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Diabetes Core Update
Special Edition - Heart Failure Part 3 - Cases-based Discussion
00:34:17
In this special episode on Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) our host, Dr. Neil Skolnik will lead a case-based discussion on HFpEF, presenting challenges and integration of emerging evidence into clinical practice....
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- [00:03]
A
Welcome to the special series of Diabetes Core Update, where we will discuss heart failure with preserved ejection fraction, I.e. hFPEF. At least half of all patients with heart failure have HFpEF. But it is really only in the last few years that we've seen the development of effective therapies for HFpEF. We've also found out it's a lot more common and important than we used to think it was. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This series on heart failure is being sponsored by Roche. In part one of this series, we discuss the epidemiology of heart failure with a focus on HFpEF. We discuss pathophysiology, staging and screening. Screening for heart failure is now part of the American Diabetes Association's Standards of care. In the second episode, we discuss treatment of HFpEF. Today we're going to bring it all together with a discussion of cases. Also, being honest about the areas of uncertainty, we often don't talk about uncertainty here. I want to make sure we know where the edges are. I want to say at the start that there's going to be a lot of evidence that we discuss. There's also going to be some opinion. And while all of the treatments that we talk about are based in published trials, they're not all FDA approved, though some are either being or likely will soon be assessed by the FDA for approval. This is all to say, this is a really cutting edge area and it's going to be a cutting edge discussion to accomplish this. Joining us today are two master clinicians. Dr. Muthu Vadaganathan is a cardiologist and co director, center for Cardiometabolic Implementation Science at Brigham and Women's Hospital and Harvard Medical School. He is an associate editor of the Journal of the American College of Cardiology. He has published over 700 articles in the medical literature. And when you peruse the heart failure literature, which I have done in preparation for this podcast, mutu, your name is coming up all the time. Welcome to our podcast.
- [02:23]
B
Thank you so much, Neil. And I'm delighted to be able to participate here, especially on one of my favorite topics.
- [02:32]
A
Well, thanks so much. And also Joining us is Dr. Susan Kucera. Dr. Kuchera is the Program Director of the Jefferson Health and Abington Family Medicine Residency Program and is an Associate Clinical professor of Family and Community Medicine in the Sydney Kimmel Medical College of Thomas Jefferson University. Welcome, Sue.
- [02:55]
C
Thanks for having me, Neal. I can't wait to get into this discussion today.
- [02:59]
A
So before we get to our cases, I want to remind our listeners that in the first installment of this special series, we discussed the recommendations from the American Diabetes association standards of care about screening people with diabetes for heart failure. If you want to look in detail about that, it is in the January edition of Diabetes Care. Let me quote from the standards of care and that is that adults with diabetes are at increased risk for the development of asymptomatic cardiac, structural or functional abnormalities. Stage B heart failure or functional abnormalities Stage C heart failure. Consider screening adults with diabetes by measuring a natriuretic peptide that's either a BNP or an NT pro BMP to facilitate prevention of stage C heart failure. Muthu, can you remind our listeners what stage B and C heart failure is and why early detection is important?
- [04:02]
B
Absolutely, Neil. The staging of heart failure is really positioned to be able to understand how heart failure risk progresses over time and attempts to map the longitudinal trajectory of that risk from at risk risk factors alone in stage A to stage B, people with clear heart failure risk but without symptoms of heart failure or signs of heart failure, and that might be designated by biomarker evidence of heart failure risk, such as the natriuretic peptides that you identified or cardiac structural and functional abnormalities most commonly detected by echocardiography. And then stage C heart failure is symptomatic patients who we consider often as having clinical heart failure. And this accounts for about 6 million Americans in the United States and about 56 million people worldwide with symptomatic heart failure. And then some of those individuals progress to stage D or advanced heart failure and that is about 1 to 2 percentage of that cohort. So really we're discussing can we identify an earlier stage of disease that precedes the symptomatic phase, that we can actually deploy potentially effective interventions to prevent the symptomatic onset of heart failure.
- [05:34]
A
And that's such an important concept. And we'll come back to the how severe symptoms are for lots of people a little bit later after our case because I think one of the important overriding themes is that it's not always like we used to think. It's not only that person with rows up to their ears and that we're admitting from the er. Sue, let's move on to a case and I'm going to present you a case of a 57 year old woman with a past medical history of long standing hypertension, hyperlipidemia and obesity. She's on hydrochlorothiazide amlodipine and atorvastatin. She's coming in for routine follow up on review of systems. You find out she's often fatigued. She has two kids, she's working a full time job, so of course she's tired. She doesn't have a chance to exercise, she feels like she's out of shape and she says she gets a bit winded or short of breath when running around with her kids. Physical exam is essentially normal. Other than a BMI of 33, her last set of labs were essentially normal. Is this someone, sue, who you feel we might consider looking for heart failure? And if so, how would you do that?
- [06:55]
C
Yeah, first let me say that those of us in primary care see this a handful of times a week, right? So so many times patients are coming in, they've got risk factors, they're a little tired, little short of breath, they're not exercising. I think, you know, the first part of this is it's really hard to know when to pursue this and look for something more. Right. This is a, this is a tough call on primary care and that sort of complexity we deal with all the time. I think the second piece of this is prior to probably the past couple years, this would be like, oh, we'll get a, you know, cbc, a CMP and maybe a thyroid. You know, maybe it's her thyroid and just sort of stop there. And then I think the other piece is, gosh, when do we push on cardiac disease? You know, do they need an ekg? Did they need a chest X ray? Right. So there's a lot of nuance to this case and we see it all the time. The one thing I will say that now that we can screen for heart failure so easily by adding a blood test to the blood test we're going to get anyway for this patient. It's something I have started doing in my practice, right? It's a little bit easier to find heart failure if we're screening with a bnp. And we know so many patients are, you know, more like subclinical, right. They're not having these overt symptoms and it's become a lot easier to screen. So for me in my practice, you know, it's become cbc, cmp, TSH and a BNP of some sort, whatever your institution offers just to screen for heart failure in this situation as well.
- [08:26]
A
I think that's so helpful, sue, because I agree with you. It's what we see in primary care all the time. And Muthu, can I ask you to comment on symptoms and how the level of symptoms relates to the clinical trials. I know you're involved in a lot of clinical trials. When I read the clinical trials, I see that a significant proportion of people are New York Heart association stage two symptoms. And when I read about stage two symptoms, it's fatigue and dyspnea, unusual activities, which is a lot of people I see who are over 50. Can you put, put that symptom burden in perspective? Should we be thinking about this with people who are a little short of breath and fit the risk factor profile?
- [09:14]
B
I couldn't agree more with both of you that this is a very challenging entity to actually tackle at scale. You know, unlike other chronic or even acute medical conditions which have a finite start time, for instance, acute myocardial infarction often is the onset of management of atherosclerotic cardiovascular disease has a finite start time. Patients can often relate to that. In contrast, heart failure is one that has insidious onset, is slowly progressive until it actually manifests in a larger way in resulting in hospitalizations. And so early detection really relies on very quantifiable elements. So I often ask about, for instance, positional changes in symptoms. Orthopnea tends to be a fairly specific specific to heart failure or cardiac cardiac disease. Furthermore, exertional dyspnea is the hallmark of heart failure, especially heart failure preserved ejection fraction. And I tried to quantify that and we're looking for more objective evidence. So if they were able to do something six months ago and they're not able to do it today, and this has been a progressive decline, that's something that's worrisome. And the third facet is you can use ancillary evidence and ancillary clues. And so if you're noticing that other clinicians or perhaps you've started a diuretic, either a thiazide or a loop diuretic for some lower extremity edema, and you may have written that off asymptomatic management or perhaps for blood pressure management, but that is actually a clue that this person might be at higher risk for heart failure and can be used.
- [11:05]
A
Thanks Muthu. So her NT Pro BMP comes back at a level of 320. Muthu, can you discuss what level of NT pro BNP should be considered positive and lead to further testing? And important here, and I think underappreciated, are there things that influence that result, things like obesity and how does that affect how we should interpret the NT probe bnt? And finally, how good of a test is it? If there's any sense of sensitivity or.
- [11:38]
B
Specificity, move to SO NT bromide P is one of the most studied biomarkers in heart failure, both in the initial diagnosis as well as the prognostic assessment. It's more commonly used in the acute phase, so in acute care settings such as hospitalizations to help differentiate acute dyspnea syndromes from heart failure from other causes like pulmonary disease. Now in the ambulatory care setting it can be very very useful, especially in this circumstance where you have some subtle evidence of potential heart failure symptoms. And can it be used to help aid in the diagnostic evaluation? NT probnp levels are highly influenced by a number of factors. There are factors that increase the levels like age, like atrial fibrillation. Furthermore, there's factors that decrease the levels, for instance obesity and even racial influence. Black Americans have lower levels of NT probnp. Now obesity is a particular factor that contributes to lower levels of NT probnp both due to lower degrees of production and increased clearance. Chest wall deformities as well as direct effects of chest related adiposity decrease transmural stress. So there's less impetus for for anti probnp production. Furthermore, peripherally adipose tissue express Neprilysin, an enzyme that actually cleaves circulating natriuretic peptides. And so because of that, obesity contributes to lower overall levels in natriuretic peptides. But the universal definition of heart failure has simplified things and has said these factors should be considered on an individual patient level. But we can move towards single cutoffs to simplify it for our community. And so 125 picograms per milliliter is a single cutoff in this type of ambulatory care Diagnostic evaluation. So this patient clearly meets that threshold and then especially when we consider obesity in the background, she should certainly be considered further for heart failure evaluation. The sensitivity specificity clearly does vary based on the individual patient circumstances. In this case I would say she has a high probability of having heart failure.
- [14:11]
A
It's really helpful and I think a lot of people don't appreciate that low of a cutoff. We're used to admitting someone from the ER, we see that BNP, that's 3,000 or something like that. And I've seen in the office where people don't necessarily attach a lot of weight to an nt pro BNP of 250 for instance. And it's really important for our listeners to understand that cutoff. And thank God they made it simple because in primary Care. We are good at taking care of people and understanding things, but when there's eight different cutoffs, it becomes hard to implement. Sue we order a echocardiogram and it returns with an injection fraction of 55 to 60%. It shows grade one diastolic dysfunction, no valvular abnormalities. How would you approach the patient at this point?
- [15:07]
C
This is a great question and I think becomes increasingly relevant in primary care. As we screen more and more people, we're going to be diagnosing more and more people with heart failure. And I think the truth is, as we find more mildly symptomatic people and diagnose them with heart failure, we're going to have to start to re, look at how we explain this to patients. I think if a patient hears the words, you know, you have, you have heart failure, that's going to mean something to them. And I think that we're going to have to take the time to explain to them what does it mean to have heart failure with preserved ejection fraction. Right. What is, does it mean how you're feeling right now and what the prognosis of this long term is. So I do think that there's going to have to be a lot of time around that discussion with patients to understand the spectrum that we as clinicians know is heart failure. And then, you know, I think the, the second point is, gosh, we, we found this early for you. This is, this is good news. You know, there are things we can do with your diet, with your exercise and lifestyle habits, and there are lots and lots of medicines now that have data to help slow down the progression of this. You know, we can intervene for you now to hopefully not become as symptomatic with, with this in the future. So, you know, for this patient specifically, you know, she has both hypertension and obesity, right? Both of those medical problems are things that we can intervene on with study proven medications to help reduce her risk of progression of heart failure. But I think the answer though here becomes very patient centric. Right? We could add an SGLT2, we could change your blood pressure medicines to, you know, an mra. We could treat her obesity with an SGLT or with a GLP one. Right. All of those things are right answers in treating heart failure. And I think it becomes very patient centered. You know, what, what matters for her, maybe giving her a menu of options or ways that we tackle this. You know, maybe we, let's treat your obesity first and then maybe we'll, we'll relook at this and, and talk about Other medications. I think it just really depends on where that patient sitting in front of you is at because there's, you know, lots of right answers here.
- [17:19]
A
That's so helpful and I think you're right. There becomes a lot of clinical judgment. We talked earlier in the introduction about how we have evidence, but then it takes some opinion and perhaps even wisdom to know how to implement the evidence. Mutu I'm interested in your thoughts. So HFpEF used to be kind of easy to address. The SGLT2s were incredibly, incredibly exciting. And it's only a few years that we've had them with very robust data showing their, their benefit. Things recently have become even more complicated though. We've had positive trials for phenuron on. We've had positive trials both for semaglutide and tirzepatide, the GLP1 and dual agonist, as well as medicines that have been around for a while that have a little bit less robust data. We don't think about them often. As sue mentioned spironolactone, there's Arnie's, there's Arbs. Can you put these treatment choices into perspective for us?
- [18:21]
B
Yeah, first of all, I couldn't agree more with Sue. I think that this is a, this is a gray area. I think there's a broad spectrum of the patients we identify in practice and where they are along the trajectory of disease progression. And this person in particular, we're detecting fairly early and in some ways that is a good thing. And we are able to offer not only a menu but also we do have time on our hands and we can do this in sequence rather than perhaps in a rushed fashion that we have a paradigm that we've applied to in heart failure with reduced ejection fraction, which tends to be associated with a much higher mortality risk and often is diagnosed later in the disease process, in which we do need to move rapidly to multiple therapies. In terms of the therapeutic armamentarium for HFpEF, as Neil, you nicely summarized, in my view, we have the strongest evidence for the SGLT2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist phenerinone. Those are the drugs that we have definitive clinical outcome trial data with large, well executed global trials we have. And so in patients with clinically overt HFpEF who are at high risk for disease progression, especially those, for instance, who have been recently hospitalized for hfp, those are drugs that I consider very early, if not at the time of hospitalization. In addition, then I use a more sequenced strategy based on their other clinical profile. For instance, if they have obesity, I consider a GLP1 receptor agonist. Those trials are quite good. If they have additional evidence of congestion, I consider a diuretic. If they have significant LV dysfunction but not quite at the HFREF boundary, for instance, if their EF is between 40 and 60%, I consider an angiotensin receptor neprolyase inhibitor or sacubetrovalsartan. So I think of this as a tiered approach. We have the strongest evidence for SGLT2 inhibitors and phenerinone and those are drugs that I think should be considered foundational pillars in patients with HFPEF or have clinically overt disease.
- [20:46]
A
That is so helpful and I think you might have answered a question I've been thinking about and I know that you've written a bit about that. In HFrEF we have in essence those four pillars of therapy and everyone needs to be on one. For HFrEF, it sounds like it's a little more nuanced. We can decide which way to proceed. Is that a correct understanding?
- [21:12]
B
That is my view. I think that in HFpEF the disease is fairly variable and heterogeneous and as such we should take a more risk based framework to our approach to their care. For instance, very low risk people who we are identifying early. I too agree with Sue. I'm not sure I would scare the patient, perhaps even disenfranchise the patient in saying you have heart failure and you're at near term risk of death and hospitalization and we need to do everything we can to keep you alive and well. Instead, I think this more layered sequenced approach makes sense for that patient. In contrast, if we're meeting a patient later in the course who has been hospitalized, who has residual symptoms of congestion, who is has rapid diuretic titration needs, that is a person that we need to halt disease progression more quickly. And that's a person I would consider these pillars of care like SGLT2 inhibitors and pheneridone more earlier in the pathway.
- [22:21]
A
That is so helpful and that leads right into our next case which is a 72 year old man. And Sue, I'm going to ask you to comment on this. A 72 year old man with a history of hypertension, hyperlipidemia, diabetes that's been well controlled, a recent A1C of 6.8, obesity with a BMI of 31 as well as osteoarthritis, he's coming in for a transition of care follow up visit After a hospitalization a week ago for heart failure, he presented to the hospital short of breath. He had two plus tibial edema. He had a chest X ray that showed heart failure and NT Pro BMP. On admission of 3500, he was treated and improved with IV furosemide and his echocardiogram showed an EF of 55% with grade 3 diastolic dysfunction, mild mitral regurgit. He was discharged from the hospital on oral Lasix, 40 milligrams daily for his heart failure. He has follow up with both cardiology and us, but he's seeing us. And we know sometimes people don't always follow up, even though they, they should with their cardiologist. He's also on amlodipine, metformin, atorvastatin, and he also takes naprosyn fairly frequently for the pain in his knees. What are your thoughts at this visit?
- [23:47]
C
Yeah, so this is the patient that Mutu just described, right? This is clearly a person who we need to intervene on quickly and in a pretty aggressive way. You know, he's been hospitalized and to be honest, right, this is how we saw HFpEF in the past. Like, this is the patient that we usually took care of with HFpEF, right? Like, we, we didn't find it on an earlier stage. So he needs our full attention. I, I think, you know, anyone listening hears his discharge medication list and like, has a moment. I think yikes was the word that, like, came to my mind as I'm hearing his discharge medicines. But I think first we're gonna have to look at those, right? So you know, he's on amlodipine, right? We know there's not really any data for amlodipine, blood pressure control and heart failure, right. So there's some optimization there. You know, he's on metformin and with a really well controlled A1C, we know there are medications that would treat both his diabetes and his heart failure. SGLT2s and GLP1s, something we might be able to treat out. And then, you know, he's still on Lasix, right? He still needs decongestion. This is a guy who's, who's sick, right, who really needs our intervention and hopefully we can, can pull back on that eventually. And then, you know, the cherry on top was the napperson, right? I think we all, we all see that and we're like, oh, my gosh, no. And so with my primary care hat on, right, it's like, gosh, we need to control your knee pain because this is really a big deal for your function but we gotta, we have to talk about, you know, the use of heavy use of NSAIDs and how that's gonna impact your, your heart failure and your cardiovascular risk long term.
- [25:21]
A
Yeah, this is a, this is a busy visit with a lot going on. Muthu, I'm interested in your thoughts and can you as, as you share your thoughts. I'm particularly interested in your sense of the urgency here because I know you were part of a multi authored paper that looked at the time to improvement in. I think it was the, was it the deliver trial, the DAPA HFpEF trial? And it was. I fell off my chair when I read that. Can you share that information?
- [25:56]
B
Absolutely Neil, and I too have a high sense of urgency when I first reacted to this case. I think that this is a person who is at very high risk unfortunately for especially readmission for heart failure. This is your typical kind of Medicare population patient who may actually contribute to a high degree of healthcare utilization and might have a large number of comorbidities so might see a number of clinicians but no one's actually tackling this underlying issue of heart failure. Preserved ejection fraction now we have those tools and especially SGLT2 inhibitors and pheneurinone acts very rapidly and we've estimated this in both the source trials. For instance Deliver and Emperor preserved the pivotal trials that set up the foundation of evidence for SGLT2 inhibition in HFPEV. The curves separated so rapidly that you saw first statistical significance on the primary endpoints within just one month of initiation. Similarly for the nonsteroidal MRA phenerinone the time statistical significance was just within one month. And so you can actually bend that trajectory very early after initiation of the therapies. And furthermore we anticipate that these drugs can actually provide additive benefits. They have entirely complementary mechanisms of action. They target two distinct really mechanisms of risk. And so you can actually start and optimize these therapies in a safe manner in the hospital. And some of our listeners might pause and say well this person is getting older and should we be concerned about some of the safety of many changes at the time of hospitalization. But I'll remind everyone that 72 was the median age of almost every contemporary HFPEF trial. This is the patient that is well represented in our trials and so we have a well represented of information about the use of guideline directed medical therapies in a person just like this. And so I think we have great comfort that we can optimize therapies, even in combination, very early, when the risk is sufficient. And this is exactly that patient, Sue.
- [28:28]
C
Yeah, me too. It's such a great explanation. And what I'm left with, right, is we have these two cases of like the very early stage of diagnosis, and then the clearly right needs aggressive treatment. You know, as a cardiologist, when do you want to see that patient with HFpEF in your office? Right. So from a primary care perspective, I think we're going to be managing a lot more HFpEF than we have in the past. Right. With early diagnosis. What is that tipping point that you think we should be referring to our cardiology team?
- [28:58]
B
So the epidemiology of heart failure is rapidly changing. We have longitudinal declines in incidence of largely heart failure, reduced ejection fraction, and that's perhaps related to improved management of coronary artery disease and post myocardial infarction survival. However, we've also seen a concomitant rise in HFpEF. And so traditionally, cardiologists haven't been actively managing all patients with HFpEF, but it will become, and it is the dominant phenotype of heart failure. And now we have a larger armentarium of therapies that can actually tackle disease progression. And so in my view, it, you know, cardiologists should be a central part of the management of HFpEF, and we should become involved very early in this process. There are over 23,000 cardiologists, for instance, in the United States. Many see heart failure commonly, especially HFpEF, in the outpatient setting and the inpatient setting. And this should be one of the referral mechanisms. I think that after a hospitalization, clearly that should be an indication for referral in that very early phase. I think when we're thinking about optimization of therapy, if a person is really on board in that shared decision making of clear, aggressive risk factor control, as well as therapeutic optimization, that might be a person that you would refer early, and then there's probably gray zone in between. But I think your clear triggers are worsening heart failure despite initial therapy. So progressive diuretic titration needs. Those would be triggers, in my view, to refer a patient early.
- [30:54]
A
That's helpful. This has been such a good discussion, and I think it's been particularly helpful teasing out the different types of patients, the patient who's early on, where we have some discretion about which medicine, which order how many medicines, and then the patient later in the course of their disease. We're clear, clearly we want to do all we can to as quickly as possible decrease the chances of readmission and improve their prognosis. We're about out of time now. Sue, are there any final thoughts that you'd like to share with our listeners?
- [31:34]
C
I think this is just a really exciting area, especially in primary care. Right. I think we're going to be finding and diagnosing a lot more heart failure with preserved ejection fraction. And so I think this is a really critical update and well timed. Thanks for having me, Neal.
- [31:49]
A
It's our pleasure. Thank you for being here. Muthu, your final thoughts for our listeners.
- [31:55]
B
Thank you so much Neil and Sue. I learned so much from you today and I'll just share that it is such an exciting time and just a few years ago we had limited tools and few diagnostic abilities to with a high fidelity, capture heart failure, preserved ejection fraction and manage it to the degree we have today. And in a few short years we are in a new era of HFpEF. And so I hope that as a broad global community, not just of cardiologists, but in close partnership with primary care doctors, we can actually work together in tackling the increasing burden of HFPEF in the community.
- [32:35]
A
Bhutu, thank you so much for joining us. And most of all, of course, thanks to our listeners. This has been the third of a multi part series on early detection and treatment of heart failure with preserved ejection fraction. An area where we continue to learn, continue to grow and continue to decide how to approach patients that we are increasingly making this diagnosis for. This is common, it is increasingly complicated and now that we're looking for it, we're going to find it. In this first part of the series, we focused on the basics, epidemiology, pathophysiology, staging and the important recommendations around regular screening in people with diabetes for heart failure using NT pro bnp. In the second part of the series we focused on treatment and did a deep dive there. And here in the third episode we brought it all together and talked about a bit of nuance and and judgment and how we use the evidence to decide how to approach HFPEF for our patients. These special editions of Diabetes Core Update have been sponsored by Roche. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.
- [34:02]
B
SA.