Guideline-Directed Therapy for HFpEF and the Use of Spironolactone and Sacubitril/Valsartan

James Januzzi, MD: What I’m going to do now in the interest of time is move us along to a subject for which maybe a year or two ago we might not have had much to talk about, and that’s heart failure with preserved EF [ejection fraction] management, but there’s a lot that is new in this area. I’m going to depend on all of you, but I really want to highlight some of the new data that have recently come out regarding a few different classes of drugs for these patients. Javed, let’s start more broadly, but what are the goals of guideline-directed medical therapy in patients with HFpEF [heart failure with preserved ejection fraction]? The ESC [European Society of Cardiology] heart failure guidelines just came out and they were immediately a day later antiquated because of data from EMPEROR-Preserved. But what are the goals in our patients with HFpEF? Do they really differ that much from HFrEF [heart failure with reduced ejection fraction]?

Javed Butler, MD: Conceptually, obviously not. What you’re trying to do for any disease state is to curb the progression of the disease and lower the risk of mortality and hospitalization. On top of that, you want to make patients feel better. Thus, it’s not only about the more medically oriented end points like mortality or hospitalization, but also quality of life. Now, the problem was that up until recently, there were no dedicated trials in HFpEF that were positive. The guidelines primarily were focused on decongesting patients so that they are not as short of breath and fluid overloaded, and treating cardiac and noncardiac comorbidities as necessary and appropriate, whether it’s ischemic heart disease, hypertension, diabetes, atrial fibrillation, etc. But that landscape is continuing to evolve. And I think they’re slowly getting into an era where we may have some focused therapies for patients with HFpEF as well.

James Januzzi, MD: That’s great. Really, now that we have therapies, it’s going to increase the urgency to understand the appropriate therapies and get them in place. It’s a little unfair to ask, but Gregg, do you envision that the United States guidelines for heart failure with preserved EF, do you think they’re going to pick up some of the newer therapies that we’ll be talking about, including SGLT2 [sodium-glucose cotransporter-2] inhibitors, but also maybe the role of spironolactone or even sacubitril/valsartan?

Gregg C. Fonarow, MD: Yes. We’ve had these important trials, and there have been refined analyses of them where overall for say the TOPCAT trial and the PARAGON-HF trial, where maybe they just missed their primary end point. We’ve been able to better define the subgroups of patients who seemed to particularly benefit, and they are on that lower end of the EF spectrum. We recognize there’s a lot of heterogeneity, but for those with EF in the 45% to 50% category, we really see more…benefit. That’s very helpful. And then as alluded to, with the landmark data from EMPEROR-Preserved, where for that group that falls into EF above 40%, patients with heart failure with mildly reduced EF and preserved EF can have a robustly positive trial to where there are significant reductions in heart failure hospitalizations. We’ve got additional data on quality of life in these patients.

Thus, these are really meaningful trial results that will get translated into the guidelines, but it’ll be so important to our discussion about how to translate these into practice. We really do see that many of the same therapies we talked about for heart failure with reduced EF have benefit in those with heart failure with mildly reduced EF, and to some degree, those with heart failure with preserved ejection fraction. It may not be that same robust, large, all-cause mortality reduction, but meaningful benefits in the composite of cardiovascular death and heart failure hospitalization. These are actionable data for clinicians who previously really had very limited therapies and very limited guideline recommendations regarding how to treat these patients.

James Januzzi, MD: Yes, there definitely will be a guideline impact. It’ll be interesting to see how the data are incorporated. You make a very important point about the differences in the journey of patients with HFpEF versus HFrEF in terms of hospitalization burden, mortality burden. These therapies in HFpEF may not have as obvious an impact on mortality as we see in reduced EF. But importantly, we’re now fortunate in that we have data in the in-between ejection fraction that was previously, I don’t want to say ignored, but not really considered in the clinical trials of heart failure, that mildly reduced EF patient population, where pretty much each of the drugs we’ve talked about, spironolactone, sacubitril/valsartan, and of course SGLT2 inhibitors, have now been shown to be of benefit. Before we get to EMPEROR-Preserved, we’re all dying to talk about it. Let’s talk first about the data regarding spironolactone from TOPCAT, and then sacubitril/valsartan and PARAGON. Gregg, do you want to take TOPCAT, and then and Nasrien, we’re going to come back to you for the ARNI [angiotensin receptor neprilysin inhibitor]. If you can take on PARAGON, that would be great. Gregg, why don’t you go ahead with TOPCAT?

Gregg C. Fonarow, MD:Yes. It looked at spironolactone, a target dose of 25 mg in those with the EFs of 45% or above, in a clinical syndrome of heart failure. There were some things related to this specific trial and some of the countries enrolling patients. If you just look at North America, we really see a reduction in not just first heart failure hospitalization, but recurrent events. But when you look at the function of ejection fraction, we really saw a more robust benefit in those in that lower range. For example, the 45% to 50%, the 50% to 55%, and as you get to the EFs of 65% and above, and there may be by virtue of some of the infiltrative cardiomyopathies and amyloid being mixed in there making the picture a little more complex. But it does appear as if we can reduce that risk of heart failure hospitalization, recurrent hospitalizations. There does seem to be a little greater benefit in women compared to men in that regard. Thus, that sex-specific consideration may be important. It is important to monitor for hyperkalemia, but this may be an important class of therapy. As Javed alluded to, there are now the additional MRAs [mineralocorticoid receptor antagonists] that are being looked at in heart failure with preserved EFs, so we may get even more robust data going on and be able to mitigate some of the risks of hyperkalemia. This does represent a class of therapy that may be considered. Even in prior guidelines, there was a 2B class recommendation to consider in select patients the use of these agents. Those are the data that we have right now. And I think more data will be coming in the future.

James Januzzi, MD: That’s great, Gregg. And yes, indeed, for example, in the EMPEROR-Preserved trial, we’ll talk about in a second, 35%, 40% were taking spironolactone or eplerenone, mostly spironolactone for preserved EF heart failure. A lot of people use it in this population. And as you say, congested patients; patients with higher natriuretic peptides, but not too high; women; and certainly, at the lower end of the preserved spectrum of ejection fraction, all of those subgroups seem to benefit. Now, the problem, of course, is those were subgroups of a neutral trial. Thus, it’s a little bit of a dangerous proposition to try to interpret those data. But nonetheless, it seems compelling. Now, Nasrien, let’s talk about sacubitril/valsartan. Very similar caveats, right? The PARAGON study looked at sacubitril/valsartan versus valsartan in a similar range of EF, patients with mildly reduced up to normal. What can you say about the role of sacubitril/valsartan for HFpEF?

Nasrien E. Ibrahim, MD: The overall trial did not show benefit in patients who had EF of 45% or less, but when they looked at patients who had EF less than 60%, there seemed to be some signal that there was benefit in that subgroup of patients. Thus, there is a new indication from the manufacturer of sacubitril/valsartan, an indication for use in patients who have an EF less than 60%.

James Januzzi, MD: Yes. Again, very much like with spironolactone. When the EF gets below normal and whatever normal may be, it’s interesting the American Society of Echocardiography has been saying for years that a normal EF is 55%. And we in the cardiology world are like, “Get out of here. Normal is down to 50%.” But it turns out actually, it seems like the benefits of these drugs that affect the renin-angiotensin system and aldosterone system seem to be more obvious when you get below around 55% to 57%. As you say, there’s now an indication for sacubitril/valsartan for treatment of people with heart failure and an abnormal ejection fraction following that point. Very importantly, there were a couple of interactions in the study that seemed to suggest greater benefit in some subgroups; for example, women, again, possibly because of the offset of ejection fraction between women and men, where the ejection fraction is abnormal in women at a different level than men. Thus, even higher ejection fractions in women seem to predict benefit. Then, also for patients who were recently hospitalized for acute heart failure. And there are trials now ongoing looking at sacubitril/valsartan in acute HFpEF. There seems to be a role there, and maybe at the end, we can all put together our own personal synthesis of how we optimize the medical therapy.

This transcript has been edited for clarity.