The FINEART of MRAs in HFpEF

Recorded September 2, 2024. This transcript has been edited for clarity. 
Ileana L. Piña, MD: Hello. I’m Ileana Piña, and I am here at the European Society of Cardiology (ESC) Congress in beautiful London. I have with me my good friend Scott Solomon from the Brigham at Harvard. Scott, welcome.
Scott D. Solomon, MD: Thanks, Ileana.
Piña: Tell me your title. 
Solomon: I’m professor of medicine Harvard Medical School and the Edward D. Frohlich Distinguished Chair of the Brigham and Women’s Hospital, which is now Mass General Brigham.
Piña: I want to congratulate you. Everybody’s been waiting for the FINEARTS-HF trial to come out. It starts with an F, like FIDELIO-DKD. How is finerenone different from spironolactone?
Solomon: Finerenone is a different type of drug from spironolactone or eplerenone. It is a nonsteroidal mineralocorticoid receptor antagonist (MRA), in contrast to the steroidal ones. Chemically, it’s quite distinct. It’s got a number of different properties. It’s got a shorter half-life; it’s actually more selective for the MR than spironolactone is. It also has a more balanced distribution between the heart and the kidney receptors than the steroidal MRAs do. So the properties are definitely different. It doesn’t have any of those nasty sexual side effects that you get with spironolactone.
Piña: The gynecomastia. So it’s clearly different 
Solomon: It is not truly in the same class. It hits the same receptor.
Piña: So you’ve been chasing the heart failure with preserved ejection fraction (HFpEF) patients, like, forever. 
Solomon: My whole life! 
Piña: What made you do this trial in the way that it was constructed?
Solomon: We’ve learned a lot of lessons along the way. We started looking at this population with the CHARM-Preserved trial many years ago, and we did TOPCAT. TOPCAT was an interesting trial that had its problems, without question. Then we did PARAGON-HF, and we did DELIVER. So this is about the fifth outcomes trial that I’ve been involved in. 
We did this trial because we believe in this mechanism. We believe that mineralocorticoid receptor antagonism could be beneficial in this disease. We have data in heart failure with reduced ejection fraction (HFrEF). We had some data from the TOPCAT trial. It was a problematic trial, as you know, when we unblinded it.
Piña: There were geographic differences. 
Solomon: There were people enrolled who probably didn’t have heart failure, many who didn’t take the drug. In post hoc analyses, if you cut out the people whom we think didn’t have heart failure, it looks like maybe there’s something going on. 
Piña: But it also mirrored PARAGON-HF, in the sense that as you went up on ejection fraction, [the treatment was less effective]. 
Solomon: We saw that also in CHARM-Preserved and TOPCAT — this attenuation of treatment benefit as you go up in ejection fraction. But I’m pleased to say we did not see that in FINEARTS-HF.
Piña: That was going to be one of my questions: Why not?
Solomon: I don’t know necessarily why. We didn’t see it with the sodium-glucose cotransporter 2 (SGLT2 inhibitor) dapagliflozin in DELIVER either. I think probably there are some differences in the way we treat our patients that are accounting for that. We will present more data on this particular topic, at the Heart Failure Society of America (HFSA) meeting in Atlanta very shortly, but we don’t see any heterogeneity in FINEARTS-HF. Of course, you haven’t asked me about the primary results yet.
Piña: We’ll get there, but I want the audience to understand why you think we need another MRA. Spironolactone is so cheap — $0.25 a tablet if you don’t even have insurance.
Solomon: It is cheap. But I think most of us, even those of us very much involved with TOPCAT, felt that it wasn’t definitive. We were throwing out a whole lot of people in the trial, so we ended up with a much smaller subgroup 
Piña: But spironolactone is in the guidelines. 
Solomon: It’s in the guidelines as a weak recommendation. So the question is, can we do better? And I think that’s important, because when we did TOPCAT and when that went into the 2017 guidelines, we didn’t have anything else. Now, at least in the European guidelines, SGLT2 inhibitors are class IA. 
Piña: I’m sure the American Heart Association/American College of Cardiology guidelines will follow. So how did you pick your endpoint?
Solomon: The primary endpoint for the trial was cardiovascular death and total heart failure worsening.
Piña: Which isn’t just hospitalizations.
Solomon: Right; it’s hospitalizations or urgent heart failure visits. Because, as you know, for the past decade or more, increasingly more patients whom we would have hospitalized previously are being treated as outpatients in an urgent care setting. 
Piña: I know, I do it all the time. We’re treating themintensively.
Solomon: These are the patients that we are trying to keep out of the hospital, but they would have been hospitalized in prior trials.
Piña: Or in a country where it doesn’t matter and they could be put into the hospital. 
Solomon: We’ve been playing around with the different ways of looking at endpoints over the years: time to first event or total events, meaning first and recurrent. We chose total events, and it turns out that it probably doesn’t make a whole lot of difference. The trial was positive, with a 16% overall reduction (P =.007) in the primary endpoint. If we look at the endpoint in the traditional way as time to first event, it’s the exact same hazard ratio and an even better P value.
Piña: Isn’t that interesting? And yet, we know that each of these presentations has different outcomes. 
Solomon: And portends worse prognosis. Every time you are hospitalized, things get worse. 
Piña: We learned this in PARADIGM-HF, and we hear this commonly at the US Food and Drug Administration (FDA). Tell me about the mortality
Solomon: We did not see a benefit in mortality. Things went in the right direction for both cardiovascular death and all-cause mortality — a 7% reduction and numerically fewer deaths, which is good to know you’re not harming people. 
In HFpEF trials, we’ve never been able to get mortality. Why? Because the event rates in these patients were low, we would have to do trials twice as long or twice as big.
Piña: And they die of other things. 
Solomon: When we put DELIVER and EMPEROR-Preserved together, we got a P value of about.05 for a 12% reduction in cardiovascular death.
Piña: There’s something there. 
Solomon: If you wait long enough, I think you would see a mortality benefit.
Piña: You’d have to run trials for 10 years, So would you now tell the clinician audience that they should switch from spironolactone to finerenone?
Solomon: First of all, there’s no indication as of yet for finerenone in this population. It’s going to go to the FDA, and they’ll eventually get approval. And as you also know, spironolactone is available to clinicians, but it is not approved by the FDA for this indication. In fact, there was an Advisory Committee for TOPCAT if you remember, and they did not act on it. 
Piña: Because no company was interested in taking it. That’s the only reason that it’s not approved (in HFpEF).
Solomon: I think that clinicians need options, and the best evidence we’re going to have now is with finerenone in this trial. We know the dose; we know the type of patients we enrolled; and by the way, we used the highest dose, which is 40 mg in the patients with estimated glomerular filtration rate > 60 mL/min/1.73 m². As an evidence-based medicine clinician, I would say we should use the drugs that we have tested and are positive. However, as a doctor treating patients, I know that I’m going to have access issues; clearly, there are cost issues. That all has to be worked out. We don’t know how that’s going to work.
Piña: You know, a lot of pharmacies look at creatinine when you order spironolactone. In our hospital, the internal pharmacists call me and say, “Do you see this creatinine? Are you sure you want spironolactone?”
Solomon: We know that spironolactone has a number of side effects that can be really pesky, including gynecomastia and other sexual side effects, predominantly in men. Finerenone doesn’t have those. But also, the degree of potassium elevation was a little bit less in this trial than we’ve seen with historic MRA trials. On average, it was 0.2, and in the HFrEF MRA trials, on average it was 0.3. Now that doesn’t mean you don’t have to worry about potassium. 
Piña: Maybe a little less anxiety, but you know, I’m not worried about hyperkalemia.
Solomon: You and I both know potassium is a double-edged sword.
Piña: Totally. I like my potassium values around 5 mmol/L.
Solomon: We saw a much higher risk for hypokalemia in the people on placebo. So the question is, can we tolerate a little bit higher potassium to not have hypokalemia, which we know confers significant risk? 
Piña: I am more scared of hypokalemia than I am of a potassium value of 5, which I actually like. Plus, we’ve got the binders. 
Solomon: We had only a total of 16 people who were hospitalized for hyperkalemia in the finerenone group, compared with 6 in the placebo group, and no deaths related to that in either group. So I think we can mitigate the risk for severe hyperkalemia with these drugs.
Piña: Congratulations on enrolling 45% women; that’s an improvement, because HFpEF is a female issue. What was your age range?
Solomon: Very broad. I think our oldest patient was 92; our mean age was 72. 
Piña: What else are you looking in the trial? Will you analyze the women separately?
Solomon: We will. A lot more will come out. At the European Association for the Study of Diabetes (EASD) meeting, we’re going to present some data about diabetes effects not just in the patients with diabetes, but the effects on new-onset diabetes. We’re going to have six presentations at HFSA in Atlanta and many more to come.
Piña: We will be there. Scott, thanks for being here with me and to my audience. I hope you’ve taken note of these pearls; jot them down and apply them to your patients. This is Piña, signing off from the ESC.
Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA’s Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.