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Modernizing the Management of Heart Failure: Implementation Is Critical to Success

  • Authors: Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC; Gregg C. Fonarow, MD, FACC, FAHA, FHSA; Muthiah Vaduganathan, MD, MPH; Ewa A. Jankowska, MD, PhD, FESC
  • CPD Released: 9/13/2022
  • Valid for credit through: 9/13/2023
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  • Credits Available

    Non-US Physicians - maximum of 0.75 CPD

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Target Audience and Goal Statement

This educational activity is intended for an international audience of non-US cardiologists and primary care physicians.

The goal of this activity is that the learner will be better able to incorporate the latest data and evidence-based guidelines on HF therapy, including use of sodium-glucose cotransporter 2 (SGLT2) inhibitors, into patient management.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Clinical data for early initiation of HF therapies
  • Have greater competence related to
    • The early initiation of HF therapies
    • Use of SGLT2 inhibitors for patients with HF across the spectrum of left ventricular ejection fraction


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  • Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC

    Senior Consultant Cardiologist
    National Heart Center
    Professor of Medicine
    Duke National University
    Singapore, Singapore


    Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC, has the following relevant financial relationships:
    Consultant or advisor for: Abbott; Actelion; Alleviant Medical; Allysta Pharma; Amgen; AnaCardio AB; Applied Therapeutics; AstraZeneca; Bayer; Boehringer Ingelheim; Boston Scientific; Cytokinetics; Darma Inc.; EchoNous Inc; Impulse Dynamics; Ionis Pharmaceutical; Janssen Research & Development LLC; Merck; Novartis; Novo Nordisk; Prosciento Inc; Radcliffe Group Ltd.; Roche Diagnostics; Sanofi; Siemens Healthcare Diagnostics;
    Research funding from: Bayer; Roche Diagnostics
    Patent beneficiary of: US Patent No. 10,702, 247 Automated clinical workflow that recognizes and analyses 2-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction and prognosis of heart disease
    Stock options from:
    Owns stock (privately owned) in:
    Other: Co-founder and Non-executive Director of


  • Gregg C. Fonarow, MD, FACC, FAHA, FHSA

    Eliot Corday Professor of Cardiovascular Medicine and Science
    David Geffen UCLA School of Medicine
    Director, Ahmanson-UCLA Cardiomyopathy Center
    UCLA Medical Center
    Los Angeles, California, United States


    Gregg C. Fonarow, MD, FACC, FAHA, FHSA, has the following relevant financial relationships:
    Consultant or advisor for: Abbott; Amgen; AstraZeneca; Cytokinetics; Egnite; Janssen; Medtronic; Merck; Novartis; Urovant

  • Muthiah Vaduganathan, MD, MPH

    Consultant Cardiologist
    Brigham and Women's Hospital, Division of Cardiovascular Medicine
    Harvard Medical School
    Boston, Massachusetts, United States


    Muthiah Vaduganathan, MD, MPH, has the following relevant financial relationships:
    Consultant or advisor for: American Regent; Amgen; AstraZeneca; Bayer AG; Baxter Healthcare; Boehringer Ingelheim; Cytokinetics; Lexicon Pharmaceuticals; Pharmacosmos; Relypsa; Roche Diagnostics; Sanofi
    Speaker or member of speakers bureau for: Novartis; Roche Diagnostics
    Research funding from: Amgen; AstraZeneca; Boehringer Ingelheim; Roche Diagnostics; Sanofi
    Other: Clinical Trial Committee for trials sponsored by Galmed; Novartis

  • Ewa A. Jankowska, MD, PhD, FESC

    Head, Department of Translational Cardiology and Clinical Registries
    Institute of Heart Diseases
    Wroclaw Medical University and University Hospital
    Wroclaw, Poland


    Ewa A. Jankowska, MD, PhD, FESC, has the following relevant financial relationships:
    Consultant or advisor for: AstraZeneca; Bayer; Boehringer Ingelheim; Cardiac Dimensions; Novartis; Respicardia; Servier; Vifor Pharma
    Speaker or member of speakers bureau for: Abbott; AstraZeneca; Bayer; Boehringer Ingelheim; Novartis; Pfizer; Servier; Takeda; Vifor Pharma


  • Anne M. Sendaydiego, PharmD

    Medical Education Director, WebMD Global, LLC 


    Anne M. Sendaydiego, PharmD, has no relevant financial relationships.  

Compliance Reviewer

  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance


    Susan L. Smith, MN, PhD, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Modernizing the Management of Heart Failure: Implementation Is Critical to Success

Authors: Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC; Gregg C. Fonarow, MD, FACC, FAHA, FHSA; Muthiah Vaduganathan, MD, MPH; Ewa A. Jankowska, MD, PhD, FESCFaculty and Disclosures

CPD Released: 9/13/2022

Valid for credit through: 9/13/2023


Activity Transcript

Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC: Hello, I'm Carolyn Lam, Senior Consultant Cardiologist at the National Heart Center and Professor at Duke National University of Singapore. Welcome to this program entitled, "Modernizing the Management of Heart Failure: Implementation is Critical to Success".

There have been an extensive amount of data published in the last 5 years on the management of patients with chronic heart failure (HF); several professional organizations have published new guidelines. In this program, the faculty and I are going to discuss how to best incorporate the latest trial evidence and guideline recommendations into the modern management of patients with HF.

In the first segment, Dr Gregg Fonarow will review some of the key data on HF management and how the data has affected guideline recommendations. In the second segment, Dr Muthiah Vaduganathan will discuss the role of ejection fraction (EF) classification with various HF therapies. In the third segment, Dr Eva Jankowska will discuss some of the barriers to appropriate HF treatment and how recent data has helped to address some of those barriers. Finally, in the last segment, I will be reviewing some clinical cases or case scenarios that highlight some of the key points that the faculty have discussed in the prior segments. So, here we go.

Gregg C. Fonarow, MD, FACC, FAHA, FHSA: Hello, I'm Gregg Fonarow and I'm delighted to present this segment entitled, "The Latest News in HF: Mandating A Modern Approach to Treatment".

HF has substantial mortality associated with it. This slide shows data looking at 1-, 5-, and 10-year survival. While there have been some recent improvements, mortality risk remains high. Despite the availability of therapy with established efficacy for heart failure with reduced ejection fraction (HFrEF), there remains very high residual risk. Thus, we need additional therapies that will improve outcomes.

The foundations of managing HFrEF, looking at the guidelines in 2013, were based on the use of angiotensin converting enzyme (ACE) inhibitor/angiotensin 2 receptor blocker (ARB) therapy, an evidence-based beta blocker, and a mineralocorticoid receptor antagonist (MRA), plus use of loop diuretics. However, patients treated with these therapies, while having a reduction in risk of mortality and HF hospitalizations, there remained residual risk. Fortunately, there have been therapeutic advances by which we can further improve on outcomes.

This data is from the PARADIGM-HF trial, which compared enalapril, an ACE inhibitor, to sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI) to see if ARNI could further improve clinical outcome. Despite high background use of beta blocker and MRA therapy, ARNI demonstrated significant reductions in the primary composite endpoint, cardiovascular (CV) death, and all-cause mortality. Thus, as this slide shows, beyond what could be achieved with an ACE inhibitor or ARB, the addition of neprilysin inhibition could double up on the CV mortality reduction. We could further and incrementally and actively improve clinical outcomes further.

We now have the sodium-glucose cotransporter-2 (SGLT2) inhibitors that have been demonstrated to not only have benefits in those with type 2 diabetes, but in HFrEF patients without type 2 diabetes to have similar benefits on CV death or HF hospitalizations, or other HF events, with no interactions and similar benefits with or without type 2 diabetes. We have the EMPEROR-Reduced trial that further confirm these benefits that were demonstrated in DAPA-HF. In addition, a meta-analysis shows in HFrEF patients on standard background therapy that SGLT2 inhibitors, specifically dapagliflozin and empagliflozin, could reduce CV death, hospitalizations for HF, but also importantly, all-cause mortality. Thus, we have a foundation of evidence-based and now guideline-recommended HFrEF medical therapies the incremental benefits or 2-year mortality without any of these therapies, 35% can reduce this mortality down to 9.1%. An important question though, is: what is the sequencing and timing of these benefits and how we should apply these therapies in practice.

What has largely been overlooked is how early the clinical benefits are with each of the foundational medical therapies for HFrEF; benefits within the first few days of initiation of beta blockers, of sacubitril/valsartan, of MRAs, and of SGLT2 inhibitors. The benefits of getting these therapies started simultaneously, or as soon as possible are profound, and additive, and incremental, but this also implies delaying any one or more of these key foundational therapies may lead to preventable hospitalizations, preventable CV deaths by virtue of unnecessary delays in therapy. We see further evidence on the timing of SGLT2 inhibitors being truly remarkable. Trial after trial showing the event curves diverging within a few days. It goes beyond just mortality and hospitalization reduction; health status improvements were seen very early on.

In-hospital initiation was evaluated in the EMPULSE trial in patients with acute HF. A large proportion of those patients in SOLOIST-WHF also demonstrated safety, as well as very early benefits. Significant clinically relevant benefits with the SGLT2 inhibitors. The benefits of simultaneously or very rapid initiation of sacubitril/valsartan, beta blocker, MRA, and SGLT2 inhibitors are truly multifaceted.

We can achieve rapid improvements in health status, improvements in ejection fraction (EF), reduction in hospitalization, rehospitalization, and mortality. Importantly, by starting therapy straight up, there's improved use, adherence, persistence, and we can overcome clinical inertia that often leads to delays as well; patients ultimately not being treated. There are tremendous and multifaceted benefits of this kind of early approach.

Guidelines have embraced this. This is from the European Society of Cardiology (ESC) guidelines, focused on the foundational therapies, which demonstrated reduced all-cause mortality in HFrEF, with an emphasis of these class I recommended therapies to start them as fast as soon as possible. Then once having done that think about additional therapies. The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of American (HFSA) guidelines also have an emphasis on the foundational therapies with sacubitril/valsartan being preferred. Renin angiotensin aldosterone (RAAS) inhibitors, beta blockers, MRAs, and SGLT2 inhibitors all have class I recommendations, specific guideline recommendations for in hospital initiation, for hospitalized patients to get these therapies started in all eligible patients.

Now what about heart failure with mildly-reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF)? We now have emerging data with regards to clinical benefits of the SGLT2 inhibitors. This is from EMPEROR-Preserved, a 21% reduction in risk in patients treated with SGLT2 inhibitor vs placebo, highly statistically significant. The top line results from DELIVER have also been announced and reported to demonstrate benefits. Now, two trials reporting to demonstrate benefits in this important patient population. We also have hints from PARAGON-HF and TOPCAT that MRAs and sacubitril/valsartan also have more modest benefits in this patient population.

The guidelines have evolved for patients with HFmrEF and HFpEF. The AHA/ACC/HFSA guidelines have a 2A recommendation for SGLT2 inhibitors and a 2B recommendation for MRA and sacubitril/valsartan. With regards to HFpEF, a 2A recommendation for SGLT2 inhibitors and 2B recommendation for sacubitril/valsartan and the MRAs. We now have important therapies for those with mildly-reduced and preserved EF in the guidelines.

As we think of the cumulative impact of our evidence based therapies, particularly with regards to HFpEF, the remarkable benefits that can be achieved in all-cause mortality is 73% relative risk reduction, 26% absolute risk reduction, with a number needed to treat to save a life of four. These are recommended in the guidelines with the highest class of recommendation class I level of evidence A, for improving clinical outcomes, including reducing all-cause mortality. There are compelling reason to apply these guidelines into clinical practice, to improve the outcomes for our patients with HF.

In summary, the approach to HF medications, the benefits are additive and incremental. No substantial overlaps have been demonstrated for any of the four key foundational evidence based therapies for HFrEF – the ARNI, evidence-based beta blocker, MRA, and SGLT2 inhibitor. The optimal approach is to utilize each medication demonstrated to reduce all-cause mortality in combination, so long as it is not contraindicated . It is critically important to start all without delay. A more serial or selective drawn out approach, unfortunately leads to delays and HF hospitalizations and CV deaths that could have been prevented with earlier use of guideline directed medical therapy (GDMT) use. Importantly, we now have ever-strengthening evidence regarding SGLT2 inhibitors improving outcomes in those patients with HFmrEF and HFpEF. Knowing a patient has HF can demonstrate the benefits of that patient being treated with an SGLT2 inhibitor. Thank you for your attention.

Muthiah Vaduganathan, MD, MPH: Hello, my name is Muthiah Vaduganathan and I'm a cardiologist and clinical trialist at Brigham Women's Hospital in Harvard Medical School in Boston, Massachusetts. It's a privilege to present this segment entitled, "The Approach to Heart Failure Management and the Role of LVEF".

Left ventricular ejection fraction (LVEF) is an integrative, but imprecise measure of cardiac function. We all know it has important limitations despite its widespread use. Its subject to significant inter-reader variability; the actual measurement of LVEF is highly operator-dependent and may even be physiologically load dependent based on afterload and preload conditions. Furthermore, the ejection fraction (EF) spectrum itself is a continuous function. However, we often apply specific cut points to categorize EF that may not be fully physiologic. The exact definitions of what normal EF may be is difficult to define at a population level for all individuals, predominantly because that definition of normal may vary, for instance, between men and women, such that women may actually have higher overall EFs at the population level.

Despite these limitations, the universal definition of HF, as well as contemporary clinical practice guidelines, and even regulatory labeling has embraced EF as a central measure to define and phenotype patients with HF. Specifically, the universal definition of HF puts forth 4 LVEF-based groups -- that is HFrEF, defined as an LVEF less than or equal to 40%; HFmrEF, defined as an EF between 41% and 49%; and HFpEF defined as an LVEF greater than or equal to 50%. Then there is a subset of individuals with improved EF; that is, previously reduced below 40%, but have subsequently improved either with time or with medical therapy to above 40% on a second measurement.

When examining the landscape of the HF population, we see that there's a tremendous distribution across the EF spectrum. In the United States, based on a recent examination of the Get With The Guidelines-Heart Failure registry, the largest ongoing registry of HF patients in the US, about 45% of individuals had an EF below 40%, so-called HFrEF. However, just expanding the bounds to include mildly-reduced EF, upwards of 50%, you encompass about 60% of the total HF population. Now, moving the bounds all the way up to an LVEF up to 60% and below, you encompass about 85% of the HF population. You can see that even at the very highest EF bounds, we have a large proportion of patients well represented. Providing clear guidance about how we should manage patients across the EF spectrum is of critical importance.

So why is LVEF critically important in guiding clinical decision making today for our patients with HF? First and foremost, guidelines, including the 2021 ESC guidelines and the 2022 AHA/ACC/HFSA guidelines, have specific recommendations based on LVEF categories, HF with reduced, mildly-reduced, and preserved EF, as well as for improved EF. That's based largely on how contemporary, as well as historical, trials have defined inclusion criteria, such that patients could only enter into the trials if they met those specific LVEF criteria based on a recent echocardiographic measurement. Secondly, clinical at risk tremendously varies across the EF spectrum. Specifically, the risk of mortality is highest among those with lowest EF and in stepwise fashion declines as you move up the EF spectrum. Furthermore, the mode of death of how patients may die also varies. For instance, the prominence of non-CV cause of deaths increases as you march up the EF spectrum. The risk of sudden death also declines as you move up the EF spectrum. Part of this heterogeneity in variation based on EF is based on the clinical profiles of individuals with low, mildly-reduced, and preserved EF, such as those at the highest end of the EF spectrum are generally older, have greater degree of comorbidities, and are more frequently women. The third and perhaps most important aspect is that our contemporary device and medical therapy decision-making today is determined based on EF. We know that implantable cardioverter-defibrillator (ICD) and chronic resynchronization therapy (CRT) eligibility, strongly determined based on ejection fraction guidelines, specify that implementation of GDMTs should be instituted subsequent proceeding repeat assessment of EFs before ICD and CRT decision making. Furthermore, we know that medical therapies, including the MRAs may vary based on EF. We know from the CHARM program, for instance, that the effects of candesartan were attenuated at the highest EF range. Additionally, we know from the MRAs data that there may be heterogeneity based on EF. We saw strong and consistent benefits in the reduced EF trials of beta blocker, more attenuated benefits as you move up the EF spectrum in the TOPCAT trial. With beta blockers, we have less substantial evidence in HFpEF. The wealth and majority of evidence exists in those patients with reduced EF. Finally, we've seen in the experience of the ARNI, sacubitril/valsartan, that the benefits of sacubitril/valsartan appear to be attenuated in those who have an EF above the median, which was the pre-specified cutoff. In fact, this evidence based on the PARAGON-HF trial was integrated into certain regulatory labeling, including the US FDA, such that the US FDA specified that the benefits of sacubitril/valsartan are most evident in those with LVEF below normal.

In contrast to these initial experiences of the neurohormonal antagonist and the ARNIs, we see that the benefits of the SGLT2 inhibitors are consistent across a broad EF spectrum, including among those with preserved EF. The EMPEROR-Preserved trial was the first unequivocally positive trial of HFpEF. A pre-specified pooled analysis across the EF spectrum of the EMPORER program showed relative consistency across most of the EF bins in this trial, except that very highest ejection fraction of an EF above 65%. A second, large-scale randomized clinical trial called DELIVER has recently been announced to be positive, at least in terms of top line results and has a pre-specified, second primary analysis looking specifically at an EF less than 60%. We'll learn a tremendous amount, more about a careful examination of the highest EF range and a pre-specified meta-analysis of the 2 trials, EMPEROR-Preserved and DELIVER, which will provide sufficient power to specifically examine this EF range.

In conclusion, LVEF is certainly an imprecise and imperfect measure, but it is an accepted standard to guide contemporary care. Not only does it provide powerful and important prognostic information to patients and clinicians, but it may actually inform the absolute and relative benefits of certain drug therapies. In practice, we can see that certain therapies may actually vary based on EF, including device therapies, as well as neurohormonal antagonist and the ARNI, sacubitril/valsartan. In contrast, other therapies, including diuretics as needed for congestion and the SGLT2 inhibitors, appear to have consistent benefits across the EF range. In practice, while assessing an initial patient, initially diagnosing a patient based on signs and symptoms of HF, even before an EF may be obtained, these therapies, SGLT2 inhibitors and diuretics as needed, may be implemented. However, echocardiography is still importantly needed. Not only does it in inform LVEF, but of course assesses other dimensions of cardiac performance, including valvular dysfunction, which may be a target of therapy, pulmonary hypertension, as well as assessment and signals towards other HF mimics such as amyloidosis and hypertrophic cardiomyopathy. For the present time, LVEF still remains the first and prioritized measure of HF status and guide contemporary decision making for drugs and devices. Thank you so much for your time.

Ewa A. Jankowska, MD, PhD, FESC: Hello everybody. My name is Ewa Jankowska. I am cardiologist and geriatrician working in Wroclaw Medical University. Welcome all of you to this segment entitled, "Overcoming Barriers to Optimal Heart Care".

We all already know that regarding the treatment of HF, we have 4 fundamental therapies -- RAAS inhibitors (eg, ARNIs/ACE inhibitors), beta blockers, MRAs, and SGLT2 inhibitors. For sure, these are drugs that should be started as soon as possible together with patients. This is emphasized in the latest (2021) European HF guidelines. The same philosophy is behind the latest (2022) American guidelines that emphasize the need to start as soon as possible even to gather these drugs. The reason behind that is that each drug is causing the reduction in HF hospitalizations and CV mortality, and the more drugs, the greater reductions and the risk of our patients.

This meta-analysis clearly shows us that the more drugs, regardless of the doses, when they have been administered, the greater reductions in CV death or hospitalization for HF, but also in the context of reduction of all-cause mortality. We also have very nice data coming from the paper, which used data from 6 major clinical trials in HF, which modeled the data that we're using these trials. Showing that if we start treating our patients quickly and try to implement the new groups of drugs quicker, then we can achieve greater benefits regarding the reduction for HF hospitalizations and CV death.

Another important problem in HF patients is HF hospitalizations, especially recurrent HF hospitalizations. This is a problem. There are some patients with HF who would have one HF hospitalization that immediately, and inevitably, would be followed by the next event. Please be aware that with more HF hospitalization, the shorter the gaps between subsequent HF hospitalizations. In other words, we need to be very quick regarding the implementing therapies that could reduce these events.

It has been emphasized and implemented in the European and American guidelines showing that life-saving therapies, whenever it's possible, are recommended to be started or restarted in patients who are hospitalized for the HF before discharge. The reason for this, there are data from some very important clinical trials. For example, the PIONEER-HF trial, in patients with acute HF and EF below 40%, clearly shows benefits regarding the reduction in B-type natriuretic peptide (BNP) in those who received this treatment. The treatment in this context was very safe. In the EMPULSE trial, in patients with acute HF regardless of EF, the composite endpoint of death, HF event frequency, time to HF event, and change in health-related quality of life (HRQoL) was significantly improved vs placebo. It was shown that starting an SGLT2 inhibitor when a patient is still in the hospitals is effective, but also safe. Finally, in the SOLOIST-WHF trial, in patients who have diabetes and also experienced a recent HF hospitalization, early starting of this drug brings a significant benefit vs placebo for patients. Last but not least, the AFFIRM-AHF trial, performed in patients with iron deficiency and a recent HF hospitalization, demonstrated a significant reduction in recurrent HF hospitalization and improvement in HRQoL when intravenous iron therapy is started before patients are discharged.

In addition to the trials, which have been executed in the more acute setting, we also have data coming from ambulatory trials, that support the early initiation of HF therapies. For example, in the DAPA-HF trial and the EMPORER-Reduced trial, which were executed in patients with stable HF, demonstrated that effects of launching SGLT2 inhibitors brings very early effects, seen within weeks, regarding the reduction in the primary efficacy endpoint.

One of the important barriers, which may be a barrier to starting the life-saving therapies, but also may cause many physicians to stop the treatments, are side effects. Different classes of drugs have different side effects, which to some extent may be common and may cause problems to patients with HF. If you look at the prevalence of the side effects, you can see that the most common are hyperkalemia, hypertension, the risk of renal impairment, among others.

With respect to starting these life-saving therapies, phenotyping patients with HF based on very simple, very simple clinical features, like blood pressure (BP), heart rate, the presence or absence of atrial fibrillation, renal function/hyperkalemia, or the presence of peripheral edema. These parameters, very simple and easily-measured during everyday clinical practice, can identify the plethora of different clinical patient profiles. Based on the patient profile, we can select which drugs can be started first-line started for our patients. For some of these drugs, like for example, SGLT2 inhibitors, the majority of phenotypes are suitable for these drugs. For example, SLGT2 inhibitors can be implemented both in patients who have low BP patients and those who have hyperkalemia, regardless of heart rate or presence of atrial fibrillation.

If we speak to how to keep this momentum and how to maintain the long term effects of our treatment, it's very important that the patient needs to feel that he or she's properly managed. There needs to be a proper long-term plan for the patient for the next years and a plan for how to achieve it. Patients should be included within multidisciplinary patient management system. It can be quite complex, but it can really be achieved, and patients may benefit from that. This is not about the drugs. It's about the devices, exercise rehabilitation, and it’s also about self-management by the patient himself. In many cases, the digital technologies, like telemedicine, can also be very helpful. In addition, it’s not just telemonitoring or telephone support that can reduce mortality or readmission rates. Even the simple nurse phone call can bring benefits in the context of this outcome measures to our HF patients.

In conclusions, I would say that we are at the very important stage now. We have great evidence showing that if we implement 4 fundamental therapies, life-saving therapies, to our patients, we can change the natural history for our patients. There are some barriers, but we need to be aware and there are tools to overcome them and something which I think is extremely important, is to consider our patients in the middle of the complex, but also easily achievable, system of comprehensive management. Thank you very much for your attention.

Dr Lam: Hello, I'm Dr. Carolyn Lam and welcome to this segment entitled, "What Changes Can I Make on Monday Morning?" As promised, I will be reviewing some clinical cases that highlight some of the key points that the faculty have discussed in prior segments.

Let's start with this first patient. It's a 70-year-old patient presenting with breathlessness and exertional intolerance in the clinical setting of the outpatient clinic, so this is an ambulatory patient. We've investigated that the patient has an EF of 30% and estimated glomerular filtration rate (eGFR) of 65 mL/min/1.73 m2. Her blood pressure (BP) is 80/55 mm Hg, although careful assessment shows that she is not symptomatic from the low BP. Her heart rate is 78 beats/min and regular. There's no atrial fibrillation and she does not have a history of coronary artery disease (CAD).

The question is, how would you adjust the medical therapy in such a patient that you see on Monday morning in the clinics? Let's remember what the guidelines say. It's basically been simplified in the 2021 ESC guidelines for patients with HFrEF, which this patient qualifies for; that is ARNI, beta blocker, MRA, SGLT2 inhibitors, and of course, loop diuretics. This is very, very similar in the 2022 AHA/ACC/HFSA guidelines where it again starts with the foundational 4 therapies, including diuretics for congestion. Easier said than done? I think so, because when we have this patient sitting in front of us with newly diagnosed HFrEF, how do we start these therapies? Do we put them all at once? Do we prioritize some over the other? Here I would like to propose that we view patients coming to see us in the clinic in a concept called the HF spending function. Me and some colleagues have written about it, where our role as physicians is to help patients spend from their reserve banks for the maximum return on investment. What is that bank? That is a bank of BP reserve, heart rate reserve, eGFR or renal function, serum potassium, and literally their bank of outpatient costs, as well as their tolerance for complexity of pharmacotherapy, because many of these patients are elderly.

What does it mean to maximize the spending, to maximize the return of investment? It means that in a case like this patient, clearly the reserve is lowest for the bank of BP. Her systolic BP is only 80 mmHg, whereas she's got a normal eGFR. We line up all the different banks and all the different types of therapies that we could initiate. It's clear that we will be most restricted by spending from BP. If you look down the list, you'll see that the medications and especially the foundational therapies that have the least effect on BP, or take away the least from this BP reserve bank, would be things like the SGLT2 inhibitors. Other proven medications, although not part of the quadruple foundational therapies, would be an agent like ivabradine.

If we put that together, I would say that in this particular patient, always start with what I call the ABCs of acute management. In other words, let's make sure this patient is not in impending cardiogenic shock. With a BP like that, make sure her peripheries are not cold and clammy and she's not super tachycardiac and about to collapse. That's the first thing. Next, let's never forget in any patient, regardless of whether we've seen them before or not, to search for a reversible cause. In this case, she does not have a history of CAD. However, perhaps we should line up some test, like coronary angiography, if she's got other risk factors to look for coronary ischemia that could be driving this HFrEF. It's very important to survey in the history for toxins, for potential infectious elements, all these other reversible causes. Then we come to the initiation of foundational therapies. As I said, since the SGLT2 inhibitors, to a certain extent the MRAs, are not so impactful on the BP, I would start those. She must be on a loop diuretic because she's clearly clinically congested. I would also reach for the beta blockers very cautiously. What I mean by that is really telling the patient the symptoms of hypotension to look out for. If we really think she's fragile, she may need some close monitoring in an inpatient setting while we initiate everything. However, the important thing to remember is that as we treat these patients’ congestion, very often the BP actually increases and that allows us then to add the other foundational pillars such as the ARNI, which can be added when the BP increases. A systolic BP less than 90 mmHg is a little bit too low for my liking to start an ARNI right off the bat. Then we need to monitor her closely; make sure she is responding to the therapies; make sure that she's not suffering any adverse effects; monitor her for any worsening and consider at a later stage, where after we've tried optimal medical therapy, if she could be a candidate for device therapies. That's 1 patient.

Now let's look at another patient. I'm going to just keep it very simple and say this patient has a similar profile, similar age, and similar presenting symptoms to the first patient, but this time she is being treated in a hospitalized setting. This time EF is 45%. BP is still low. How would we adjust the medical therapy?

Let's look at what both the latest ESC and AHA/ACC/HFSA guidelines say. You'll notice for this patient with EF in the mildly-reduced range of 45%, it is the same four therapies, only they have a class II recommendation vs. a class I recommendation.

We could just stop there and say perhaps it's all the same considerations, but I want to add to that the consideration that there are non-intrinsic EF reasons to start certain therapies. For example, SGLT2 inhibitors are class I recommendation by both guidelines to be used for the treatment of diabetes in patients with HF, and may I say HF regardless of EF. I'd also like to remind everyone that the EMPULSE study where SGLT2 inhibitors were initiated in decompensated or hospitalized HF patients after stabilization was performed in patients regardless of EF and with or without diabetes, and showed that patients benefited from empagliflozin initiated during the hospitalization. Furthermore, we have data from the PRESERVED-HF study where symptomatic patients with EF above 45% really benefited in terms of quality of life and six minute walk test when they were given dapagliflozin versus placebo. Putting all of that together, may I suggest that beyond looking at EF and the class II recommendations in patients with diabetes, I would be very comfortable to already reach out for an SGLT2 inhibitor and especially in those with an impaired quality of life.

How would I treat this patient? Very similar to the patient in the outpatient setting, the first thing is to make sure they're not impending cardiogenic shock. In addition, when that EF is reported as between 41% and 49%, please assess the EF and the echocardiogram yourself, if you could. Be very sure that there's no evidence of systolic dysfunction because if the patient has HFmrEF, it's very clear what needs to be done.

It's this middle ground. I would convince myself whether or not there's systolic dysfunction. If there is, I would be more inclined to using the foundational four therapies. Definitely search for treatable causes and here in the case of mildly-reduced and preserved EF HF, there is a strong emphasis, especially in the new AHA/ACC/HFFA guidelines, but also in the ESC guidelines, that we must look for and treat cardiac amyloidosis.

Another little catch when it comes to patients with EF above 40% is, where the EF came from really matters. If this is a patient who somehow had a history of a lower EF in the past that was below 40%, this is now a patient with improved EF. In these patients, it is very important that we continue the GDMTs; even if the patient is asymptomatic, we should continue. The TRED-HF study showed us that withdrawal of these therapies leads to relapse of the symptoms and a reduction in EF.

Let's go on to a last case. This is a common garden-variety case of a patient hospitalized with worsening HFrEF. This time, the patient is a little bit older. We're talking about a hospitalized, but pre-discharge setting, so not the acute decompensated emergency department with acute pulmonary edema setting, but just pre-discharge. Here we see that the eGFR is 38 mL/min/1.73 m2; his potassium is 5 mmol/L; BP is 130/80 mm Hg. How would we choose therapies in this case?

While going back to the spending function, this time the limiting banks are eGFR and serum potassium. I think here I want to really emphasize that guidelines really give very nice guidance on what to do if there is worsening renal function or hyperkalemia. One of the main messages to reinforce is that we should not be withdrawing all therapies as a knee-jerk reaction. Yes, this is bordering on the cutoff of an eGFR of 30 mL/min/1.73 m2, for example, below which the RAAS blockers may be contraindicated. He is bordering on a potassium above 5. However, there is every hope that we can persist with trying to keep these patients on these life-saving medications when it's, in this case, an eGFR of 38 mL/min/1.73 m2 and a serum potassium of just at that border of five. We really owe the patient that. Examine the patient's diet. Do they need to stop taking a high potassium diet, for example?

Please remember that another reason to carry on quadruple therapy is that the medications actually enable tolerance of each other. For instance, SGLT2 inhibitors and ARNI have the ability to enable MRA use by reducing the incidence of hyperkalemia.

Also, it is very important to embrace what we heard in the earlier segment that pre-discharge, it's now a class I recommendation that we optimize the evidence-based medical therapy in patients. We're not just going to kick them out with more diuretics. We really want to try to optimize the background GDMT before they leave the hospital. This is very consistent in both the European and American guidelines.

When we say optimize, what does that mean? I try to keep it simple. Javed Butler and I tried to come up with a 5/4/3 rule, which is remember that there are 5 pathways to block the angiotensin, norepinephrine, aldosterone, neprilysin, and SGLT2 pathways. These 5 pathways can be blocked by 4 drugs, which are the ARNI, beta blocker, MRA and SGLT2 inhibitors. Then there are 3 other mediations that you consider if this patient is suitable for -- ivabradine if there is normal sinus rhythm and the heart rate is still above 70 beats/min; hydralazine or isosorbide dinitrate if this is a self-identified black patient; and vericiguat if this is a worsening HF event. Those are the 5/4/3 considerations.

In summary, what would I do for this patient? First of all, I would bravely try to continue the SGLT2 inhibitor, ARNI, beta blocker, MRA, and diuretic. I would watch potassium closely. I'd advise the patient, "don't go and have a big load of bananas," for example. Be very careful of their diet. I would indeed consider if the potassium goes above 5.5 mmol/L the need to down titrate first, or even potentially suspend MRA and ARNI if potassium keeps going higher. I would be already considering adding the other medications, things like ivabradine, vericiguat, or even a potassium binder to enable the life-saving therapies to be continued. Finally, importantly, pay a lot of attention to the transition from the hospital to the outpatient setting and multidisciplinary team care; things like cardiac rehabilitation and the management of comorbidities and precipitating factors, all of which are also emphasized in the guidelines.

I hope the discussion of these 3 cases have really helped to bring to life the segments that we heard earlier and have indeed made you feel more confident and perhaps even enthusiastic about starting Monday, seeing patients and helping them.

I would like to thank Gregg, Muthu, and Eva for participating in this program and providing their unique insights, and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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