Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is

Narrator - ?  00:12
provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

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And now on to the show.

Speaker 1  00:31
Welcome to HelixTalk episode 147 I'm your co-host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is key recommendations from the 2022 AHA/ACC/HFSA heart failure guidelines. So clearly, we're talking about these brand new guidelines that have been recently posted, and we're going to go through some of the most important clinical pearls and what you need to know from those guidelines.

Dr. Khyati Patel  00:56
And I believe Dr. Kane there was a full update of heart failure guidelines back in 2013 and then a focus update came out in 2017 but as we know, there has been mounting evidence for particularly SGLT2 inhibitors that needed to be included and the guidelines needed to be updated. So here we are with the 2022, full guideline update that was released in April, so it's fresh off the press, actually, exactly.

Speaker 1  01:25
And I just want to highlight this is a full guideline update. So they literally went a to z in terms of all of the recommendations. This is not just a tweak or a minor update, and they actually said in the document that, moving forward, their plan is to update sections, or what they call chunks of the guideline as new evidence comes out, as opposed to what they have been doing, which are those kind of focused updates followed by their full updates. So they are planning to change how they release the updates. But this particular 2022, guideline is the full shebang, A to Z. And for the listeners, if you want to go through all 100 something pages of the guidelines. They're linked in our show notes, HelixTalk.com, then again, this is episode 147 Yeah.

Dr. Khyati Patel  02:07
So those of you have saved a copy of 2013 or 2017 on your laptop, you can feel free to erase this and replace it with this one, because this includes everything, exactly.

Speaker 1  02:17
And you know, Dr. Patel, clearly, we're not going to talk about every aspect of the guideline, but we have kind of outlined, we'll call it five ish, core things to talk about in terms of what's new or different or noteworthy from these guidelines. So one thing is that they have standardized the definitions of four. That's right, four different definitions of heart failure, and we'll get to those four categories later on.

Dr. Khyati Patel  02:43
And additionally, as I mentioned, there was some evidence available for SGLT2 inhibitors as a drug class, particularly coming from two agents, empagliflozin (Jardiance) or dapagliflozin (Farxiga). So we get to see appearance of SGLT2 inhibitor evidence in multiple areas in those guidelines,

Speaker 1  03:05
and kind of in the same vein, ARNIs. And there's only one ARNI on the market: Entresto (sacubitril/valsartan). ARNIs have continued to be reinforced as the preferred renin‑angiotensin‑aldosterone system inhibitor for heart failure with reduced ejection fraction. That's not necessarily new, but the new thing is that they are making new recommendations for ARNIs and heart failure with preserved ejection fraction. And we'll talk more about that. Yeah.

Dr. Khyati Patel  03:30
And then again, a lot of disappointment. However, there is no specific recommendations on dietary intake of the sodium. We will shine a little bit more light on an additional trial that was published, maybe right after those guidelines were published.

Speaker 1  03:48
Then finally, our fifth thing is, you know, as a critical care pharmacist, Dr. Patel, I was really hoping to see some updates or new language about the management of acute decompensated heart failure. We do have some data that has been published since 2013 that helps us understand therapies that shouldn't be used or should be used in acute, decompensated heart failure, and there were actually very few updates with respect to the management of someone with acute heart failure in the hospital. So we'll talk about kind of areas that we would have liked to see some changes, but really didn't see those changes.

Dr. Khyati Patel  04:19
So diving into the different definitions of heart failure. Dr. Kane, I think we were aware of the reduced ejection fraction acronym, h f, R, E F, and then the preserved ejection fraction acronym, the H F, P, E, F, but there's two more that are added now. Is that right? Yeah.

Speaker 1  04:44
So you know, historically, with HFpEF, the preserved ejection fraction, we didn't really agree on the diagnostic criteria or the ejection fraction threshold for that particular type of heart failure, so historically, it was anyone with an EF. More than 40% or more than 45% or more than 50% kind of good? I guess the guidelines picked a specific number that hopefully everyone will use moving forward. So the new number is preserved. Ejection fraction. Means that you have an EF that is 50% or better and and this is new, you also have to have some evidence of increased left ventricular filling pressures, and we'll talk about what that means. But that is really a two fold criteria for the definition of heart failure with preserved ejection fraction, or some historically called diastolic heart failure.

Dr. Khyati Patel  05:32
And the cut off for reduced ejection fraction remained the same, so 40 or below. But then there is a new category that says moderately reduced. So there is a, H, F, M, R, E, F, moderately reduced ejection fraction, where you see the ejection fraction ranging somewhere between 41 to 49 however, there is this addition of an increased LV pressure, filling pressure, as you talked about, that's added to this definition as well.

Speaker 1  06:01
And then we have another new category of heart failure that we're established in these 2022, guidelines, and it's heart failure with improved EF, or HF, imp, EF, and this is someone who used to have an ejection fraction less than 40% so they historically had a reduced ejection fraction, but now it's more than 40% basically, this is someone who has recovered their ejection fraction. And the guidelines, even though we treat these patients almost identically to heart failure with reduced ejection fraction, it is technically a subgroup of patients, and we'll talk very briefly about them,

Dr. Khyati Patel  06:35
so broadening the definition of the component where it says it needs to account for increased left ventricular filling pressure. What is really that increased left ventricular filling pressure? And there's a two criteria that is accounted for. And this is again, more important when you're looking for that preserved ejection fraction heart failure, or moderately reduced ejection fraction heart failure.

Speaker 1  06:59
Yeah. So the main criteria that you're going to see in clinical practice is that these patients have to have an elevated natriuretic peptide. So it's a BNP level, or an NT pro BNP level, which is a metabolite of BNP. So this is a protein naturally produced in the body. When the atrium the ventricles get stretched from flu to overload, and that level will go up, indicating that you have excessive fluid in your vasculature and it's stretching out the heart. Interestingly, the guidelines picked a pretty ridiculously low threshold in terms of how, how high the BNP level has to be for it to constitute an elevated LV filling pressure. You know, Dr. Patel, when I teach heart failure, I talk about BNP levels less than 100 generally mean you don't have heart failure. Around 100 to 500 is kind of a gray zone. Then more than 500 means that you very likely have heart failure. It typically does rule in heart failure, the guidelines didn't pick 500 or even 100 they said any BNP level more than 35 which is a really low threshold, constitutes an elevated left ventricular filling pressure. So this is more likely going to include a lot of people who don't really have the thing that we're talking about, heart failure, but have a very mildly increased BNP level. So I was a little bit surprised, and I actually wasn't very happy with the level of evidence that they provided to support a 35 threshold, but that's what's in the guidelines

Dr. Khyati Patel  08:26
that is very, very interesting. And I believe in addition to looking at the BNP level, we are looking at hemodynamic measurements that actually show that that ventricular filling pressure is increasing. And a way of doing this hemodynamic measurement is, you know, a couple different ways, a non invasive and an invasive and non invasive way would be just doing an echocardiogram and reading the report. And in more invasive method of measuring this would be checking for elevated pulmonary artery systolic pressure,

Speaker 1  09:03
yeah, and again, most people you're just going to do the blood test because that's easy. If you can get specific measurements on echocardiogram, the guidelines do provide a bunch of different measures that you might consider and what a threshold would be to constitute elevated LV, filling pressure. So there are a lot of complexities to that. The BNP just ends up being a little bit easier. But of course, all of these patients are going to have an echocardiogram so that you know what their EF is anyway. So oftentimes you're going to get it from the echo as well. So another category that was interesting, or kind of warranted in the guideline update was the incorporation of SGLT2 inhibitors throughout the guideline. So again, SGLT2 inhibitors, these are drugs, historically or originally, for diabetes, type two diabetes, but we found that they actually have benefit in heart failure too. So Dr. Patel, where were these incorporated in the guidelines?

Dr. Khyati Patel  09:54
Yeah, so they're, they're incorporated at couple different places. You know, we have the stage a pain. Patients with heart failure. These are the patients who don't have any clinical or structural heart disease, indicating heart failure, but they do have risk factors. So they have risk factors of heart failure, but they're not experiencing any symptoms. For these patients, they're recommending SGLT2 inhibitors if they have diabetes, type two diabetes, who are going to be at a higher risk for atherosclerotic cardiovascular disease. This is a particular patient population. Again, keep in mind they're treating type two diabetes as kind of like that risk factor, and so this is only for that sub category of the

Speaker 1  10:40
patients and Dr. Patel, what's kind of interesting is that you know, in the management of diabetes, we know that there are other drug classes that decrease the risk at least of ascvd, so having heart attacks and strokes, GLP, one agonist is an example, or Metformin. These are therapies that we try to add on early on, especially for patients at higher risk for cardiovascular disease. I was a little bit disappointed that the guidelines didn't talk about these other drug categories, but really only mentioned that if you're a high risk type two diabetic, that SGLT2 inhibitors are what you should be on. But in reality, there are other therapies that you should also consider as well.

Dr. Khyati Patel  11:19
Yeah, and those are your GLP one receptor agonist, or even Metformin having some evidence for it. And the good thing is that the American Diabetes Association guidelines make it really clear that any of these three agents are okay, especially any of the SGLT2 inhibitors or the GLP-1 RAs are okay when you have a patient with higher risk for atherosclerotic cardiovascular disease. I think the giving the benefit of a doubt for this guidelines, Dr. Kane, I think they're focusing more on the risk factors for the heart failure patients, and kind of aligning sglt Two inhibitors as the first line therapy for them.

Speaker 1  11:58
Yeah, and then, you know, another place that sglt Two inhibitors made their way in the guidelines was for symptomatic heart failure patients who have a reduced ejection fraction. So this is stage C or stage D, so that's symptomatic heart failure or advanced heart failure. And this is new, because they've now incorporated SGLT2 inhibitors as one of the four kind of must have drug classes that are started early in those symptomatic patients. So symptomatic means at least in New York Heart Association, class two, if not three or four, and this is now one of our four core therapies. So sglt, two inhibitors now join whatever renin angiotensin aldosterone system inhibitor you're doing, a RAAS inhibitor (ACEi or ARB), plus your beta blocker, plus your mineralocorticoreceptor antagonist or MRA, this would be your spironolactone or your eplerenone.

Dr. Khyati Patel  12:50
So to keep in mind, for Stage C and D patients that you're referring to, Dr. Kane, the recommendations for SGLT2 inhibitors is, regardless of the presence of type two diabetes. So that's the distinction to be made: for stage A you were looking for that type two diabetes as a risk factor and using an SGLT2 inhibitor; for stage C and D it doesn't matter if your patient has diabetes or not, they are recommending SGLT2 inhibitors. And the evidence for this comes from a couple of trials for particular agents in this category: for dapagliflozin (Farxiga) it's from the DAPA-HF trial, and for empagliflozin (Jardiance) it's from the EMPEROR‑Reduced trial.

Speaker 1  13:35
And really, in both those trials, the benefit, the reason why this is one of our four go to therapies and reduced ejection fraction heart failure. Is it reduced heart failure hospitalization on its own, and also it reduced the composite of heart failure, hospitalization or cardiovascular death. And in the case of the dapagliflozin in the DAPA‑HF trial, it also independently reduced cardiovascular death and all‑cause mortality. So it wasn't just a composite, but the individual endpoint of mortality on its own was also better with the SGLT2 inhibitor in that case, the dapagliflozin versus placebo.

Dr. Khyati Patel  14:10
And something to keep in mind, since patients with heart failure may have additional conditions, especially renal issues, as well that both of these studies excluded patients with CKD, especially those who had lower EGFR. We're talking about less than 20 or 30 type one diabetes patients were excluded because SGLT2 inhibitors are not indicated for type one diabetes yet, and obviously the low systolic blood pressure patients were also excluded. We're talking about SBP of less than 95‑100 because, as these agents produce diuresis, the risk of low blood pressure and hypotension can increase as well. And so we want to be careful, as you mentioned, Dr. Kane, these are being added on to additional therapy which have antihypertensive effect. We don't want to drive that effect further by adding SGLT2 inhibitors. And of

Speaker 1  15:04
course, any drug in this category does not come without risk. So the main thing that comes to my mind Dr. Patel, is genital infection. So these are yeast infections, Mycotic yeast infections, urinary tract infections, even soft tissue infections. We've seen, actually, in my clinical practice, a number of euglycemic DKA patients, where they come in with DKA, but it kind of goes under the radar a little bit because their glucose is not very elevated, because they've peed out all the extra glucose from the sglt two inhibitor. And then finally, you know, this does make you pee out calories and water as you're peeing out sugar. So especially in diabetic patients, they're more likely to diurese more with this medication, and they can get volume depleted if they're already on, let's say, Furosemide or lasix for their heart failure as well. So we just have to be careful about that.

Dr. Khyati Patel  15:51
Yeah, and it's always about, you know, keeping the benefits we talked about from those two trials, plus these risks, in mind for your patient and in your risk and benefit calculation, then you throw in the cost of the agent too. And we know that SGLT2 inhibitors, there's no generic available yet in the market. Both of these agents are brand name only, and they're expensive. You're talking, you know, upwards of $500 per month for cash price. And if you're talking about coverage for insurance, these are usually covered as the lowest brand copay in the tiers.

Speaker 1  16:29
Yeah. And we also see SGLT2 inhibitors be incorporated for heart failure with moderately reduced ejection fraction. Again, this is an EF between 41 and 49% and they have a stronger recommendation for SGLT2 inhibitors compared to all of the other four drug classes that we talked about previously. So this is a moderate strength of recommendation for SGLT2 inhibitors among these. Yes, 41 to 49% compared to a weak recommendation for our Spironolactone or ARBs, arnies, things like that. And the main reason is that in the Emperor preserve trial, which we'll talk about in just a second, they did include people who had EFS more than 40% not just more than 50% for preserved ejection fraction. So they're kind of using that subgroup to justify a little bit more data in those with moderately reduced ejection fraction in support of SGLT2 inhibitors, as opposed to many of the other therapies that we use in heart failure. Yeah.

Dr. Khyati Patel  17:27
And segueing to use of SGLT2s in preserved ejection fraction, as you mentioned, the evidence really comes from empagliflozin (Jardiance) in the EMPEROR‑Preserved trial, as the name suggests. They included patients with preserved ejection fraction, and we found a reduced composite outcome of heart failure–related hospitalization. However, the overall evidence or benefit was driven by the reduction in heart failure hospitalization itself. And so looking at that trial and the data and outcome, the recommendation that was taken is very similar to the moderately reduced ejection fraction recommendation, where now SGLT2 inhibitors have a stronger recommendation in the category of moderate compared to other therapies like the MRAs, the ARBs or the ARNIs, which garner a weaker recommendation,

Speaker 1  18:24
yeah, and then switching gears a little bit, you know, ARNIs. So this is Entresto (sacubitril/valsartan). The role has been reinforced again. So the main thing that happened in the 2017 focused update was the support of ARNIs or Entresto over ACEs and ARBs, and we actually talked about the trial that drove this, called the PARADIGM‑HF trial, back in 2015 we talked about that in HelixTalk, episode number 32 long time ago, so that these current guidelines from 2022 basically reinforce that same thing. For those with reduced ejection fraction, they say that you should be using an ARNI as your first line, but if it's not feasible, then you should use an ACE inhibitor. So an example would be like lisinopril or enalapril; they don't care which one, but ARNI first, if you can't do an ARNI, then you do an ACE inhibitor. And then they say that an ARNI is not feasible and you can't do an ACE inhibitor because of cough or angioedema or some other reason, you can consider an ARB. So an example of an ARB could be something like losartan or valsartan. And I thought it was interesting. The guidelines actually have some of these value statements built into them. And one of the value statements was they claim that the ARNI is cost effective and it's based on quality‑adjusted life years. They have specific thresholds, and they have kind of pharmacoeconomic data to support that. And while that may be true, that they have that data, I would argue that the patient at the cash register in the pharmacy where you tell them that this is a $600 per month medication compared to something like an ACE inhibitor that is less than $10 a month, I think they may disagree in terms of its cost effectiveness, even if it reduces, you know, the variety of endpoints that were reduced in the PARADIGM‑HF trial. And again, the cynic in me wonders, maybe because six of the 26 authors had a conflict of interest with Novartis, which is a manufacturer of Entresto, maybe there is some conflict of interest or more support than you would have seen with Entresto. I don't know, but I have a hard time still, even in 2022 believing that this is truly a cost effective medication when we have these very cheap alternatives available in the market.

Dr. Khyati Patel  20:27
you're 100% right. You know, we illustrated the cost of sglt, two inhibitors, and you know, that's adding on top of the Arni and the other two medications. It adds up, even if it's you have a patient who has insurance and these therapies are covered. Multiples of tier three level co pays do add up at the end of the day. And we know that, you know, cost prohibitive therapies do impact adherence as well. And so, yeah, you're absolutely right. Well, you know, the those pharmacoeconomic trials are probably portraying this as a cost effective therapy at the end of the day, patient's pocket do matter, and therefore the adherence matters too. But kind of moving on to the use of Arni for preserved ejection fraction. Now this is something new. In the previous guidelines, Arni did not have any evidence. Therefore it was there was no recommendation for place in therapy for the preserved ejection fraction. However, there is a recommendation for this guideline. Dr. Kane, can you tell us a little bit more about what this recommendation was? Yeah, the 2022,

Speaker 1  21:39
guidelines now offer a weak strength of recommendation on par with the same weak strength of recommendation for using something like spironolactone, a mineralocorticoid receptor antagonist, or an ARB, and those with preserved ejection fraction. And it's interesting. We'll go through more of the data later on in the episode. But you know, the FDA actually does have as of February 2021 about a year ago, the FDA actually approved ENTRESTO for heart failure with preserved ejection fraction. And we'll talk about the data. I don't know if I agree with that. To be honest with you, I think it's a little bit controversial to have done that. But partially because of that, partially because of the data that we have, the new 2022 guidelines do have a weak recommendation for ENTRESTO and those with preserved injection fraction. And again, the cynic in me wonders, Is this because of that conflict of interest with the authors? I don't know, but it's hard not to think about that, given the cost of the medication and the relatively small benefit that you see in using it versus an ARB as an example, which is a very cheap medication in those with preserved ejection traction,

Dr. Khyati Patel  22:44
and it's always good to have healthy skepticism. Dr. Kane, so I don't blame you, for sure, we drive evidence based therapy, and that's what the guidelines should also drive as well. But moving on from the classes of drugs, the sglt, two eyes and the Arni, we do have an update, or, like I said, No update earlier, on the dietary sodium restrictions. And again, this pertains to patients with Stage C heart failure. These are symptomatic patients, and whether avoiding extra sodium in the diet, does that help reduce congestive heart failure symptoms? What is the evidence there? Dr. Kane, yeah, so

Speaker 1  23:24
the guidelines make the statement that avoiding excessive sodium is reasonable to reduce congestive symptoms, and this is a moderate strength of recommendation with limited data. And interestingly, they actually don't provide a specific sodium intake threshold, so less than 2000 milligrams a day, or less than 1500 milligrams a day. And the guidelines say that it was difficult to come up with a recommendation, because most of the data is actually for hypertension and the use of sodium restriction and hypertension, as opposed to in heart failure. And I think the choice of wording is actually really telling here. So they say avoiding excessive sodium to reduce congestive symptoms, as opposed to other clinical endpoints, like to reduce heart failure hospitalization or to reduce mortality or something like that. So of the data that we have, it may be reasonable to help with some symptoms, but potentially not for a hard clinical outcome

Dr. Khyati Patel  24:18
that is very interesting to know. You kind of have to read the lines and see what data and outcomes they're pointing to. In this case, it is reduction of congestive symptoms and not really anything else or other outcomes pertaining to heart failure. They couldn't make or add this particular study that came out later in this April. It's a sodium Heart Failure study, sodium HF study, that has probably the best data regarding the impact of sodium, dietary sodium, on heart failure outcomes. However, the guidelines couldn't include it, because the guideline was published before the study was published. Can you tell us a little bit more about what this study showed?

Speaker 1  24:59
Dr. Pain. Yeah, so this is an open label randomized control trial comparing very low sodium intake versus low sodium intake among about 800 patients with heart failure. All of these patients had New York heart association class two or three. And regardless of the goals that they set, it's really important that you actually look at how much they actually took in. So if I told you that could tell that your goal is 500 milligrams of sodium, but you actually, on average, took in 1500 milligrams. Then we're really comparing 1500 milligrams between the two groups. And in this case, the median intake was about 1600 milligrams versus about 2000 milligrams per day of sodium. So at first glance in my head, I'm thinking is 400 milligrams of sodium per day, really that different between the two groups? Would I expect a clinical difference? And in fact, we did not see a clinical difference. And the endpoint was heart failure, hospitalization or death a composite so therefore I would say that based on the sodium HF trial, whatever new guidelines we'll see for heart failure in the future probably will still have a similar recommendation of no specific sodium threshold for maximum intake, and probably a fairly lukewarm reception in terms of the importance of sodium restriction because of the lack of data showing a clinical benefit in doing so. So I guess that

Dr. Khyati Patel  26:18
kind of settles our discussion on sodium, I feel that is always an ongoing discussion among the students when we are teaching in the classroom, but at least good to know that for heart failure, the data is not as clear as the mounting data we have for the hypertension benefit and the sodium restriction, kind of moving From talking about the agents and the dietary changes, the guidelines re structured or reorganized recommendations for different categories of heart failure. So let's dive into each of them. And we'll start with the reduced ejection fraction heart failure, where ejection fraction is either 40 or below. Again, we are talking about this because it's a comprehensive update. And so just kind of summarizing the recommendations here for Stage A which are at risk, patient with risk factors, however, no structural abnormalities or no symptoms, the recommendation for these patient is to do risk factor management, so if they have hypertension, control their hypertension. If they have, you know, bad lifestyle, maybe help them improve their lifestyle. If they have, I don't know, smoking, their tobacco use disorder, maybe help them with smoking cessation, etc.

Speaker 1  27:34
Then for our stage B patients with a reduced ejection fraction, these are pre heart failure patients, meaning that their EF is low, but they don't have any symptoms yet. And the recommendation here is that you give them an ace or an ARB, and the guidelines say that they prefer an ace but an ARB if you're ace intolerant, and then beta blockers as well. So Acer ARB and beta blockers if you have a low ejection fraction and no symptoms.

Dr. Khyati Patel  27:59
And then we can move on to stage C and D patients. These are our symptomatic heart failure patients, as we kind of summarized earlier, to the initial management will be again symptomatic management, where we help patient reduce the fluid overload and the congestive symptoms. And this will be done by using a PRN or as needed diuretic therapy, but while also making sure that chronic therapy wise, they are on the four must have therapies. Some of these therapies were established in the previous guidelines as guideline directed medication therapy. These are the classes of drugs that reduce all cause mortality by an estimated 73% versus not using the treatment, we try our best to put the patient on the agents and also titrate their doses to the target doses. The guideline directed medication therapy doses as much as possible. In the first class is your RAS inhibitor, the first and foremost that's recommended, or most preferred, is the Arni, and we can use aces and ARBs as an alternative. If Arni is not feasible, you know, we got to go with the ace. If ace and Arni are both not feasible, then we can go with the ARB.

Speaker 1  29:17
And just to highlight a couple easy things, you never combine these three or two of these together. You pick one renin angiotensin aldosterone inhibitor drug category. And also, if someone has a history of angioedema, and the guidelines say any angioedema, not just like an ace, inhibitor induced angioedema, so anyone with a history of angioedema, the guidelines say, don't use an ace. Don't use an ARNI, but you should be using an ARB in those patients. And then, of course, we've covered this previously. You can't be on an ACE inhibitor and an ARNI like Entresto at the same time. You actually have to have a 36 hour washout period, whether you're going from Ace to Arni or Arni to ace. It doesn't matter. You have to have 36 hours with no drug on board, because. If you overlap them more than that 36 hour period, the risk of angioedema goes up, right?

Dr. Khyati Patel  30:06
And the next agent in the four‑drug category is beta blockers. There's no update in the recommendation. They're the same three beta blockers that are still equally preferred: carvedilol, metoprolol succinate (Toprol XL), and bisoprolol (Zebeta).

Speaker 1  30:26
And then our third of four must have drugs for these patients that have symptomatic, reduced ejection fraction heart failure, are mineralocorticoid receptor antagonists or MRAs. If the patient has an eGFR above 30 and their potassium is less than five then these are therapies that we can consider historically instead of mra. Some guidelines used aldosterone antagonists as the category of drug class, but they've now since moved to the MRA mineralocorticoid receptor antagonist term instead. And in this category, we have two drugs, Spironolactone or Aldactone, it's the cheaper one, but also blocks some androgen receptors, so it can cause some gynecomastia and some other kind of hormonal problems. Then we also have a eplerenone (Inspra), which is a little bit more expensive, but it does not have that androgen blockade. So for the most part, most people will start with spironolactone, and if they have some of those side effects like gynecomastia, then they'll switch them over to a player known

Dr. Khyati Patel  31:24
and last but not the least in this four‑drug regimen, SGLT2 inhibitors now come in the picture, and this is the fourth agent, the newest one that's recommended. We kind of talked about the evidence behind dapagliflozin and empagliflozin earlier. Again, this is not to be used if your heart failure patient also has type one diabetes, they have low blood pressure, low systolic blood pressure, and then also not to be used in those with eGFR that's reduced less than 20 to 30.

Speaker 1  31:57
and what's the guideline directed medical therapy or gdmt is optimized in terms of getting to the highest tolerated target dose. Now we can consider other therapies if the patient is still symptomatic, and these other therapies are more or less similar to what we've seen in previous guidelines. For example, if someone self‑identifies as African American with New York Heart Association class III or IV, or anyone, regardless of race, who can't tolerate the RAS inhibitor, then the recommendation is to use hydralazine with nitrates. Dr. Patel actually found this really interesting for a couple reasons. One, they did retain the same nomenclature from the original FDA approval of BiDil, which is the branded version of hydralazine and nitrate, which came from the A‑HeFT trial, where the inclusion was anyone who self‑identified as African American. It's interesting, because especially in the last several years, we've seen a huge push in medicine to move away from race as something that we use to diagnose or treat patients, because it's a social construct, and because we're trying to move away from that, I was a little bit surprised that the guidelines didn't also choose different terminology. I understand why they did it, because that's how the A‑HeFT trial was defined. That's how the FDA approval of the drug is. But I would have liked to see some mention that that may not be the most appropriate inclusion criteria for use of that drug.

Dr. Khyati Patel  33:19
I 100% agree with you. I think that this particular drug and this particular trial and the guideline has been scrutinized when we are talking about race based medicine. So I too am surprised that the recommendation stayed put, and

Speaker 1  33:37
then, of course, we still have a number of other therapies that generally they these either improve heart failure, hospitalization, but not mortality, or they have some symptomatic benefit. So those other therapies, in no particular order, that are mentioned in the guidelines, are evaporating. Varassaguat, digoxin, Omega three polyunsaturated fatty acids, potassium binders, if a patient is hyperkalemic with a RAS inhibitor, and then also devices so ICD or CRT, devices that can either, you know, shock your heart if you go into an arrhythmia, or actually pace your ventricles to make them synchronous with each other. Both of those therapies, those devices, are based on your life expectancy, your ejection fraction, how long you've had a low ejection fraction, different EKG parameters. There's a lot to those devices. But again, all of these therapies are recommended, but not like those core four must have therapies for those with reduced ejection fraction.

Dr. Khyati Patel  34:34
So that was a mouthful, you know, talking about summary of how to treat the reduced ejection fraction. Again, that's going to be kind of the most common Heart Failure Type that you would see. But now the guidelines are also breaking it down to other categories or types, and that's, you know, heart failure, where ejection fraction has improved. So it used to be less than 40, but now maybe with the treatment or. Um, you know, conditioning, it has increased to more than 40 and this is a new section because it wasn't part of the older guidelines. But honestly, the treatment for this is going to be very similar to the reduced ejection fraction category, because the goal now becomes that we don't want patients to relapse having a reduced ejection fraction, or have any the ventricular dysfunction. So you're still going to use the four different drug categories that we talked about in the reduced ejection fraction, and

Speaker 1  35:32
then another new category, or new to the guidelines, is heart failure with moderately reduced ejection fraction. This is where your ejection fraction is 41 to 49% and you have evidence of an elevated left ventricular filling pressure. And this is new, just because this category of heart failure was not present in the previous guidelines. And basically, the overarching theme here is that you more or less treat these patients similarly to heart failure with reduced ejection fraction, with the exception that the strength of evidence is a little bit lower. So for sglt, two inhibitors, we have a moderate strength of evidence because we actually have a little bit more data with this patient population. And all of our other kind of core therapies have a weak strength, just because we don't have really good, randomized, controlled trial data. But you're still going to be giving your renin‑angiotensin‑aldosterone system inhibitor, your mineralocorticoid receptor antagonist or beta blocker. All that's still good. So your overall management is not different, but the guidelines do draw a distinction between the level of evidence, between sglt, two inhibitors, which is a little bit better, versus everything else which is not as good.

Dr. Khyati Patel  36:35
And then last but not the least, we have the preserved ejection infraction category, where patients have ejection fraction of 50 or more, again, you have the caveat of or the added caveat of elevated left ventricular filling pressures. So keep those in mind and starting off reducing risk factors. I think treatment of blood pressure is one of the biggest modifiable risk factors we are speaking about for this particular heart failure patients, and the goal blood pressure is less than 130 over 80 when it comes to treatment,

Speaker 1  37:08
and in terms of treatment, specifically, that isn't just modifying a risk factor. There's only one therapy that has a moderate strength of evidence for that preserved ejection fraction, or diastolic heart failure patient, and it's the sglt two inhibitors. And again, this was from the Emperor preserve trial. They included anyone with an EF more than 40% not necessarily more than 50% but they did do some subgroup analysis that shows that it's really all of the EFS that benefited, as opposed to just those that were in that moderately reduced category.

Dr. Khyati Patel  37:38
So great to see the SGLT2 inhibitors are making a recommendation for this category of heart failure. We always have talked about this, Dr. Kane to students and say, oh, there is not really good evidence for agents to be used. So it's good to see sglt twos are mounting it. But we still say the quote, unquote, other therapies that have weak strength recommendations, these therapies are believed to be more effective with lower left ventricular ejection fraction, so above 50, but maybe, like closer to 50, and not as opposed to somebody who was in the 60s, or, you know, upper 60s or 70s. And so these are our mineral corticoid receptor antagonists, the ARB and the Arni and Dr. Kane, what is kind of like a high level evidence for these three agents, even though they're on the weak strength recommendation. Yeah.

Speaker 1  38:28
So what's interesting about these three categories for heart failure with preserved ejection fraction is that all three of the trials that looked at this had some flaw with them, or some reason why this is not a compelling indication for preserved ejection, fracture, heart failure. So if we look at spironolactone, which is a mineralocorticoid receptor antagonist, it was top cat trial that looked at this, and the primary endpoint, which was death or heart failure, hospitalization, was not different, but one of the secondary endpoints was better, and that was heart failure hospitalization. So whenever your primary endpoint fails, but you have a significant secondary endpoint. It does weaken the trial a lot because of a variety of issues with type one error. In addition, the top cat trial had some issues with geographic differences that threaten the internal validity of the trial. So there's kind of an asterisk on Topcat. Terms of ARBs, there was a trial called the charm preserves trial, and they used an ARB called Candice art, and we don't see that commonly. And just like Top Cat, the primary point of heart failure, hospitalization or death, was not different, and they kind of showed a significant improvement in heart failure hospitalization, but only after they adjusted for some covariates. And usually you don't need to do this in a randomized, controlled trial. So again, weakens the strength of recommendation here. And I just wanted to note that aces are actually not recommended in the guidelines for preserved ejection fraction, because we have even less data for that. And then finally, for arnies. We kind of alluded to this earlier. It was called the Paragon HF trial. This was with sacubitril/valsartan, Entresto, and just like the other two trials, the primary endpoint they. Child. So heart failure, hospitalization or death, was not different, and they describe it as a signal of secondary endpoint benefit. In terms of heart failure hospitalization, the P value was 0.056, so that's technically not statistically significant. And despite that, the FDA actually approved ENTRESTO back in February 2021, for heart failure with preserved ejection fraction. But again, maybe it's because of the FDA approval. I don't know, but I would, I would view this as a weaker recommendation versus the other two therapies that did have, you know, some benefit with heart failure hospitalization. I think it's a mixed picture here, and kind of speaks to the evidence that we still don't have, aside from sglt Two inhibitors, we don't have a lot of good treatments to give these patients that clearly has a benefit, and certainly the cost benefit is not going to be there with your RNAs.

Dr. Khyati Patel  40:51
That is interesting. And so bottom line for preserved ejection fraction heart failure, you want to prioritize the treatment with SGLT2 inhibitors, and then move on to the MRAs and the ARB thereafter, moving on to the last point that you mentioned earlier, you kind of are disappointed with this one. Dr. Kane, this is important to you in your practice setting for the acutely decompensated heart failure recommendation, there wasn't a whole lot that guidelines included. Is that right? Yeah.

Speaker 1  41:25
I mean, they did more or less reiterate what we saw in the 2013 guidelines, and I would have liked to see them build a little bit more on it. So, for example, they do talk about diuresis, which is a cornerstone of what we do for these heart failure hospitalization patients. But I would have liked them to provide better context, or some amount of recommendation towards a specific dosing strategy, or an escalation strategy for diuretics, if a patient's not diurecing Well, they basically equally favor increasing the loop diuretic dose to adding a thiazide. They don't provide a recommendation on a loop diuretic infusion, so kind of an IV drip versus just giving IV push doses of diuretics. They did look at vasodilation. So in someone who comes in with shortness of breath, that has heart failure, that has a normal or high blood pressure, vasodilation is one of the therapies we can give those patients. And it was a little bit disappointed that they equally preferred nitroglycerin to nitropresside. And the reason, with that, in my mind, being somewhat controversial, is that nitropresside is a mess. It's a very expensive medication, even though it's very old. Nitroglycerin is very cheap. Nitropresside has a ton of issues with it where, and they highlight some of these issues in the guideline. Generally, you're going to need an arterial lane because it can be very potent and drop a patient's blood pressure very quickly, just the risk of severe hypotension in general. Usually, patients have to be in the ICU to receive that medication. It has a good amount of cyanide in it. So if you, especially, you're on higher doses, or you have hepatic or renal impairment, you can actually get cyanide toxicity, although it's rare, why would you not just pick nitroglycerin? I would have liked to see them weigh in a little bit more with that.

Dr. Khyati Patel  43:06
I think Dr. Kane clinicians like you, as well as the PMT committees at the hospital, will probably eliminate this confusion and nitroglycerin on on the formulary or recommendation over nitro plus side. But yeah, you're absolutely right. That's that's concerning that they're both viewed equally.

Speaker 1  43:23
Dr. Patel, the last thing that kind of stood out to me was they do comment on inotropic or vasopressor support in patients with cardiogenic shocks. So these are patients that are hypotensive, that have heart failure, and that hypotension is because they have inadequate cardiac output. And I was disappointed that they didn't provide a recommendation on choice of therapy for vasopressor specifically, I would have liked them to say that dopamine should not be used based on evidence that we have from shock trials in general. Soap two trial is a great example where we demonstrated that the risk of arrhythmia if you get dopamine is double that of norepinephrine. And although that wasn't a cardiogenic shock trial, specifically, the adverse effect profile, I think, is concerning. And there were subgroup analyzes and secondary analyzes done of that sub two study that really did suggest that maybe dopamine has worse outcomes versus norepinephrine in cardiogenic shock patients. So again, they talk about the pressures, but they don't really provide a firm recommendation of avoiding one or preferring one. And I would have liked to see just a little bit more, at least in my ICU clinician heart. I was a little bit disappointed there,

Dr. Khyati Patel  44:36
and I think that sets a good case for evidence based practice, where, hopefully the guidelines will include it in the future focused or chunk update as you, as you said, they will plan on doing. But if not, guidelines are not the end all be all answers, you definitely need to look into primary evidence for a particular case or patient situation that you are. Are accounting for, and look and see what the evidence is, and make those applicable to your patient cases. Absolutely.

Speaker 1  45:08
Well, Dr. Patel, I think we've covered kind of our five core components of big updates in the 2022, guidelines. Why don't we kind of run through some of those just very briefly? So for me, number one was we now have four ways to classify heart failure. We've got reduced ejection fraction with an EF less than or equal to 40% an improved ejection fraction heart failure. This is where you used to be below or equal to 40% but now it's above 40% we have moderately reduced ejection fraction heart failure, where your EF is between 41 to 49% with increased LV, filling pressure. And then our last category, our heart failure with preserved ejection fraction. This is now defined as an EF more than, or equal to 50% with increased LV filling pressure. And for the most part, our drug therapy is not that different between reduced ejection fraction, improved ejection fraction and moderately reduced ejection fraction, but our therapies for preserved ejection fraction, where the EF is 50% or higher, those are a lot different. That's a different animal for treatment,

Dr. Khyati Patel  46:09
and these updated guidelines are recommending use of SGLT2 inhibitors, particularly dapagliflozin and empagliflozin in patients who have the reduced ejection fraction heart failure, moderately reduced ejection heart failure and preserved ejection heart failure.

Speaker 1  46:27
And as we mentioned, another big update in these 2022 guidelines is preferring arnies Like ENTRESTO over ACE inhibitors and ARBs, not just in those with reduced ejection fraction, but based on the Paragon HF trial and the FDA approval, RNAs are now recommended by the guidelines with preserved ejection fraction, albeit with a weak recommendation.

Dr. Khyati Patel  46:45
And when it comes to dietary sodium restriction, guidelines are saying that it's reasonable to avoid sodium in diet to reduce congestive symptoms in patients who have heart failure. However, there is no particular recommendation as to what that specific amount should be, nor that these data are enough to say that their clinical outcome impact for heart failure when it comes to reducing dietary sodium.

Speaker 1  47:16
So I think that wraps things up quite nicely. Dr. Patel for the listeners, if you want to see the guidelines are linked in our show notes at HelixTalk.com Again, this is episode 147, we also threw the sodium HF trial in there because it was new and not really evaluated by the guidelines. And we kind of mentioned the findings of that in terms of dietary sodium restriction and heart failure. We love the five star reviews in iTunes. We're on Twitter at HelixTalk. So with that, I'm Dr. Kane

Dr. Khyati Patel  47:41
and I'm Dr. Patel, and as always, study hard.

Narrator - Dr. Abel  47:44
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Narrator - ?  47:56
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