HFpEF* with LVEF below normal

Hospitalization matters

After each hospitalization, patients are at increased risk of death, rehospitalization, and other poor
outcomes1-3

HFpEF=heart failure with preserved ejection fraction; LVEF=left ventricular ejection fraction.

HFpEF with LVEF below normal defined as LVEF 41% to 60%.4

*In PARAGON-HF, defined as LVEF ≥45% with structural heart disease (LAE or LVH); median LVEF was 57%. LVEF is a variable measure and the normal range can vary.9

Help keep patients out of the hospital

ENTRESTO® reduced total heart failure hospitalizations and CV death9-11

For the primary end point, reduction in the composite of total (first and recurrent) HF hospitalizations and CV death, ENTRESTO did not achieve statistical significance vs valsartan (RR 0.87; 95% CI: 0.75, 1.01; P=0.06).

ARR=absolute rate reduction; CV=cardiovascular; HR=hazard ratio; LVEF=left ventricular ejection fraction; RR=rate ratio; RRR=relative rate reduction.

The median LVEF was 57%. LVEF is a variable measure that can change over time, and the normal range differs according to patient characteristics and method of assessment.9

§Event rate per 100 patient years.

ENTRESTO reduced total heart failure hospitalizations vs valsartan9,11

PARAGON-HF: Total heart failure hospitalizations in patients with LVEF at or below the median

ARR=absolute rate reduction; HF=heart failure; LVEF=left ventricular ejection fraction; RR=rate ratio; RRR=relative rate reduction.

The median LVEF was 57%. LVEF is a variable measure that can change over time, and the normal range differs according to patient characteristics and method of assessment.9

Event rate per 100 patient years.

PARAGON-HF STUDY DESIGN

PARAGON-HF study design9

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, and structural heart disease. 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=2419) or valsartan 160 mg BID (n=2403). The median follow-up duration was 35 months, and patients were treated for up to 4.7 years. For the primary end point, reduction in the composite of total (first and recurrent) HF hospitalizations and CV death, ENTRESTO did not achieve statistical significance vs valsartan (RR 0.87; 95% CI: 0.75, 1.01; P=0.06).

BID=twice daily; HFpEF=heart failure with preserved ejection fraction; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association.

See the proven safety profile of ENTRESTO

EXPAND

INDICATION

ENTRESTO 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.

IMPORTANT SAFETY INFORMATION

WARNING: FETAL TOXICITY

  • 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

COLLAPSE

INDICATION

ENTRESTO 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.

IMPORTANT SAFETY INFORMATION

WARNING: FETAL TOXICITY

  • 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.

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References:

1. Carson PE, Anand IS, Win S, et al. The hospitalization burden and post-hospitalization mortality risk in heart failure with preserved ejection fraction: results from the I-PRESERVE trial (Irbesartan in heart failure and preserved ejection fraction). JACC Heart Fail. 2015;3(6):429-441. 2. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116(13):1482-1487. 3. Bello NA, Claggett B, Desai AS, et al. Influence of previous heart failure hospitalizations on cardiovascular events in patients with reduced and preserved ejection fraction. Circ Heart Fail. 2014;7(4):590-595. 4. Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50(8):768-777. 5. Ibrahim NE, Song Y, Cannon CP, et al. Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry®. ESC Heart Fail. 2019;6(4):784-792. 6. HCUP Fast Stats. Healthcare Cost and Utilization Project (HCUP). May 2020. Agency for Healthcare Research and Quality, Rockville, MD. www.hcup-us.ahrq.gov/faststats/national/inpatientcommondiagnoses.jsp. Accessed February 19, 2021. 7. Cheng RK, Cox M, Neely ML, et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. Am Heart J. 2014;168(5):721-730. 8. Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction. J Am Coll Cardiol. 2017;70(20):2476-2483. 9. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; February 2021. 10. U.S. Food and Drug Administration. Novartis Cardiovascular and Renal Drugs Advisory Committee Briefing Document, December 15, 2020. ENTRESTO® (sacubitril/valsatan) for chronic heart failure and preserved ejection fraction. https://www.fda.gov/media/144379/download. Accessed February 18, 2021. 11. Data on file. Novartis Pharmaceuticals Corp; February, 2021.

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