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Welcome to ReachMD.

This medical industry feature, titled “Conversations With Cardiologists: A Paradigm Shift, It’s Time to Switch,” is sponsored by Novartis Pharmaceuticals Corporation, which participated in the review of this content. This program is intended for US health care professionals.

The Important Safety Information for ENTRESTO^®, or sacubitril/valsartan, will be available at all times underneath the player of this audio presentation. Please see full Prescribing Information, including Boxed WARNING and Patient Prescribing Information accompanying this podcast or at www.ENTRESTO.com.

The speakers have been compensated by Novartis Pharmaceuticals Corporation to conduct this presentation. Here’s your host, Dr Jennifer Caudle.

Dr Caudle:

Heart failure is a continuous progressive disease affecting approximately 6,000,000 patients in the United States. Even if patients seem stable, their underlying disease may be progressing. So, the question we want to answer today is: How do you know when it’s time to switch heart failure therapies? This is ReachMD, and I’m your host, Dr Jennifer Caudle. And joining me to discuss when it’s time to switch heart failure therapies in patients with heart failure and reduced ejection fraction, or HFrEF, are two leading cardiologists—Dr Javed Butler and Dr Stephanie Saucier. Dr Butler is the President of Baylor Scott and White Research Institute, Senior Vice President of Baylor Scott and White Health, and Distinguished Professor of Medicine at the University of Mississippi Medical Center. Dr Butler, thanks so much for being here today. 

Dr Butler:

Delighted to be here. Looking forward to the discussion. 

Dr Caudle:

Well, thank you. And Dr Saucier is the Director of the Women’s Heart Wellness Program at Hartford Hospital and Medical Director of the Cardiac Rehabilitation Center for the Hartford Region at the Hartford Hospital and Hospital of Central Connecticut in New Britain. Dr Saucier, it’s great to have you with us. 

Dr Saucier:

Thank you, Dr Caudle. I’m excited to be here with you. 

Dr Caudle:

Well, we’re excited for both of you to be here. Thank you both. So, I’d like to come back to the question we started with, which is: How do you both determine when it’s time to make a switch in your HFrEF patients’ therapies? Dr Butler, I’d like to start with you. Can you provide the audience with a historical perspective on the treatment of HFrEF? 

Dr Butler:

Yeah, very happy to do that. So, you know, if you sort of look back at the development of therapies for patients with heart failure and reduced ejection fraction, you know, up until the mid-1980s, late 1980s, all we had was digoxin and diuretics. They were good therapies for improving symptoms, but these patients are at an extraordinarily high risk for mortality and hospitalization. Now, what we realized at that time that, interestingly enough, the primary cause that led to development of HFrEF is actually how the body reacts to the development of heart failure, which is related to the neurohormonal changes that the body goes through. So, in reaction to a fall in ejection fraction, you have neurohormonal activation, and that neurohormonal activation in the long run actually determines further progression of heart failure. So, once we realized that, that was sort of a golden era of developing heart failure therapies – ACE inhibitors and beta blockers and MRAs – and we modulated the neurohormonal system in multiple different ways, and really multiple trials positive for improving in mortality and morbidity for these patients, but then we hit a ceiling; and then we tried some other medications like endothelin receptor blocker and vasopressin antagonists, some other neurohormonal modulators, and really they were not improving outcomes any further, but at that time we also realized that Mother Nature has good neurohormones. These are a bunch of vasoactive peptides like ANP, BNP, CNP, adrenomedullin, etc, except, that they are metabolized pretty rapidly by the body, and they are not in enough concentration to completely counteract the bad neurohormones. So, that’s where we developed this concept of not only attenuating the bad neurohormones but accentuating the good neurohormones, and that’s where valsartan/sacubitril comes into play because sacubitril is [a] neprilysin inhibitor, and neprilysin is the enzyme that metabolizes these good neurohormones. So, by inhibiting this neprilysin, you increase the half-life of the circulating good neurohormones and bring that balance, and that’s where sort of ARNIs were born, and then we have multiple clinical trials – we’ll discuss those results. So, that’s how our thought process has sort of evolved in the management of heart failure, and now you’re looking at therapies that are not particularly related to modulation of [the] neurohormonal system, for example, things like SGLT2 inhibitors; but today we’ll be focusing more on ARNI and neurohormonal modulation – both attenuation and accentuation of various, different neurohormones. 

Now, before we continue, I think it’s a good time to let our listener[s] know that ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalizations for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction, or LVEF, below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat. Also note that ENTRESTO has a boxed warning for fetal toxicity. If a patient becomes pregnant, ENTRESTO should be discontinued as soon as possible, as drugs that act directly on the renin-angiotensin system can cause injury or death to the developing fetus. There are important contraindications you should keep in mind. ENTRESTO is contraindicated in patients with hypersensitivity to any [component]. ENTRESTO is contraindicated in patients with [a] history of angioedema related to previous angiotensin-converting enzyme inhibitor (ACE inhibitors) or angiotensin receptor blocker therapy. ENTRESTO is contraindicated with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor. ENTRESTO is contraindicated with concomitant use of aliskiren in patients with diabetes. Please note additional Important Safety Information will be provided throughout this podcast. Full Prescribing Information, including Medication Guide, is available below this presentation. 

Dr Caudle:

Thank you for that. And Dr Butler, you mentioned that cardiologists were excited to have this therapy for their HFrEF patients. Can you describe what made this product unique?

Dr Butler:

So, the community was really excited about this therapy for a whole bunch of reasons. So, first, we have now a new class of drug, if you may. Remember that sometimes we have a tendency to lump ARNI with other RAS inhibitors, and we sort of commonly say, “ACE, ARB, or ARNI,” but ARNI is a completely different molecule. It’s a combination of two drugs. So, this is really a replacement strategy that makes it unique. You know, our heart failure patients, just for their heart failure, take multiple medications; and then there are multimorbid patients who they – you know, polypharmacy is a big issue in our patients, so another reason why this is unique is that it is replacing the standard of care with a new standard of care without increasing the polypharmacy or the pill burden for our patients because you’re replacing one therapy with another therapy. So, we have a new class of drug that has been shown to improve outcomes that we can think about – mortality [and] morbidity. 

Dr Caudle:

Dr Butler, thank you so much for that historical perspective. You know, Dr Saucier, the 2022 AHA/ACC/HFSA Heart Failure Guideline had some recommendations for the use of ENTRESTO in patients with stage C, New York Heart Association Class II to III HFrEF. Can you provide an overview of those recommendations? 

Dr Saucier:

Absolutely. The 2022 guidelines were really exciting, and they made a Class 1A recommendation that patients with HFrEF stage C New York Heart Association symptom Class II to III not already on an ACE inhibitor or an ARB be started on an ARNI to reduce that morbidity and mortality that Dr Butler was mentioning before. These guidelines also made a very exciting update to past guidelines that in patients who tolerate and already are on ACE inhibitors/ARBs should be switched to ENTRESTO. The guidelines comment on the initiation of ENTRESTO, and this supports the fact that we should be initiating ENTRESTO as soon as possible and [as] safely as possible. Keep in mind that patients who are already on an ACE inhibitor require a 36-hour washout period to initiation of ENTRESTO and that ENTRESTO cannot be used in addition to an ARB. It’s also important to note that ENTRESTO should not be administered to patients with a history of angioedema, and that’s what the 2022 AHA/ACC/HFSA [HF] guidelines recommend in terms of initiation of ENTRESTO. This is going to be one of the four main pillars that the 2022 guidelines recommend. 

Dr Caudle:

And I’d like to talk a little bit about this idea of a HFrEF patient being stable. Dr Saucier, could you talk about what that means to you? 

Dr Saucier:

I think that “stable” is really misleading. Chronic heart failure with reduced ejection fraction is a chronic, progressive disease, and, you know, there’s no real clear definition of the term stable when we’re discussing heart failure patients. It’s really important that the patients’ treating physicians, health care team, family, and the patients’ own interpretation of their functional status really [play] a key role in assessing what someone may or may not consider stability but I really want to stress the importance that there’s no true stable heart failure patient. In reality, it’s not so simple. Chronic heart failure, again, is progressive. Patients may adjust their daily life and adjust their activities to prevent themselves from having symptoms. So, it’s really key to look at your patients and to dig deep and to see if they truly are having progression of symptoms, and that way you can get them on guideline- directed medical therapy and optimize guideline-directed medical therapy regardless of if patients are having progressive symptoms or, quote unquote, stable symptoms. It’s really important to optimize all of these therapies for their patients. 

Dr Butler:

You know, Dr Saucier makes such an incredibly important point, and I really want to expand on that a little bit. We should really not use the term stable heart failure at all, because there is no such thing as a stable heart failure. Even on medical therapy, there’s a substantial residual risk, and then there is sort of this inadvertent notion that when we say, “a stable heart failure”, as if we don’t need to optimize medical therapy. I think as cardiologists, it is our job to optimize therapy across the entire spectrum of risk for these patients. So, maybe I should just wait for this person to get worse, and when they come into the hospital, I will initiate therapy, right? This will be completely antithetical to the way we think about practicing medicine. Our whole idea is to prevent worsening disease – not wait for worsening disease before we initiate the therapy. 

Another fallacy in this notion of stable heart failure is that, you know, sometimes we say that we will wait for symptoms to get worse before we initiate the therapy, but remember, patients with heart failure are at a particularly higher risk of sudden cardiac death, and in a large proportion of patients, this sudden cardiac death occurs before the patients get hospitalized, so we may not get that opportunity. So, the time to optimize medical therapy is actually today, but then if somebody does get hospitalized, please realize that these patients are at a particularly higher risk, and now the guidelines are giving a pretty strong recommendation that guideline-drive[n] medical therapy should be initiated in the hospital predischarge, and if, for whatever reason, if it cannot be achieved, soon thereafter the discharge, that these therapies should be given. So, it’s really critical, to reduce the risk of hospitalization and mortality. Therefore, optimizing therapy in these patients across the spectrum before, during, and after hospitalization—whenever we get the opportunity—is really critical. 

Dr Saucier:

Dr Butler makes such an incredible point. The strong recommendations that we’re giving here in terms of switching patients from their ACE inhibitors and ARB over to ENTRESTO is supported by the clinical data from the landmark PARADIGM-HF trial, which showed that there was a significant reduction in cardiovascular death and heart failure hospitalization by 20%, and that’s relative to enalapril. I know Dr Butler’s we’re going to chat about this a little bit later, but it’s important to recognize where these strong recommendations come from. 

So, I think before we review the clinical data, this is a good time to discuss more of the ENTRESTO Important Safety Information. So, ENTRESTO may cause angioedema, and when associated with a laryngeal edema, this can be fatal. ENTRESTO has been associated with a higher rate of angioedema in Black patients and in patients with prior history of angioedema. Therefore, ENTRESTO really should not be used in patients with hereditary angioedema. If angioedema occurs, it’s important to discontinue ENTRESTO immediately, provide appropriate medical therapy, and monitor for airway compromise. ENTRESTO must not then be re-administered. 

Clinicians should also be aware that ENTRESTO lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume depletion, salt-depleted patients – these patients are at greater risk. So, it’s important to correct volume and salt depletion prior to administration of ENTRESTO or start at a lower dose and up titrate as tolerated by the patient safely. If hypotension persists despite dose adjustment of diuretics, concomitant antihypertensive medications, and treatment of other causes of hypertension, such as hypovolemia, make sure to reduce the dosage of, ENTRESTO, or you can even temporarily discontinue it. Permanent discontinuation of therapy is usually not required. 

Decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO. Those are patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system, so patients with severe congestive heart failure, treatment with ACE inhibitors and angiotensin receptor antagonists, have been associated with oliguria, progressive azotemia, and very rarely acute renal failure and death. So, it’s important to monitor serum creatinine and down-titrate or interrupt ENTRESTO in patients who develop clinically significant decrease in renal function. ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, make sure to monitor renal function. Avoid use with aliskiren in patients with renal impairment, and those are patients who have an eGFR of less than 60 milliliters per minute. 

In patients who are elderly, volume depleted, those on diuretic therapy, or who have compromised renal function, use of non-steroidal anti-inflammatory drugs, including COX-2 inhibitors, with ENTRESTO may result in worsening renal function, including possible acute renal failure. These effects are usually reversible, and it’s again very important to monitor renal function periodically. This information is not comprehensive. Please see full Prescribing Information, including Boxed WARNING and Patient Prescribing Information accompanying this podcast or at www.ENTRESTO.com 

Dr Caudle:

Dr Saucier, thank you for that overview. Dr Saucier, you mentioned that ENTRESTO has a lot of clinical data. Dr Butler, can you share some of the key data for those that may not be as familiar? 

Dr Butler:

Yeah. I mean, there’s a lot of data with ENTRESTO, so let me try to briefly recap some of the important points here. So first, the main trial that really established ENTRESTO as a standard of care for patients who have HFrEF was PARADIGM-HF. Now, the first thing to realize about PARADIGM-HF that this was not a placebo-controlled trial but it was actually comparing ENTRESTO to enalapril, the standard of care in patients with HFrEF. So, this was not an incremental but a replacement strategy where you’re taking the standard of care, that is, ACE inhibitors, and saying that if the therapy works, we will be replacing the current standard of care with a new standard of care, which is ENTRESTO, and that’s exactly what happened in the clinical trial. So, this was a large clinical trial – over 8,400 patients were followed for a median duration of 27 months. So, first, if you look at the primary end point, which was a composite of cardiovascular death or first heart failure hospitalization, that was reduced by ENTRESTO as compared to enalapril by 20% relative risk reduction and an absolute risk reduction of 4.7%. That translated into a number needed to treat of only 21. Now, if you have a composite endpoint, which part of the end point was related to the improvement in outcome? Could it be possible that there was no improvement in cardiovascular mortality and that all the benefit was because of heart failure hospitalizations? So, it’s really important to look at each component separately as well. Note that the analyses of the components of the primary end point were not prospectively planned to be adjusted for multiplicity, and in this trial, both components contributed equally to the improvement in outcomes for our patients. There was a 20% relative risk reduction in cardiovascular death, with an absolute risk reduction of 3.2%,  and a 21% relative risk reduction in time to first hospitalization, with an absolute risk reduction of 2.8%. Based on these results, the Data Safety Monitoring Board felt that the benefits were overwhelming, that it was not ethical to continue therapy with the control arm with enalapril, and the trial was stopped early. 

Dr Caudle:

So given that, Dr Butler, how did the cardiology community then react to this data? And why do you think it supports switching HFrEF patients to ENTRESTO? 

Dr Butler:

Yeah, so the cardiology community really embraced the therapy. For example, if you look at the guidelines and were to specifically look at the language that the guideline uses – I mean, it clearly states that ARNI therapy is a first-line therapy for the management of patients with HFrEF, and if I were to read the guideline recommendations specifically to you, what this states [is] that in patients with chronic symptomatic HFrEF New York Heart Association Class II or III, who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. That’s a Class I recommendation. Now, also, the [AHA/ACC]/HFSA [HF] guideline in the new duration did something new, and that is beyond the clinical outcomes, which obviously all of us are clinicians and that’s what our primary focus is, but remember, these recurrent hospitalizations and high morbidity/mortality risk is a big societal burden in terms of cost as well, so they have now started giving a value statement as well in the guideline, and it states that in patients with chronic symptomatic HFrEF, treatment with an ARNI instead of an ACE inhibitor provides high economic value. Value statements for select therapies were created based upon benchmarks adopted by the committee where high-quality cost-effectiveness studies of the intervention had been published. So, the cardiology community was very excited, that now we have a new standard of care. It is replacing the old standard of care, which is [the] ACE inhibitor, with now ENTRESTO, or valsartan/sacubitril, and that this should really occur across the spectrum of symptoms and venue of care—whether you’re in NYHA 2 or 3, whether you’re in the outpatient setting or the inpatient setting. 

Dr Caudle:

Well, the data is impressive. Dr Saucier, with this clinical evidence and the strong recommendation in the 2022 AHA/ACC/HFSA Heart Failure Guidelines to switch to ENTRESTO, I’d like to hear what data is most important for you when considering switching your HFrEF patients to ENTRESTO. 

Dr Saucier:

So, some of the data that’s most important to me when switching my HFrEF patients over to ENTRESTO is really the totality of data. Dr Butler just explained the importance and the benefit to using ENTRESTO in these patients. The PARADIGM-HF was a head-to-head study against enalapril. Enalapril is a medication and a therapy that had been used for many years to help patients, and yet the PARADIGM-HF trial came in, in a head-to-head study, and showed that [ENTRESTO] was better. It showed that it improved cardiovascular mortality and heart failure hospitalizations for patients, so that’s really important to me. In my clinical practice, as Dr Butler had mentioned, I really make it a point to get all of my patients on guideline-directed medical therapy prior to their first heart failure hospitalization. My goal is to try to keep them out of the hospital by initiating ENTRESTO and additional guideline-directed medical therapy right away. My clinical practice with ENTRESTO – I find that my patients have less heart failure hospitalizations, if any, [and] they have less cardiovascular death. My patients on ENTRESTO, and especially on maximal-tolerated doses of ENTRESTO, really do well in my clinical practice. So, all of the data, the strong evidence really supports, and now the guidelines support that. The guidelines really help to guide us in terms of best practice for our patients, and I think that’s so important for the cardiovascular community to take this opportunity to reeducate our patients and really focus on getting patients onto that guideline-directed medical therapy with ENTRESTO. So, it’s really quite exciting for our patients.

Dr Butler:

Great points, Dr Saucier. Now, I think before we end, we should note a few additional important points. So first, all RAS inhibitors and, of course, valsartan/sacubitril has valsartan and [an] ARB, they can cause hyperkalemia – so hyperkalemia may occur with ENTRESTO as well. So good medical practice is to follow serum potassium concentrations periodically and treat it accordingly—especially in patients who are at high risk like those with CKD, diabetes, hypoaldosteronism, or those who are on a high potassium diet—dosage reduction or interruption of ENTRESTO may be required in some cases. This is also particularly an issue for patients who are on potassium-sparing diuretics like spironolactone, or are on potassium supplements, so some adjustments may be needed there as well. We should avoid the use of ENTRESTO with concomitant ARB because ENTRESTO already contains an angiotensin receptor blocker, valsartan. There are data that it increases the serum lithium concentration, and lithium toxicity has been reported with concomitant use with lithium and angiotensin II receptor antagonists. So, measuring serum lithium levels, concurrently during the use of ENTRESTO, is also recommended. If you look at overall clinical trials in heart failure with reduced ejection fraction, the most commonly observed adverse events with ENTRESTO versus enalapril, were the following – there were the side effects, or adverse events, that were reported in more than 5% in either of the two groups. There was more hypotension with ENTRESTO – 18% versus 12%; more hyperkalemia with enalapril – 12% versus 14%; similarly, more cough with enalapril – 9% versus 13%; and dizziness was 6% versus 5%; and renal failure, or acute renal failure, was reported in 5% of both therapeutic arms. No new adverse reactions were identified in a trial for the remaining indicated population. This information is not comprehensive. Please see full Prescribing Information, including Boxed WARNING and Patient Prescribing Information accompanying this podcast or at www.ENTRESTO.com 

Dr Caudle:

This has really been a fantastic conversation. Dr Saucier, do you mind giving the audience some key takeaways to walk away with? 

Dr Saucier:

I’d be happy to give some key takeaways. So, my key takeaways that I have for listeners is [that] the 2022 guidelines strongly recommend switching your heart failure with reduced ejection fraction patients who tolerate ACE inhibitors and ARB[s] over to ENTRESTO. The data from the PARADIGM-HF demonstrated superiority to enalapril – I think that’s a really important point – and these together, along with my own clinical experience, [support] switching appropriate HFrEF patients to ENTRESTO. 

Dr Butler:

And what I would say is that at this point we have clinical trial evidence and we have over 7 years of real-world experience in the clinical use of this therapy—all of it consistently showing improvement and with the strongest possible recommendation from the American [College of] Cardiology, American Heart Association, and the Heart Failure Society of America guidelines as well. So, I think now, the issue is not, whether there is evidence or whether there is convincing evidence – the issue now is really implementation, and it is now up to us, the clinical community [and] the cardiology community, to take that extra effort, and get over sort of the inertia that sometimes because of the real-world considerations in the clinical practice may preclude us from guideline-drive[n] medical therapy. So, I think it’s up to us. And I will end by again emphasizing there is really no such thing as a stable heart failure. If you have reduced ejection fraction, you really need to be optimized, regardless of your symptom status and regardless [of] whether you’re in the outpatient setting or the inpatient setting. 

Dr Caudle:

Thank you. That is a great way to round out our discussion, and I’d like to thank my guests for helping us better understand when it’s time to switch heart failure therapies to ensure patients with HFrEF are being properly optimized. Dr Butler and Dr Saucier, it was great speaking with you both today. 

Dr Butler: