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ENTRESTO® (sacubitril/valsartan) efficacy and clinical trials
In Ireland, ENTRESTO is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction (HFrEF).1
In your outpatients with HFrEF:
In the largest heart failure (HF) trial ever conducted (N = 8442), ENTRESTO showed superior efficacy in reducing HF hospitalisations or CV death vs ACEi (enalapril).2
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IN CV DEATH OR HF HOSPITALISATION AS A FIRST EVENT
4.7% ARR, p<0.001
CV death or hospitalisation
21.8% S/V vs 26.5% enalapril
NNT: 21
vs enalapril
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IN CV DEATH
3.1% ARR,
CV death
13.3% S/V vs 16.5% enalapril
NNT: 32
vs enalapril
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IN FIRST HF HOSPITALISATION
2.8% ARR,
hospitalisation
12.8% S/V vs 15.6% enalapril
NNT: 36
vs enalapril
1. PARADIGM-HF PRIMARY ENDPOINT
PARADIGM-HF demonstrated a lower risk of CV death or HF hospitalisation with ENTRESTO vs ACEi (enalapril).1,2
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Adapted from McMurray JJ, et al. 2014.2
Study design
PARADIGM-HF was a multinational, randomised, double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic (NYHA Class II–IV) chronic HFrEF patients (LVEF ≤40%, amended later to ≤35%).2
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Adapted from McMurray JJ, et al. 2014.2
PARADIGM-HF: Sudden cardiac death post hoc analysis
In PARADIGM-HF, 561 deaths were sudden cardiac death. When compared to enalapril, ENTRESTO reduced sudden cardiac death by 20%3
This study was a secondary analysis and no confirmatory clinical conclusions can be drawn from such an analysis.
In your hospitalised patients:
ENTRESTO showed significantly greater reductions in NT-proBNP vs ACEi (enalapril), when initiated in hospital following haemodynamic stabilisation after an ADHF episode.4
ENTRESTO is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction. ENTRESTO is not indicated for the treatment of acute HF.1
Patients in the PIONEER-HF trial were required to be haemodynamically stabilised from an ADHF episode while in hospital.4
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Adapted from Velazquez EJ, et al. 2019.4
Study design
PIONEER-HF was a prospective, multicentre, double-blind, randomised, active-controlled trial designed to assess, over an 8-week period, the safety, tolerability and efficacy of in-hospital initiation of ENTRESTO compared with enalapril in 881 adult patients in the United States with chronic HFrEF (EF ≤40% and NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL) haemodynamically stabilised during hospitalisation for an episode of ADHF.
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Adapted from Velazquez EJ, et al. 20194 and DeVore AD, et al. 2019.5
Regardless of where eligible symptomatic chronic HFrEF patients are in their hospitalisation journey, starting ENTRESTO as early as possible may improve outcomes vs ACEi (enalapril).4–6
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Adapted from Morrow DA, et al. 2019.6
ENTRESTO keeps patients from rehospitalisation longer vs ACEi6 |
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Adapted from Morrow DA, et al. 2019.6
In a secondary analysis of PIONEER-HF, delaying the initiation of ENTRESTO was observed to increase the risk of HF rehospitalisations and CV death.5
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Adapted from DeVore AD, et al. 2020.5
Patients started on ENTRESTO at baseline experienced greater reduction in events vs patients started on enalapril5,7 |
Patient characteristics
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Adapted from Ambrosy AP, et al. 2020.7
A prospective exploratory analysis showed a statistically significant observed correlation between the reduction in NT-proBNP and echocardiographic measures between baseline, 6 months and 12 months (all correlations/r values were < ±0.4 and p<0.001).‡8
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Adapted from Januzzi JL Jr, et al. 2019.8
ENTRESTO was associated with increases in LVEF from baseline to 6 and 12 months (p<0.001)8
Remodelling parameter | Mean change from baseline at 6 months | Mean change from baseline at 12 months |
LVESVi (mL/m2) | −8.7 | −15.3 |
LVEDVi (mL/m2) | −6.7 | −12.3 |
LAVi (mL/m2) | −4.4 | −7.6 |
E/e’ | −1.2 | −1.3 |
In PROVE-HF, over 75% of HF patients were previously on an ACEi/ARB before switching to ENTRESTO.8
In a prospective exploratory analysis, ENTRESTO was observed to be associated with reverse cardiac remodelling measures and improvement in cardiac volume and function from baseline8
PROVE-HF study design
PROVE-HF was a prospective, Phase IV, 52-week, open-label, single-group exploratory analysis (n=794). The primary endpoint was the correlation between changes in NT-proBNP concentration and cardiac remodelling, assessed by change in LVEDVi, LVESVi, LVEF, and LAVi from baseline to 12 months. Correlation between the change in concentration of NT-proBNP and E/e’ was added to the statistical analysis plan prior to database lock.
Consider prescribing ENTRESTO to act directly on the heart and you could help improve cardiac function for your symptomatic chronic HFrEF patients.8
What would it mean for your HFrEF patients to feel better during social and physical activities?9–11
Most patients with heart failure report limitations in their daily activities due to physical symptoms such as dyspnoea, fatigue, oedema, sleeping difficulties and chest pain.12
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Adapted from Chandra A, et al. 2018.9
In a post hoc analysis of PARADIGM-HF: observed long-term responses of ENTRESTO vs ACEi (enalapril) modelled up to 2 years of increased life expectancy11Freedom from the composite primary endpoint of CV death or HF hospitalisation after age 55 years:11 Enalapril: 7.4 years vs ENTRESTO: 9.6 years Freedom from the composite primary endpoint of CV death or HF hospitalisation after age 65 years:11 Enalapril: 7.6 years vs ENTRESTO: 9.2 years Based on actuarial estimates from the PARADIGM-HF trial and assuming that protective effects of ENTRESTO remain consistent with long-term use. Extrapolated from available short-term follow-up data.11 |
See the safety profile of ENTRESTO
Learn more about the effect ENTRESTO has on cardiac remodelling
Hypersensitivity to the active substances or to any of the excipients listed in the SmPC
Concomitant use with ACEi. ENTRESTO must not be administered until 36 hours after discontinuing ACEi therapy
Known history of angioedema related to previous ACEi or ARB therapy
Hereditary or idiopathic angioedema
Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 mL/min/1.73m2)
Severe hepatic impairment, biliary cirrhosis and cholestasis
Second and third trimesters of pregnancy
The combination of ENTRESTO with an ACEi is contraindicated due to the increased risk of angioedema. ENTRESTO must not be initiated until 36 hours after taking the last dose of ACEi therapy. If treatment with ENTRESTO is stopped, ACEi therapy must not be initiated until 36 hours after the last dose of ENTRESTO
The combination of ENTRESTO with direct renin inhibitors such as aliskiren is not recommended. The combination of ENTRESTO with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 mL/min/1.73m2)
ENTRESTO contains valsartan, and therefore should not be co-administered with another ARB-containing product
Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with ENTRESTO during clinical studies, especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg)
When initiating therapy or during dose titration with ENTRESTO, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of ENTRESTO is recommended. Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered
Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with ENTRESTO; however, such corrective action must be carefully weighed against the risk of volume overload
Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild and moderate renal impairment are more at risk of developing hypotension. There is very limited clinical experience in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) and these patients may be at greatest risk of hypotension. There is no experience in patients with end-stage renal disease and use of ENTRESTO is not recommended
Use of ENTRESTO may be associated with decreased renal function. The risk may be further increased by dehydration or concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs). Down-titration should be considered in patients who develop a clinically significant decrease in renal function
Treatment should not be initiated if the serum potassium level is >5.4 mmol/L in adult patients. Use of ENTRESTO may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur. Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high-potassium diet or on mineralocorticoid antagonists. If patients experience clinically significant hyperkalaemia adjustment of concomitant medicinal products or temporary down-titration or discontinuation is recommended. If serum potassium level is >5.4 mmol/L, discontinuation should be considered
Angioedema has been reported in patients treated with ENTRESTO. If angioedema occurs, ENTRESTO should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. It must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, e.g. adrenaline solution 1 mg/1 mL (0.3–0.5 mL), and/or measures necessary to ensure a patent airway, should be promptly administered
Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if ENTRESTO is used in these patients. ENTRESTO is contraindicated in patients with a known history of angioedema related to previous ACEi or ARB therapy or with hereditary or idiopathic angioedema
Black patients have an increased susceptibility to develop angioedema
Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including valsartan. These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, ENTRESTO should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred
ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis
Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended
Caution should be exercised when initiating ENTRESTO in patients with NYHA functional classification IV, due to limited clinical experience in this population
BNP is not a suitable biomarker of heart failure in patients treated with ENTRESTO, because it is a neprilysin substrate
There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. In these patients, exposure may be increased and safety is not established. Caution is therefore recommended when using it in these patients
ENTRESTO is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification)
Psychiatric events such as hallucinations, paranoia and sleep disorders, in context of psychotic events, have been associated with ENTRESTO use. If a patient experiences such events, discontinuation of ENTRESTO treatment should be considered
Contraindications:1
Special warnings and precautions for use1
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Hypotension
Impaired renal function
Worsening renal function
Hyperkalaemia
Angioedema
Patients with renal artery stenosis
Patients with NYHA functional classification IV
B-type natriuretic peptide (BNP)
Patients with hepatic impairment
Psychiatric disorders
*This secondary analysis investigated the effect of ENTRESTO (n=4217) versus ACEi (enalapril; n=4182) on the mode of death in PARADIGM-HF. The overall risk of CV death was reduced by 20% with ENTRESTO treatment (HR 0.80; 95% CI 0.72–0.89; p<0.001) in PARADIGM-HF.
†Serious clinical outcomes include HF hospitalisation or CV death.
‡PROVE-HF is a Phase IV, single-arm, multicentre, open-label trial in the United States, of which 654 (82.4%) patients completed the 52-week study. This open-label study evaluated the effects of ENTRESTO on biomarkers, cardiac remodelling, and patient-reported outcomes in heart failure with reduced left ventricular ejection fraction. The correlation between the change in concentration of NT-proBNP and E/e′ was added to the statistical analysis plan prior to the database lock. The primary endpoint was the correlation of NT-proBNP concentrations with LVEF, LVEDVi, LVESVi and LAVi measures. At 12 months, NT-proBNP concentrations were associated with changes in these cardiac measures (all p<0.5). A secondary endpoint was the change in cardiac remodelling with ENTRESTO treatment at 6 and 12 months.
§In PARADIGM-HF, KCCQ (an HF QoL composite measurement score) was a pre-specified secondary study endpoint. Change in KCCQ clinical summary score at 8 months −2.99±0.36 (ENTRESTO) vs −4.63±0.36 (enalapril); HR=1.64 (0.63–22.65); p=0.001.
||The study did not investigate, nor provide any evidence that sacubitril/valsartan has any direct effect on, sexual function, and this finding may be a surrogate
for overall well-being. The PARADIGM-HF trial did not collect erectile dysfunction data, and few patients reported taking erectile dysfunction medication.
¶LSM estimation (SE) ENTRESTO vs enalapril: 0.80 (SE 0.20) vs −0.39 (SE −0.20). LSM estimates (SE) difference: 1.19 [0.28], p<0.001. Overall score comprising KCCQ measurement differences at pre-determined study KCCQ questionnaire administrations study timepoints of: Months 4, 8, 12, 24 & 36 (from randomisation).
ACE, angiotensin-converting enzyme; ACEi, angiotensin-converting enzyme inhibitor; ADHF, acute decompensated heart failure; ALT, alanine aminotransferase; ARB, angiotensin II receptor blocker; ARR, actual risk reduction; AST, aspartate aminotransferase; BID, bis in die (twice a day); BNP, brain natriuretic peptide; CI, confidence interval; CV, cardiovascular; E/e’, ratio of early mitral inflow velocity to mitral annular early diastolic velocity; EF, ejection fraction; eGFR, estimated glomerular filtration rate; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; KCCQ, Kansas City cardiomyopathy questionnaire; LAVi, left atrial volume index; LSM, least squares mean; LVEDVi, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVi, left ventricular end-systolic volume index; NSAIDs, non-steroidal anti-inflammatory drugs; NT-proBNP, N-terminal-pro brain natriuretic peptide; NYHA, New York Heart Association; QoL, quality of life; RAAS, renin-angiotensin-aldosterone system; RRR, relative risk reduction; SBP, systolic blood pressure; SE, standard error; SmPC, summary of product characteristics.
References
ENTRESTO® (sacubitril/valsartan) Summary of Product Characteristics. Available on www.medicines.ie.
McMurray JJ, et al. N Engl J Med 2014;371(11):993–1004.
Desai AS, et al. Eur Heart J 2015:36(30); 1990–1997.
Velazquez EJ, et al. N Engl J Med 2019;380(6):539–548.
DeVore AD, et al. JAMA Cardiol 2019;5(2):202–207.
Morrow DA, et al. Circulation 2019;139(19):2285–2288.
Ambrosy AP, et al. J Am Coll Cardiol 2020;76(9):1034–1048.
Januzzi JL Jr, et al. JAMA 2019;322(11):1085–1095.
Chandra A, et al. JAMA Cardiol 2018;3(6):498–505.
Lewis EF, et al. Circ Heart Fail 2017;10(8):e003430.
Claggett B, et al. N Engl J Med 2015;373(23):2289–2290.
Heo S, et al. Heart Lung 2009;38(2):100–108.
IE11605932 | April 2026
