Javed Butler, MD, MPH, MBA

 Looking forward, how do you envision implementing therapies in a more aggressive fashion? I’m going to go to each of you to share some clinical pearls about how you envision the heart failure world getting its arms around the need to take a chemotherapy-like approach to our patients in getting them on therapy. Since you were the last to speak Muthiah, I’ll ask you to be the next to speak.

I’m going to jump forward, I’m going to look to the future. I think we are looking at an environment in which these drugs are going to be accessible, affordable, easy to administer, and I think we should start to engage our patients and have patients have a more active role in the initiation and titration of these drugs. We can envision a system much like insulin titration, in which at least some patients who are engaged in their care could modulate dosing, could initiate new drug therapy, in their home environments with relatively limited monitoring structures.

We’ve got a cancer analogy, now we have an endocrinology analogy, that’s great. Rob, what do you think? What does the future hold in structuring rapid titration and getting patients to target?

I’m really hopeful on a couple of fronts. One is that we strike this term “consider.”“We’ll consider starting ARNI [angiotensin receptor-neprilysin inhibitor] at follow up.” We’ve got to eliminate that from our vernacular, that can’t be in a discharge summary. We need to start these therapies in the hospital, and I think it’s all as others have highlighted, this multidisciplinary team. We’ve learned about the tremendous success of having a pharmacist who can help a case manager if there’s paperwork and other financial limitations. So the future is multidisciplinary teams, it’s rapid sequence. We’ve got to do better for our patients.

Javed, what do you think? At Baylor Scott and White [Health], how are you thinking about this?

No, I don’t have much to add on top of what Muthiah and Rob said. Let me just take a moment and make a plea to all our listeners. Symptoms should be targets of therapy in heart failure, not a guide for therapy. Things like high blood pressure, diabetes, lipids, these diseases by definition are asymptomatic. We have many cancers that are diagnosed on screening, and that comes as a surprise to patients, they are asymptomatic. We would never leave these patients alone because their symptoms are OK. You treat the biology of the disease. Heart failure is the same thing. Whether you have a lot of symptoms or you have few symptoms, we need to target the underlying biology and treat them aggressively with appropriate indicated therapies. Just because somebody says they’re doing OK is not a reason to not treat them appropriately.

Absolutely, an important take-home message from Dr Javed Butler. At our institution at [Massachusetts General Hospital], we recognize the need for infrastructure for rapid sequence initiation and titration, even before STRONG-HF trial data came out. We have a clinic called the GDMT [guideline-directed medical therapy] clinic, and it is in existence for one job, which is education, initiation, and titration of GDMT. We’ll either start outpatients or we will take patients who have just been discharged in continuity to get them to target. It’s a 12-week process or shorter. We utilize many of the tools Dr Vaduganathan mentioned, not only education, but home-based titration, including virtual care, virtual laboratory testing as well, in order to get patients to target, because by and large that’s really the most important monitoring piece in this process. Blood pressure matters to be sure, but provided patients are not symptomatically hypotensive, we will continue titrating. We get patients in the office periodically, however, we have a nurse practitioner-based approach but we also have a pharmacist, as Dr Mentz mentioned. In our patients in our GDMT clinic, we are achieving quadruple therapy in over 90% of our patients, with nearly 90% on sacubitril/valsartan, and over 60% on target doses of all 4 drugs.

We’ll close with the point, Rob, in the CHAMP-HF Registry, how many patients were at target dose?

 This is striking, you can count it on a couple of hands.

It was single digits. The point is that it can be done. GDMT works for our patients, it reduces morbidity and mortality. We should not wait for initiating and titrating, getting patients feeling better and living longer. Four drugs, 5 pathways, 6 years of extra survival.

Thanks to all of you for this rich and informative discussion, and thank you for watching this peer exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming peer exchanges and other great content right in your inbox. I’m Jim Januzzi, thanks for watching.

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Drs James Januzzi, Javed Butler, Robert Mentz, and Muthiah Vaduganathan share practice pearls for treating patients with heart failure, focusing on the future of treatment.

Clinical Pearls for the Treatment of Heart Failure

: That’s a great setup for us to talk about those trials now. Muthiah, what I think I hear from you is that we can no longer sit back and titrate slowly. It’s going to take infrastructure, of course in order to do this, and we’ll talk about how we do it at our institutions. But first let’s talk about recent data from our colleague Alexandre Mebazaa,[MD, PhD,] in the STRONG-HF trial. Rob, do you want to review the structure of the STRONG-HF trial?

: This was a really important trial that just reported out this past year that looked at patients in the hospital with heart failure, and just as in your recent example, it was agnostic about ejection fraction, so it included patients across the spectrum. At the time, where we were with the evidence, it was looking at ACE [angiotensin-converting enzyme], ARB [angiotensin receptor blocker], ARNI [angiotensin receptor-neprilysin inhibitor] initiation, beta blockers, and MRAs [mineralocorticoid receptor antagonists]. We didn’t yet have the totality of evidence with the SGLT-2 inhibitors. But what it looked at was a randomized comparator of usual care, what we’re doing every day in many places, vs rapid sequencing. So, this idea of while in the hospital, getting patients on these therapies, at least at half doses, and rapidly seeing them back in the clinic, and within 2 weeks getting patients all the way up to the full doses as best we could.

: That’s incredible. Was it tolerated, was it safe?

: It was tolerated, safe, and importantly, the trial stopped early. There were over 1000 patients, but it stopped early for improvements in clinical outcomes, a large reduction in heart failure hospitalizations, and improvements in quality of life too.

: My understanding was that in the usual care arm, the investigators were seeing the improvements in the accelerated patients. So in the study design, the patients were discharged to usual care, and that meant typically waiting a few weeks to months before seeing their cardiologist. But then all of a sudden, therapies would get loaded in because the doctors were seeing the benefits on the other side. But by that point, the trial was already positive, favoring that short time to benefit that occurs with the initiation of these therapies. So, there was a reduction in cardiovascular events. Javed, what about health status? Did the patients feel better or worse if they got lots of medications thrown at them quickly?

: Not only was there was significant benefit in patients symptoms, and this is exactly what you would expect because these therapies individually in the clinical trials have been associated with improvement in symptoms. But what was a pleasant surprise, because remember, we did not have the data from PARAGLIDE-HF at that point when that [STRONG-HF] trial was done, not only was there benefit seen across the spectrum, but patients with HFpEF [heart failure with preserved ejection fraction] numerically tended to benefit more.

: We’re at the ESC [European Society of Cardiology]Heart Failure annual meeting, and part of the reason why I think that is, it was a bit of a eureka moment for me because I wasn’t sure I understood how patients with preserved EF [ejection fraction] heart failure would have as much if not greater benefit, until I saw that the number of patients with an ejection fraction at or below 60% was the majority. They had relatively very few people in that range where drugs like spironolactone don’t benefit. I think that explains it for me, although there are gaps in STRONG-HF. There’s no question that it’s an important study, but what about the gaps in STRONG-HF, therapeutically, were there drugs that were missing from the contemporary list?

There are important gaps. I would start by saying that this was conducted in select regions of the world, and so the transposability, the generalizability to care settings outside of those select regions, like the United States, is as yet uncertain. These protocols need to be adapted and incorporated into health systems worldwide. Furthermore, they had a very aggressive follow-up protocol, requiring almost weekly in-person follow-up visits. Many hospitals systems may not have the capacity to do that, or the personnel to do that, in real-world clinical care. I will say that these therapies that were studied were of a prior generation, and some of the newer therapies, especially more common use ofsacubitril/valsartanand use of the SGLT-2 inhibitors, were largely absent in the STRONG-HF trial.

: No SGLT-2 inhibitor and only 10% of sacubitril/valsartan, so even in that circumstance, we can do better, I suspect.

Robert Mentz, MD, reviews the results of the STONG-HF trial for patients in the hospital for heart failure.

Use of Guideline-Directed Medical Therapy in Hospitalized Patients With Heart Failure

: I’m going to give Dr Butler a 10,000-foot-view question now. We’ve got results from PARAGLIDE-HF, we’ve got other contemporary trials. What do you think the impact on clinical practice is going to be for HFpEF [heat failure with preserved ejection fraction], specifically?

: After 3 decades of nihilism that we can do nothing about HFpEF, that none of the trials are positive, things are really changing. Between the MRA [mineralocorticoid receptor antagonist] secondary analysis, ARNI [angiotensin receptor-neprilysin inhibitor] trials and SGLT-2 inhibitor trials, we now have several therapies we can give our patients with HFpEF. The thing that PARAGLIDE-HF really helps with is that, when new trials come out, and you see some subgroups here or there, people make a bit too much out of it and argue about it. For instance, with the SGLT-2 inhibitor, there was this whole thing about whether with higher ejection fraction there is benefit, and the second trial came out and that discussion ended. Here with PARAGON-HF, there was again this question that it was secondary analysis, and now PARAGLIDE-HF is so consistent that I think that question just goes away.[It determined] you should be using it in these patients. The second thing is that we have been emphasizing so much that these therapies should be started in the hospital setting, and now we have evidence of the benefit of starting it in the hospital setting. I think in that sense, it makes the implementation a whole lot easier.

: So now we have evidence for in-hospital initiation. Regarding implementation, I’m going to turn to the co-director of the [Center for Cardiometabolic Implementation Science, at Brigham and Women’s Hospital] to ask him about implementation. What is the current state of the art with respect to heart failure therapy implementation? Let me give you a best case scenario. A patient is in the hospital, they’ve got HFpEF or HFrEF [heart failure with reduced ejection fraction], let’s be agnostic to the ejection fraction now. They’ve been started on either the 3 or 4 pillars, but they are at low doses, and they’re about to go home. What is the optimal state for their care at this point?

: We’ve learned a wealth of information about optimal pathways for implementation over the last severalyears and turning that page from discovery science to implementation science. There are various tools now available to us, some embedded in the EHR [electronic health record], some based on multidisciplinary care teams, some based on post-discharge accelerated care models. I think in this patient who’s ready for discharge, first and foremost, again, [we need to be] arming that patient with education, a look forward of what’s to come. Then, rapid sequence optimization in the early outpatient period is going to be critical, not only to ensure that the patient continues to recover in that post-discharge window, but also to get the patient on target doses as studied in these pivotal randomized clinical trials.

Experts in cardiology comment on the impact of recent trials on heart failure with preserved ejection fraction (HFpEF) in clinical practice.

Impact of Clinical Trials on Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF)

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?

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.

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?

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.

 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?

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.

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?

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.

Another thing is that the study had was 22% Black patients. Is that correct?

Why is that important? Do you want to explain to the viewers?

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.

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?

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.

Muthiah Vaduganathan, MD, MPH, provides an overview of the pooled data from the PARAGLIDE-HF and PARAGON-HF clinical trials in heart failure.

Javed Butler, MD, MPH, MBA

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