Conversations With Cardiologists: Clinical Perspectives on the Treatment of HFmrEF and HFpEF

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Conversations With Cardiologists: Clinical Perspectives on the Treatment of HFmrEF and HFpEF



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Catch up on clinical data in patients with HFmrEF and select patients with HFpEF.

Please see

Important Safety Information, including Boxed WARNING.

  • Overview

    Dive into the results of PARAGLIDE-HF and what they could mean for your patients with heart failure with mildly reduced ejection fraction (HFmrEF) and select patients with heart failure with preserved ejection fraction (HFpEF) with Dr Sophia Airhart and Dr Jayne Morgan. Dr Airhart is the Medical Director of Heart Failure, Mechanical Circulatory Support, and Pulmonary Hypertension at Saint Alphonsus Medical Center, and Dr Morgan is a cardiologist, a researcher, and Executive Director of Health and Community Education at Piedmont Healthcare.



    ENTRESTO® (sacubitril/valsartan) tablets 24/26 mg, 49/51 mg, 97/103 mg, is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

    LVEF is a variable measure, so use clinical judgment in deciding whom to treat.


    • When pregnancy is detected, discontinue ENTRESTO as soon as possible
    • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

    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 (ACE) inhibitor or angiotensin receptor blocker (ARB) 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.

    Angioedema: ENTRESTO may cause angioedema. Angioedema 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.

    Hypotension: ENTRESTO lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), 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 antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia), reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.

    Impaired Renal Function: 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 (e.g., 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 renal function. Avoid use with aliskiren in patients with renal impairment (eGFR <60 mL/min/1.73 m2).

    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 (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.

    Hyperkalemia: 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 (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium, may lead to increases in serum potassium.

    ARBs: Avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan.

    Lithium: 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.

    Common Adverse Events: In a clinical trial of patients with heart failure with reduced ejection fraction, the most commonly observed adverse events with ENTRESTO vs 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/acute renal failure (5%, 5%). No new adverse reactions were identified in a trial of the remaining indicated population.

    Please see accompanying full Prescribing Information, including Boxed WARNING.

  • Study Details and Limitations of Analysis

    PARAGON-HF was a randomized, double-blind, active-controlled trial comparing ENTRESTO to valsartan in 4796 adult patients with symptomatic (NYHA Class II–IV) HFpEF (LVEF ≥45%, elevated levels of natriuretic peptides, structural heart disease [LAE or LVH], and no prior echocardiographic LVEF <40%). After completing the run-in period with valsartan, followed by ENTRESTO, patients entered the double-blind period and were randomly assigned (1:1) to ENTRESTO 97/103 mg BID (n=2407) or valsartan 160 mg BID (n=2389). The median follow-up duration was 35 months, and patients were treated for up to 4.7 years.1,2

    PARAGLIDE-HF was a multicenter, double-blind, randomized, controlled trial designed to assess changes in NT-proBNP, safety, and tolerability of ENTRESTO (n=233) vs an active comparator, valsartan (n=233), in stabilized patients with HFmrEF and HFpEF (LVEF >40%)* and elevated levels of natriuretic peptides who experienced a recent worsening HF event. Patients were randomized 1:1 to ENTRESTO (target dose: 97/103 mg BID) or valsartan (target dose: 160 mg BID), as tolerated. Patients were randomized to study drug following stabilization at the time of the worsening HF event, or within 30 days of a worsening HF event. Medically stable was defined by a systolic blood pressure >100 mmHg 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. All deaths, hospitalizations, and urgent HF events were adjudicated by an independent blinded committee.3,4


    Adverse event, n (%)

    ENTRESTO (n=233)

    Valsartan (n=233)

    Symptomatic hypotension

    56 (24.0)

    36 (15.5)


    45 (19.3)

    43 (18.5)

    Worsening renal function‡ 

    50 (21.5)

    72 (30.9)




    • No new safety signals were identified5
    • The exposure-adjusted incidence rates of serious adverse events were 103 (122.2 per 100 patient treatment years) for the ENTRESTO group and 103 (122.2 per 100 patient treatment years) for the valsartan group
    • There were 18 deaths in the ENTRESTO group (10 CV) and 26 deaths in the valsartan group (18 CV)

    *PARAGLIDE-HF defined HFmrEF and HFpEF as patients with LVEF >40%. The median LVEF was 55%. LVEF is a variable measure that can change over time, and the normal range differs according to patient characteristics and method of assessment.

    Worsening HF event was defined as an HF hospitalization, emergency department visit, or out-of-hospital urgent HF visit, all requiring IV diuretics.

    The worsening renal function adverse event of special interest was defined as an increase in serum creatinine of ≥0.5 mg/L and worsening of the eGFR (mL/min/1.73 m2) by ≥25%. 


    Primary end point: The sample size was relatively modest. In addition, approximately 19% of patients did not contribute to the primary end point given the lack of NT-proBNP data. 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.3

    Safety: 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 be interpreted in the context of prior trials with a longer duration.3


    1. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 2. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609-1620. doi:10.1056/NEJMoa1908655 3. Mentz RJ, Ward JH, Hernandez AF, et al. Angiotensin-neprilysin inhibition in patients with mildly reduced or preserved ejection fraction and worsening heart failure. J Am Coll Cardiol. 2023;82(1):1-12. 4. Mentz RJ, Ward JH, Hernandez AF, et al. Rationale, design and baseline characteristics of the PARAGLIDE-HF trial: sacubitril/valsartan vs valsartan in HFmrEF and HFpEF with a worsening heart failure event. J Card Fail2023;29(6):922-930.   
    5. Mentz RJ, Ward JH, Hernandez AF, et al. Angiotensin-neprilysin inhibition in patients with mildly reduced or preserved ejection fraction and worsening heart failure. J Am Coll Cardiol. 2023;S0735-1097(23):05429-3. doi:10.1016/j.jacc.2023.04.019

Schedule18 Apr 2024