Clinical Trial and Biomarker Data | ENTRESTO® (sacubitril/valsartan)

In HFrEF,

PARADIGM-HF: In the largest heart failure (HF) trial ever conducted, ENTRESTO^®was superior in keeping patients alive and out of the hospital vs an ACEi^1-3

PROVEN RISK REDUCTION IN COMPOSITE END POINT, WITH CONSISTENT RESULTS ACROSS INDIVIDUAL CV DEATH AND HF HOSPITALIZATION COMPONENTS^1,2

In PARADIGM-HF, 70% of patients were NYHA Class II.¹

In an exploratory analysis, ENTRESTO lowered NT-proBNP by 32% vs 7% with enalapril, compared to baseline (screening), at 4 weeks after randomization. NT-proBNP was analyzed in a subgroup and may not represent the full population. ENTRESTO CV effects are due to increased peptides and decreased angiotensin II effects, which result in decreased NT-proBNP.^1,4,5

^†Analyses of the components of the primary composite end point were not prospectively planned to be adjusted for multiplicity.
^‡Includes all CV deaths, with or without prior hospitalization.

PARADIGM-HF PRIMARY END POINT

PARADIGM-HF: Sudden cardiac death post hoc analysis

PARADIGM-HF STUDY DESIGN

PARADIGM-HF: Sudden cardiac death analysis limitations⁶

This was a post hoc analysis of adjudicated death events
Attributing causes of death in clinical trials is especially challenging in cases of suspected sudden cardiac death, and this classification does not necessarily imply a common pathophysiology
Autopsies were available in the minority of cases in PARADIGM-HF

^§Number of sudden deaths/CV deaths. Sudden death accounted for 45% of CV deaths.

PIONEER-HF: Starting early counts—in-hospital initiation of ENTRESTO reduced heart failure biomarkers and improved outcomes in stabilized patients^7,8

29% greater reduction in NT-proBNP from baseline vs enalapril at Weeks 4 and 8.
Ratio of change 0.71 (95% CI: 0.63-0.81); P<.001.⁷

A decrease in NT-proBNP of >30% from baseline has been associated with reduced risk of CV death and HF hospitalization.^5,9

See PIONEER-HF primary end point data below.

PIONEER-HF STUDY DESIGN

ENTRESTO can help your patients with HFrEF stay alive and out of the hospital longer^1¶

ENTRESTO reduced the risk of CV death and heart failure readmission vs enalapril in a post hoc analysis^8,10#

^¶Vs enalapril.
^#Readmission was defined as the first hospitalization after inpatient initiation of study drug.

When started in the hospital in stabilized patients, ENTRESTO reduced risk of CV death and HF readmission vs enalapril over 8 weeks.**^††

ENTRESTO reduced the risk of CV death and heart failure readmission vs enalapril in a post hoc analysis¹⁰**^††

**Readmission was defined as the first hospitalization after inpatient initiation of study drug.⁷
^††CV death and heart failure rehospitalizations (8-week, double-blind followed by 4-week, open-label period) events have been adjudicated as defined or probable. A patient is counted only once.

Patients started on ENTRESTO at baseline experienced greater reduction in events vs patients started on enalapril.

PIONEER-HF CV DEATH OR HEART FAILURE REHOSPITALIZATION ANALYSES LIMITATIONS

PIONEER-HF: CV death or heart failure rehospitalization analyses limitations⁸

These were post hoc analyses of a composite of retrospectively adjudicated (definite or probable) CV death or heart failure rehospitalization events; the study was powered for changes in NT-proBNP
Weeks 8-12, being open-label, could have an unknowable influence on observed outcomes
Results should be interpreted with caution due to the short time frame and infrequency of events

ENTRESTO delivered rapid and sustained reductions in NT-proBNP vs enalapril^4,5

When started in the hospital in stabilized patients, reduction in NT-proBNP was shown as early as Week 1 with ENTRESTO⁷

A decrease in NT-proBNP of >30% has been associated with reduced risk of CV death and heart failure hospitalization^5,9

In a real-world analysis within the Cleveland Clinic Health System, ENTRESTO patients had lower heart failure hospitalization rates vs an ACEi/ARB over 6 months¹¹

In addition to demonstrated outcomes from landmark clinical studies, ENTRESTO has gained experience in both real-world inpatient and outpatient settings^1,11

REAL-WORLD ANALYSIS STUDY METHODS, POPULATION, AND LIMITATIONS

Study Methods¹¹

Within a large multistate health care system (OH and FL) with 12 hospitals and over 100 outpatient practices, adult patients prescribed ENTRESTO were matched to patients prescribed an ACEi/ARB
The study cohort was retrospectively identified from August 2015 through July 2018, which preceded the FDA approval of the adult chronic HF indication of ENTRESTO to include HF patients with LVEF below normal in February 2021. The patients identified from these claims data and included in this analysis are considered to reflect the current on-label patient population of ENTRESTO^‡‡
Matching variables: age, sex, and EF%; hospital care vs outpatient care at baseline; index (baseline) date; Charlson Comorbidity Index; systolic blood pressure
HF hospitalizations were compared between the 2 groups
Eligible patients must have had HF and available EF data in the electronic medical record in order to be included

Study Population¹¹

Of 1794 patients who initiated ENTRESTO, 95.1% initiated it in an outpatient department
Baseline mean (SD) age was 64.2 (13.0) years; male: 70.3%
Baseline EFs are shown in the below table

Limitations¹¹

Patients with EF of 40% to 65% are underrepresented (<15%) in the sample identified
Patients were treated in 1 health care system
Medication decisions could have been influenced by system, provider, and patient factors
Patients were not randomized to groups
Nonstudied factors could have influenced findings as is inherent in such retrospective analyses

^‡‡Prior to February 2021, ENTRESTO was indicated for adult patients with HFrEF.

Decrease in rate of HF hospitalization

These real-world data complement clinical trial data from the PARADIGM-HF and PARAGON-HF clinical trials^1,11,12

In PARADIGM-HF, ENTRESTO reduced the risk of HF hospitalization^§§ in patients with HFrEF by 21% (2.8% ARR) vs enalapril
In PARAGON-HF, ENTRESTO reduced the rate of total HF hospitalization in patients with LVEF at or below the median (57%) by 25% (3.6 ARR^‖‖) vs valsartan

^§§Analyses of the components of the primary composite end point were not prospectively planned to be adjusted for multiplicity.
^‖‖Event rate per 100 patient-years.
ARR (PARADIGM-HF), absolute risk reduction; ARR (PARAGON-HF), absolute rate reduction; CI, confidence interval; OR, odds ratio.

PARADIGM-HF STUDY DESIGN

PARAGON-HF STUDY DESIGN

*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.¹

Definitions
ACEi, angiotensin-converting enzyme inhibitor; ADHF, acute decompensated heart failure; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; ARR, absolute risk reduction; BID, twice daily; BNP, brain natriuretic peptide; CI, confidence interval; HR, hazard ratio; KM, Kaplan–Meier; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NNT, number needed to treat; NYHA, New York Heart Association; OR, odds ratio; RR, relative reduction; RRR, relative risk reduction; SD, standard deviation; SBP, systolic blood pressure.

References
1. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.
2. McMurray JJV, Packer M, Desai AS, et al; on behalf of the PARADIGM-HF Committees Investigators. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16(7):817-825. doi:10.1002/ejhf
3. Kristensen SL, Martinez F, Jhund PS, et al. Geographic variations in the PARADIGM-HF heart failure trial. Eur Heart J. 2016;37(41):3167-3174. Nov 1;37(41):3167-3174. doi:10.1093/eurheartj/ehw226
4. Data on file. LCZ696 Clinical Study Report (CLCZ696B2314). Novartis Pharmaceuticals Corp; 2014.
5. Zile MR, Clagget BL, Prescott MF, et al. Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol. 2016;68(22):2425-2436. doi:10.1016/j.jacc.2016.09.931
6. Desai AS, McMurray JJ, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. 2015;36(30):1990-1997. doi:10.1093/eurheartj/ehv186
7. Velazquez EJ, Morrow DA, DeVore AD, et al; for the PIONEER-HF Investigators. Angiotensin–receptor-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548. doi:10.1056/NEJMoa1812851
8. Morrow DA, Velazquez EJ, DeVore AD, et al. Clinical outcomes in patients with acute decompensated heart failure randomly assigned to sacubitril/valsartan or enalapril in the PIONEER-HF trial. Circulation. 2019;139(19):2285-2288. doi:10.1161/CIRCULATIONAHA.118.039331
9. Bettencourt P, Azevedo A, Pimenta J, et al. N-terminal–pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110(15):2168-2174. doi:10.1161/01.CIR.0000144310.04433.BE
10. DeVore AD, Braunwald E, Morrow DA, et al; PIONEER-HF Investigators. Initiation of angiotensin-neprilysin inhibition after acute decompensated heart failure: secondary analysis of the open-label extension of the PIONEER-HF trial. JAMA Cardiol. 2020;5(2):202-207. doi:10.1001/jamacardio.2019.4665. Accessed December 12, 2019. Supplementary material accessed at https://jamanetwork.com/journals/jamacardiology/articleabstract/2756356
11. Albert N, Bena J, Morrison S, et al. Clinical outcomes when utilizing sacubitril/valsartan vs. ACEi/ARB in patients with HF and ejection fractions spanning from reduced to preserved—a retrospective, parallel, multi-group study. Paper presented at: Heart Failure Society of America. September 10-13, 2021.
12. US Food and Drug Administration. Novartis cardiovascular and renal drugs advisory committee briefing document, December 15, 2020. ENTRESTO^® (sacubitril/valsartan) for chronic heart failure and preserved ejection fraction. Accessed October 3, 2023. https://www.fda.gov/media/144377/download ↗

In HFrEF,

PARADIGM-HF: In the largest heart failure (HF) trial ever conducted, ENTRESTO^®was superior in keeping patients alive and out of the hospital vs an ACEi^1-3

PROVEN RISK REDUCTION IN COMPOSITE END POINT, WITH CONSISTENT RESULTS ACROSS INDIVIDUAL CV DEATH AND HF HOSPITALIZATION COMPONENTS^1,2

PARADIGM-HF PRIMARY END POINT

PARADIGM-HF: In HFrEF, ENTRESTO reduced heart failure hospitalization and CV death vs an ACEi

PARADIGM-HF: Sudden cardiac death post hoc analysis

PARADIGM-HF STUDY DESIGN

PARADIGM-HF: Sudden cardiac death analysis limitations⁶

PIONEER-HF: Starting early counts—in-hospital initiation of ENTRESTO reduced heart failure biomarkers and improved outcomes in stabilized patients^7,8

PIONEER-HF STUDY DESIGN

ENTRESTO can help your patients with HFrEF stay alive and out of the hospital longer^1¶

PIONEER-HF CV DEATH OR HEART FAILURE REHOSPITALIZATION ANALYSES LIMITATIONS

PIONEER-HF: CV death or heart failure rehospitalization analyses limitations⁸

ENTRESTO delivered rapid and sustained reductions in NT-proBNP vs enalapril^4,5

When started in the hospital in stabilized patients, reduction in NT-proBNP was shown as early as Week 1 with ENTRESTO⁷

In a real-world analysis within the Cleveland Clinic Health System, ENTRESTO patients had lower heart failure hospitalization rates vs an ACEi/ARB over 6 months¹¹

In addition to demonstrated outcomes from landmark clinical studies, ENTRESTO has gained experience in both real-world inpatient and outpatient settings^1,11

REAL-WORLD ANALYSIS STUDY METHODS, POPULATION, AND LIMITATIONS

These real-world data complement clinical trial data from the PARADIGM-HF and PARAGON-HF clinical trials^1,11,12

PARADIGM-HF STUDY DESIGN

PARAGON-HF STUDY DESIGN

Important Safety Information

Indication

Definitions & References

In HFrEF,

PARADIGM-HF: In the largest heart failure (HF) trial ever conducted, ENTRESTO® was superior in keeping patients alive and out of the hospital vs an ACEi1-3

PROVEN RISK REDUCTION IN COMPOSITE END POINT, WITH CONSISTENT RESULTS ACROSS INDIVIDUAL CV DEATH AND HF HOSPITALIZATION COMPONENTS1,2

PARADIGM-HF PRIMARY END POINT

PARADIGM-HF: Sudden cardiac death post hoc analysis

PARADIGM-HF STUDY DESIGN

PARADIGM-HF: Sudden cardiac death analysis limitations6

PIONEER-HF: Starting early counts—in-hospital initiation of ENTRESTO reduced heart failure biomarkers and improved outcomes in stabilized patients7,8

PIONEER-HF STUDY DESIGN

ENTRESTO can help your patients with HFrEF stay alive and out of the hospital longer1¶

PIONEER-HF CV DEATH OR HEART FAILURE REHOSPITALIZATION ANALYSES LIMITATIONS

PIONEER-HF: CV death or heart failure rehospitalization analyses limitations8

ENTRESTO delivered rapid and sustained reductions in NT-proBNP vs enalapril4,5

When started in the hospital in stabilized patients, reduction in NT-proBNP was shown as early as Week 1 with ENTRESTO7

In a real-world analysis within the Cleveland Clinic Health System, ENTRESTO patients had lower heart failure hospitalization rates vs an ACEi/ARB over 6 months11

In addition to demonstrated outcomes from landmark clinical studies, ENTRESTO has gained experience in both real-world inpatient and outpatient settings1,11

REAL-WORLD ANALYSIS STUDY METHODS, POPULATION, AND LIMITATIONS

These real-world data complement clinical trial data from the PARADIGM-HF and PARAGON-HF clinical trials1,11,12

PARADIGM-HF STUDY DESIGN

PARAGON-HF STUDY DESIGN

Important Safety Information

Indication

Definitions & References

PARADIGM-HF: In the largest heart failure (HF) trial ever conducted, ENTRESTO^®was superior in keeping patients alive and out of the hospital vs an ACEi^1-3

PROVEN RISK REDUCTION IN COMPOSITE END POINT, WITH CONSISTENT RESULTS ACROSS INDIVIDUAL CV DEATH AND HF HOSPITALIZATION COMPONENTS^1,2

PARADIGM-HF: Sudden cardiac death analysis limitations⁶

PIONEER-HF: Starting early counts—in-hospital initiation of ENTRESTO reduced heart failure biomarkers and improved outcomes in stabilized patients^7,8

ENTRESTO can help your patients with HFrEF stay alive and out of the hospital longer^1¶

PIONEER-HF: CV death or heart failure rehospitalization analyses limitations⁸

ENTRESTO delivered rapid and sustained reductions in NT-proBNP vs enalapril^4,5

When started in the hospital in stabilized patients, reduction in NT-proBNP was shown as early as Week 1 with ENTRESTO⁷

In a real-world analysis within the Cleveland Clinic Health System, ENTRESTO patients had lower heart failure hospitalization rates vs an ACEi/ARB over 6 months¹¹

In addition to demonstrated outcomes from landmark clinical studies, ENTRESTO has gained experience in both real-world inpatient and outpatient settings^1,11

These real-world data complement clinical trial data from the PARADIGM-HF and PARAGON-HF clinical trials^1,11,12