EMPEROR-Preserved Trial and Medical Optimization When Treating HFpEF

James Januzzi, MD: Javed, I hate to only give you 5 minutes, but that’s what we have in this program for this. Can you tell us about the EMPEROR-Preserved trial? I have to say when this study came out, I went around telling people that I knew Javed Butler because it was like cachet to know one of the folks who did the EMPEROR-Preserved trial, this is such an important study. Can you tell us about the design, the population, and what the results were?

Javed Butler, MD: Yes. You’re way too kind. Thank you very much. Concerning EMPEROR-Preserved, there were 2 sister trials that were started in heart failure with preserved ejection fraction [HFpEF] in patients with SGLT2 [sodium-glucose cotransporter-2] inhibitors, the liver trial with dapagliflozin, we will be getting the results of that trial early next year, and EMPEROR-Preserved, which was presented a couple of weeks ago. It had 6000 patients randomized to empagliflozin versus placebo on top of standard comorbidity management; 80%-plus of the patients were on RAS [renin-angiotensin system] inhibitors, 80%-plus were on β-blockers, and about 35%, 40% were on MRA [mineralocorticoid receptor antagonist] use. The primary end point was cardiovascular death, heart failure hospitalization, which was reduced by 21% relative risk reduction, both clinically relevant, highly statistically significant. The trial was designed to answer 3 questions. The primary end point, which I just mentioned, then total heart failure hospitalization, first and recurrent. That went down by about 27% relative risk reduction. The third was renal function preservation, which was assessed as estimated GFR [glomerular filtration rate] preservation. That also was preserved, highly significant, about 1.36 mL/min per year.

Now, unlike in HFrEF [heart failure with reduced ejection fraction], where subgroups are boring because if we know the drug works, they tend to work in all the subgroups, in HFpEF, there’s a lot of interest in subgroups. The subgroups of interest that we looked at, diabetes, no difference whether you have diabetes or not. EGFR more than or less than 16, no difference. Atrial fibrillation, no difference. Interestingly, we actually did not find the sex interaction, both men and women benefited to the same degree. Baseline medical therapies…all of those things made no difference, which brings us to the most contested of the subgroups, which is ejection fraction. The prespecified analysis of mildly reduced, 41% to 49%, or the true HFpEF of over 50%, we saw no interaction. Having said that, that’s not where most of the interest is. Most of the interest is in this higher-range ejection fraction and what to do about that. We have done really continuous analysis to look at the data across the spectrum. The good thing is, between EMPEROR-Reduced and EMPEROR-Preserved, we have close to 10,000 patients, ranging from an EF of 10% to 88%. We have a really wide group here. What we find is that up to an ejection fraction of 65%, both men and women benefit, and the magnitude of benefit is similar and more than some of the other therapies that we have mentioned. Over 65%, there is a lot of noise. It was only 10% of the patients, at 65% to 70%, there is some attenuation, and all of a sudden, more than 70%, we start seeing the benefit.

Thus, at least my interpretation of that is that from a research perspective, we really need to understand that group better. But from the clinical perspective, considering that there is a good 7% EF read difference as well, if you have heart failure with preserved ejection fraction, you should be on these therapies, irrespective of ejection fraction, provided you don’t have an identifiable secondary cause like tight aortic stenosis or something like that. In terms of safety and tolerability, no new signals, it was pretty well tolerated.

James Januzzi, MD: Yes, it was very well tolerated. Also, the fact that you see a benefit up to an EF of 65% may explain why we didn’t see a sex interaction, given this maybe slight difference in what a normal EF is in a woman versus a man. Then of course, the individuals with EFs of 65% or greater with heart failure, that’s a tough population. I’m not even sure sometimes what diagnosis may be present in some of these patients, infiltrative cardiomyopathy as well as some other challenging to manage diagnoses like hypertrophic cardiomyopathy. OK. You made the statement that I suspect we all agree on, which is that anyone with heart failure up to an EF maybe of 65% should probably be on an SGLT2 inhibitor. Now of course, the indication’s not here yet, and the guidelines aren’t here yet, but I must admit I’m already doing this. Let me see, do you all agree or disagree? I’m curious.

Javed Butler, MD: I agree.

Nasrien E. Ibrahim, MD: I definitely agree.

Gregg C. Fonarow, MD: We agree.

James Januzzi, MD: OK. We’re 4 out of 4. I’m going to go around the horn here and each person has 30 seconds to a minute at most. Gregg, what is your approach to HFpEF with respect to drug therapy? We have the foundation of an SGLT2. When do you bring spironolactone or sacubitril/valsartan into play?

Gregg C. Fonarow, MD: Actually, in most patients, clearly, those with the lower ejection fraction, I’m thinking about it more strongly, but I think each patient deserves consideration for these therapies. Given the underlying risks for these patients after a heart failure or hospitalization, your 1-year or 5-year mortality rate is every bit as high in these patients with midrange and preserved ejection fraction as those with reduced. We really need to be thinking about combination of evidence-based therapies in these patients as well.

James Januzzi, MD: Great. I love simplifying it, and I think that’s going to be important. Nasrien, what do you think?

Nasrien E. Ibrahim, MD: Everybody with HFpEF gets a mineralocorticoid receptor antagonist, and as long as I’m not getting pushback from the payers with sacubitril/valsartan, I also put patients on sacubitril/valsartan if their EF is 60% or less.

James Januzzi, MD: Perfect. Following the data, and then of course, with the foundation of an SGLT2. And Javed, any differences there?

Javed Butler, MD: No, this is my opinion. The guidelines have been written. We’ll see what they say, but my opinion, 55% EF or less gets quad therapy, everybody gets an SGLT2 for now. And let’s wait for more data.

James Januzzi, MD: Yes. It’s funny, Javed. You and I frequently share similar styles. I use 55% as well, just because again, that’s where we can go with the data about what a “normal” ejection fraction is.

This transcript has been edited for clarity.