Heart Failure with Preserved Ejection Fraction (HFpEF) and Use of Sacubitril/Valsartan in Heart Failure

James Januzzi, MD: We talked a few times about the stage IIB recommendations for spironolactone as well as sacubitril-valsartan. Muthiah, how did we get to a place where patients appear to benefit? Rob mentioned that there are patients who have ejection fractions [EFs] below normal, but it’s more complicated or more extensive than that. What are your thoughts?

Muthiah Vaduganathan, MD, MPH: Guideline writers and our community at large view these trials in a more nuanced fashion, saying that they aren’t black orwhite, positive or negative. Rather, there are clear subsets in these trials that may benefit to a greater degree. It seems there’s a gradual attenuation of benefit with many of these drug therapies, specifically ARNI [angiotensin receptor/neprilysin inhibitor], MRAs [aldosterone receptor antagonists] and ACE inhibitors, and ARBs. Once the EF is above about 60%, those benefits don’t appear to be robust.

James Januzzi, MD: That’s evident. Is it in everyone? Or are there differences between men and women, for example?

Muthiah Vaduganathan, MD, MPH: There are population-based differences in men and women in terms of their ejection fraction distributions. On average, women have higher ejection fractions. You made the great point that once the ejection fraction falls below a normal level, we start to think about treating these patients more aggressively with multidrug regimens. For women, an ejection fraction that’s normal might be at a higher level. In fact, that’s exactly what we see in the clinical trials. The benefits of these therapies seem to extend to a higher ejection fraction in women compared with men.

James Januzzi, MD: That’s helpful. The ACC [American College of Cardiology] Expert Consensus Decision Pathway document on heart failure with preserved EF [HFpEF] makes the suggestion to consider3 pillars rather than 4,with beta-blockers for patients who have an indication. It recommends sacubitril-valsartan and an MRA in women across the spectrum of EF until you get to high normal values. What’s missing in this whole story is acute HFpEF. Muthiah, historically speaking—it’s not long history; it’s just a few years—what do we know about response to sacubitril-valsartanin acute HFpEF? Holding back from the recent studies, but really what was the background here?

Muthiah Vaduganathan, MD, MPH: Unfortunately, that was a large evidence gap. The largest clinical trial to evaluate this population was the PARAGON-HF trial, which randomized 4796 participants. Those patients were mostly enrolled in ambulatory care settings. They were clinically stable and had residual symptoms of heart failure.

James Januzzi, MD: How many were enrolled in the back end of a hospital stay?

Muthiah Vaduganathan, MD, MPH: A subset of patients were enrolled early after hospitalization, about 622 patients within 30 days of a hospitalization. Those patients appeared to benefit to a greater degree, in terms of absolute terms from sacubitril-valsartan.

James Januzzi, MD: It sets up the obvious opportunity to study this question in hospitalized patients. We’re privileged to have Rob Mentz with us because he was the principal investigator of a pivotal study.It puts the key in the lock and opens it up for hospital administration, recognizing the critical aspect from an implementation perspective for hospitalized patients with HFpEF. Let’s focus on the PARAGLIDE-HF trial. We have new data presented at the ESC [European Society of Cardiology] heart failure meetings. Rob, can you give us an overview on this? We heard what the previous studies said might be the case, but what did you find in PARAGLIDE-HF?

Robert J. Mentz, MD: That’s exactly right. Muthiah and colleagues had a nice secondary analysis showing that not only was that recently hospitalized group at the highest risk for events, but the treatment benefit looked even greater there. We wanted to further explore that in a trial that enrolled the patients we see every day in practice. These were patients with heart failure, EF greater than 40%, who were in the hospital with worsening heart failure or who recently had a worsening heart failure event within 30 days. This mirrored your secondary analysis for that latter component. We looked at a primary endpoint of change in NT-proBNP [N-terminal pro-brain natriuretic peptide] from baseline to weeks 4 and 8. We also wanted to look at clinical outcomes—cardiovascular renal outcomes. We were fortunate to show in 466 patients who had an average follow-up of 6 months that we met our primary endpoint. Comparing sacubitril-valsartan with valsartan, we saw a 15% greater reduction in NT-proBNP with sacubitril-valsartan. I ’ll underscore that this wasn’t a placebo-controlled trial. This was an active comparator trial showing a greater reduction in NT-proBNP.

James Januzzi, MD: What did you compare with again?

Robert J. Mentz, MD: This was compared with valsartan.

James Januzzi, MD: What dose of valsartan was used?

Robert J. Mentz, MD: As with some of the earlier programs, this was titrating up in both to the target dose of 97/103 mg twice daily with sacubitril-valsartanand160 mg twice daily with valsartan.

James Januzzi, MD: Was there a run-in period with this study?

Robert J. Mentz, MD: This was 1of the important pieces, but no. As with the PIONEER-HF trial that looked at her HFrEF [heart failure with reduced ejection fraction] in the hospital, we didn’t have a run-in period. We looked at in-hospital initiation and had a broadly inclusive population.

James Januzzi, MD: We’ll talk about that population. We should talk about some of the key subgroups because that was a special aspect of this study. The patients in PARAGLIDE-HF were hospitalized, so they should, but did they have an elevated NT-proBNP to start with?

Robert J. Mentz, MD: They did. In order to get into the trial it was an NT-proBNP of 500 pg/mL or greater in normal sinus rhythm, or 1000if they were in atrial fibrillation. The median NT-proBNP was 1600.

James Januzzi, MD: They’re modestly congested but not drowning. This is HFpEF, so you expect lower values. In fact, the data in the MRA world suggest that this modest elevation of NT-proBNP identifies a sweet spot for treatment where even MRAs are effective. That’s interesting. The primary endpoint of reduction of NT-proBNP was met. Then you looked at clinical events as well as renal outcome. For individuals viewing this discussion, why is the reduction in NT-proBNP above and beyond the active comparator? Why does that matter?

Robert J. Mentz, MD: As you’ve taught us in many ways, NT-proBNP is 1of our best measures for prognosis. As we look at the multitude of measures, that 1gives you so much information about the clinical outcomes that that patient will experience.

James Januzzi, MD: That’s amazing. Then thereare clinical event reductions. This wasn’t a study powered for clinical events. What did you see in this population? Were there specific groups that show different results?

Robert J. Mentz, MD: I’ll walk you through this because some may be less familiar with this type of endpoint. We had a hierarchical composite that looked at cardiovascular death, heart failure, hospitalizations, urgent heart failure visits, and that change in NT-proBNP. This was over that longer period, and we compare the 2 groups.

James Januzzi, MD: For viewers, a hierarchical composite looks at each endpoint and asks how patients in each arm of the study did in terms of winning. Did they do better in this 1 vs not better in that 1?

Robert J. Mentz, MD: That’s right. Ultimately, what we see is a win ratio of 1.19, or 19% more wins with secure sacubitril-valsartan.

James Januzzi, MD: If the drugs were equivalent, it would be a win ratio of 1.

Robert J. Mentz, MD: That’s right.

James Januzzi, MD: It favored secure sacubitril-valsartan. Were there patients who got a larger benefit?

Robert J. Mentz, MD: One of the most important pieces was based on data from PARAGON-HF, which prespecified a focus on those with EF below normal as well—60% or less. Strikingly, the win ratio in that case is actually 1.46, with46% more likely to have wins and meeting a nominal statistical significance.

James Januzzi, MD: If that’s what the study was designed around, that would have been a win, without question. Let’s talk about renal composite. I’ll be honest: as a clinician, that’s one of the most exciting results from PARAGLIDE-HF.

Robert J. Mentz, MD: I agree. We had a key secondary endpoint that looked at renal composite. We saw nearly a 40% reduction in worsening renal function with sacubitril-valsartan compared with valsartan. But we know that ARB benefits renal function in many patients with different comorbidities.

James Januzzi, MD: It’s eerily reminiscent of the experience in PARADIGM, where patients were expecting worse kidney function outcomes. In fact, it was the opposite at every level of kidney function or dysfunction. Sacubitril-valsartan was superior to the comparator. In that case, it was an ACE inhibitor; in this case, it’s an ARB. Javed, this is an analogy to SGLT2 inhibitors’ protection of the kidneys. Do you expect that to translate to protection of the heart?

Javed Butler, MD, MPH, MBA: The connection between heart failure and the renal function is pretty tight. Obviously, we have to be careful because some studies are designed to answer specific questions. I’m not saying in terms of indication what we should use for those purposes. If you look at SGLT2 inhibitors and ARNI, there’s a lot of overlap. We forget that there was a very nice paper from PARADIGM-HF, about hemoglobin A1C [glycated hemoglobin] reduction and also less need for insulin.

James Januzzi, MD: Why would there be a hemoglobin A1C reduction?

Javed Butler, MD, MPH, MBA: It’s complicated. Neprilysin inhibition has a lot of effect on other enzymes, and that can impact the metabolic profile. You’re seeing the renal benefits, and this isn’t the first time. Other ARNI studies and PARAGON-HF have shown this result as well. If you put the 2 things together, it looks like atherosclerotic events is 1set of pathways and then you modulate that. Cardiorenal events go hand in hand with myocyte and renal function and anything that’s has a favorable impact on heart failure. It invariably affects kidney function favorably as well. We give SGLT2 inhibitors, ARNIs, ACE inhibitors, and now there areMRA data coming out.

James Januzzi, MD: Yes, nonsteroidal MRAs.

Javed Butler, MD, MPH, MBA: Absolutely.

James Januzzi, MD: That’s very interesting. Clinically speaking, there are biological benefits but also implementation benefits. If a patient’s glomerular filtration rate drops below 30 mL/min, we have to withhold MRAs. Protecting kidney function and utilizing other drugs facilitates use. You’ve done nice work with SGLT2 inhibitors, showing that they facilitate use of spironolactone and allowing for persistence, which is critically important for our patients.

Transcript edited for clarity