PARAGLIDE-HF and PARAGON-HF Trials in Heart Failure

James Januzzi, MD: We have some sense that in acute HFpEF [heart failure with preserved ejection fraction],regardless of the ability to continue the drug after starting in the hospital—I’ve said repeatedly that this is critical—there’s probably some impact on short-term events. Muthiah, you mentioned the 622 patients in PARAGON-HF who were hospitalized within 30 days. We have 466 from PARAGLIDE-HF. Did you consider looking at how these patients compare with one another, their prognosis, and the effect of sacubitril-valsartan?

Muthiah Vaduganathan, MD, MPH: Prior to the unmasking of PARAGLIDE-HF, we had prespecified bringing together the new line of evidence with that of the established evidence from PARAGON-HF. Those 1088 participants formed the primary pooled analysis that we analyzed. In fact, consistent with what we see with individual trials, this pooled analysis brings greater power and precision to the estimates. When examining clinical outcomes of interest, we see a significant reduction in a cardiovascular composite endpoint, total worsening heart failure events, and cardiovascular death. That was a large magnitude risk reduction of 22%. Furthermore, there was a large magnitude absolute risk reduction of 700 patient years, and a number needed to treat it only 14 for 1 year to prevent an event.

James Januzzi, MD: These are patients in that vulnerable period after discharge. You mentioned earlier about how hospitalization is a threat moment for patients with acute heart failure. How soon after initiating secure sacubitril-valsartan did you see a benefit?

Muthiah Vaduganathan, MD, MPH: When looking at the totality of evidence, pooling both clinical trials—with 5262 participants—we see first nominal statistical significance reached by day 9 after randomization.

James Januzzi, MD: That’s saying that you can’t wait. It’s not a situation where starting sacubitril-valsartan at discharge or soon thereafter is going to be critically important. The totality of evidence includes not only efficacy but also safety. Rob, what did you see in PARAGLIDE-HF as far as tolerability? One thing I’ve heard from my colleagues is that starting sacubitril-valsartanin an acute setting sometimes comes with hypotension if a patient is over-diuresis, for example. Was there more hypotension? Did it have a clinical impact? What doses did patients achieve in PARAGLIDE-HF?

Robert Mentz, MD: This is an important piece. As we look at all the evidence, we saw more symptomatic hypotension with sacubitril-valsartan compared with valsartan. It’s a73% increase. Your points are well taken that in this higher-risk period, we need to make sure we’re looking at all the information we have: understanding the patient’s volume status, making sure they’re not getting volume depleted, and realizing that many of these patients are on other medications managing blood pressure. They may be on a calcium channel blocker, so we may consider backing down on the dose or stopping some of other medications that don’t have data to support their use.

As you nicely highlighted, looking at dose is going to be a very important consideration. In this setting of a trial, at 1-week intervals we were up titrating the dose. Now we’ll take a deep dive into that to better understand, who are those patients for whom we see more symptomatic hypotension? When does that occur? How can we best manage that or even prevent that? I’ll underscore that this was symptomatic hypotension documented by the PI [perfusion index].When we look at all the evidence combining it with PARAGON-HF, we see a significant increase in symptomatic hypotension, but it’s a little less as you get further out from this event.

James Januzzi, MD: My message is always that hypotension maybe more common, but that doesn’t mean you have to stop the medication. Your point is on target: find mechanisms by which the drug can be more tolerable. Reducing diuretics is our first step in non congested patients, but looking for other opportunities to make adjustments and therapeutics is critically important .Above and beyond, an ARB like sacubitril-valsartan reduces risk. Things about PARAGLIDE-HF that I thought were important were the renal endpoint and the short time to improvement. PARAGLIDE-HF had subgroups that are important to focus on. In PARADIGM-HF, for example, there was no one with de novo heart failure. We showed in the PROVE-HF study, the TRANSITION study, and other trials that [patients with] de novo heart failure tolerate sacubitril-valsartan quite well and with good efficacy. How do de novo heart failure or patients with obesity do?

Robert Mentz, MD: This is an important piece as we look at the trial population—52% of women, with a median age of 72 years and a BMI [body mass index] of 33. We included a GFR [glomerular filtration rate] down to 20mL/min with no run-in period. These are the patients we’re seeing in practice. As we look at some of the other components you mentioned, like denovo heart failure in one-third of patients. This is their first time coming into the hospital being identified as heart failure with preserved or mildly reduced ejection fraction. Whether it was de novo or those who hadn’t previously been on an ACE or an ARB, we saw consistent reductions and NT-proBNP in different groups.

James Januzzi, MD: Another thing is that the study had was 22% Black patients. Is that correct?

Robert Mentz, MD: Yes.

James Januzzi, MD: Why is that important? Do you want to explain to the viewers?

Robert Mentz, MD: This is a very important piece. You and others have taught us that natriuretic peptide levels can be different in different subsets based on demographics. We wanted to make sure we recruited a diverse population that represents who we’re seeing in practice. I’ll highlight an important effort partnering with the cardio nurse team that helped not only with the trial but training the next generation. They help support the diversity of trial recruitment in this program.

James Januzzi, MD: It’s a priority to get a representative patient population among the patients we see with respect to underlying genetic differences, like the natriuretic peptide differences in Black individuals and the purported higher risk for angioedema in Black patients. How many angioedema cases are we seeing in PARAGLIDE-HF?

Robert Mentz, MD: There was 1 case in the valsartan arm.

James Januzzi, MD: Therefore, we’ve addressed now with PARAGLIDE-HF, PROVE-HF, PARADIGMand many other studies that the angioedema rate is extraordinarily low, despite the previous concerns.

Transcript edited for clarity