Transcript
Dr Caudle:
Welcome to “Conversations With Cardiologists: Clinical Perspectives on the Treatment of Heart Failure With Mildly Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction.”
This podcast is sponsored by Novartis Pharmaceuticals Corporation and is intended for US health care professionals. The speakers have been compensated by Novartis Pharmaceuticals Corporation to conduct this presentation.
The Important Safety Information for ENTRESTO®, or sacubitril/valsartan, will be available at all times adjacent to the player of this audio presentation. Please see full Prescribing Information, including Boxed WARNING, accompanying this podcast or at www.ENTRESTO.com.
I’m your host, Dr Jennifer Caudle. And it’s important to note that based on data from 2015 to 2018, an estimated 6 million American adults have heart failure. Approximately 40 to 60% of individuals with heart failure have heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction, or HFpEF. These patients are at high risk for heart failure hospitalizations and mortality.
Joining me to discuss clinical data in these patients are two leading cardiologists, Dr Sophia Airhart and Dr Jayne Morgan. During this podcast, we will consider how these data help to inform treatment decisions for patients with heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction. Dr Airhart is the Medical Director of Heart Failure, Mechanical Circulatory Support, and Pulmonary Hypertension at Saint Alphonsus Medical Center. Dr Airhart, thank you so much for being here today.
Dr Airhart:
Thank you, it’s great to be joining you.
Dr Caudle:
Well, we’re happy that you’re here. And Dr Jayne Morgan is a cardiologist, a researcher, and Executive Director of Health and Community Education at Piedmont Healthcare. Dr Morgan, it’s great to have you with us.
Dr Morgan:
Thank you, Dr Caudle. It’s a pleasure.
Dr Caudle:
Great! Well, thank you both for being here. I’d like to start this conversation by asking you, Dr Airhart, to provide your perspective on how heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction have historically been treated.
Dr Airhart:
Yeah, thank you—really great question. I want to start by reiterating what you said. That HFpEF is really a significant disease burden. It’s a disease with rising prevalence and a poor prognosis. It includes over 50% of all new heart failure diagnosis/[diagnoses] and is thought to be really the single largest unmet need in cardiovascular medicine.
Until recently, few treatments have been effective in HFpEF.
Historically, clinical trial data has been disappointing in this population, and apart from identifying and treating the underlying condition – such as hypertension or coronary artery disease – the treatment has focused on achieving euvolemia, exercise, and treating comorbidities. It remains a high-risk population, and despite higher LVEF, hospitalized mildly reduced EF and HFpEF patients have similar prognosis/[prognoses] to HFrEF and really comparable 5-year mortality rates.
A Get With the Guidelines analysis showed the median survival in hospitalized heart failure patients in all three groups: HFpEF, mildly reduced EF, and reduced EF were all similar, with 5-year mortality [of] about 75% after hospitalization. So, we know HFpEF is a complex condition. It’s not a single disease. And it has many faces depending on the comorbidities. There’s actually an emerging body of literature that within this EF range, there are diverse clinical and hemodynamic phenotypes associated with different risks. This heterogeneity of the HFpEF population makes it very challenging to treat.
Dr Caudle:
Thank you for providing that background. And Dr Morgan, with all these points in mind, what are some things cardiologists can do to improve the diagnosis of heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction?
Dr Morgan:
Well, we should keep in mind that diagnosis may require multiple data sources and/or methods, including clinical history symptoms and laboratory tests. One way to aid in diagnosis is the biomarker NT-proBNP. NT-proBNP, as we know, is an inactive peptide formed in the heart and released into the bloodstream in response to increased cardiac pressure or stretch. The 2022 Heart Failure Guideline strongly recommends measuring levels of the biomarkers, BNP or NT-proBNP, at admission in patients hospitalized for heart failure to establish prognosis; this is a Class 1 recommendation.
Dr Airhart:
Thank you so much, Dr Morgan. You bring up a really important point about the utility of elevated BNP and NT-proBNP. I think it’s a myth that diagnosing HFpEF is difficult, but HFpEF is definitely underdiagnosed. What heart failure with preserved ejection fraction is, is really the inability of the heart to pump blood adequately at normal filling pressures in patients with an ejection fraction over 50% or equal to 50%. Heart failure with mildly reduced EF is that same thing in the population of patients with an ejection fraction of 41 to 49%. So if you have a patient with signs and symptoms of heart failure, such as dyspnea or fluid retention and an ejection fraction greater than or equal to 41% and objective evidence of a cardiac problem, which includes a lab value of elevated BNP or NT-proBNP, then that patient has this condition. You know, BNP or NT-proBNP isn't always elevated. It's affected by different things, including obesity. So, you can also look for other underlying cardiac problems such as on echo left atrial enlargement, left ventricular hypertrophy, or, if there's any doubt, then invasive hemodynamics can be extremely helpful for this diagnosis but as a routine screening tool BNP and NT-proBNP will capture the majority of patients.
Dr Caudle:
Thank you for that. And just as a reminder, for the remainder of this podcast, we will review clinical data for ENTRESTO and patients with heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction.
Dr Airhart:
Before we continue, I think now is a good time to let our listeners 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. It is also contraindicated in patients with a history of angioedema related to previous angiotensin-converting enzyme inhibitors or angiotensin receptor blocker therapy. ENTRESTO is contraindicated with concomitant use of ACE inhibitors, and do not administer it 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 information regarding safety information will be provided throughout this podcast. And full Prescribing Information, including the medication guide, is available below this presentation.
Dr Caudle:
Thank you for that. Now, Dr Morgan, I’m most familiar with the outcomes for ENTRESTO in patients with heart failure with reduced ejection fraction. Before we discuss the data for ENTRESTO, can you remind our audience about the prior data for ENTRESTO beyond those diagnosed with heart failure with reduced ejection fraction?
Dr Morgan:
Yes, absolutely. PARAGON-HF was a randomized, double-blind, active-controlled trial comparing the effect of ENTRESTO to valsartan on total heart failure hospitalizations and cardiovascular death in almost 5000 patients: 4796 patients with an EF greater than or equal to 45% and evidence of structural heart disease. The median follow-up was 35 months, and patients were treated up to 4.7 years. The primary end point for the study, which was a composite of total first and recurrent heart failure hospitalizations and cardiovascular death, was not met with the P value of 0.06. However, ENTRESTO reduced total heart failure hospitalizations and cardiovascular death by 22% compared to valsartan in a prespecified subgroup analysis in patients with an ejection fraction at or below the median of the trial, which was 57%, with the rate ratio of 0.78 and an absolute rate reduction of 3.6 events per 100 patient-years. This reduction was primarily driven by a reduction in heart failure hospitalizations. ENTRESTO also reduced the rate of the prespecified exploratory, composite end point of total worsening heart failure events defined as heart failure hospitalizations and urgent heart failure visits and cardiovascular death by 14% compared to valsartan, which was driven by a reduction in the rate of total worsening heart failure events. Additionally, in a prespecified exploratory analysis, ENTRESTO reduced the biomarker of NT-proBNP by 24% from baseline at week 16, compared to 6% with valsartan. NT-proBNP was analyzed in a subgroup and may not represent the full population.
ENTRESTO CV and renal effects are due to increased peptides and decreased angiotensin II effects, which result in decreased NT-proBNP. In PARAGON-HF, the safety of ENTRESTO was comparable to valsartan.
Dr Caudle:
Dr Morgan, thank you so much for that review of data from PARAGON-HF. Now, Dr Airhart, let’s turn to you for a moment. What was the reaction from the cardiology community when they first saw these data?
Dr Airhart:
The reaction was very favorable. To put this in context prior to this data, remember that symptom and comorbidity management was the primary recommendation by the 2017 ACC/AHA/HFSA guidelines. Granted, now we have new guidelines and new data, but this study was the first really breakthrough in HFpEF treatment, and while the primary end point wasn’t met, the results, as Dr Morgan pointed out, of the prespecified subgroup analysis with regard to EF was very exciting. I mean, in these sub-populations of EF <57%, there was a decrease in the total heart failure hospitalization and cardiovascular deaths compared to valsartan.
And as we’ve discussed, HFpEF and mildly reduced EF is a heterogeneous population, so it’s not surprising that we see a more pronounced response in certain populations. Notably, this data led to the expansion of the ENTRESTO label to include patients with heart failure with LVEF below normal.
Yet, as cardiologists, additional clinical data for ENTRESTO in this patient population would be helpful. The majority of patients were functional Class II, and those patients who were in decompensated heart failure were excluded.
Dr Morgan:
Before we review additional clinical data, I think this is a good time to discuss some more of the ENTRESTO Important Safety Information. ENTRESTO may cause angioedema and, when associated with laryngeal edema, may be fatal. ENTRESTO has been associated with a higher rate of angioedema in black patients and in patients with a prior history of angioedema.
ENTRESTO should not be used in patients with hereditary angioedema. If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not 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- and/or salt-depleted patients, are at greater risk. Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose.
If hypotension persists despite dose adjustment of diuretics, concomitant anti-hypertensive drugs, and treatment of other causes of hypotension, for instance, hypovolemia, reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.
Decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO. In patients whose renal function depends upon the activity of the renin- angiotensin-aldosterone system, for example, patients with severe congestive heart failure, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine and down-titrate or interrupt ENTRESTO in patients who develop a 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, monitor the renal function, avoid use with aliskiren in patients with renal impairment, an estimated glomerular filtration rate of <60. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of non-steroidal anti-inflammatory drugs, or NSAIDs, including COX-2 inhibitors, with ENTRESTO may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. 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 Airhart, I heard ENTRESTO released clinical data in May of 2023. Can you tell our audience more about this?
Dr Airhart:
Yeah, thank you. Let’s talk about the PARAGLIDE-HF study, which was designed as a follow-up to help inform some of the gaps around the PARAGON study. So PARAGLIDE looked at heart failure with mildly reduced EF or HFpEF and compared sacubitril/valsartan to valsartan. Importantly, in patients who recently had a worsening heart failure event within 30 days. And that worsening heart failure event was defined as being hospitalized, or being in the ER, or having an urgent heart failure visit that required IV diuretics.
This study design was multi-center, double-blind, and randomized, and patients who were medically stable – which was defined by systolic blood pressure over 100 millimeters of mercury for the preceding 6 hours, no increase in IV diuretics or use of IV vasodilators within the last 6 hours, and no IV inotropes administered for 24 hours prior to randomization – were randomized to study drug following stabilization at the time of worsening heart failure event, or within 30 days of a worsening heart failure event. And then, those patients who were receiving ENTRESTO were titrated to a target dose of 97/103 [mg] twice daily, and those on valsartan were titrated to 160 [mg] twice daily as tolerated.
And another very exciting thing about the study was that it included, intentionally, a diverse range of US and Canadian patients who would better reflect those seen in real-world practice. In this patient population, the median age was 70, and 52% of participants were female, with a median EF of 55%. There was also 30% of trial participants who were [of] non-white race or ethnicity, and 22% were black, and almost 70% of trial participants were randomized in the hospital setting following stabilization. So this cohort includes over 50% females, which is rare in clinical trials, and a balanced proportion of trial participants of non- white race or ethnicity. All deaths, hospitalizations, and urgent heart failure events were adjudicated by an independent committee.
Dr Caudle:
Dr Airhart, thank you so much for that recap. And, Dr Morgan, I’d love to get your reaction to this. What do you think about the patients enrolled in this trial?
Dr Morgan:
As we know, historically, marginalized communities, populations of color, and certainly the black population has not been included in clinical trials for a number of reasons. So these types of gains have been incredibly important and, certainly, we should applaud the ability of these trials to be able to enroll these participants that really gets to the matter of specifically looking for inclusion, but also making certain that your principal investigators are focused on bringing in a large variety of patients.
Dr Caudle:
You know, Dr Morgan, I do agree with your sentiments. It is exciting to see a clinical trial enroll a broader patient population that is more representative of what’s real life. As an African American female and a physician, you know. Certainly, including all races, cultures, [and] sizes, especially gender, is so important. It’s exciting to see over 50% female enrollment. And you did make some excellent points about the lack of inclusion that we have often seen from a racial standpoint in previous trials. It is nice to see a greater diversity, which really is what should be the standard for all trials going forward. You know, Dr Airhart, can you tell our audience what the outcome of this trial was?
Dr Airhart:
Yeah, thank you. The primary end point in PARAGLIDE-HF was the time-averaged, proportional change in NT-proBNP from baseline to Weeks 4 to 8. So let me put this in context for you: patients with mildly reduced EF and HFpEF commonly have markedly elevated levels of BNP and NT-proBNP after a worsening heart failure event, and a decrease in NT-proBNP of greater than 30% from baseline has been associated with a decreased risk of cardiovascular death and heart failure hospitalization. In the study, ENTRESTO did meet the primary end point, demonstrating a reduction from baseline in NT-proBNP versus ARB at Weeks 4 and 8. ENTRESTO was superior to valsartan in reducing NT-proBNP and reduced levels by 28% compared to 16% with valsartan, which was a proportional difference of 15%.
Dr Morgan, can you discuss some of the additional outcomes from PARAGLIDE-HF?
Dr Morgan:
Absolutely, in the prespecified subgroup of patients with ejection fractions ≤60%, patients on ENTRESTO had a greater reduction in NT-proBNP versus those on valsartan.
ENTRESTO reduced NT-proBNP by 33% versus 14% on valsartan from baseline to Weeks 4 and 8, with [a] proportional difference of 22%. This prespecified subgroup analysis was not powered for determining the significance of the findings. For primary outcomes, there are some limitations to consider. The sample size was relatively modest. In addition, approximately 19% of the patients did not contribute to the primary end point given the lack of NT-proBNP data. So, it is important for us to address the limitations of the study.
Limitations of this analysis are compounded by the inherent limitations when examining subgroups, including reduced sample size, selection bias, multiple comparisons, and lack of power.
Dr Caudle:
Dr Morgan, thank you for that. Those are really great points. Can you also comment on the safety observed in this trial? You know, was it comparable to other phase 3 studies with ENTRESTO?
Dr Morgan:
You know what? There were no new safety signals identified. In the PARAGLIDE-HF, 24% of patients on ENTRESTO and 16% of patients on valsartan experience symptomatic hypotension. The number of cases of hyperkalemia was similar between treatment arms, approximately 19%, and angioedema occurred in only one patient on valsartan, and worsening renal function occurred in both ENTRESTO and valsartan. The exposure-adjusted incidence rates of serious adverse events were 103 for the ENTRESTO group and also 103 for the valsartan group. Management of symptomatic hypotension was at the discretion of the physician and consistent with guidance in the package insert for ENTRESTO. Let’s note that safety data were collected for only 8 weeks. Therefore, adverse events that take longer to transpire may not have appeared in this study. Safety information should, therefore, be interpreted in the context of prior trials with longer durations.
This may be a good time to review some more of the important safety information for ENTRESTO. Note [that] hyperkalemia may occur with ENTRESTO. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia, such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of ENTRESTO may be required.
Concomitant use of potassium-sparing diuretics – such as spironolactone, triamterene, or amiloride – potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium.
Avoid [the] use of ENTRESTO with ARBs, because ENTRESTO contains the angiotensin II receptor blocker, valsartan. Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with ENTRESTO.
In a clinical trial of patients with heart failure with reduced ejection fraction, the most commonly observed adverse events with ENTRESTO versus enalapril occurring at a frequency of at least 5% in either group were hypotension (18%,12%), hyperkalemia (12%, 14%), cough (9%, 13%), dizziness (6%, 5%), and renal failure or acute renal failure (5% and 5%). No new adverse reactions were identified in a trial of 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:
Well, this has really been a fantastic overview. You know, Dr Airhart, I’d like to come back to you. Would you mind telling the audience how you’ll use this data to make treatment decisions for patients with heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction?
Dr Airhart:
Yeah, thank you, Dr Caudle. I think that’s what really it comes down to. How do we use this data for patient treatment on a day-to-day basis? This is particularly important because heart failure is often diagnosed in the hospital setting.
ENTRESTO has also been incorporated into the 2022 AHA/ACC/HFSA heart failure guidelines, and also has an important place in the 2023 Expert Consensus Decision Pathway put out by the ACC, with ENTRESTO favored over ARB therapy in patients who have an ejection fraction of less than 55 to 60% unless there is a contraindication, cost issue, or intolerance. So, we’ve learned a lot today, and this is reflected really in the guidelines and is an important opportunity to improve the care of our patients.
Dr Morgan:
Additionally, with the 2022 guidelines, the 2023 Expert Consensus Decision Pathway, or ECDP, and 2023 clinical data, [it] is really an exciting time for [the] heart failure community and our patients. We just reviewed data from both PARAGON-HF and PARAGLIDE-HF, where ENTRESTO went head-to-head against valsartan, an ARB. Therefore, consider ENTRESTO as part of your treatment approach for appropriate patients with heart failure with left ventricular ejection fractions ≤60%.
Dr Caudle:
Thank you both for your expert perspectives. Dr Airhart, can you summarize our conversation for our audience.
Dr Airhart:
Sure, we’ve talked about how ENTRESTO was the first heart failure medication to demonstrate efficacy in patients with heart failure beyond HFrEF, as shown in the PARAGON-HF study. We also discussed data from the PARAGLIDE-HF study where ENTRESTO demonstrated superiority to valsartan in patients with mildly reduced and preserved ejection fraction. We’ve reviewed the place of ENTRESTO in the 2022 AHA/ACC/HFSA guidelines and discussed the 2023 Expert Consensus Decision Pathway for HFpEF. We’ve also shared our perspectives of ENTRESTO and how it’s included as part of our treatment plan for appropriate heart failure patients with EF ≤60%.
Dr Caudle:
Thank you. This is a great way to round out our discussion, and I’d like to thank my guests for helping us better understand heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction and for participating in this discussion on the PARAGLIDE-HF data. Dr Airhart and Dr Morgan, it was great speaking with you both today.
Dr Airhart:
Thank you, Dr Caudle.
Dr Morgan:
Thank you, as well; it’s a pleasure.
Abbreviations: ACC, American College of Cardiology; ACE, angiotensin-converting enzyme; AHA, American Heart Association; ARB, angiotensin II receptor blocker; BNP, B- type natriuretic peptide; COX-2, cyclooxygenase-2; CV, cardiovascular; ECDP, Expert Consensus Decision Pathway; EF, ejection fraction; ER, emergency room; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFSA, Heart Failure Society of America; IV, intravenous; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NSAID, non-steroidal anti-inflammatory drug.
