ReachMD

Transcript

Dr. Shah:
Hello, thank you for joining this Novartis-sponsored disease state presentation entitled “Heart Failure with Preserved Ejection Fraction: Current Perspectives and Opportunities to Optimize Care Surrounding Hospitalization.” My name is Dr. Sanjiv Shah. I am the Neil Stone Professor of Medicine, Director of Research for the Bluhm Cardiovascular Institute, and Director of the Heart Failure with Preserved Ejection Fraction, or HFpEF program at the Northwestern University Feinberg School of Medicine.

The presentation that I’m about to give is an unbranded disease state presentation and will include no mention of products or clinical trials by name. It is sponsored by Novartis Pharmaceuticals, and I am being compensated for my time.

The objectives of today’s presentation are to review the current perspectives on HFpEF, including disease burden, underlying pathophysiology, diagnosis, management, and clinical manifestations. I’m also going to discuss hospitalization as a pivotal point in the clinical trajectory of HFpEF. And, finally, I will provide practical guidance for identifying predictors of worsening heart failure and highlight strategies for optimization of care surrounding hospitalization.

First, let’s start with an overview of the types of heart failure: heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction. Heart failure with reduced ejection fraction, previously called systolic heart failure, is typically defined as an ejection fraction of less than or equal to 40%. The LV remodeling is eccentric, so there’s eccentric hypertrophy and LV cavity dilation. In addition, because of this, the LV mass to volume ratio is low. Global LV systolic function, and therefore ejection fraction, is often severely depressed, and the median age can be across the spectrum, but is typically younger than heart failure with preserved ejection fraction. It does not preferentially affect women, and although it is associated with comorbidities, it is not associated with comorbidities as much as heart failure with preserved ejection fraction, such that the prevalence of one or more comorbidities is lower.

Compare this to heart failure with preserved ejection fraction, which was typically previously termed diastolic heart failure. First of all, the ejection fraction has been variably defined, but the most recent guidelines suggest that the heart failure with preserved ejection fraction be used for an ejection fraction of greater than or equal to 50%, whereas heart failure with midrange or borderline ejection fraction is somewhere in the range of 40% to 50%. And, again, heart failure with reduced ejection fraction is less than 40%.

Here, the LV remodeling is often concentric. Now, the vast majority of patients have concentric remodeling, and a portion of these have concentric left ventricular hypertrophy, but not all of them, and that’s an important distinction. The LV mass to volume ratio is, therefore, high. LV systolic function based on global ejection fraction is typically normal or preserved, but LV systolic function, if we examine the longitudinal fiber contraction or systolic function of the left ventricle, is often mildly depressed. These patients are often older, they’re more often women than men, and the association with comorbidities is quite high.

For example, in some clinical trials, the prevalence of systemic hypertension is greater than 90%. Prevalence of diabetes, obesity, and chronic kidney disease are also quite high. And even though we typically think of coronary artery disease associated with heart failure with reduced ejection fraction, in heart failure with preserved ejection fraction the prevalence is still 50%, so it’s lower, but it’s still quite prevalent. And, of course, as I said earlier, the prevalence of comorbidities is quite high. Now it’s important to note that the LV cavity size of heart failure with preserved ejection fraction is typically normal. In some cases it will be decreased or small LV cavity, but the vast majority have a normal LV cavity size.

So, HFpEF is expected to become the most prevalent form of heart failure. First of all, it already accounts for approximately 50% of all heart failure cases. And evidence suggests that the prevalence of HFpEF relative to HFrEF is increasing at a rate or 1% per year.

Now, if we look at overall mortality and heart failure hospitalization, those rates are lower in HFpEF than in HFrEF, especially if we’re looking at outpatients, and especially if we’re looking in clinical trials. If you look here on the left side of the slide, the heart failure with reduced ejection fraction trials show that the mortality in HFrEF is quite high, and much higher compared to HFpEF in these clinical trials. In addition, the incidence of death and hospitalization are lower in heart failure with preserved ejection fraction, as shown on the right-hand side of the slide, in the bluish green bars. Whereas all-cause admission and non–heart failure admission are similar or higher in HFpEF, which goes along with the older age and higher number of comorbidities.

That said, when we look at after hospitalization, what happens after hospitalization for heart failure? Mortality and readmission rates are similarly high. So this graph shows that, basically, mortality, readmission — whether that’s cardiovascular readmission or heart failure readmission — it’s quite similar across the spectrum of ejection fraction in patients with heart failure based on 5-year outcomes in patients in the Get With the Guidelines Heart Failure registry, which is examining patients who are hospitalized with heart failure; thus, hospitalization really is an important marker in the journey of these patients, where we are compelled to intervene to improve their outcomes.

Now there’s an evolving paradigm for heart failure with preserved ejection fraction, as shown here. Heart failure with preserved ejection fraction was first described in publications in the early 1980s. And those publications really focused on diastolic dysfunction as the main pathophysiologic abnormality in these patients. As shown on the upper left, it was thought that these patients had a small left ventricular cavity, significant concentric left ventricular hypertrophy, and decreased LV compliance, as shown in the pressure volume loop to the left-hand side of the screen. Thus, their end diastolic pressure volume relationship was shifted up and to the left.

Now, however, in 2020, we realize, and have realized over the last 15 years, that heart failure with preserved ejection fraction, while definitely associated with diastolic dysfunction and a stiff LV cavity, is no longer just that. It’s really a systemic syndrome that not only involves the heart but the lung, the liver, the visceral adipose tissue, the kidney, and the skeletal muscle. And we now know that although there is concentric cardiac remodeling and ventricular and vascular stiffening, that there’s also a big component of a sedentary lifestyle, metabolic stress, and, of course, aging that culminate in the loss of cardiac, vascular, and skeletal muscle reserve and, therefore, result in the heart failure with preserved ejection fraction syndrome.

I’d like to stress on two things on this slide. First is sedentary lifestyle. It’s quite significant that in population- based studies, if we look at a sedentary lifestyle, it’s a much stronger risk factor for heart failure with preserved ejection fraction than heart failure with reduced ejection fraction.

It’s a similar thing with metabolic stress, so obesity, and especially visceral adiposity, is a much stronger risk factor for heart failure with preserved ejection fraction. And what’s thought is going on is that both the sedentary lifestyle and this metabolic stress is resulting in a systemic inflammatory milieu that then results in the heart failure preserved ejection fraction syndrome. Thus, there’s secondary myocardial damage occurring.

One of the challenging things about heart failure with preserved ejection fraction is there’s no easy diagnostic test. We can’t just do an echocardiogram and show that the ejection fraction is very low and diagnose the patient with heart failure. We can’t use a biomarker, even. BNP has shown to be, although helpful in diagnosis, can be — can be within the normal range or below a diagnostic threshold in up to 30% of HFpEF patients. So, there’s no biomarker, there’s no troponin, there’s no elevated LDL, so it’s very — been very difficult in some cases to diagnose patients with HFpEF.

And so, in the next few slides I’ll talk about two diagnostic scores. Now it’s important to note that this first score was really developed for patients in whom there’s dyspnea, and there’s a clinical question about heart failure with preserved ejection fraction. There’s no question about the diagnosis in a patient who has signs and symptoms of heart failure, an elevated B-type natriuretic peptide and a preserved ejection fraction onechocardiography. So, these are really reserved for patients in whom there may be breathlessness alone without overt signs of fluid overload, without an elevated BNP.

And in the study in which this was derived, all patients underwent invasive hemodynamic testing with cardiopulmonary exercise analysis at the same time. And so, it was really the gold standard to diagnose heart failure with preserved ejection fraction. And if patients had an elevated pulmonary capillary wedge pressure above 25 millimeters of mercury during exercise, that was diagnostic of the HFpEF syndrome.

So, these investigators found that the H2FPEF score really helped them diagnose patients, and this was validated prospectively in a separate cohort of patients.

So, what is the H2FPEF score? It’s very easy. It’s heavy, a BMI greater than 30; hypertensive, two or more antihypertensive medications; atrial fibrillation, either paroxysmal or persistent; pulmonary hypertension, PA systolic pressure on echo greater than 35; elder, so age greater than 60; and filling pressure, a Doppler echo E/e’ greater than 9.

Now, note that that E/e’ is different than our typical cut across that we use in the echo lab, but this study found that that threshold was best for this score. Now what’s great is that once these points are added up and the score is determined, the probability of HFpEF can be determined by the nomogram as shown here. Such that if you have an H2FpEF score of 0 to 1, HFpEF is unlikely, six or more HFpEF is likely, and if you’re between 2 and 5, additional testing is required.

Now let’s look at the next score, which is the HFA-PEFF score. This score was developed by expert consensus by the European Society of Cardiology Heart Failure Association. So, this was a group of experts who know a lot about HFpEF and have a lot of experience studying these patients. And they came up with an assessment that was based on their expertise and not based on a study per se.

So, what they did was they really devised this PEFF score. So, “P” is pretest assessment, “E” is echocardiographic and natriuretic peptide score, which I’ll get into. Three is functional testing in case of uncertainty, and three is F1, and four is F2. So that the last “F” in the PEFF score is the final etiology. And that’s really, really important because figuring out why this patient has HFpEF and if they have a rare cause of HFpEF is really important because that would be treated differently and the first step; the functional testing’s important, as we just talked about.

But let’s focus in on this “E.” That has been expanded, and although we’re not going to go into it in detail here today, what I like about that is it really uses multiple aspects of echocardiography and natriuretic peptide testing. So, it’s not just cardiac structure, but it’s also function, so things like PA pressure, filling pressures, and e’ velocity and — and longitudinal strain of the left ventricle, and then adds it to the natriuretic peptides. And natriuretic peptides’ thresholds are quite low and consistent with what we know about HFpEF today.

So, if you have a patient with dyspnea and you do the clinical evaluation and standard diagnostic tests, you then apply the HFA-PEFF score. And if it’s intermediate or high, you either do noninvasive or invasive diastolic stress testing, or go straight to the diagnosis and then determine the etiology.

There’s quite a bit of controversy in the literature about whether heart failure with preserved ejection fraction is truly heterogenous. Some are “lumpers” and talk about a single disease entity, whereas others are “splitters” and have thought that heart failure with preserved ejection fraction really consists of multiple syndromes. As a single disease entity, we must consider that there are commonalities in clinical presentation that have been observed. All patients with HFpEF by definition have reduced exercise tolerance and most have evidence of left ventricular diastolic dysfunction. And, of course, they have a preserved ejection fraction. And there has been a proposed unifying hypothesis that there’s a comorbidity driven systemic proinflammatory state that drives a series of events leading to myocardial remodeling and dysfunction.

On the other hand, some have argued that HFpEF is heterogenous and that there are multiple syndromes. Heterogenous pathophysiologic abnormalities, also older age of the patients, may indicate intersection of age-related changes with heterogenous pathophysiologic processes resulting in the syndrome. It is well known that patients with HFpEF display a wide spectrum of clinical phenotypes, and the results from large-scale clinical trials of HFpEF have been largely neutral. Finally, there is no universal animal model that has been identified that truly represents HFpEF.

Here’s some ways where we may classify the heterogenous HFpEF syndrome, which may assist in diagnosis and management. On the left is pathophysiologic classification. We’ve talked about diastolic dysfunction, longitudinal fiber systolic dysfunction in the left ventricle, coronary microvascular dysfunction.
There’s also endothelial dysfunction, abnormal ventricular arterial coupling, chronotropic incompetence, extracardiac causes of volume overload, autonomic dysfunction, arterial stiffness, pulmonary hypertension, and right ventricular failure. There’s also skeletal muscle dysfunction. So, there’s quite a bit of abnormalities that we now know are present in HFpEF, and in the individual patient these may predominate one over the other.

And so, it’s important to understand what the pathophysiologic abnormalities are that are present in the specific patient and target therapy towards that.

Then there’s clinical or etiologic classification, so there’s what we call garden-variety HFpEF associated with hypertension, obesity, diabetes, metabolic syndrome, and/or CKD.

Then there’s coronary artery disease predominant HFpEF. These patients typically have had multi-vessel percutaneous coronary intervention, coronary bypass grafting, or similar. There’s Afib predominant HFpEF.

Now, these patients don’t have a lot of the comorbidities or risk factors, but they have predominant atrial fibrillation, and they have a left atrial myopathy phenotype. There’s also right- sided heart failure–associated HFpEF or pulmonary hypertension HFpEF. And although it’s not as common as previously acknowledged, hypertrophic cardiomyopathy-like HFpEF does exist.

So, what is this? These are patients who phenotypically resemble hypertrophic cardiomyopathy but don’t have any genetic mutations, typically present when they’re much older than a typical genetic form of HCM will present.

There’s also multivalvular HFpEF. I know many of us have patients in our clinic who are in their 80s and 90s, are quite symptomatic, and have moderate aortic regurgitation, moderate mitral regurgitation, moderate tricuspid regurgitation. And you put all that together, you’ll get the HFpEF syndrome.

And then, finally, more rare types like the restricted cardiomyopathies, cardiac amyloidosis, which we’re recognizing more and more.

Current guideline-directed management of HFpEF focuses on symptoms and comorbidities. No treatment has yet been convincingly shown to reduce morbidity or mortality in patients with HFpEF. Thus, the goals are to alleviate symptoms and improve well-being and manage comorbidities.

There’s evidence that diuretics improve congestion symptoms, and this is consistent across the ejection fraction spectrum within patients with heart failure. The evidence that beta blockers, ARBs, mineralocorticoid receptor antagonists, or MRAs, and ACE inhibitors ameliorate symptoms is inconsistent in HFpEF based on the trials.

The 2017 ACC/AHA/HFSA focused update to the 2013 guideline added MRAs for consideration in appropriately selected patients to decrease hospitalizations. Comorbidities should be managed with therapies that attenuate symptoms without exacerbating heart failure.

Now we talked earlier about mortality in HFpEF. And as I said earlier, following hospitalization, mortality rate is quite high. The 5-year mortality rate, in fact, is greater than 50%. In some studies, it’s as high as 65%. And, in fact, this is why we call heart failure in general and HFpEF more malignant than more cancers, than most cancers.

Following hospitalization for HFpEF, this is really sobering statistics, as shown on the right. The in-hospital mortality is 2.4 to 4.9%, the 60- to 90-day mortality rate is 9.5%. And the 5-year mortality rate is up to 76%.

Hospitalization for HFpEF is common. First of all, multiple hospitalizations are common in HFpEF. Over a mean follow-up of 5 years, greater than 80% of patients with HFrEF or HFpEF were hospitalized one or more times. In addition, rehospitalization rates are high early after discharge and remain elevated. Nineteen percent of patients with HFpEF were rehospitalized within 30 days, and 66% of patients with HFpEF were rehospitalized within 1 year.

Identifying factors contributing to worsening heart failure is key. Eighty-one percent of patients hospitalized with heart failure have at least one precipitating factor that can be identified. Potential factors include acute myocardial ischemia, uncontrolled hypertension, atrial fibrillation and other arrhythmias, nonadherence with medication regimen, sodium restriction or fluid restriction, medications that increase sodium retention, excessive alcohol intake or illicit drug use, anemia, hyper- or hypothyroidism, acute infections, and additional acute cardiovascular diagnoses.

In addition, although we typically think of medications with a negative inotropic effect causing exacerbations of heart failure with reduced ejection fraction, they may also have an adverse effect and precipitate hospitalization in patients with heart failure with preserved ejection fraction, especially those who have longitudinal fiber contractile dysfunction.

Now, as you might expect, the signs and symptoms of worsening heart failure are generally similar in HFrEF and HFpEF. Signs and symptoms of congestion are the most common presenting clinical features at the time of hospitalization, and so dyspnea on exertion, peripheral edema, and rales is what we see, and that can occur in greater than 60% of patients regardless of their ejection fraction. The vast majority will have dyspnea followed by some indication of volume overload or weight gain.

Now given the importance of congestion, implantable hemodynamic monitoring devices may enable early detection of congestion and reduce the risk of hospitalization. So, changes in pulmonary artery diastolic pressure can be detected by implantable hemodynamic devices much ahead of a decompensation event. Compared with control patients who are not monitored in a large clinical trial evaluating an implantable hemodynamic monitoring device, patients with HFpEF who were monitored experienced vastly improved outcomes: a 40%, 46% relative reduction in the risk of heart failure hospitalization over 6 months, a 50% relative risk — relative reduction in risk of heart failure hospitalization over an average of 17.6 months, and a twofold or greater medication change based on pressure measurements over 6 months. So, what it showed was that when these pressures are elevated, their clinicians are acting on these, changing things, and getting out of the hospital.

And beyond the clinical trial, there have been further observational studies with these technologies showing that, really, in the “real world” (quote unquote), it really seems to be working quite well. And so, monitoring congestion, whichever way it can be done, whether it’s low tech or high tech, and acting on it, can really help prevent the patient from coming to the hospital.

In patients with HFpEF who are hospitalized with heart failure, the goals of hospitalization must focus on both immediate and long-term care needs. We often focus on the immediate care needs in the hospital, but the long-term care needs are equally important. The goal for the hospitalized patient include decongestion, the initiation, titration, and/or optimization of guideline-direct recommended therapies.

Importantly, we must evaluate the primary etiology of heart disease. It baffles me that when patients with HFpEF get hospitalized, oftentimes the knee-jerk reaction is for clinicians to throw their arms up and say that it’s diastolic heart failure, nothing can be done about it.

Well, would you ever imagine in heart failure reduced — with reduced ejection fraction, not looking into the etiology? We must evaluate for coronary disease. We must examine whether there are factors that are contributing to the syndrome, and of course, we want to rule out rare causes, or relatively rare causes, like cardiac amyloidosis. We want to identify all contributing factors of decompensation that can be managed. We, of course, want to manage comorbid conditions because these are often the things that exacerbate and lead to heart failure hospitalization.

And, finally, we want to identify barriers to care, limitations to postdischarge support and adherence, and patient education needs so we can determine prognosis for the patients at highest risk because we want to identify these high-risk patients who need closer follow-up.

In-hospital clinical trajectories can be identified with a thorough evaluation. So, I think a lot of this is common sense stuff. Determinants of their clinical trajectory, of course — how severe are their symptoms? How many clinical signs, and how severe are those clinical signs? What are their laboratory markers, like BNP or troponin? What are their complications? Are they there and what are they? We need to assess and treat their comorbidities.

Obviously, a patient with a lot of comorbidities that are active is going to be at much higher risk. And then we need to align their treatment with their goals of care.

And so, once we can kind of predict their trajectory and see how it’s playing out, they may be improving towards a target. They may be initially improving and then stalled, or they’re not improving or worsening.

So, if they’re improving towards the target, we need to continue towards decongestion. If on track to reach decongestion, we need to consider optimization of guideline-directed medical therapy.

Now I’ll make a note here. Oftentimes what happens in patients hospitalized with heart failure of any kind, but especially HFpEF, where there’s oftentimes concomitant chronic kidney disease, with diuresis the creatinine will go up. And oftentimes the knee-jerk reaction is to stop diuretics or even give fluids back. And the worst thing that can happen is the patient gets discharged inadequately decongested.

Here we need to remember that a vast majority of these cases is simply hemoconcentration. So, what’s happening is, as we remove fluid, creatinine is getting hemoconcentrated, and thus GFR, which is calculated based on creatinine, is going down. But, when in fact, the patient’s actually improving. If we look at other markers of hemoconcentration, such as the hematocrit, total protein, those are going up. That, those are additional signs of hemoconcentration.

If hemoconcentration is happening in the hospitalized heart failure patient, it doesn’t matter what happens to the creatinine, they’re going to do better. It’s in the patients who have true worsening renal failure without hemoconcentration due to some renal injury. Maybe they were on a nephrotoxic medication. Those are the patients that do worse. And that’s really, really important because oftentimes because of this creatinine bump, patients are not getting decongested fully. In fact, if I see one of my patients come into the hospital with a normal or relatively normal creatinine and they have HFpEF, I often think that they’re very volume overloaded because almost no patient with HFpEF will have normal renal function.

Well, let’s look at the gray and purple boxes. If you’re not getting better, or if you got better and the patient then stalled, we need to evaluate the current therapy, consider additional diagnoses, consider invasive hemodynamic assessment. And we need to consider advanced therapies, consider enrolling in a clinical trial, address prognosis with the patient and reassess goals of care at time.

I think that the current therapy is often diuretics, and often we are not using high enough doses of diuretics, we’re not using sequential nephron blockade; those are extremely important.

And we know that decongestion is the primary target of management, especially in HFpEF. This quadrant has been developed primarily for patients with heart failure with reduced ejection fraction, but we can take a look at it. There are occasional situations in which patients with HFpEF will be dry and cold, especially if they have a restricted cardiomyopathy; maybe they have amyloidosis, but by far, what we’re seeing is wet and warm and wet and cold. And these patients are at very high risk. Obviously, if they have HFrEF we know that, but HFpEF as well.

So, what are the clinical measures to determine whether decongestion has been achieved? Well, people have looked at a lot of different things. First of all, there are simple things. We want resolution of signs and symptoms of congestion, including all of those physical exam signs that are shown on the left-hand side of their slide.

But then there’s objective imaging, laboratory and hemodynamic measures. So, there are many echocardiographic measures, left and right atrial area or volume, E/e’ ratio, PA systolic pressure, IVC diameter. Of these, I think probably the best one to look at is IVC diameter. First of all, it’s the easiest to get reliably and, also, with handheld ultrasounds proliferating, this is something that increasingly will be able to be done at the bedside.

The problem with the E/e’ ratio is that it’s not really associated with filling pressures, and so it can be hard to interpret at times, often in the intermediate range. However, if it came down during the hospitalization, that can be helpful.

Hemoglobin or hematocrit levels can be helpful. If those are going up, that’s a good sign. Natriuretic peptide levels, if they’re going down, that’s a good sign. And when in doubt, I often will do invasive hemodynamics, especially in that recurrently hospitalized patient, because I want to make sure that when I think that they are adequately decongested, they are adequately, actually adequately decongested.

I’ll first start with an echo, but if I’m not sure, I will have a low threshold to do invasive hemodynamics. We don’t want to send them home until they’re properly decongested.

Now, this is a really interesting slide, although we don’t have data from randomized clinical trials, if guideline-directed medical therapy is given to these patients with HFpEF they, just like HFrEF, have improved outcomes.

If you can see on the right-hand slide, the hazard ratio was 0.7, although it crosses 1, so it wasn’t statistically significant like we saw in heart failure with reduced ejection fraction; but, clearly, some patients with HFpEF improve. And if these therapies are discontinued, patients worsen, as shown in the bottom right.

So, you know, I think that it’s important to note that we’re still trying to figure this out, but there’s clearly a subset of patients with HFpEF who seem to benefit from these drugs. And I would really zero in on those patients with heart failure with midrange EF, patients with heart failure with preserved ejection fraction who have very impaired longitudinal strain indicative of significant LV systolic dysfunction. I would think about patients with significant multivessel coronary disease, ischemic heart disease. Those are the patients that I think will often be on these medications already and will benefit with keeping them on them.

So, it’s really important that as more therapies come out, we need to use these guideline-directed medical therapies and, hopefully, we’ll have more guideline-directed medical therapies and maybe even some device-based therapies for HFpEF in the future.

So, in summary, HFpEF accounts for 50% of heart failure cases and is increasing in prevalence. HFpEF is a heterogenous syndrome, and emerging classification systems may facilitate diagnosis, therapeutic targeting, and management. Hospitalization is a pivotal point in the clinical trajectory of the HFpEF patient and has considerable prognostic impact. Remember that after the hospitalization for heart failure, the survival of HFpEF and HFrEF are equal, and they’re equally bad — more malignant than cancer.

Close monitoring of worsening HFpEF and early recognition of symptoms that are leading to congestion is key in mitigating adverse outcomes. And, finally, assessment or the in-hospital clinical trajectory, decongestion, and optimization of guideline-directed medical therapy are key goals for hospitalized patients with HFpEF. 

Thank you very much.