REBOOT: #460 Heart Failure with Preserved Ejection Fraction

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Hey, Paul, it's pretty easy to convince ladies not to eat Tide Pods. Oh, I don't like where this is going at all. All right. But it's harder to deter gents. All right, that's... It was catastrophic in a different way than what I was anticipating.

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Welcome back to The Curbsiders. I'm Dr. Matthew Frank-Watto here with my great friend and America's primary care physician, probably the primary care physician, Dr. Paul Nelson-Williams. Hey, Paul. Hey, Matt. How are you? I'm doing well. This is our second of two episodes on heart failure with Dr. Kittleson, Dr. Michelle Kittleson. This is our hef-pef episode, heart failure with preserved ejection fraction.

And Paul, I know you're a huge fan of the heart failure acronyms. Yeah, we didn't get into like HEFMREFs and some of the more nuanced HEFF abbreviations, but we covered a lot of ground here. I think on the first episode we talked about, well, we talked about...

heart failure improved ef which is hef imp f i guess yes right so that one's great that's especially awful yeah Let's remind people what we do on the episode and then remind them who our guest is in case they haven't heard an episode before with Dr. Kittleson.

Sure, Matt. As a reminder, we are the internal medicine podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. And boy, howdy, what an expert we have for you. I assume that you already heard our recent episode on Hef Ref, as you alluded to from Dr. Michelle Kittleson. And Dr. Kittleson is...

back to just about HEF-PEF. Dr. Kittleson, as a reminder, is a lot of things, but she is a professor of medicine at Cedars-Sinai and director of education in heart failure and transplantation. She is also part of the ACCHA hypertrophic cardiomyopathy guidelines and heart failure guidelines. She's on the board of directors for the Heart Failure Society of America. She is the former interim editor-in-chief of the Journal of Heart and Lung Transplantation.

associate editor for the Journal of American College of Cardiology, and her writings are available in all of the major journals. If you think of one that is important to you, her writing has been in it. So she's... hugely impressive, and further so because she actually wrote down some of her words of wisdom, her Kittleson maxims in Mastering the Art of Patient Care, which is available from Springer Publishing. And in this episode, she teaches us all about HefPef, what...

guideline-directed medical therapy looks like, what things that we have evidence for, what things probably we should be doing, even though the evidence isn't as strong, how to make the diagnosis, and then how to sort of guide patients to the process, what their timeline might look like, and sort of what to expect with these patients who...

actually may present very differently despite sort of having this very broad phenotype applied to them. And a reminder to the audience that this and most episodes are available for all health professionals for CME through VCU Health at curbsiders.vcuhealth.org. And if you haven't done so yet, sign up for our Patreon at patreon.com slash curbsiders, where you can get twice monthly bonus episodes, ad-free episodes, access to the Discord, Cash Slack Vault, all sorts of cool stuff.

patreon.com slash curbsiders. Michelle, we're lucky enough to have you back for another heart failure episode. We've covered Hef Ref. Now we're going to do... hef pef i know paul loves those you love those abbreviations right paul every single one of them yeah big fan and uh since the audience knows you know they know your your hobby is baking uh they know you've written a book

But you're someone with a lot of advice to offer. So what is some advice that you might offer to the audience before we get into the clinical topic of this episode? Absolutely. I would say the one most important skill to be a successful physician, to take the best care you can of your patients, is to have a checklist of things you need to do. And there's two kinds of doctors. who write things down and ones that let things fall through the cracks.

So whatever your system happens to be about following up with stuff, identify it and use it because so much of medicine is just checking off the boxes and showing up. Yeah. Fantastic. There's whole books written about checklists. Checklist Manifesto is a good one if people haven't read it. And I love a good checklist. Paul, are you a fan of checklists?

No, I like to leave things in my inbox in perpetuity just to remind me that I haven't yet addressed them. And I feel like that's the best way to generate maximal anxiety while not actually accomplish anything. So for all the young trainees out there, I recommend if you want to not sleep well.

Yeah. Ever want me to take a look at your inbox? I'm really, I really, yeah. I like the Marie Kondo of inboxes. So I'd be happy to help you tidy up. I, can we use that in promotion for this episode? The Marie Kondo of inboxes? You may. I'd be delighted. All right, Paul, let's get to the case.

Sure. Let's talk about, we'll call her Ms. Smith. Ms. Smith is a 62-year-old patient. She's coming to your office because she has been experiencing worsening shortness of breath, decreased exercise capacity, and she's had some lower extremity edema for about the past three months. So this is not an acute change.

She has a past history noteworthy for high blood pressure, hyperlipidemia, obesity with a BMI of 35, type 2 diabetes that is well-controlled metformin. She has a remote history of preeclampsia, and she smokes one cigar a week during her Friday Texas Hold'em poker nights.

Just nothing ever going to Texas Holden poker? All right. That's fine. I thought it was... Did I ever tell you that I used to play Texas Holden poker? I would go to actually poker tournaments. I included that in my medical school application. And that was the one thing everyone asked me about. Like no one cared about.

research or anything else, but invariably I was asked about poker specifically. Why have you never played poker together? Well, you've never invited me to play poker. This is the first I'm hearing about this. It's because I value your friendship and I am the most competitive poker player and the worst loser that ever lived. Anyway, so back to back to Miss Smith. Forgive me. So she's she's having some.

Some worsening shortness of breath, increased edema, decreased exercise capacity over the past three months. She would previously walk the mall with her friends on Wednesdays, but she stopped doing the business over the past month because she can't make it further than 200 meters between the Jamba Juice and the Hot Topic without taking a break. though I would argue Hot Topics is a great place to stop.

Her feet are so swollen that she can barely squeeze into her joggers anyway. A week ago, she woke up in the middle of the night feeling like she couldn't catch her breath, so she called an ambulance and went to the emergency department. They ruled out acute coronary syndrome and then treated her with albuterol apotropium nebulizers, two doses of IV diuretics. And this made her feel a little bit better, and she was discharged home with instructions to follow up with her primary care doctor.

Today in her office, she still isn't feeling as good as she used to, but she at least made it from the car to the office without having to catch her breath. She's taken to sleeping in her recliner now, so she can't sleep in her bed anymore because it's so hard to breathe, so she sleeps in front of her TV set. And it's just better than laying flat. Her blood pressure, 146 over 92. And she did take her hydrochlorothiazide and losartin this morning.

Her rate is 94 and a regular, and she's breathing without difficulty. You cannot appreciate her JVP due to some challenging neck anatomy, but you do think that you hear an S3 gallop. So we've already given away... the episode with the title for the listeners. They probably figured out what we're going to be talking about here, but this is ostensibly a patient possibly with FPEF. I don't even go with that. So tell us.

I guess one of the reasons I hesitate to even call it that is because I'm still not entirely sure how it's defined or sort of how we even know if someone has HFPEF or something else. So can you just sort of give us the 30,000-foot view and then we can sort of narrow things down as we know the patient better?

Absolutely. You know, I think it's a challenge too. I mean, HEF-REF is easy. The echo shows you the ejection fraction is reduced. How hard could this be? HEF-PEF is much harder because there is no smoking gun to tell you, aha, I know exactly what you... And you have to start with the cardinal symptoms of dyspnea and edema. And if you were to check an echocardiogram, the ejection fraction would be 50% or higher.

The first thing I always ask myself in this situation is differential diagnosis, right? The hardest thing to learn in medical school because patients don't have diseases, patients have symptoms, you have to learn how to work backwards. One of my other rules in life is don't memorize things, reason them out, try to understand etiology through pathophysiology and anatomy. So let's start with dyspnea. Where could dyspnea come from?

Well, it could be the heart's fault. And then what in the heart causes dyspnea? Well, it could be the heart muscle, a cardiomyopathy. It could be the arteries, coronary artery disease. It could be the valves, valvular heart disease. It could be the electrical system, arrhythmias, or the pericardium. What about the lungs? It could be the lungs fault. It could be the airways, obstructive disease, the parenchyma, restrictive disease, the vasculature, pulmonary embolism, or the pleura.

Or it could be other stuff like anemia, the oxygen carrying capacity of the blood is reduced, neuromuscular, they can't expand their lungs, deconditioning anxiety. So that's how you think about the dyspnea. Then what about edema? How do we think about the cause of edema? Well, we remember that edema comes from either... increased hydrostatic pressure or decreased oncotic pressure. So increased hydrostatic pressure could be cirrhosis with portal hypertension, kidney failure, venous insufficiency.

heart problems, cardiomyopathy, valvular disease. medications like calcium channel blockers and said steroids. Or it could be decreased oncotic pressure. Well, why do you have decreased oncotic pressure? You don't have enough protein. You're malnutritioned. You are not making protein. Cirrhosis. You are loose. protein through the kidney, nephrotic syndrome, or gut malabsorption. So when you think about it that way, when your patient shows up to your office with

dyspnea and edema, and their ejection fraction happens to be 50% or higher, the first question I ask myself is, is it actually the heart's fault? Maybe they have cirrhosis portal hypertension. Maybe they have kidney failure and nephrotic syndrome. Maybe they have...

mean it's insufficiency. And you don't want, it's very hard if a patient's told they have heart failure when it's actually another organ's fault to unring that bell of misinformation and anxiety. So always try to figure out, is it really the heart's fault?

Since it is the heart's fault, the next question you must ask yourself is, is there an underlying cause for this? And that gets us to. the universal definition of heart failure. So the universal definition of heart failure is pretty straightforward and obvious. You have to have symptoms of heart failure, okay?

And you have to have some objective evidence that there's a problem with the heart, like cardiogenic, pulmonary, or systemic congestion. So symptoms of heart failure, that can include ortho. Thopnea, dyspnea, edema, elevated JVP, S3. a hepatojugular reflux, so symptoms. And then what else is the corroborating evidence? Is there an elevated BNP? Is there objective evidence of cardiogenic systemic congestion? So that's how you think about...

the differential diagnosis of the presenting symptoms, and then narrow it down to the heart. Yeah, and I know there's this HEF-PEF score. What do you think about that? Are you a fan of the, it's like H2? f pef yeah how do you however you say it You know, I think it's actually really nice because the H2F PEF score uses very clinically accessible, readily available variables to translate into score that leads to a probability of PEF.

PEFs. So what are they? H2, so there's two H's. H1 is heavy, BMI above 30. The second is hypertensive. If they're on two or more antihypertensive, since hypertension is so common as a comorbidity of patients with HFPF, they have atrial fibrillation. They have pulmonary hypertension on their echo. cardiogram typically because of chronic elevation of their left-sided filling pressures. The elder age above 60 years.

And they have evidence of elevated filling pressures on their echocardiogram by their EE prime ratio of the mitral valve. So the H2F PEF score will use things you have anyway just by seeing the patient and getting... getting their echocardiogram, and a score of six or higher is suggestive. So I find it useful, almost more just to remind me of all the comorbidities that are common in HEF-PEF, but like with anything.

You can't hang your hat on one test result. You have to interpret it in the lens of your pre-test probability of the patient's other history and physical exam findings. And the most important thing you do not want to miss... In someone who presents with dyspnea, edema, and a preserved ejection fraction, when you are confident it is the heart's fault,

is amyloidosis. You guys have a whole amazing episode on cardiac amyloidosis, but it's not one you want to miss. And you might still have an elevated H2F PEF score, so you must not let it lead you down a path without... considering the entirety of the patient's history, past history, physical exam. I will say I had one patient.

since our amyloidosis episode that presented with it. And the resident that I was working with actually had listened to it and was like, I think we should do this testing. you know, it went very smoothly and we all felt very smart that we were able to make the diagnosis because of that episode. So it's, people should listen, go back and listen to it.

And you saved that patient's life because without considering amyloidosis and your differential diagnosis of a patient with HEPF, you're withholding life-changing therapy that can help them live longer and stay out of the hospital. So kudos to you. your resident. And to the people that haven't heard that episode yet, we talked about on that episode that in some studies, up to 15% of patients admitted with heart failure.

with preserved ejection fraction could be found to have amyloidosis, cardiac amyloidosis. So you really should think about it. It's not like this crazy zebra that you're never going to see in your career. Amen. This episode is brought to you by FIGS. Here at the Curbsiders, we are always talking about the latest medical breakthroughs. But if I'm being honest, there was one thing we weren't seeing any major advancements in, and that's medical scrubs.

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All right. So our patient is coming in with dyspnea and edema. And we talked about how those can come from lots of different things. So we have our differential. Anything... for you that you put more weight in like on the history and physical to, to say that this, this person probably has half peff and not something else. Yeah. You know, when we think about.

Cardiac causes of dyspnea edema with a normal ejection fraction. So we focus a lot on amyloidosis. It could also be valvular disease. It could be a pericardial disease, constrictive pericarditis. It could be hypertrophic cardiomyopathy. It could be high output heart failure. Those are the other things on your list. Now, an echo is going to rule out most of those things. And your history is also really helpful. I mean, have I ever seen a case of wet berry berry?

causing high output heart failure? No, I have not. But if my patient has other evidence consistent with a malnutrition picture, it's going to raise a red flag for me. If they have a strong family history of sudden death and their walls are thick, maybe I'm going to think more about hypertrophic cardiomyopathy. If they've had prior heart surgeries and they've got calcification of their pericarditis.

on their chest x i'm like wait a minute am i missing something else so you can there's so many clues you can draw from really from your history and then your echocardiogram to help differentiate and when in doubt you can do your directed amyloid work That's hugely helpful if you're smoking guns for amyloidosis, as we've talked about in the other episode, those red flags and clinical clues.

But maybe you don't. Maybe you're like, I just don't know. The heart might be stiffer. Maybe it's a hemochromatosis. Gosh, maybe there's a pericardial disease. I don't really know. An MRI is useful in that setting. So I don't get an MRI in everyone with HF-Tuff, but I will get an MRI. They just don't fit my classic demographic older.

more likely a woman, comorbidities and diabetes, AFib, coronary disease, chronic kidney disease, hypertension, but they're presenting with a heart failure exacerbation. The other thing that leads me away... from Hefpeth is that they have a progressive decline because every disease has a rhythm and a trajectory and the rhythm and trajectory of Hefpeth tends to be... periods of quiescence punctuated by discrete exacerbations triggered by clear

problems like she took an NSAID, she got fluid overloaded, she felt worse. And then they kind of go back to their baseline once their fluid balance is improved. Other conditions are far more progressive. things like amyloidosis, things like a constrictive pericarditis, you're very unlikely to get them to a point of perfection as you can in between bouts of exacerbations from HEPF. Oh, I never really thought of it that way. Yeah, because you do meet the patient.

once in a while that has heff peff and they say, yeah, I had heart failure exacerbation like three years ago and I haven't, you know, I haven't really had trouble with it since. And they're, they're not, sometimes they're not even on a diuretic or anything and they're, they're just doing okay. Yeah, exactly.

I was going to ask about the BNP in this case, because it's something that I find kind of bewildering, especially since these patients phenotypically often have obesity as sort of part of what their phenotype looks like, which I think is also complicated. So can I ask you... I guess what the guidelines show or sort of how you use that in a sort of what ways we talked about this in our half wrap episode, but I wonder if it's different in patients with half.

Yes, it is. So one of the pitfalls of using BNP to diagnose heart failure is that patients with HEPF tend to have a lower BNP. For the same level of congestion, volume, overload, increased filling pressures in someone with HFREF, and that's likely tied to obesity. So BNP is reduced in patients with excess. adiposity. Why? Well, it turns out a high-fat diet can increase neprolysin. Neprolysin degrades BNP. That's the new neprolysin inhibitors or cubitril. That's that.

enzyme, and also the natriuretic peptide clearance receptors. There's more of them in patients who are obese, so they remove the BNP from the circulation. So that's the potential reason why. But on a practical level, you may find a lower BNP than you were suspecting. So if a patient comes to you with dyspnea and edema,

And you have gone through the mental exercise to convince yourself it's not the liver's fault. It's not the kidney's fault. It's not just venous stasis or post-phlebitic syndrome from DVTs. You're convinced it's the heart's fault. NP is low, don't just throw up your hands and say, oh, this can't be heart failure. It very well could be pest, especially in someone who's obese because In one study, 70% of patients with a BMI above 30 and HFPEF had a normal BNP. Don't let it dissuade you.

Yeah, and I was reading in the, I think it was the Jack paper was talking about how some guidelines say... you can use your BM, what is an elevated BNP for patients with obesity? Maybe you cut, you lower the threshold by 50%. So let's say the threshold is going to be 500 for someone with obesity, you would put it at 250. But in the next sentence they say, but that's not really evidence-based. So we can't really put too much stock in that.

Yeah. You know, I rarely, if ever, check a BNP in anyone ever. I just because I find there's too many pitfalls where it can be falsely low or falsely high. I feel it's trust your history and your physical. Check the JVP. It will serve you so much better than the JVP. Yeah, I don't find it as clinically helpful either. And you just know it's a poor prognosis for the person if it's really high. I mean, that's kind of...

That's kind of it. Okay. I know we're going to talk about medications, but we're talking about testing here with BNP. You mentioned the person should have an echo.

assuming we're not going to go down the amyloidosis diagnosis pathway, what other testing might you think about getting for someone if we're thinking they have heart failure with preserved ejection fraction? You know, you're going to want to pay a lot of mind.

to their comorbidities. You know, so you're going to, you will get your laboratories to look at their kidney function, their liver enzymes, their albumin. You'll get a urinalysis to look for proteinuria. You'll do that kind of due diligence. Lymphedema is something that's often placed on the differential, but really on physical examination, lymphedema is quite distinct from... edema. And the skin is often thickened. There's this thing called the stemmer sign where there's thickened skin.

at the base of the second toe or second finger so you can't pinch it because there's skin fibrosis in addition to edema. Not a great sign. There can be false positive and obesity, but just really you should think about lymphedema as its own bucket of a vascular condition.

You may want to get an abdominal ultrasound to look for cirrhosis in some of these patients. And then again, do they have chronic kidney disease? Do they have diabetes? Do they have coronary artery disease, hypertension, obstructive sleep apnea? atrial fibrillation, these other comorbidities that need to be optimally managed. So let's talk about managing these other comorbidities. Like what special considerations do we need to have here? Yeah.

So hypertension, right, kind of just whatever works is the right answer. You want a medicine that controls the blood pressure, minimizes side effects. But it would be nice to give something that does double duty, right? So thiazides are great. We know that they can reduce the...

progression or the incidence of heart failure. I also think the RNAs and the MRAs, for which there's some data, In HEPF, it'd be nice to use, if you have an excuse to give an ARNI MRA, ARB, give it to someone for their blood pressure.

When it comes to atrial fibrillation, really anticoagulation for thromboembolic prophylaxis is going to be indicated in just about everyone because their CHAD2-VASC score is going to be elevated because they have heart failure. They're typically old and they have a lot of comorbidities. You know.

The benefit of rhythm versus rate control is still not 100% established. And for me, I go by symptoms. If they are well rate controlled and asymptomatic, the data, the guidelines certainly aren't strong enough to advocate. control for all, but there is some suggestion in some trials that rhythm control may improve outcomes, but really it should focus on symptoms and on anticoagulation for stroke prevention.

When it comes to chronic kidney disease, again, your friendly nephrologist can often assist you. But remember those medications that can also improve. kidney function like the SGLT2 inhibitors, the magical, mysterious SGLT2 inhibitors.

And then sleep apnea. You know, there's no data to say that if you treat sleep apnea, heart failure gets better. But if you treat sleep apnea, patients feel better. So certainly screening with daytime somnolence, snoring, headaches, it's important to rule that out. because if you can treat it, you'll improve their quality of life. As America's primary care physician, Paul, do you feel like this is in your wheelhouse? It seems like it would be, you know, just managing comorbidities.

Yeah, bread and butter. Yeah, I think that's right. And I guess along those lines, I wanted to ask, because it's going to come up. So weight loss specifically, I wonder if you couldn't speak to the benefits there. And also... Is that independent of things like improvement in sleep apnea or atrial fibrillation? Like, you know, does, does, is it going to improve things regardless or does it improve things? I guess I'm leading the witness here a little bit.

Yes, you're allowed to lead the witness. So I'll talk about the non-pharmacological interventions, and it is absolutely clear. that weight loss and exercise improve quality of life and exercise tolerance in patients with HFPEC. There's beautiful trials to show that things like calorie restriction by 400 calories a day or supervised exercise training three days a week, like a cardiac rehab type program, help patients with HFPEF feel better quality of life scores and also better exercise capacity.

And things like six-minute walk test or cardiopulmonary exercise stress testing. It is a grave injustice, I think, that insurance in America does not cover cardiac rehab for HES-PEF, only for HES-REF. And there's many... people working very hard to change that because exercise training makes a huge difference. And I think what that speaks to is that I, in a way, I think of HEF-PEF as the rheumatology of cardiology. Like HEF-REF, it's all about the heart.

But HEPF is a multi-system condition. There's so many intertwined comorbidities. You're exactly right. Exercise and weight loss will make your blood pressure better. It will make your AFib better. It will make your diabetes better. It can make your coronary disease better.

better. So everything feeds on everything else in a condition like half-feb, which is also why, quite interestingly, If you look at the survival of patients with HEF-PEP, their cardiovascular and non-cardiovascular causes of mortality are evenly split, unlike someone like HEF-REP, speaking to how this is a global condition and often a condition. of aging, so it needs a multidisciplinary approach to improve quality of life as well as outcomes.

So the medications, it seems like it's been harder to find a medication that has a clear, really strong benefit in people with HEF-PEF. Can you speculate a little bit as to why that is? Yeah, absolutely. I think we can think of HFREF as a triumph of translational medicine, where our understanding of tiny little molecules has translated into therapies that help patients feel better, stay out of the hospital.

longer, potentially improve heart function. We know about our neurohormonal axis of the sympathetic nervous system, the renin-angiotensin-aldosterone system, the natriotic peptide system, the SGLT2 mysterious system. And it's amazing. Everything just seems to work. The problem with HES-PETH is we don't understand those pathophysiological mechanisms at all. There is no unifying pathophysiological mechanism. There's observations, but there's no...

And likely that's because hefpeth is a heterogeneous condition. There's different... Let's say there's some people have predominantly right heart dysfunction with pulmonary hypertension. There's other people who have more chronotropic incompetence. There are other people who have more diastolic stiffness. There's other people who have more...

differences in their skeletal muscle oxygen extraction. Others who have differences in their vasculature. So these different phenotypes all lumped into a trial. We're not sure what therapy pinpoints what patient. And that has been the huge

challenge of randomized controlled trials of therapies for HEPF. So in the past few years, it seems like they've started to add the, so the SGLT2s and the ARNIs were added. So maybe if you could... Talk us through that evidence a little bit. And are they for everybody like they are with HefRef or not? Yes, I'd be delighted to. Okay.

Diuretics are going to be a necessary evil. You're not going to give a patient a diuretic. If they need a loop diuretic to help them feel better and breathe, give them their loop diuretic. But what else is out there? Really, SGLT2 inhibitors are the first medications. to meet their primary endpoint in a clinical trial of HEF-PEF. Hugely exciting. We have the DELIVER trial. We have the EMPER-PRESERV trial, DAPIGLIFLOZEN, EMPIGLIFLOZEN. In patients with symptomatic HEF-PEF, meet their...

combined endpoint of a reduction in death and cardiovascular hospitalization. If you look at the 2022 heart failure guidelines, it gives it a 2A indication, which isn't as strong as a class one. Why wasn't it a class one? Well, historically, at the time the guidelines were published, only one of these two trials had come out. So the committee wasn't clear if it was a true, sustained, reproducible benefit.

Now it's clear. SGLT2 inhibitors for everyone across the spectrum of ejection fraction. Give it to your patients with heart failure. The next medicine that I would put on that list to me is quite fascinating, which is spironolactone. So the TOPCAT trial came out 10 years ago, took patients with symptomatic HEPF, randomized them to spironolactone versus placebo, did not meet its primary.

endpoint of a reduction in death and heart failure hospitalization, but didn't meet its secondary endpoint of a reduction in heart failure hospitalization. And so Evan was like, meh, not so great. But the clinical trialists looked at the data really closely and said, there's something really funny here.

It's very funny that this is an international trial, and half the patients are from North and South America, and half the patients are from Russia and the former Soviet state of Georgia. And these two populations are dramatically different. The Russia-Georgia patients have very low event rates.

1 to 2 percent by the end of the study had death or heart failure hospitalization, 20-something percent in the Americas. And patients in the Americas who were assigned to spironolactone had a bump in their potassium and creatinine when they took it. Patients in Russia and Georgia did not.

Very concerning. Was there some clinical trial and nefarious goings on? We will never know. No one will ever repeat the trial. And I'm the first one to tell you that subgroup analyses are inherently hypothesis generating. However, the North and South American... Subgroup analysis of the TOPCAT trial did show spironolactone had benefit, so I do believe it is beneficial for our patients. The guidelines will give it a relatively weak class 2B indication because it didn't meet its primary endpoint.

Maybe better for women, maybe better with men with ejection fractions on the lower end of the spectrum. But for me, I do put it very close to my SGLT2 inhibitor based on that analysis. Yeah. And I mean, a lot of these patients have hypertension too. It's a good hypertension medication. Yes. Better than hydralidine. Let's say that. I mean, that's a low bar to clear, but sure.

Fair enough. So now, you know, this acubitral vasartan, the ARNI, has gotten a lot of press because of the Paragon HF trial. Symptomatic HF-PF ARNI versus placebo. It did not meet its primary endpoint of a reduction in death and cardiovascular hospitalization.

It also did not meet its secondary endpoint of a reduction in cardiovascular hospitalization. But, you know, the pundits out there were like, well, the p-value is 0.056. And if there were just X number more events in the placebo group, it would have been positive. but it wasn't positive. And then you have the subgroup analysis. Well, there's a signal for effect in women. There's a signal of effect if your EF's on the lower end of the spectrum.

but subgroup analyses are hypothesis generating. So it does get a 2B weak indication in the guidelines. And I say, if I have an excuse to give it. gosh, you're still hypertensive after your SGLT2 inhibitor and your spironolactone and your ES a little bit lower. You know, you happen to be a woman. Let me put it on board. But as we talked about in the HefRef episode,

cost becomes an issue. Now, if I'm going to spend my money on a drug that's not generic, I will spend it on my SGLT2 inhibitor over the ARNI. And if they need something for blood pressure, I'll reach for the ARB. Now, the ARB evidence is like... 20 years old. Charm Preserve came out in 2003. Other studies showed that maybe ARBs aren't that great in symptomatic HEF-PEF, but certainly no harm. And that would be my next line if I have an excuse to give it for blood pressure.

Yeah, so it's just not, you know, because for the guideline-directed therapy for HEF-REF, I think almost everything is a class one indication. Yes. Yeah, so these 2B is like, it goes like 1, 2A, 2B. Diuretics are a class 1 because they're a necessary evil. SGLT2, I think, will become a class 1. We should think of them as class 1. And then I do think spironolactone should be up a little bit higher.

But then the ARNI and the ARB, if you have an excuse to give it for blood pressure, give it. Okay. Fair enough.

Where are we with the GLP-1s? Because I feel like this should be slam dunk home run. Like there's the weight loss, so that's great. But then also I think they're approved for cardiovascular risk reduction, which many of these patients would have those comorbidities. So I would think. Yes. You'd expect the trials to be amazing and there'd be parades about them, but I've not heard a whole lot definitive yet. So where do we stand with those? Yes. So the landmark trial in Heth-Peth to date.

is the STEP-HFPEF trial. So the STEP-HFPEF trial took about 500 patients, symptomatic HFPEF, obesity. The median BMI was 37, so quite obese. They gave them semaglutide. So actually, guys, did I pronounce that correctly? You're closer to GLP-1s than I am. I think that was, I think that's, yeah, that's how I say it. Cool. All right. Thank you. You say get some agnotide weekly for 52 weeks. So after a year. The primary endpoints were...

quality of life, six minute walk test. Patients walked farther. They felt better. They also had a reduction in weight over the first year, 13% reduction in weight. So that's the only end points we have thus far. in Hespeth. They lose weight, which is not a surprise. We have that they feel better and that they walk farther. So your next question, of course, is going to be, well, is this because they lost weight or is there some magical intrinsic benefit to the GLP ones?

And no one knows yet in HEF-PEF. A subgroup analysis by degree of weight loss of STEP-HEF-PEF showed that, in fact, the patients who lost the most weight felt the best and walked the farthest. So not a medical mystery here. We need trials with longer endpoints, which will answer that question. What you alluded to, Paul, was the SELECT trial, which is also very, very exciting for us cardiologists. These took patients who had coronary artery disease and a BMI 26. or higher, average BMI was 33.

And they gave them some maglutide, followed them for about three years. And they found that the cardiovascular endpoint, composite of death from cardiovascular causes, MI stroke. was reduced. So this is really, really exciting. The SELECT trial is telling us it doesn't just help you lose weight, it actually improves cardiovascular markers. Now, does it do that because you lost weight? I mean, it's hard to...

say, because it's really hard to lose weight without these GLP-1 receptor agonists. But that's what we can say so far. And we look forward to studies in HEFPEF to give us those clinical endpoints of death and hospitalizations. In the meantime, however, If you have a patient with hepaths who would meet criteria to take a GLP-1 receptor agonist anyway because of diabetes, obesity, CAD, certainly that's a good excuse to give them one.

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Yeah, I also wonder how much of just any of the benefits we're seeing with semaglutide and other meds like that are just because... People just tell me it's so much easier to control their eating. Their snacking just goes away. Some people are just not hungry at all. So they have to, they're just, it's like easier for them to just be like, I'm only going to eat healthy foods because I'm barely eating. Yes. Which, you know.

Yeah. The craving for the unhealthy food seems to go away. So it serves double duty when you eat as healthier and you're eating less to begin with. I totally agree. Yeah. And we know those foods. I mean, they're like, you know, the snack foods and the processed foods filled with all. sorts of ingredients that are not good for the body. So maybe I wonder how much of it is the actual GLP one and what's doing to the body or how much it's just keeping stuff out of the body that's really bad for it.

And a good, you know, comparison would be, you know, bariatric surgery. You can achieve extraordinary weight loss. But, you know, I think the problem is it's a bigger barrier. to overcome, to go for a hugely invasive surgery than to take this amazing medication that works. Yeah. Yeah. Well, hopefully by the time this episode airs, people will be able to get the medication. It's still very hard right now to, you can get it approved sometimes, but then the pharmacies don't have it still.

I imagine the supply will be ramped up because I think those are supposed to be the most successful drugs of all time, or they're on their way. So we talked a little bit last time, you told us for HefRef, you tell people...

salt and water, you're not super strict about it. You tell them they may or may not be more sensitive and they can kind of play around with that. Is it any different for HEF, like how you talk to them about salt and water intake? It's actually very interesting because with HEF-PEF, remember their hearts are stiff. And when your heart's stiff and you've decreased compliance, little changes in volume can lead to big changes in pressure. So I often find that patients with HEF-PEF...

PEF tend to be more salt sensitive than patients with HEF-REF. So I counsel them a little bit differently. I tell them the same principle, which is salt is not inherently toxic to your heart. However, if you were to do the experiment of having a little extra salt and seeing if you felt

puffy and congested, chances are you would find out that there is a correlation there and you will feel better if you avoid salt. So I do counsel them a bit more strongly than I do patients with HefRef. Okay. And Michelle, when...

should these patients see you my sense of things and i'd be curious to know how others feel is that these patients for a couple of reasons, are less referred to cardiology or heart failure specialists. I think in part because the diagnostic criteria people are kind of fuzzy about to get these anecdotal diagnoses. We, for a long time, didn't have great...

evidence-based medications for them. So what was the point anyway? And so as a result, I think we just kind of neglected them and diuresed them as we needed to. So I guess, when should they see you or when would you like to see patients with HFPEF diagnoses? Great question. I think really, number one, if the diagnosis is unclear. So you have the patient, you say, I think this is HEF-PEF.

But I don't really know if I've truly ruled out a severe valvular disease as contributing or a pericardial disease, or could they have amyloidosis? And I've done the initial workup based on the Amazing Curbsiders episode, but I'm still not sure how to put this all. together. So number one, your diagnosis is in question. Second, I empower every internist, every clinician out there to start the foundational therapy. So diuresis, they need SGLT2 inhibitor for everybody.

Do consider the MRA and then... lower down the ARB and the RNA. But say you do all of that and the patient just isn't feeling better. Like they're having a trajectory that doesn't make sense to you. They're having frequent hospitalizations and you feel like something is being missed.

not right. Maybe there's another diagnosis that needs to be entertained, or maybe they have more advanced therapies. And because this is a disease of older patients, typically things like heart transplant would not be. indicated or it would not be the right approach, but even just the counseling with a specialist to talk about prognosis and give them a better understanding may be useful. So if diagnosis is unclear or what you're doing for treatment isn't working, please refer.

Yeah, I can get on board with all that. Well, this is... I guess our third heart failure episode with you now. This has been great. Thank you for updating us. And in the future, when more evidence accumulates, we'll have to probably do another one of these with you.

But for now, what are some take-home points that you'd like the audience to remember about heart failure with preserved ejection fraction? So number one, your patient presents with dyspnea and edema and their ejection fraction is 50% or more.

first ask yourself, is it the heart's fault? Don't forget, problems can be caused primarily by the liver, the kidney, things like venous stasis. Don't give the patient a heart failure diagnosis if it's not warranted. Number two, if you convince yourself it is the heart's fault, do not... missed cardiac amyloidosis, a hugely pivotal diagnosis for which there is now therapy to help patients stay out of the hospital and live longer.

And then finally, if you're convinced it's HFPEF and you're managing all the comorbidities, the best GDMT is SGLT2 inhibitors for everybody. Consider your MRA if you have an excuse about congestion or hypertension. And if you still have hypertension, consider your ARNI and your ARB.

All right. And once again, remind me, is there a book out there people should check out? You're so kind to plug my book, Mastering the Art of Patient Care by Springer. It's based on all the wisdom of my mentors and the mistakes I have made. So no one has to make them themselves. And it's very cool. I got an email from a trainee who told me that she just bought a copy for her best.

friend, which I think is great. Medical students should cooperate so everyone gets better as opposed to being competitive. So please buy a coffee for your best friend. Yeah. And, you know, aunts and uncles, whoever. The patient seen me in clinic yesterday. Actually, the wife of the patient. And she said, I love your book.

And it was a little disconcerting because neither of them are in medicine at all. I'm like, how do you know about my book? And you said I read it on your CV and I was glad to say, how do you know about my CV? But then I figured out we better just get back to the matter at hand. We should say. Our producer, Deb, the great Dr. Deb Gore, said her favorite advice from the book was be nice and work hard, which is, I think, just how can you go wrong with that following that advice, which is.

good advice especially i need to remember the be nice thing sometimes paul you're always nice paul i you know that is categorically untrue which you know but i appreciate you saying that at least publicly All right. Well, thank you so much, Michelle. This has been great. You guys are awesome. If you need anything else from me, you know how to find me. I look forward to doing this again in a few years. Hopefully with some peanut butter cookies as well.

This has been another episode of the Curbsiders, bringing you a little knowledge food for your brain hole. Yummy? Still hungry for more? Join our Patreon and get all of our episodes ad-free, plus twice monthly bonus episodes at patreon.com slash curbsiders.

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