which one do you prioritize first? Dare I say, should we be thinking about initiating them at the same clinic visit simultaneously? Any practical considerations? So I'll turn to Orly first for any thoughts on this.

Dr. Vardeny:
With the question of SGLT2 inhibitor or finerenone, I agree that we need to use both. With some data supporting the fact that if we start an SGLT2 inhibitor first, that may mitigate or offset some of the potassium changes that tend to occur with MRAs. So, if I were to start just one today, I would start SGLT2 inhibitor, but shortly on its heels would be finerenone.

Dr. Greene:
Any other thoughts from the panel? Practical considerations and thoughts about starting them both at the same time versus a staggered rapid sequence approach.

Dr. Vaduganathan:
Yeah, I think that even for clinicians who feel that both drugs are going to be important, ultimately it becomes an issue of considerations around safety of simultaneous initiation, as well as patient comfort and sort of systems and care structures in place for follow-up. And so in an individual like her with sort of chronic kidney disease, you wonder about what the baseline GFR is, what the starting blood pressure is, and if the person has already evidence of sort of clinical congestion on exam that's persistent after hospitalization. In general, there may be a little more decongestive effects of early initiation of SGLT2 inhibitors, and so in that sort of persistently congested individual, maybe SGLT2 inhibitors would be favorable.

When the GFR is already reduced, the nice thing is that there is actually limited fluctuation in GFR after you start SGLT2 inhibitors or finerenone. And so, for instance, if you start an SGLT2 inhibitor or finerenone with a GFR between 30 and 45, there, you're going to expect pretty limited changes, or that eGFR dip is going to actually be pretty limited or attenuated compared with if you have a person who has completely normal kidney function. There, that individual you'd anticipate much more kidney function fluctuation when you start these therapies.

Dr. Butler:
Can you cite some data from CONFIDENCE and what you learned?

Dr. Vaduganathan:
Sure. So we actually studied this in a mechanistic trial called CONFIDENCE that studied empagliflozin, an SGLT2 inhibitor, and finerenone compared with either drug alone in exactly a patient like this with type 2 diabetes and albuminuric chronic kidney disease, and found that first that the simultaneous initiation led to exactly additive clinical benefit. So starting both of these drugs doubled the benefit of starting one alone. The second was that it was entirely safe. There was modest expected reductions in blood pressure, modest reductions, early reductions in GFR, but all this was entirely reversible. Once you stopped these therapies, was not associated with sort of significant safety issues. They didn't have to go to the hospital. They didn't have to seek urgent clinical attention, and so this was a feasible approach. And so we are moving towards starting these drugs together, even in a patient like what's presented with multiple medical comorbidities, because this appears to be a safe and effective strategy.

Dr. Greene:
I appreciate Muthu citing the CONFIDENCE trial, which for those aren't familiar, again it was a diabetic CKD trial. Which technically, this patient does have diabetic CKD, and they started both drugs, empagliflozin and finerenone, at the same time, and saw the safety data that Muthu highlighted. But also specifically with that eGFR dip, they get so much attention. I think as Muthu highlighted, the patients where you're potentially most worried about that eGFR dip, theoretically you're like their kidney function is reduced, you're worried they're on thin ice; they're actually less likely to have that dip. And remember that both SGLT2 inhibitors and finerenone are both kidney therapies. They're kidney safe and actually kidney efficacious. And there's certainly fewer clinically recognized acute kidney injury events in the clinical trials as well.

So when we think about how are we going to get, we have now fortunately I would argue multiple pillars for HFpEF therapy just a decade ago and years ago we were talking about how we've said diuretics and optimization of comorbidities. From an implementation perspective, myself, Dr. Butler, or Gregg Fonarow, we have advocated strongly for the default approach being one where we start all three definitively proven disease-modifying drugs without delay on day 1, or in rapid sequence, arguably within 1 week or so.

But regardless of what we're going to nickel and dime over, well, when we say rapid sequence, how rapid is it? 1 week? Is it 2 weeks? Is it 3 weeks? I would ask us all to agree on what the wrong answer is, and we should get comfort behind what the wrong answer is. And the wrong answer is start one today, and I'll see the patient back in 3 or 6 months. That's the wrong answer. And if we do anything incremental to that, we are certainly moving the field in the right direction.

And the rationale for why we need to have this sense of urgency, simultaneous, rapid sequence initiation for our HFpEF therapies really relies on first, for all three of those therapies that I showed in the past slide, the clinical benefits don't just show up within months or years after starting these drugs, but just within days to weeks of starting them, you see benefits on hard clinical events in terms of SGLT2 inhibitors or nonsteroidal MRA, and within weeks you see benefits on quality of life with GLP receptor agonists. And these are the data that Muthu published from FINEARTS that show you see first sustained clinical significance in statistical significance in the FINEARTS trial for CV death and heart failure events just by day 28. So to put this in a clinical context, if you delay initiation even a few weeks in an otherwise eligible patient, again, that is needless exposure to excess clinical risk.

And the other thing to highlight is again going back to this idea of combination therapy; it's not that, well, once you're on one drug, the second drug doesn't have much to offer. In all the clinical trials for our GDMTs, really for HFrEF, and now we're seeing the same thing in HFpEF, the key concept is that the drugs are incremental and essentially fully additive to each other, one plus one equals two. And when you go back and think about heart failure, I would argue it's an extreme risk condition. We need all the help we can get. We need to leverage these fully additive properties. And here you see these are the data from FINEARTS among people, more than 800 patients who were already on an SGLT2 inhibitor, again, you see the additive risk reduction of finerenone on top of treatment with an SGLT2 inhibitor.

So back to our patient case, we're seeing the patient in clinic. You see their vital signs, normotensive 127 systolic, heart rate's okay at 66. eGFR is right around their baseline at 39. Potassium 4.2. NT-proBNP 560. You know, overall they're feeling better since being in the hospital a month or so ago, but they're still not satisfied. They still feel more fatigued than they were several months ago, although they do have no edema now. But at this clinic visit, again embracing this concept of simultaneous or rapid sequence initiation, embracing the concept of urgency, we're willing to make multiple medication change at the same visit, and this includes initiation of empagliflozin 10 mg daily, and initiation of finerenone 10 mg daily, and we also decrease the dose of the furosemide from 40 to 20 mg daily, and we can have the expert panel weigh in on that.

But specifically, now I will get our expert panel curious to see what you guys think of the management of this patient, and specifically, I want to talk about follow-up and potentially titration of, there's more than one dose of finerenone as we know. So Orly, I'll start with you. What are your thoughts on but we just started two medicines for this patien, when do we need to see him back? What parameters do we need to be paying attention to?

Dr. Vardeny:
Sure, and a great question. In terms of follow-up, there are a couple things we need to think about with respect to safety. So we're starting an MRA, so we know we need to follow up and monitor potassium closely. So we don't want to start it until we know that the patient is able to get to a lab for that monitoring. With finerenone, the trials usually monitor potassium a month after starting, with nonsteroidal MRAs it tends to be a little bit sooner. So certainly potassium and renal function is something that we want to monitor a month later, and that's when we would potentially follow up.

For titration, we adequately or appropriately dosed her with finerenone 10 mg a day based on her baseline eGFR. We know that the target dose is 20 mg a day. So after confirming that potassium elevation is not above the threshold of being unsafe, we would double that and go to a target dose of 20 mg a day.

Dr. Greene:
Excellent. In the interest of time, I'm going to keep going. So, just as Orly suggested, we had the patient come back. We had him come back 4 weeks later to clinic. You see the repeat vital signs, blood pressure approximately stable, eGFR also approximately stable, down to 34 but still relatively at baseline. Potassium went up just a smidge. But despite going down on the loop diuretic dose, NT-proBNP had fallen. And when you ask the patient how they're doing, they are feeling better at this clinic visit, but again, just because they're feeling better does not mean we start falling asleep at the wheel. We want to keep pushing to the target dose that Orly just mentioned. So we're going to escalate the finerenone to the 20 mg daily target dose for this eGFR. And in fact, in this case, we actually decrease the loop diuretic altogether.

So with that, I think I'm going to turn it over to Dr. Butler for our close, and we'll hopefully get some audience participation here.

Dr. Butler:
Great, we have a few more minutes. Thanks, team. So, if you want to just come up with the mic and ask questions, but in the meantime, while you're warming up, I have a couple of questions as well, so I'll open it up. Anybody can answer. So, a few tricky scenarios: EF is 30% and has diabetes and diabetic kidney disease. Which MRA to use, spiro or finerenone?

Dr. Vaduganathan:
You know I think there's equipoise here. Both have been well studied. In general, I still sort of preference spironolactone if there is acceptable sort of safety in this population, mostly because finerenone was studied in diabetic kidney disease, but the trials excluded those with HFrEF, and so this is still relatively understudied with finerenone. And ongoing trials are underway with finerenone in this population.

Dr. Butler:
Anybody like to disagree with the professor?

Dr. Greene:
I don't try to disagree with Muthu. And I do agree with him here. I think we have to acknowledge that yes, when you have HFrEF, and you have diabetic kidney disease, I mean they're both bad diseases, but the truth is, HFrEF is the life-limiting condition for most of those patients, and I think we can't take any chances with undertreating or mistreating that diagnosis. So again, I give preference to steroidal MRA in that patient population. But again, we'll see what trials like FINALITY, which is a nonsteroidal MRA trial in people that are steroidal MRA intolerant, but we'll see if we see efficacy in that population. But I do prioritize the HFrEF in those patients.

Dr. Butler:
Will somebody disagree with the two of them. Okay, so I will disagree with the two of them. So again, I mean, look, we are in the data-free zone, right? So there is no theoretical reason to believe that nonsteroidal MRA will not work in heart failure with reduced ejection fraction. The problem here is that there is no data; we have only done trials in HFpEF. But there is a trial going on right now called FINALITY in HFrEF patients who are intolerant to steroid MRA. So we will get some data, but there is no theoretical reason.

But we actually have three trials in CKD patients that spironolactone did not improve outcomes. Not one, three outcome trials: one in dialysis, two in advanced heart failure patients. So I think one can make a reasonable case that if you're faced with two comorbidities and when you have the data that spironolactone did not work, I think finerenone probably would not be the wrong answer. I don't know what the right answer is though.

So the panel here is known for very strong proponents of evidence-based medicine. So here's the question: You have a person with an EF of 35% got started on spironolactone, and their EF went to 50%, but still had the syndrome of heart failure. And another person who started with EF of 50%, you started them on finerenone, had a heart attack, and dropped their EF to 35%. Do you switch between finerenone or spironolactone, or just continue what they were on? The evidence-based answer?

Dr. Vaduganathan:
So my own practice is to continue what they were previously on, mostly because this is a therapy that they have been able to continue. So they've sort of moved past the early period of time in which intolerability is often presents. They've improved their ejection fraction, so they've actually demonstrated clinical benefit on the drug, and in fact, our trials are designed exactly as such. Even with interval clinical improvement and shifting in phenotypes, you continue the therapy, and so that my sense, at least for the scenario one is.

Dr. Butler:
What about scenario two?

Dr. Vaduganathan:
Scenario two is also a scenario where I would continue therapy. If a person starts out with heart failure with preserved ejection fraction, has an interval myocardial infarction, that's a patient that was well represented in a trial like FINEARTS-HF, even with interval fluctuation in ejection fraction.

Dr. Butler:
Any alternative answers from the other two?

Dr. Greene:
I agree. I mean, like EF falling is a question I haven't really thought about before with this situation. If your EF falls despite being on finerenone and everything. I mean, the bottom line is now the patient has new HFrEF, we need to get him on quad therapy, and I think it's like not the top priority. Oh my God! I got to think about switching it from nonsteroidal to steroidal MRA. I mean, I think that's probably overthinking it. But the first priority is make sure they're on the other pillars now, like a beta blocker, for example, for HFrEF and ARNI and all that.

Dr. Butler:
So we’ll conclude the session by a last comment.

Guest:
Great session, by the way. Your discussion just now clearly shows that EF is not it. It's not the be-all and end-all, and we need more. And so, a patient who starts at 50 and goes to 30, what's the disease? A patient starts at 30, goes to 50, what's the disease? And we need to figure that out, you know. And in going forward, stop being stuck in a specific ejection fraction.

Dr. Butler:
Great. Well, thank you very much on that wise comment. We will conclude. I can guarantee you, not only in this meeting, for the next at least 5 years, you will continuously see a lot of new data coming out on aldosterone antagonism in one way or another. So, a lot of data that will be coming out. I really want to appreciate all the panel members here. Also, the European guidelines, the updated heart failure guidelines are coming out next month. The American guidelines are coming out next year. So a lot of debate will go on in that direction. Thank you so much, everybody, for attending.

Announcer:
You have been listening to CME on ReachMD. This activity is provided by Voxmedia. To receive your free CME credit or to download this activity, go to ReachMD.com/CME. Thank you for listening.