Entresto (sacubitril/valsartan) efficacy and clinical trials
Heart Failure
Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
Entresto is usually administered in conjunction with other heart failure therapies, in place of an angiotensin converting enzyme (ACE) inhibitor or other angiotensin receptor blocker (ARB).1
Hypertension
Entresto is indicated for the treatment of essential hypertension.
For more information, please visit
http://www.novartis.com.sg/product-list/entresto to access or download the Package Insert.
HEART FAILURE
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
1. PARADIGM-HF PRIMARY ENDPOINT
PARADIGM-HF demonstrated a lower risk of CV death or HF hospitalisation with ENTRESTO vs ACEi (enalapril).1,2
Adapted from McMurray et al. 2014.
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
Adapted from McMurray et al. 2014.2
PARADIGM-HF: Sudden cardiac death post hoc analysis
ENTRESTO was observed to reduce the risk of sudden cardiac death (n=561) vs ACEi (enalapril) (35.2% [n = 250] vs 37.2% [n = 311] [HR 0.80, 95% CI 0.68–0.94, P = 0.008]).*3
This study was a secondary analysis and no confirmatory clinical conclusions can be drawn from such an analysis
*This secondary analysis investigated the effect of ENTRESTO (n = 4,217) versus ACEi (enalapril) (n = 4,182) 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
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
Adapted from Velazquez 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.
Adapted from Velazquez et al 20195 and DeVore 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
Adapted from Morrow et al. 2019.6
Entresto as first choice was observed to keep patients from hospitalisation vs ACEi patients from rehospitalisation longer vs ACEi6 |
Adapted from Morrow et al. 2019.6
In a secondary Analysis of Pioneer-HF, delaying the initation of Entresto was observed to increase the risk of HF rehospitalisations and CV death.5
Adapted from DeVore et al. 2020.
These data include HF hospitalisations.
Patients who started on ENTRESTO at baseline experienced greater reduction in events in CV death or HF rehospitalisation events vs patients started on enalaprill.5,7 |
In newly diagnosed patients:
In a pre-specified subgroup analysis of PIONEER-HF, ENTRESTO as first choice helped reduce cardiac stress and improve outcomes vs ACEi.7
Adapted from Ambrosy et al 2020.7
Patient Characteristics
Adapted from Ambrosy 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
ENTRESTO was associated with increases in LVEF from baseline to 6 and 12 months (P<0.001)
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 (-7.11 to -6.19) | -12.3 (-12.92 to -11.58) |
| LAVi (mL/m2) | -4.4 (-4.73 to -3.99) | -7.6 (-7.98 to -7.15) |
| E/e’ | -1.2 (-1.63 to -0.83) | -1.3 (-1.74 to -0.86) |
In PROVE-HF, over 75% of HF patients were previously on an ACEi/ARB before switching to ENTRESTO
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
LVEF increase observed in ACEi/ARB-naive patients
In a 12-month prospective exploratory analysis, in ACEi/ARB-naive patients, there was an observed increase in the ENTRESTO arm in median LVEF to 43.5% from baseline (28.4%)8
Adapted from Januzzi et al. 20198
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 NTproBNP 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
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 expectancy11
Freedom from the composite primary endpoint of CV death or HF hospitalisation after age 55 years: 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: 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 shortterm follow-up data. |
See the safety profile of Entresto
HYPERTENSION
Japanese study
Efficacy and safety of ENTRESTO® compared to olmesartan in japanese patients with systolic hypertension2
Multicenter, randomized, double-blind, parallel-group, and active-controlled study conducted between June 2012 and April 2013 in Japan.
*All eligible patients were randomized using an Interactive Web Response System (IWRS); **Uptitrated following 1 week of 200 mg.
msSBP: mean sitting systolic blood pressure.
Study population
*Mean sitting diastolic blood pressure [msDBP] ≥110 mmHg or msSBP ≥180 mmHg.
msSBP: mean sitting systolic blood pressure.
Patient demographics and baseline characteristics2
Data are presented as mean ± standard deviation unless specified.
*Defined as patients having a history of hypertension receiving antihypertensive medications within 4 weeks prior to screening, with mean sitting systolic blood pressure (msSBP) ranging from ≥150 to <180 mmHg at randomization and ≥140 to <180 mmHg at the visit immediately before randomization; **Defined as patients having a history of hypertension who had not been taking any antihypertensive medications for at least 4 weeks prior to screening, and had msSBP ranging from ≥150 to<180 mmHg at both screening and randomization; #Newly diagnosed hypertensive patients who had never taken any antihypertensive medications.
BMI: Body Mass Index, DBP: Diastolic Blood Pressure, eGFR: Estimated Glomerular Filtration Rate, ms: Mean Sitting, NA: Not Available, PP: Pulse Pressure, SBP: Systolic Blood Pressure, LSM: Least-Squares Mean, msSBP: mean sitting systolic blood pressure.
Efficacy of sacubitril/valsartan versus olmesartan in Japanese patients with essential hypertension: a randomized, double-blind, multicenter study2
Sacubitril/valsartan 200 mg provided a significantly greater reduction in msSBP than olmesartan 20 mg at Week 8 (P < 0.05 for non inferiority and superiority)
BP: blood pressure, CI: confidence interval, LSM: least square mean, msDBP: mean sitting diastolic blood pressure, msPP: mean sitting pulse pressure, msSBP: mean sitting systolic blood pressure.
Overall blood pressure control
BP: blood pressure.
The safety and tolerability profiles of ENTRESTO® were generally comparable to those of olmesartan2
AE: adverse event, SAE: serious adverse event.
The safety and tolerability profiles of ENTRESTO® were generally comparable to those of olmesartan2
Incidence of AEs*
AEs: Adverse Event, AE: adverse event, SAE: serious adverse event, SAEs: Serious Adverse Events.
Please click here for safety information
*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, NTproBNP 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).
References
ENTRESTO (sacubitril/valsartan) Summary of Product Characteristics.
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. Initiation of angiotensin-neprilysin inhibition after acute decompensated heart failure: results of the open-label extension of the PIONEERHF trial. Data presented at American College of Cardiology 68th Annual Scientific Session, March 2019.
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.