COMMENTARY

Making Room in the Regimen and Guidelines for New Drugs for Heart Failure

Ileana L. Piña, MD, MPH; Mary Norine Walsh, MD

Disclosures

November 26, 2019

This discussion was recorded on November 17, 2019, at the American Heart Association meeting. The transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña, professor of medicine at Wayne State University, and I am so proud to be here at the American Heart Association sessions. Lots of energy outside these doors. We are in the City of Brotherly Love, Philadelphia.

There have been some really excellent late-breaking trial sessions, as there usually are in these meetings. I am really happy to be joined here by my friend and colleague, Dr Walsh, from Indianapolis, who treats heart failure like me. She's part of the heart failure mafia, as I call us.

We had the pleasure of chairing a session on late-breaking trials having to do with heart failure, and it was standing room only.

Mary, it was a really interesting session, I thought. If we break it up into pieces, there was a presentation of the FUEL pediatric trial on congenital heart disease.[1] What did you think?

Mary Norine Walsh, MD: Yes, it was from the Pediatric Heart Network Investigators. This was a trial looking at medical therapy with phosphodiesterase inhibitor for this patient group that had Fontan physiology.

I think the importance of this trial was really that these were adolescents. I love the fact that, at the end of the presentation, the presenter commented on the patients, their ability to do the trial, their families, and the complexity. They ended up answering the question that was really important.

Piña: They were looking at exercise function. I kept talking about a ceiling of exercise function, as measured by the O2. These are usually small groups of patients in the center. You may have five or six Fontans here and maybe at the other hospital, but they managed to get almost 400 patients?

Walsh: Yes. I know, Ileana, that you know a lot about exercise and how to measure exercise capacity. They really showed that even though the VO2 max didn't change so much, these kids' effort tolerance on a day-to-day basis increased.

It really is, to some extent, almost a patient-reported outcome where they showed that these kids were able to do more and maybe that the measure of VO2 wasn't as important in this trial.

Piña: I love the fact that the ventilatory thresholds seemed to get better so that they could do more at the sub-max level, which is really where people live. I think we need to congratulate the researchers for having done the study and getting the data. Apparently, the exercise tests were very well done because they selected the test that had enough effort.

Walsh: Also, a very interesting piece to this whole session was the fact that they had a press release at the end of the session. There was a very obvious interest in how this medication was going to do.

Piña: We know that a lot of these congenital heart patients end up with us as adults. And many of them end up getting transplanted later on. It's an interesting area.

SGLT2 Inhibitors Beyond Diabetes

One of the other two sections had to do with DAPA-HF.[2] I want to remind our audience that DAPA-HF was presented at the ESC, and it was really an amazing trial with amazing results, where the event curves separated almost immediately, and it compared dapagliflozin with a placebo control. They also had some really good data on health status. But these were looking at some very specifics. Mary?

Walsh: Well, what they really wanted to look at was, how do we subsegment this population? I think the big question for all of us is, how is this SGLT2 inhibitor class of medication going to fit into our practice?

Piña: Do we see it as a heart failure drug?

Walsh: Are we going to treat patients with diabetes? Are we going to treat all heart failure patients? The question that came out, especially in the end with the discussants, was how will this fit into our everyday prescribing?

Piña: First of all, we don't even know the mechanism. We know their mechanism in lowering hemoglobin A1c and maybe losing weight and improving glucose excretion. But what are they doing to the heart?

Walsh: They also improve renal function and a little bit of weight loss.

Piña: They have a low side-effect profile.

Walsh: Very low. And no dehydration. So to your point, no—we don't know the exact mechanism in regard to the cardiac effects and why we see so much benefit.

I think a major question on the table is whether cardiologists are now going to prescribe these drugs, and if so, to which patients at risk? For example, is it those who are currently stage A heart failure and those at risk because of diabetes? And maybe even more important, what about our HFrEF patients? Is this going to be the next thing that we add or do we add it first?

Piña: We don't know that.

Walsh: We have no idea because there are no trials that address that at all.

Piña: It's a new chapter.

Walsh: Right. It is so exciting. I think this session and the presentation at ESC were so great because we have had two, sequentially, new drugs that we can use for our HFrEF patients.

Patient-Reported Outcomes

Piña: There are trials with empagliflozin and sotagliflozin in HFrEF still to come out that will either confirm or not confirm this. The other talk, as you heard, was about the health status of the patients because there was a significant improvement in the clinical symptom score. Something has happened regarding symptoms that the patients are detecting.

Walsh: Yes. This is not just an outcome that is death, hospitalization, or a combined endpoint. This was actually people feeling better on drug. This was looked at across all strata and it seemed to work for all patients.

I think this is really important because you and I also have been involved recently in work looking at how we incorporate endpoints that are not mortality, hospitalizations, and other hard endpoints. But what about those that are patient reported and what things matter to patients? I think the results today show that this does matter to patients because they feel better.

Piña: And did you see the NT-proBNPs? They weren't low. They were high. They were in the thousands, so there must have been some symptoms.

Walsh: Yes, they were sick people. This was not only patients with mild symptoms.

Piña: We're going to wait and see what the next two trials show. I had been sending patients to the primary care programs to get them to start the SGLT2 inhibitors. Now, the price is going to be important. Are we going to be able to get these drugs to our patients?

Walsh: Well, as of now, at least in our practice and with our payer mix, we've faced a lot of headwinds on this. The prior authorization process is draconian. One cardiologist, who is not a heart failure specialist, is very interested in the cardiometabolic syndrome and has asked us to send all of our patients to him. One of our nurses is working with him on the prior authorization process.

Hopefully, down the road, this will get better. A change in FDA indication may help, but just as with some of our other expensive medications, prior authorization is a real issue.

Piña: And a difficult one, because it takes time for the staff to sit there for hours talking to the insurance companies. Do you think DAPA-HF is going to change the guidelines?

Walsh: Yes.

Piña: I think so too.

Walsh: I'm not on the guidelines writing committee, so I'm not giving any secrets away. But I can't imagine that these won't enter the guidelines. The committee is reorganizing for another update.

Piña: And they're going to do it much more rapidly.

Walsh: Yes. That process will be much more nimble. The organizations involved have committed to being more nimble when new data come out.

Piña: Hopefully we're going to hear about that soon. I think we're going to have to go back to this group—many of them were already on medications—and see what they were on.

Walsh: They were well medicated.

Piña: What were they on, and at what doses? Dapagliflozin would have been an add-on drug. And remember, it's patients both with and without diabetes.

Walsh: Right. I also think it's really important to understand our CMS Medicare patients, because aside from prior authorization for private insurance, some of those patients are paying full price already. I think that having shared decision-making with our patients around this is going to be really critical.

Piña: And I recommend including the diabetologist. You have a good one at your place.

The next presentation was about PARAGON-HF.[3] PARAGON-HF, for some people, was a disappointment because it didn't meet their endpoint, but there were a couple of interesting subgroups.

One was the women, which Professor McMurray presented today, and I was happy to hear him say that this finding could be the play of chance because they had more women in the trial. Do you think there is something to this?

Walsh: I would not argue with John McMurray about this point. But I think PARAGON-HF enrolled more women than we usually see in heart failure trials.

Piña: As did CHARM-Preserved.

Walsh: Yes, but I would say that compared with the prevalence of the disease in the population of women, it still totally underenrolled women.

Piña: Absolutely.

Walsh: They found that for women with slightly low ejection fraction, not typical HFrEF—you know, middle zone—those women seem to benefit.

Those men in that same EF range did not seem to benefit. So maybe a play of chance.

I've wondered, since hearing the results: What if they had enrolled more women in the trial, and the primary endpoint for all of PARAGON-HF, not only the subgroup, may have been a positive trial and maybe they wouldn't have even explored these other issues?

Think about how PARAGON-HF would have played out if there were 50% women and 50% men. Would the primary endpoint have been met? I can't say that for sure, but I think it goes to the importance of why we should be enrolling patients like those who have the disease. In any HFrEF trial, if there aren't 50% women, you've got to wonder: Where did we go to find the patients?

Piña: And if you enroll enough women, then you can decide prospectively that you're going to study that subgroup. Most of the other stuff becomes post hoc because you didn't decide it ahead of time.

Walsh: But the question again is, will the guidelines shift toward recommending ARNI for HFrEF with ejection fraction up to 45%? And will the guidelines even reflect sex-specific recommendations?

Piña: I doubt we're there yet, but we've had discussions about whether sacubitril is more important for women. For example, we know that the bradykinin effects also have endothelial effects. Of course, women have more endothelial issues with their heart failure. Most of them don't have ischemic heart failure. So thinking about the nonischemic cardiomyopathies, maybe there is something genetically different?

Walsh: Maybe.

Piña: But we need to test it. I thought it was a fascinating section. The questions coming from the audience were equally important.

Walsh: We should probably emphasize the fact that Dr Mark Drazner was the social media moderator for the session—that's a new thing. His job was to field questions from the audience instead of us asking questions of the presenters or the discussants. He got some interesting comments.

Piña: And there were many questions about the difference in the women.

Walsh: Right. That seemed to grab the audience.

Piña: Let's see. We're going to have a new heart failure drug.

Walsh: Maybe a new indication for the ARNI.

Piña: Right. Exactly. And we're going to get the SGLT2 inhibitors, which is now a heart failure drug, not only a diabetes drug. When are we going to add it? And when are we coming to precision medicine?

Walsh: The last question is harder. But when do we add it, I think will be asked. And do we use current guideline-directed medical therapy and add on, because that's the way the trials were done? Will we add it in the hospital?

Piña: Are we bold enough yet to reverse the order? Maybe we should give the SGLT2 inhibitor first and see how the patients do. Some of these patients may have had symptoms, whereas some probably did not have many HF symptoms.

Walsh: So, a new chapter.

Piña: Exactly. I want to thank you for spending time with me. It was a lot of fun, both in the session and here.

Walsh: Thanks for having me.

Piña: I hope that you take this back to your practice. And I hope we're giving you points to think about when you have the patient in front of you. What are you going to do? Nonetheless, good drugs.

I'm Ileana Piña. Thank you very much for joining me. Signing off.

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