Missed Opportunities in HF Diagnosis: Clinical Manifestations and Biomarkers for Early Detection

Dr Butler: Let us start with the first section titled Missed Opportunities in Heart Failure Diagnoses. I mean, this is 1 of the biggest issues in patients with heart failure is either misdiagnosis or significantly delayed diagnosis.

[00:07:21]

Patient Case

Let us start with a case in this one as well. Mr. Reed is a 67-year-old patient, a history of hypertension for a long time, type 2 diabetes and dyslipidemia. Pretty common type of patient phenotype as you would see in your clinical practice.

He is a former smoker for a long time but does not smoke anymore, lives alone and has limited physical activity. He takes atorvastatin, lisinopril and metformin. Presents to the primary care physician complaining of increased fatigue, increased exertional dyspnea over the past 6 months.

Additional symptoms include occasional swelling of both ankles, which he has attributed to prolonged sitting because he is not doing much, and some orthopnea as well. Blood pressure is 142 over 88. Heart rate is 78. Respiratory rate 16. Oxygen saturation okay. Heart sounds are okay, no murmur. Lungs is clear. But he does have lower extremity edema.

The initial impression was that this is age-related deconditioning because the physical examination looks pretty good. Maybe the edema is because of deconditioning, blood pressure. It is recommended that he increases his physical activity, lose some weight, reduce his dietary salt intake, and no further evaluation was performed.

[00:08:41]

          Poll 3

What do you think about this case so far? If you can just type in some of your responses, that will be great.

[00:09:20]

Importance of Early Detection

Okay. Sounds great. Let us start. Why should we worry about early diagnosis of patients or timely diagnosis?

Well, the reasons are pretty self-explanatory, right? Because the longer you wait to diagnose heart failure, several things happen. One, the disease continue to progress. By the time you diagnose and if the diagnosis is delayed:

1. The patient has suffered during that time;
2. Diseases like heart failure have a finite risk of sudden cardiac death, so patient may have sudden cardiac death in the absence of therapy;
3. By the time you get the therapy to the patient, if their heart failure has advanced enough, reversing heart failure is a little bit more difficult than preventing progression of the disease.

For all the reasons, early detection of heart failure, it will limit the disease progression, reduce the risk of hospitalization, reduce the risk of mortality, and potentially avoid suffering by the patient and reduction in quality of life.

[00:10:25]

Clinical Manifestations of Early Heart Failure

Now, why doesn’t heart failure get diagnosed? I can tell you when patients present to the clinic and they have these nonspecific symptoms, as it is noted here, all of these symptoms are really nonspecific, right?

• Dyspnea,
• Lower extremity edema;
• Weight gain.

Really these are nonspecific symptoms. If you have somebody with very focal specific symptoms, new onset low back pain, chest pain on exertion, slurred speech, none of those things are ever ignored. We go for evaluation for whatever evaluation needs to happen. But when you have these nonspecific symptoms, it is so common that the clinicians would rule out all the common things like hypothyroidism and anemia and COPD and asthma.

At that point, it is just a culture to blame either obesity or aging, not realizing that a person had the same age and was equally overweight if the person is overweight 6 months ago when the person did not have these symptoms. So new onset symptoms not prompting evaluation for heart failure is very common.

What data do I have on the basis of which I am saying so emphatically that this happens? There are 2 papers published, 1 in US from a large healthcare system database and 1 from UK, and both showing the same thing that the number 1 place that heart failure gets diagnosed is in the emergency room. People come in, shortness of breath, edema, really not doing well. In the emergency room, the diagnosis is made.

But then when you go back and look at the electronic medical records on those patients, within the last year, over 80% of those patients had some symptom consistent with potential heart failure, although nonspecific, but some symptoms potentially indicative of heart failure, where either no evaluation was done or evaluation was done for other comorbidities except heart failure, till the person got into extremis and ended up showing into the emergency room.

[00:12:29]

Biomarker-Based Risk Stratification

Now, how do you think about it? One is low clinical threshold, obviously. Two, there are some risk scores out there that one can use, the commonest 1 at least for heart failure with preserved ejection fraction. There used to be a little bit more complicated 1 called H2FPEF score, but that required an echocardiogram.

But if you have really high positive predictive value, there is a score by colleagues at Mayo Clinic that they publish, ABA, which is age, body mass index and atrial fibrillation. If you have an older person or obese person, an atrial fibrillation, that is pretty much gives you the diagnosis of HFpEF. But that has a very good positive predictive value, but there is a lot of other people who may not have all of those characteristics.

How do you think about diagnosing heart failure? One thing is to have a low threshold of suspicion. That is the first thing because if you do not have a low level of suspicion, a good history and physical examination.

Now, today, where the world is, is that the predominant biomarker that we use are natriuretic peptides. And natriuretic peptides really give us a very good indication whether somebody has a potential for heart failure or not.

What are some of the good biomarkers characteristics that can help you develop further biomarkers? I will give you some examples. Many of these biomarkers may not be in clinical use today but maybe in the future. How to think about it?

The characteristic of an ideal biomarker is that, A, it is in the pathophysiologic pathway of the development of the disease that it has multiple functions. It can allow for early diagnosis, screening, prognosis, and in ideal cases, can actually help you manage the patients as well. It is easily available. It is not very expensive. It is globally available and provides additional information to what is already available on in the clinical practice.

[00:14:15]

Types of Biomarkers

Biomarkers can be used for a whole bunch of reasons. You can use it:

• To predict the future risk of development of heart failure;
• To screen for subclinical disease;
• For diagnosing when people have nonspecific symptoms and you do not know whether it is COPD or it is heart failure;
• To stage the disease, what is the severity of the disease; and
• Related future prognosis;
• Potential therapeutic intervention that you can target the therapy to lower that; and
• To use it as a surrogate endpoint as well.

I would say at least with natriuretic peptide, we are almost all the way down, not totally all the way down, because we do not necessarily use it as a surrogate endpoint in clinical trials per se right now. In the discussion, we can go into the details of why not. But natriuretic peptide really fulfills most of these criteria.

[00:15:05]

Biomarkers for Early Detection of Heart Failure

Now, heart failure is a condition that has multiple different pathophysiologic pathways that are activated. There is fibrosis and there is inflammation and there is ischemia. There is microvascular ischemia. There is a stress. There is a whole lot of things that can occur. So you have all of these biomarkers that are lined up that can give you some idea. These biomarkers are looking at various different aspects of the pathophysiology of both development and if you have heart failure, progression of heart failure overall.

[00:15:33]

Role in Screening and Diagnosis: Pros and Cons

Now natriuretic peptide is the one which is the most commonest biomarker used. It is in the guidelines already for almost all of those purposes other than a surrogate marker, which we use it in phase II.

Cardiac troponins, I think they are a little bit underutilized overall. There is this thing called malignant LVH. So if you have left ventricular hypertrophy, that puts you at a higher risk if you have hypertension for developing heart failure. But on top of LVH, if you natriuretic peptide elevation or high sensitivity troponin elevation, that is called malignant LVH. And those people are really at a high risk of developing heart failure per se.

Galectin-3 good, fibrosis, ST2, inflammation. These are all of these other markers, maybe not as much in use as natriuretic peptide or cardiac troponins.

[00:16:22]

Integration With Imaging Modalities

The other place where these biomarkers really come in handy is integration with imaging. A lot of the papers have been published. If you talk about echocardiography, remember that there is no risk with echocardiography. It is ultrasound. There is no radiation. There is nothing. The reason why echocardiography is not cost-effective. Remember, there are certain diseases where we have decided as a community that we want to screen those things. So we do mammography. We do colonoscopy. We do those things at certain age, certain risk factors.

But we do not do screening echocardiography on everyone. The reason for that is that it is considered cost ineffective. Now, as I mentioned, there is no ineffectiveness in terms of either the risk or the diagnosis. Like you do an echo, you know whether somebody has low ejection fraction or LVH or whatever it is. I mean, it is a pretty good test and there are no risks.

But the reason it is that it is an expensive test, it is not very widely available, especially in some settings. If you start doing an echocardiogram on everybody over the age of 40 or some risk factors or whatnot. At the end of the day, you will be doing a ton of echos that will not be positive for heart failure. So it has never come up as a screening tool.

But a combination use of biomarker and echocardiography starts becoming a whole lot more cost-effective that if you have a person who has nonspecific symptoms and if you do the natriuretic peptide level.

How do you diagnose heart failure? What is the universal definition of heart failure? Three things:

• Signs and symptoms of heart failure;
• Two, some evidence of structural heart disease. Anything, atrial fibrillation, LVH, left atrial enlargement, but there should be something wrong with the heart. So some structural abnormality of the heart; and
• Evidence of congestion. In evidence of congestion, we usually use natriuretic peptide as an evidence of congestion because not everybody gets a right heart cath. And physical examination may be a little bit more nonspecific.

I think it makes a ton of sense that the first screening tool you do in the clinic setting is to do natriuretic peptide. If the natriuretic peptide are elevated, then you can go ahead and get an echocardiogram in that person, and it will be a little bit more cost effective.

Now the issue is the other way around. If your natriuretic peptide levels are high and you are asymptomatic, then you go into this bucket of high risk for future heart failure. And if you are already symptomatic, tiredness, shortness of breath, fatigue, then you already are getting to the diagnosis of heart failure.

However, we are also living in the midst of an obesity epidemic, and obese patients tend to have lower natriuretic peptide level, not necessarily normal. That can occur, but not that frequently. And in that case, so if you have a high natriuretic peptide, it has a very good positive predictive value.

If you have a low natriuretic peptide, then the best thing to do is to rule out other diseases, obviously. But if you ruled out other diseases and a person is persistently having symptoms, then do not ignore the symptoms and before we blame it on obesity or aging, refer to a cardiologist that can do a right heart cath with some provocative maneuvers to just make sure that the pressures do not go up with exertion, because there is a group of people who will raise their pressure and hemodynamics with exertion, but not necessarily overall at rest. So this combination therapy really works well.

[00:19:43]

Conclusion

To conclude:

• Early diagnosis of heart failure is crucial to improve outcomes and not delay the effective therapy;
• Biomarkers offer valuable diagnostic and prognostic insights; and
• Integration with imaging and clinical evaluation is the key.

That is how we can have a little bit more cost-effective management of these patients.

[00:20:07]

Revisiting Our Patient Case

This was our patient. If you look at it, this person has diabetes, has hypertension. Even in the absence of coronary disease or myocardial infarction, would be at a higher risk of LVH and development of heart failure. But this person comes in with everything that is shouting at us as heart failure: orthopnea, shortness of breath symptoms and whatnot. Has edema but did not get evaluated.

[00:20:36]

Faculty Commentary

Dr Gluckman, do you have any comments? What would you do?

Dr Gluckman: I think you summarized things really nicely. The only thing I might submit to all of you, and maybe everybody in this room is a cardiovascular care team member, a cardiovascular clinician. These patients are disproportionately presenting to primary care clinicians. So I would submit that a takeaway for this is, while it may be self-evident that this is a patient we are talking about, in particular heart failure tonight. So that is obviously the focus. How do you educate, inform and raise that pretest probability or suspicion for your primary care colleagues such that when they come in this person gets additional testing, whether it be natriuretic peptides, echocardiogram? Easier said than done. But I think ongoing education, even if it is not formal, is going to be a key important thing to take away and support your clinical colleagues overall.

Dr Butler: I will make a couple of points. Your comments are very apt and it reminded me of a couple more things. One is prevention of heart failure has not been in vogue. We have already talked about prevention of vascular disease for 30 years, right. Stroke, myocardial infarction, Framingham risk score, PREVENT heart score, all that kind of stuff. We have been at it pretty long.

But we never went into prevention of heart failure because the idea was that if you prevent ischemic heart disease, you are by definition preventing heart failure. And heart failure is a complication of ischemic heart disease. That statement is true, but is only partially true and is becoming less and less true as we live in this obesity cardio kidney metabolic world where now a large proportion of patients, almost half the patients who present with new onset heart failure do not have manifest vascular disease.

Now, I have no idea who has subclinical coronary disease or not, but they do not have manifest vascular disease. No history of angina, myocardial infarction, stroke, claudication, all that kind of stuff. Because through these alternate non-ischemic pathways, you develop heart failure with preserved ejection fraction. So we have to think about it.

Of course, I do not want to only talk about SGLT2 inhibitor, although this session is about SGLT2 inhibitor. Early diagnosis is to get all the appropriate therapy, like the ARNIs and beta blockers and MRAs and whatever you need to give to the patient.

But remember, with SGLT2 inhibitor in high-risk patients, even if you do not have heart failure, appropriate therapy prevents the development of heart failure in type 2 diabetes and in patients with chronic kidney disease, at least in those 2 high-risk patients we know.

The second thing that I would highlight is that, yes, really important point that these patients are in the primary care setting. I am going to assume a lot of the audience member here are actually in cardiovascular practices. But if you can just talk to your primary care colleagues and tell them that the American Diabetes Association now has a recommendation of annual NT-proBNP, because if a person is asymptomatic, does not mean that person is not at risk of developing heart failure. In that case, certain things need to be done, or if they are symptomatic, not to delay the diagnosis of heart failure.

Annual NT-proBNP assessment is diabetes ADA guidelines today already.

[00:23:45]

Missed Opportunities in HF Treatment: Optimizing Guideline-Directed Medical Therapy

Okay. Let us move on. And from diagnosis, talk a little bit about therapy at this point.

[00:23:51]

Patient Case Continued

Okay. Let us revisit the case. Now patient presents to the urgent care facility 3 weeks later with more shortness of breath, weight gain of about 3 pounds. Dyspnea is now present with minimal exertion. So I just cannot do enough at work.

Now you are like, even if I go room to room, person is getting short of breath. Also notes a dry cough at night, which worsens when the person lies down flat, so have orthopnea. Low grade temp 99.6, blood pressure 150 over 95, heart rate is 84. A little tachypneic, a little lower oxygen saturation than before. Some jugular venous extension, has an S3 gallop, bibasilar crackles, pitting edema comes up to mid shin.

This is really exactly what happens that this is when the diagnosis of heart failure is made in emergency room, whereas this potentially could have been avoided if the suspicion was high in the outpatient setting and appropriate therapies were given.

BNP levels are raised, so BNP to NT-proBNP conversion anywhere 4, 5. So if it is 520, say 2000, 2500, something like that. Has mild vascular congestion, some cardiomegaly, sinus rhythm, LVH on the ECG and was diagnosed with heart failure and was started on beta blockers and furosemide and was referred to a cardiologist.

[00:25:15]

          Poll 4

Okay. What do you think now? If you can take a few minutes and jot down some of your initial thoughts.

[00:25:51]

2022 AHA/ACC/HFSA Guideline Updates for HF

Okay. Now let us move on with the management of the patients. We have a couple of bad news here and 1 really good news. A couple of bad news is that we are living in this midst of cardio kidney metabolic syndrome. Obesity is through the roof right now, and along with obesity comes either diabetes or pre-diabetes and insulin resistance. Because of these 4, 5 things that come with this adiposity phenotype that we are seeing more and more, and remember when I say adiposity, I actually mean adiposity, not obesity, because there is a reasonable disconnection between BMI or what we call obesity based on BMI and actually visceral adiposity. So a lot of the people who traditionally we do not call obese actually may have a lot of visceral adiposity.

The problem with adiposity is that you get inflammation, you get oxidative stress, you get endothelial dysfunction, you get insulin resistance. This is the milieu in which the body lives puts you at a high risk of end organ damage and involvement for multiple organ systems at the same time, cardiovascular, kidney, liver, all of these things are affected at the same time.

Now, I do not totally understand why the trajectory is different for different patients, for different diseases. So some people may present with heart failure first. Some people may present with CKD first. But I can guarantee you that if you present with 1 disease, you are almost guaranteed that the other disease process has already started, and it is only a matter of time that they will progress from subclinical to clinical disease.

This is precisely the reason why our patients have so many comorbidities that are together. That is 1 bad news.

The second bad news is that these things tend to complicate each other's prognoses as well. So if you have 1 organ system dysfunction that accelerates the other disease organ progression and also the prognosis. So heart failure has bad prognosis, CKD has bad prognosis. If you have both, then the prognosis is even worse.

If you have heart failure, you are at a high risk of developing diabetes. If you have diabetes, you are at a high risk of developing heart failure. If you have both, your prognosis is even worse.

What is the good news? The good news is that because it is the same pathophysiologic mechanisms that is driving both the development of the disease and once you develop the disease, the progression of the disease, that if you have effective therapies that are not necessarily affecting the manifestation of the disease, but 2 steps back, affecting the cause of the disease. While you may be giving it for 1 reason or another, you are going to get the benefit of everything.

If you do not have the disease, you will prevent the disease. And if you have the disease, you will prevent the progression of the disease. And you might give it for disease X, you are invariably going to benefit for disease Y and disease Z as well.

Which brings me to the SGLT2 inhibitors. If you look at this big spectrum of heart failure guidelines overall, because we wanted to promote this idea of prevention of heart failure, this is staging system came about. So stage A are patients at high risk of development of heart failure, but their hearts are okay and they do not have any symptoms. So high blood pressure, diabetes, chemotherapy exposure or something, all those kind of stuff.

Now when the stage A patient progresses and now they have structural heart disease. Again, no signs symptoms of heart failure but they have structural heart disease that those risk factors like hypertension or diabetes are now affecting the function or the structure of the heart, LVH, left atrial enlargement, diastolic function, atrial fibrillation, whatever. Now you are getting 1 step closer to heart failure, and that is a stage B.

Stage C is your run of the mill heart failure, what we call heart failure symptomatic, shortness of breath, tiredness, edema and stuff like that. Then that is, as you know, divided into 3 groups:

• Heart failure with reduced ejection fraction, less than 40%;
• Mildly reduced, 40% to 50%; and
• Preserved ejection fraction, greater than 50%.

That group, once you have given an appropriate therapy, at some point when they start becoming resistant and none of the therapies are working, that is what we call advanced heart failure or stage D.

If you look here, there is only 1 therapy which is consistent across the entire spectrum, and that is the SGLT2 inhibitor. SGLT2 inhibitors are going to prevent the development of heart failure if you have stage A characteristics like type 2 diabetes, CKD with ischemic heart disease, etc., or even more so if you have stage B heart failure. So these drugs will prevent heart failure.

If you have heart failure, then it really does not matter what kind of heart failure you have, heart failure with reduced, mildly reduced, or preserved ejection fraction, this therapy is also indicated for those patients.

Now what are the practical implications of this? The practical implications are that for the first time we have therapy that works across the spectrum of ejection fraction. What used to happen in the past is that if you have somebody with edema or shortness of breath, tiredness, you are concerned about heart failure, maybe you have access to natriuretic peptide elevated. You are pretty sure clinically that this person has heart failure. But you had to wait for an ejection fraction to know what kind of heart failure the person has to be able to figure out what therapy to give. The only therapy you gave to those patients was diuretic therapy for symptomatic management.

But now with the paradigm that we are living in, that is not necessary. Again, if you are in a high tech practice like Dr Gluckman, he walks his patient and gets the echo right away. But that is not real life, right? Many patients in the rural setting, in primary care setting, you may not get an echo for 2 weeks or 3 weeks or whatever. But now, because it really does not matter what the EF is, it really does not matter what the etiology is, you can at least start them on an SGLT2 inhibitor while they evaluate them.

And suppose you are wrong for some reason and the person does not have heart failure. Well, if they have those characteristics on which you can prevent heart failure and it is indicated, you can go ahead and you are still giving patient a potential beneficial chance. Then of course this is a heart failure talk, but there are benefits for CKD as well.

[00:32:19]

Guideline Incorporation of SGLT2 Inhibitors

Major HF Guidelines Strongly Recommend Foundational Use of SGLT2 Inhibitors Across LVEF Spectrum

Now if you look at the guidelines, the European guidelines has a Class I recommendation for SGLT2 inhibitor across the entire spectrum. American guidelines have not been updated. So guidelines have certain rules for the right reason. Then a Class I recommendation would require at least 2 trials, and when American guidelines were written, only 1 trial was out for HFpEF. Two trials were out for HFrEF. So you can see that it is a Class I recommendation to give an SGLT2 inhibitor. And there was a specific focus on SGLT2 inhibitor, empagliflozin and dapagliflozin, for which we had clinical trials and not necessarily any SGLT2 inhibitor.

When it came to heart failure with mildly reduced and heart failure with preserved, the only trial that was out at that time was EMPEROR-Preserved. There is only 1 trial. So they gave it a Class IIA recommendation at that time.

Now, subsequently, the European guidelines have already been updated. As you can see here, there is a Class IA recommendation. Really does not matter whether you have HFpEF or HFrEF. It is a Class I recommendation.

[00:33:23]

SGLT2 Inhibitor Underuse in Patients With HF Discharged From the Hospital

Because the guideline process takes some time to be updated, I think it is only a matter of time when the guidelines will be updated pretty soon.

Here is the problem. If you think about the bar, medicine is a really, really conservative discipline and for the right reason, maybe it should be. What does it take to get a Class I recommendation?

First, you have to have a clinical trial with a p value of less than 0.05, which means that you are 95% certain. When our economists in government have to make a decision as to what to do with X amount of dollars and whether to build a bridge or school or whatever, when they evaluate the chances of success, they use a p value of about 0.3. In other words, if I am 70% certain, then it is worth it to go ahead and do it.

We are a very conservative discipline, so we want 95% guarantee. But guess what? We actually do not want 95% guarantee. We want 2 trials to be less than 0.05. So 2 trials less than 0.05 is 0.05 times 0.05 is equal to 0.00125, which is that you need a 99% guarantee.

Okay. Now 2 trials are positive. You are sure. Then it goes to the regulatory agencies. And the regulatory agencies are to make sure that it is not only the benefit but the risk benefit is in the right place and you are not taking some inadvertent risk. Then it goes to the professional societies where conservative people like Dr Gluckman sits and looks at the data, and they just really tear it apart in any different way that they can.

By the time it gets a Class I recommendation and what Class I recommendation means for some of our colleagues who may not live the guideline lingo. Class III really bad idea, do not do it. Class I really good idea. In the absence of contraindication, there is no reason not to do it. So Class I is a must do it. Class III is a must not do it. Then class II is in the middle that there is either evidence coming or considered.

By the time you have a Class I indication, there is really no reason not to do. But still, if you look at it, there is huge inertia. There is huge inertia of uptake of these applications. You can see Get With The Guidelines registry that there are hospitals where the use is like very high, and then there are other places that are barely using it at all.

But on average the use is about 20%. So 80% of the patients still come in and they do not get the therapy that they deserve overall.

[00:35:56]

SGLT2 Inhibitor Underuse in Patients With HF and Class Ia Recommendation With or Without Diabetes

SGLT2 inhibitor underuse. Remember that the drug was being developed originally as a diabetes drug, and that is appropriate that it does manage diabetes. But the cardio-kidney benefit has nothing to do with diabetes. Regardless whether you have diabetes or not, it is a Class I recommended therapy.

Here are some of the data from large databases that aggregate data from multiple healthcare systems in the US, about 3 million adults. If you look at it, there is a little bit higher use in those with diabetes, even lower, negligible in those without diabetes. We are talking about, again, 11%, 10%. These data have improved over time a little bit. But improve means up to 20%, right. Again, there is a huge gap that that these drugs are not given.

[00:36:44]

SGLT2 Inhibitors: Their Role Beyond Glucose Lowering

Remember again that these drugs are used for management of patients irrespective of diabetes. Heart failure benefit and CKD benefit has nothing to do with diabetes, and you need to give the therapy at both ends are important. One, give the therapy as soon as possible because the therapy acts pretty fast.

In EMPEROR-Preserved trial in heart failure with preserved ejection fraction, the first time that Kaplan-Meier curve separated statistically significantly was on day 18. Remember, EMPEROR-Preserved were all outpatient. This was not inpatient or really, really sick patient. Day 18, where there was already a statistically significant benefit. And in EMPEROR-Reduced, it was day 12. So this whole paradigm that we have that we talked to the patient and then we will do something in the next clinic visit 3 months down the road is really not serving our patients best.

But then if you move to the other end of the spectrum that patient is on chronic therapy and is doing well, most of the patients do not want to take 3 or 4 medications. So they will come to you and they will say to you, “Well, you know, can I just stop the medication? I am doing okay”, and stuff like that.

So I would say 2 points. Even if their EF is completely reversed and normalized, we know the data from the DELIVER trial and other trials that those patients also benefit. But also there are 2 really nice papers, 1 with empagliflozin and 1 with finerenone.

What happens is in the clinical trials, at some point the clinical trial has to stop. Guess what? When the clinical trial stops, you stop the medication because you have not looked at the data. You do not know whether the medication is working or not. Then you follow the patient after the trial is stopped. Now there is randomized withdrawal just part of the way you do things. You have 2 arms. One is getting placebo, 1 is getting the real drug. The trial ends and you stop both therapy. Now both are on placebo.

What ends up happening is you have this event rate and the treatment event rate is low. We have now seen it in 2 trials, both with finerenone and with empagliflozin. And after 2, 3, 4 years of patients on discharge, you stop it. And literally in 1 month, their event rate starts going up and start matching placebo. The quality of life scores starts coming down. Therefore, it is really important to give this therapy on a chronic basis.

[00:39:08]

Clinical Evidence for SGLT2 Inhibitors in HFrEF

DAPA-HF and EMPEROR-Reduced: SGLT2 Inhibitor Use Among Ambulatory Patients With HFrEF

What is the evidence on the basis of which I am saying all of these things? For heart failure with reduced ejection fraction, there are these 2 large trials: DAPA-HF and EMPEROR-Reduced. Both trials pretty similar with 2 different drugs. The primary endpoint was cardiovascular death, heart failure hospitalization. Not only both of them were highly statistically significant. By the way, these patients were excellently treated at the baseline overall.

We are talking about 90%-plus RAAS inhibitor used, 90%-plus beta blocker use, 70%-plus MRA use. Whatever the benefit you are seeing is incremental to really, really good background medical therapy.

Then not only was this a highly statistically significant result, it was a very clinically meaningful result. There was about a 25% relative risk reduction in the primary endpoint of cardiovascular death, heart failure hospitalization in both of these trials.

[00:40:03]

Clinical Evidence for SGLT2 Inhibitors in HFpEF

EMPEROR-Preserved and DELIVER: SGLT2 Inhibitor Use Among Patients With HFpEF

What about heart failure with preserved ejection fraction? Again, there were 2 trials done parallel, EMPEROR-Preserved and DELIVER in heart failure with preserved ejection fraction. Again, outpatient same thing. And by the way, these are the first drugs ever to convincingly improve outcome of patients with heart failure and preserved ejection fraction. But same thing. Not only did you see a highly statistically significant but highly clinically relevant, greater than 20% relative risk reduction. Now finally we have therapy across the entire spectrum of patients with heart failure.

[00:40:42]

Acute HF: The Missing Link

Now, do we really need a clinical trial in patients with acute heart failure? Remember, it is the same disease whether you come in with HFpEF, if you come into the hospital, it is not really a different disease.

Historically, over the past 20 years when we have developed therapies, the reason we did studies in acute heart failure was not efficacy, was safety. The idea here is that your blood pressure is going all over the place and your creatinine and you are getting IV diuretics and this, that or the other is happening. Is it safe to start in a hospital setting?

The traditional trial design was that at the time of discharge, we will start a chronic therapy and make sure that the patient tolerates in the hospitalization.

With the SGLT2 inhibitor, it is actually a little bit of a different issue. With SGLT2 inhibitors, there is a hypothesis that early use not only will be safe, but will be efficacious. The reason for that is that we all know how you develop diuretic resistance Day 2, Day 3, Day 4 of hospitalization, and you do not pee as much with loop diuretics. There is a whole bunch of mechanism, braking phenomenon, etc. because of which that happens.

Then we are all sort of struggling that the person needs to go home, the family wants to go home, the hospital administrators want you to send the patient. Length of stay is a big deal, that we can see visible congestion of the patient, right? The edema is still there. They feel a whole lot better, but they are not really tuned up as much as you want to. But you invariably discharge the patient.

Any measure of congestion. If you had a swan[?], the last wedge pressure, simple physical examination or NT-proBNP at discharge, any level of congestion. Residual congestion is associated with risk of readmission and a higher risk of mortality post discharge.

Now the hypothesis is because SGLT2 inhibitor, although we are giving it for its cellular effects for long-term remodeling and clinical outcome benefit. But in the short term, at the kidneys, it has 2 functions. One is it blocks the sodium hydrogen exchange receptor. So you have natriuresis. So you have some degree of diuresis because of natriuresis, and also osmotic diuresis because of glucose excretion. And along with glucose, some fluid comes up as well.

The hypothesis is that early use of this therapy in the acute heart failure setting would lead to better decongestion and improvement in outcome. So that was tested in this trial called the EMPULSE trial in acute heart failure, where the whole criteria was that you got to be a little bit stable, right? So you are not in the emergency room, hypotensive on inotropes or whatnot, but you could be getting IV diuretics.

Day 2, you are on the hospital floor. You could be getting IV diuretic, but you are not unstable. And initiating this therapy led to, in the short term, substantial improvement in outcomes.

[00:43:34]

SOLOIST-WHF and EMPULSE: SGLT2 Inhibitor Use Among Patients With Acute HF

EMPULSE was in the hospital setting. Then sotagliflozin, which is a combined SGLT2 and SGLT1 was in worsening heart failure, which was in the peri discharge phase. And both of these trials were also positive, not only for better decongestion, but clinical outcomes, including risk of mortality, hospitalization in the short term, and indeed, there was more weight loss in the SGLT2 inhibitor arm, and more weight loss was sustained in the long run in these patients as well.

[00:44:06]

Clinical Evidence for SGLT2 Inhibitors Across the EF Spectrum

Meta-Analysis of 5 Large Placebo-Controlled Trials

If you put all the data together from all the SGLT2 inhibitors, as you can see, a consistency of benefit, about 20 to 25% relative risk reduction across all the trials and HFrEF and HFpEF made no difference whatsoever.

[00:44:22]

Who Should “Own” the Prescribing of SGLT2 Inhibitors?

However, the issue is that we live in a pretty fragmented healthcare system. Some people are seeing nephrologists, some people are seeing primary care, some people are seeing cardiology, some people are seeing endocrinologists, some people are seeing a mixture of these things. In my mind, this is a good news. Of course, fragmented healthcare is not a good news. But the good news is that these therapies are really easy, simple to use. It is not high tech, there is no tolerability is very good.

The reason why I say it is good news is that now the patient has like 5 touchpoints that somebody can start it. Wherever you go, whether you have diabetes and you go into an endocrinologist, whether you have CKD, you are going to nephrologist, whether you are going to cardiologist for some reason or whether you are only in the primary care setting, you are seeing a nurse practitioner, you are seeing a clinical pharmacist, you are seeing primary care physician. It does not really matter. We all have the opportunity to get to these patients and start the therapy overall.

[00:45:18]

Challenging Traditional GDMT Initiation

The traditional use of the medication is that you first give diuretic therapy and then diurese the patient first. After diuresis, you start 1 therapy, you start them, go uptitrate the dose, get them back in a month or 2, then uptitrate the dose, then go to the next medication and all that kind of stuff. So that traditional paradigm has a lot of problem.

[00:45:41]

Consequences of Trading Sequencing

One, traditional paradigm is a typical reason because of which inertia sets in in the patient. So, so much time and then a person feels better. Nobody up titrates, that is 1 issue. The second thing is you are buying in some risk of sudden cardiac death because you are not giving appropriate therapy. The heart failure is slowly worsening. In the meantime, a lot of people get ICDs that they may not need because they may get reversal.

Some people get mitral procedures, but that could have been reversed if early therapies are given. There is a lot of reason why delay in therapy is not a good thing. I mean, just think about it. If somebody comes in with myocardial infarction, we start them on an ACE inhibitor beta blocker, MRA, statin, dual antiplatelet therapy, 6 drugs in the matter of 5, 6 days. Why does it take months on end?

[00:46:25]

The Need for Speed

Now there is a lot of interest in pushing. If you look at the guidelines, the recommendations are that at least low doses of all the medications should be given in the outpatient setting if the outpatient diagnosis is made within 6 weeks. And if the diagnosis is made in the hospital setting, try to get it done in the hospital setting. This is by Milton Packer and John McMurray.

The idea here is that usually polypharmacy leads to more intolerance. But this is 1 case where polypharmacy may actually help tolerance of each other. For instance, if you are congested, you are not going to tolerate beta blocker. But with SGLT2 inhibitors and ARNI, both have diuretic properties and will make tolerability of beta blocker better.

If your potassium and creatinine is borderline, you may not tolerate MRAs, but SGLT2 inhibitors lower the risk of hyperkalemia and increase MRA tolerability. So for all of these reasons, now the rapid sequencing is really being promoted. That does not mean that you have to start 4 drugs at 12:30 on Thursday afternoon all at the same time. But the idea here is that do not wait for weeks on end. Maybe 1 thing can be started today, the second tomorrow in the hospital setting, or on some telephone visit next week in the outpatient setting. But get these therapies done pretty fast.

[00:47:40]

Why Is Rapid Initiation Important in HFrEF?

Remember that the cumulative benefit is about 25% absolute risk reduction and 75% relative risk reduction with these therapies. We are talking about some big benefits which we do not give to the patient if we wait too long.

[00:47:55]

STRONG-HF: Uptitration of GDMTs for Acute HF

This is not opinion. There are actually data for that. STRONG-HF was a trial that basically was 3 steps. You come into the hospital. At the time of discharge, you are given 50% doses of the target dose. You come at Week 1, make sure everything is okay. And in Week 2, whoever could tolerate goes to the maximum dose. Just 3 steps.

[00:48:15]

STRONG-HF: Target GDMT Doses in High-Intensity vs Usual Care

This is a little bit of a complicated slide. But the bottom line is if you can read this, the use of RAAS inhibitor beta. This was a pre-SGLT2 inhibitor era trial. But if you can look at this rapid titration, how much more medication was given in terms of RAAS inhibitor, beta blocker, MRA.

[00:48:30]

STRONG-HF: All-Cause Mortality

That in 6 months post discharge was associated with 8% absolute and 34% relative risk reduction in the risk of dying or getting re-hospitalized. So there is something to be said about rapid uptitration as well.

[00:48:48]

Patient Case Revisited

Coming back to this case. You all sort of put in some of your opinions. What say you, Dr Gluckman?

[00:48:56]

Faculty Commentary

Dr Gluckman: Yes. I mean, I would just say I think you brought up a lot of great points. What I would say is 1 of the challenges is, and I do not fault an urgent care facility for trying to figure out how do I effectively triage this person. In our location, getting into cardiology is a month, 2 months, 3 months or longer, and there is a vulnerable period and an opportunity to your point of STRONG-HF, our data that we have from SOLOIST-WHF and from EMPULSE, getting people on therapy.

Again, this is 1 of those situations where this is staring you in the face. This is a heart failure patient, how do we complement what the urgent care facility did? And trying to get people on guideline-directed medical therapy as quickly as possible. You laid it out beautifully, though.

Dr Butler: Super. Well, I will hand it over to you from here on.

[00:49:39]

Missed Opportunities in Patient-Centered Care: Strategies for Managing Treatment Side Effects With Effective Counseling

Dr Gluckman: Awesome. That was a great setup. This last portion is really about practical application. So how do we put this all together? What are perhaps the pitfalls from a clinician or a patient perspective? And maybe some unanticipated things at least you should be aware of.

[00:49:54]

Patient Case Continued

I am going to represent this same case, but now a little bit further. Patient is not getting any better. It is now 4 days later and the patient has worse shortness of breath. This is after leaving urgent care. Two pillow orthopnea, continued weight gain. The exam findings are listed. Hypertensive, afebrile, heart rate 70 beats a minute, now hypoxic on room air. Moderate jugular venous distention, crackles extending a third of the way up their lung fields, pitting edema to his knees.

Echocardiogram shows severely reduced left ventricular systolic function. Left ventricular ejection fractions 25%. Substantially elevated NT-proBNP level. Not surprising, this patient is sent to the emergency department where he is admitted to the hospital. Started on an IV diuretic. Carvedilol is continued. Started dapagliflozin, an SGLT2 inhibitor, lisinopril, spironolactone. Discharged with planned follow up in 4 weeks.

Again, the hope is this patient has established with a cardiologist now in the acute care setting. But it is not unlike many of the scenarios is this is the time that they are meeting the cardiologist, in spite of the fact that, ideally, this person would have meant them weeks earlier.

[00:51:02]

          Poll 5

I am going to ask for a moment for you just to key in, what do you think now? Does this reaffirm a lot of the things that you have been thinking about? Please key in your answers.

[00:51:41]

Faculty Commentary

Dr Butler, any brief thoughts?

Dr Butler: Yes. Look, I mean, this whole cycle could have been stopped if the diagnosis was made early and the person could have been started on the therapy. The person has now been started on a pretty reasonable medical therapy. One can talk about dose titration. One can talk about moving from lisinopril to an ARNI, and what is the appropriate way to do this.

All I would say is that hopefully this person is on the right track from now on, but a lot of this could have been prevented.

Dr Gluckman: Yes. Well said.

[00:52:12]

          Patient Case Continued

He returns 4 weeks later, noting that he is been feeling more tired with frequent trips to the bathroom that is particularly bothersome to him. He reports some previous itching and discomfort that began a few weeks ago, self-treated with over-the-counter medication. He cannot recall the name. Despite these symptoms, he has not discontinued any medication because he believes that this regimen has helped with his diabetes.

On examination, you can see blood pressure markedly improved now. His oxygen saturation is great on room air. No signs of acute illness or volume depletion. Genital exam is deferred per patient preference. We can come back to that in a moment. And he has told to return back in follow up in 3 months.

Obviously not mentioned in all of this is how we are, as Dr Butler just said. How are we titrating these therapies? Because we know very well that it is not just about getting people on therapy, it is about getting people to target doses of therapies for which there is more than 1 dose.

[00:53:07]

          Poll 6

Just for a moment, anything that you would think about further for this patient that is going through your head at this moment? Please write in your answer.

[00:53:43]

          Concerns in Patients With and Without T2D When Using SGLT2 Inhibitors

Great. This is going to be followed now by some rapid fire discussion about some of the items that I suspect if patients have not brought up to you, they will. If your colleagues have not brought them up, your primary care clinicians. These are the things that practically we all get questions about.

It is about infection, hyperglycemia, euglycemic DKA. These are practical pearls hopefully that you will take away with you.

[00:54:06]

SGLT2 Inhibitors and GU Infections in Patients With HF

The reality, and this has been observed. You can see along the orange bar at the top here, these are the list of many of the trials that were covered by Dr Butler. But the risk for genital mycotic infection, urinary tract infection.

Patients with SGLT2 inhibitors should receive education about how to reduce the risk. There are some practical things that can be done, informing them and giving individuals that information. I find it helpful. I usually include it as part of an after visit summary or communicating. If it is through links or practical information, that people will just be given pearls for themselves to apply to mitigate that risk overall.

[00:54:44]

GMI and UTI Risk Factor Assessment Prior to Starting SGLT2 Inhibitors

A question that often comes up about this is what do you do if someone has an active infection as it relates to the initiation of an SGLT2 inhibitor, somebody develops an infection. Can I continue the SGLT2 inhibitor, or do I need to stop it?

If you start at the top, if someone is having an active infection or they are having recurrent infections, or these individuals have polycystic kidney disease really should not be initiating the therapy at that moment right now. After their acute infection has resolved, you can initiate therapy. Then in those individuals that are having recurrent infection in coordination with a specialist, most often a urologist, can help guide the decision making.

If they are not having any of these things listed in green, initiate the SGLT2 inhibitor while assessing and mitigating risks.

Now what happens under the circumstances in blue? You have initiated the therapy. They now develop a genital mycotic infection or urinary tract infection. If it is simple, it is uncomplicated, you treat through it. Treat through it from the standpoint of managing the infection, but continuing the SGLT2 inhibitor. In those individuals that are having complicated infections, stopping the SGLT2 inhibitor, addressing the infection, and then revisiting all together.

This is sort of a practical how do I deal with the issues, whether to start and then stop or whether or not in someone who has been started to treat through with an SGLT2 inhibitor, or to interrupt therapy to be revisited on the back end.

[00:56:13]

GU Infection Prevention With SGLT2 Inhibitor Use

Overall, putting it from the standpoint of an infection standpoint, raising awareness proactively. It is always more challenging on the back end to say, I wish I had been able to provide that instruction to you up front, but being able to manage expectations, provide information. As listed in the second graphic there or bullet point, it is really about providing practical hygiene advice both to the patients and their partners to prevent or mitigate that risk of genital infection, including advice about rinsing and drying the genital area after using the toilet and before going to sleep.

Topical treatments can be used for most, in particular genital mycotic infections. Then when candidiasis does occur, it is usually mild. It usually responds to treatment, does not require medication discontinuation. For those with recurrent infections, despite all the appropriate guidance, counsel by others is what at least I embrace.

[00:57:04]

Hypoglycemia Rates With SGLT2 Inhibitors in Patients Without T2D

What about hypoglycemia? We talked about beforehand that the benefits of SGLT2 inhibitors extend to individuals equally with and without type 2 diabetes, but in the presence of type 2 diabetes, is there a risk of hypoglycemia? In general, the trial data would suggest similar proportions of patients on an SGLT2 inhibitor and placebo in terms of the risk for hypoglycemic events. Those risk of events are very, very low.

In general, rates of hypoglycemia are not increased with those on an SGLT2 inhibitor, in those with heart failure, with or without type 2 diabetes. However, concomitant use of oral sulfonylureas and/or insulin may predispose to hypoglycemia. In those individuals with heart failure and obviously type 2 diabetes who are on concomitant therapy with an oral sulfonylurea or insulin, it is really in coordination with an endocrinologist or a primary care clinician, whoever may have initiated or are managing those therapies to stop the oral sulfonylurea back often the dose of insulin to avoid precipitating hypoglycemia.

[00:58:13]

Proposed Insulin and Other Diabetes Medication Adjustments When Initiating SGLT2 Inhibitors

This gives some practical guidance, at least in terms of those individuals who happen to have type 2 diabetes, again reinforcing that for most individuals not on these therapies with type 2 diabetes, and certainly in the absence of type 2 diabetes, we really do not see meaningful hypoglycemia in this patient population. If they have a history of hypoglycemia, reducing the dose of hypoglycemic agents.

The list of medications in that second blue rectangular box highlights those classes of medications for which there is a potential risk of hypoglycemia and should be looked to. In those with decreased levels of an estimated GFR, verifying the possible hypoglycemia by self-monitoring their blood glucose and if they are in fact hypoglycemic, adjusting the dose of those hypoglycemic agents. And in those individuals that may have hemoglobin A1Cs that are particularly well controlled, you may want to proactively reduce the dose of those hypoglycemic agents, knowing that you will get the added benefit of improved glycemic control with an SGLT2 inhibitor.

[00:59:18]

Ketoacidosis Concerns With SGLT2 Inhibitors

What about the risk of ketoacidosis? We talk about individuals with diabetic ketoacidosis that may exist in general, but there is an entity known as euglycemic ketoacidosis. For those that do not have particularly elevated levels of blood sugar, what are the symptoms that you should be watching out for? Because this is a red flag, this is an emergency and attention needs to be made as a result.

But those individuals presenting with confusion, nausea, excess thirst, difficulty breathing, vomiting, these may be indicators of ketoacidosis. It is a rare entity, but it is potentially life threatening. It is increased in prevalence amongst those individuals that have restricted food intake, severe dehydration, acute medical illness. Obviously, you start thinking about these in individuals who present with GI illness. They may be made by NPO or nothing by mouth.

These individuals may present with normal or only moderately elevated blood glucose levels. So do not be fooled into thinking that simply because their blood sugars are not through the roof, this patient is not experiencing ketoacidosis. If you think that this patient may have ketoacidosis, reflexively move towards an approach and prove otherwise that they are not having ketoacidosis. As a result, under those circumstances, with DKA markedly elevated blood sugars, euglycemic ketoacidosis, individuals should have their SGLT2 inhibitors stopped until you can actually more fully evaluate those individuals.

And as part and parcel of that, evaluating serum ketones to help detect these individuals who may have ketoacidosis.

[01:00:52]

Dosing Considerations in Patients With HF

Very quickly, dosing consideration. For most of these therapies, particularly dapagliflozin and empagliflozin, standard dose. It is very nice that it does not require dose titration. Sotagliflozin, you can see they are starting at the 200 mg once daily and titrating after 2 weeks if tolerated at a higher dose.

[01:01:10]

Diuretic Considerations With SGLT2 Inhibitor Use

What about diuretic considerations with SGLT2 inhibitors? In meta-analyses that have been done thus far, volume depletion occurs in the low to mid-single digits. We see it up to about 5% of individuals. In DAPA-HF, there was an excess of volume depletion in patients taking SGLT2 inhibitor, plus higher doses of oral diuretics.

For the most part, most individuals do not see a substantial predisposition to volume depletion. However, at higher doses of maintenance loop diuretics, you want to be attuned to this overall. For the most part, the dose of a loop diuretic may not need to be routinely reduced, but in individuals in whom they are on SGLT2 inhibitors, ARNIs, loop diuretics, it is important to recognize that these have synergistic effects, and concomitantly co-administering all these drugs can predispose to volume depletion. It happens infrequently, though.

[01:02:07]

Surgery Considerations With SGLT2 Inhibitors

What about surgery? Obviously, surgery is a situation where somebody comes in. They are often made nothing by mouth after midnight, or they may not have taken any food in for 6 hours. Depending upon what their recovery looks like, they may not be able to eat right away. So treatment in general should be interrupted, and monitoring of blood ketones is recommended for those individuals undergoing surgery, with restarting the SGLT2 inhibitor on the back end once the patient's condition has stabilized, blood ketone levels have returned back to normal and the patient is eating normally for at least 24 hours.

This generally applies to larger abdominal surgeries, bigger surgeries. I would say that for lower risk, more procedures that do not require much in the way of interruption, the plan can be adjusted accordingly.

[01:02:51]

When Should SGLT2 Inhibitor Therapy Be Paused?

When should SGLT2 inhibitors be paused? If they have acute serious medical illness, you are predisposed to intravascular volume depletion, you may not be taking in a lot thinking about the predisposition to ketoacidosis. They have a condition that leads to volume depletion or dehydration. They are not able to eat or drink normally. They have vomiting, diarrhea, fever. They have a major infection, including kidney infection. They may present with a fever. They are hospitalized for a major surgical procedure. These are all the scenarios under which temporary interruption is warranted.

[01:03:29]

General Patient Counseling Points for Possible Adverse Effects Related to SGLT2 Inhibitors

General patient counseling regarding the potential for adverse effects related to SGLT2 inhibitors. This highlights it nicely, really about genital or perineal hygiene. The potential for monitoring for orthostatic hypotension as a reflection of potential intravascular volume depletion, symptoms or signs of ketoacidosis, avoidance of excess alcohol use that can potentiate lots of these different effects, and then should always be held prior to surgery in coordination with whoever's doing the procedure, their primary clinician.

[01:04:03]

Financial Toxicity in HF Management

I could not go through a talk like this without recognizing that in heart failure, in general, there is the potential we obviously bring about polypharmacy, but the financial toxicity of being on lots of medications. I would say that there are a number of strategies to lessen financial toxicity on the right-hand side. We could have a talk for an hour onto itself about these. I do not want to short shrift the risks that all of us face in terms of challenges in interacting with patients about how to overcome some of these.

I would leverage these where possible, and broader access to some of our key therapies that we have in heart failure in a generic formulation will only make this easier in our conversations with patients.

[01:04:45]

          SGLT2 Inhibitors: The Ideal HF Therapy

I would submit that SGLT2 inhibitors are ideal heart failure therapy for many of the reasons that Dr Butler nicely outlined. Overall, single pill, most often taken without the need for dose titration, substantially improves survival, quality of life, functional status, helps to prevent the risk of hospitalization. Largely well tolerated and safe, with minimal effect on blood pressure. No renal adverse effects, rather renal protective, and to a large degree, affordable and accessible.

[01:05:12]

Patient Case Revisited

We are going to revisit our case. This is what we discussed previously. This patient comes back with some of these symptoms that are particularly bothersome. He has told to return in 3 months.

[01:05:24]

Faculty Commentary

Dr Butler, I know we already talked about this a little bit. Any final thoughts just for this patient?

Dr Butler: No, I mean I think you are very adequately covered it, but at the end of the day, the genital hygiene becomes really important. And if somebody is really peeing a lot, then maybe their glucose is not controlled. But as their glucose gets controlled, that goes down as well. But washing the area with water and keeping the area dry would substantially reduce the risk.

I mean, you would, at the end of the day, will run into 1 or 2 patients a year that will have so many recurrent UTIs and genital mycotic infections that they are unable to tolerate this therapy. But that usually occurs in like incontinence or older patients in diapers or whatever. But by and large, that should not be a reason that you cannot give the therapy.

[01:06:13]

          Posttest Assessment

Dr Gluckman: Really helpful. Thank you. We are coming to the end here and we have the post-test assessment. I am going to ask each of you to bring up your tablets. In addition to this on the back end, we are going to open it up for Q and A. We will ask you to type in your questions. We already have some coming in, but if there is specific questions as time allows, we will do our best to be able to handle those.

[01:06:32]

          Posttest 1

First post-test question. This is the same ones that you saw early on. So they should be well familiar. Which of the following is most indicative of early stage HFpEF?

1. Presence of mild ankle edema and elevated high sensitivity troponin I level;
2. Fatigue and exertional dyspnea with elevated NT-proBNP and soluble ST2 levels;
3. Orthopnea and cough with a normal natriuretic peptide level and an elevated CRP level; or
4. No abnormalities on physical examination, but an elevated galectin-3 level.

Please key in your answer.

[01:07:24]

          Posttest 1: Results

Awesome. In green, that is the correct answer. Saw a nice movement as a result of this.

[01:07:32]

          Posttest 1: Rationale

Again, I think this was nicely covered by Dr Butler earlier, recognizing that some of these biomarkers may be less familiar to some of you. Some of these are figuring out where to define their role, with really the natriuretic peptides being foundational biomarkers for evaluation of patients with suspected heart failure.

[01:07:54]

          Posttest 2

Question 2, I will go through this quickly. 62-year-old heart failure with reduced ejection fraction, type 2 diabetes, started empagliflozin in addition to GDMT, sacubitril/valsartan, carvedilol, and spironolactone. Three months of follow up symptoms and functional status have improved. He asks whether there is value in continuing the empagliflozin in long term, and whether it affords additional benefit beyond glycemic control. Which of the following summarizes the evidence regarding early but also sustained SGLT2 inhibitor use in heart failure treatment?

1. Sustained use of an SGLT2 inhibitor reduces heart failure hospitalization and cardiovascular mortality, as well as increased renal protection;
2. SGLT2 inhibitors reduce plasma glucose and blood pressure, but lacks sufficient data to support their use in patients with heart failure with preserved ejection fraction;
3. SGLT2 inhibitors are only indicated in patients with heart failure with reduced ejection fraction, with Class III to IV functional status, given their limited tolerability in patients with lesser degrees of functional limitation; or
4. Long-term SGLT2 inhibitor therapy improves left ventricular ejection fraction and improves mortality, but not hospitalization rates.

Please key in your answer.

[01:09:21]

          Posttest 2: Results

You all did such a great job beforehand. It is great to see we hit 100%, which is fantastic. I think Dr Butler did such a great job highlighting not just the early but the continued sustain.

[01:09:33]

          Posttest 2: Rationale

He nicely showed with his hands, what has been observed as trials end and seen within very short periods of time that all of the gains that were achieved during the trial unfortunately get lost by stopping the therapy. Again, an affirmation of the importance of long-term continuation.

[01:09:51]

          Posttest 3

The last post-test question. 72-year-old woman with a history of hypertension, CKD, estimated GFR of 42 mls per minute presents with exertional dyspnea. Class II functional status. Elevated NT-proBNP. Echocardiogram reveals an ejection fraction of 58%, moderate concentric LVH and left atrial enlargement. Which of the following is the most appropriate approach to incorporation of an SGLT2 inhibitor into her treatment plan?

1. Defer initiation of an SGLT2 inhibitor because she does not have type 2 diabetes or heart failure with reduced ejection fraction;
2. Avoid an SGLT2 inhibitor because her estimated GFR is less than 45, which is a contraindication to its use;
3. Initiate an SGLT2 inhibitor only if she develops Class III or IV functional status heart failure. Use in patients with lesser degrees of functional limitation is to be avoided; or
4. Start an SGLT2 inhibitor promptly, as it is recommended for patients with HFpEF and offers cardiorenal benefits even in non-diabetic patients.

Please key in your answer.

[01:11:16]

          Posttest 3: Results

I think we have to scroll down the page. If you could just scroll down for us. D is the correct answer. Again, great job. I know you all started with it, but for those that had gain of knowledge, appreciate it. Again, I think this is really nicely highlighted that those benefits extend across wide groups of individuals.

[01:11:45]

          Poll 7

I know we are going to move into a limited amount of time for Q&A, and so we will encourage you to type your questions. I have a polling question. My apologies. I am going to get in trouble if I do not ask these. Do you plan to make any changes in your clinical practice based on what you learn in today's program? Please key in your answer.

1. Yes;
2. No;
3. Uncertain.

Please key in your answer.

[01:12:17]

          Poll 8

Great. Now there is another part of this is, please type in what is 1 key thing that you plan to do as a result of tonight's program as it relates to your clinical practice?

[01:12:42]

Q&A

While you are typing that in, Dr Butler, I am going to key up to you and we will go back and forth with questions in the last 6 minutes here. But I am going to sit down. We did not have time for tonight. But you have done such a great job in the past. We highlighted that the patient's creatinine clearance was around 45. A question that probably is top of mind for a lot of people is, at what point do you get worried? We know it is indicated for chronic kidney disease. Is there a point at which you do not initiate an SGLT2 inhibitor based on renal function?

Dr Butler: Yes. Great question. If your GFR is all the way down to 20, you initiate based on evidence base. So in the heart failure trials we went down to GFR of 20. During that therapy, if it goes down to less than 20, no problem, continue.

It used to be said that by the time you go to end-stage kidney disease, then you stop it. When the kidney trials came out, even that was taken away and it was left to the clinicians. So if your GFR is less than 20, it is left to the clinician. There is no contraindication. There are trials going on in dialysis patients. They are going to come out next year. But it is entirely up to the clinician. But initiation is all the way down to 20. If it goes less than 20, no problem, continue.

This whole issue of 45 was related to the effect of glucose urea. But for heart failure, for CKD, no problem, you can go ahead and get started.

I will also just answer some rapid fire here because you are sort of running short on time, so maybe we can go back and forth. One question is, dapagliflozin is 5 mg and 10 mg and empagliflozin is 10 mg and 25 mg. When do you use those doses?

The 25 and the 5 mg, that is all about diabetes management. Nothing to do with heart failure or CKD management for those trials have been done with 10 mg. And that is the standard dose. With 25 mg, as you might expect, you may have a little bit more extra diuresis or whatnot. But clinically for heart failure, it is 10 mg dose, which is pretty standard.

There is another question here about what BNP level for diagnosis of heart failure? Again, if you look at the guidelines, it is NT-proBNP of 125 of BNP of 35, because BNP levels are much lower. Remember, normal BNP is in the teens. That is when the suspicion should go up.

Maybe I will take a third one.

Dr Gluckman: Yes. Just to say an elevated NT-proBNP or BNP suggests myocardial stress. By definition it is not all heart failure. Just to acknowledge there are other processes that one needs to think about in the right scenario.

Dr Butler: Yes, you can have aortic stenosis and it goes up. I mean exactly. Very true.

Dr Gluckman: Somebody from the audience asked a question virtually, I think, about CT angiography in heart failure. I would say echocardiography by far and away represents the mainstay of imaging in this patient population. That being said, if you are evaluating for ischemic heart disease, CTA can be useful, particularly in younger individuals. High negative predictive value can help to exclude obstructive coronary artery disease. Cardiac MRI and then invasive monitoring can be helpful as well.

Dr Butler: I completely agree. What else is here? Somebody is working outside in hot weather, the risk of dehydration. Yes. That is a concern in general. But by and large, the benefits are such that if a person has diabetes, and there is no particular concern about volume repletion, then I think if a person can drink and not necessarily miss out on the medication. In heart failure patients, that does come a little bit of an issue about dehydration and we try to cut down their dose of loop diuretics.

Again, easier said than done. But if at all possible, you are better off giving the medication and giving instructions to keep hydrated.

Dr Gluckman: Question about how long do you wait to resolve a urinary tract infection? Again, to reinforce, for genital mycotic infections and uncomplicated UTIs, you should be able to continue the SGLT2 inhibitor straight through. If in fact, you are just starting therapy and you want to begin an SGLT2 inhibitor, I would wait until those resolved. Usually, it is in terms of symptom resolution. It is not a certain number of days after completion of an antibiotic in the case of a UTI. But again, for most individuals with uncomplicated and they are on an SGLT2 inhibitor, interruption is not required.

A question that I get a lot in this regard is, your role increasingly for evaluating invasively, is there a role or how do we incorporate right heart catheterization? Is it more the exception than the norm in this patient population?

Dr Butler: Yes. If you are not concerned about something else going on like pulmonary hypertension or whatever, that is a different story. But by and large, NT-proBNP physical examination will give you the diagnosis, very good positive predictive value. And echocardiogram, you really do not need much more.

As I mentioned, negative predictive value is a little bit tricky. If you have ruled out other comorbidities and a person does not have really elevated NT-proBNP, then you are stuck. There is a BNP deficiency syndrome. Many of the obese patients may not have elevated NT-proBNP. So if you do not have any other diagnoses and NT-proBNP is not raised, that is where the right heart cath with some provocative measure, either leg raise or 500 CCs of saline infusion or something like that, and see what happens with pulmonary pressures can really help you with differential diagnosis. You can also do stress echocardiogram. There are some protocols for that as well.

Dr Gluckman: Another question that people have put up is, the role for remote patient monitoring. I guess the question is, do you use serial natriuretic peptides to guide decision making and treatment? And do you use whether it is measurement of intracardiac hemodynamics on an ongoing basis? And maybe briefly, if so, are there things that will guide you to that?

Dr Butler: Yes. There are really convincing data with CardioMEMS both in HFrEF and HFpEF patients that if you know the patient's pressure and give appropriate medical therapy, not only diuretic, but optimize their other heart failure medication, that it can lead to improvement in outcomes. However, because it is relatively more invasive and relatively more costly, there are a whole bunch of other mechanisms that are being developed that percutaneously either through skin or minimally invasive subcutaneously. You can get the same parameters and can improve the outcome.

So all of those trials going on, but really good data with things like CardioMEMS and PA pressure monitoring overall in this population.

What was the second question?

Dr Gluckman: Whether or not you use natriuretic peptides on an ongoing basis to guide your titration of meds, etc..

Dr Butler: Yes. Natriuretic peptide-guided therapy, there have been some trials done. There is a whole lot of issues with those trials. The bottom line is that that is not recommended and that is not standard of care. But if you come into the hospital, yes, at the time of discharge, definitely for prognosis. If somebody is not doing well, then doing it and those things. But it is not something that you would want to do on a weekly, monthly basis, regardless of how the patient is doing.

Dr Gluckman: Great.