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PARADIGM-HF
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ENTRESTO® can help your patients with HFrEF stay alive and out of the hospital longer1†
In PARADIGM-HF, the largest heart failure trial ever conducted, ENTRESTO was proven superior to enalapril1-3

ARR=absolute risk reduction; CV=cardiovascular; HFrEF=heart failure with reduced ejection fraction; NNT=number needed to treat;
RRR=relative risk reduction.
†Vs enalapril.
‡Analyses of the components of the primary composite end point
were not prospectively planned to be adjusted for multiplicity.1
§Includes all CV deaths, with or without prior
hospitalization.1
PARADIGM-HF PRIMARY END POINT
PARADIGM-HF: Time to first occurrence of CV death or heart failure hospitalization1

IN CV DEATH OR HF HOSPITALIZATION
AS FIRST EVENT
ARR=absolute risk reduction; CI=confidence interval; HR=hazard ratio;
KM=Kaplan–Meier; NNT=number needed to treat; RRR=relative risk reduction.
The median follow-up duration was 27 months and patients were treated
for up to 4.3 years.
PARADIGM-HF STUDY DESIGN
PARADIGM-HF study design1,4

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There were two 36-hour washout periods during the PARADIGM-HF run-in period to minimize the potential risk of angioedema due to overlapping ACE-neprilysin inhibition—the first after completing the enalapril run-in period and the second after completing the ENTRESTO run-in period2
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin ‖ receptor blocker.
∥All patients were on an ACEi or ARB prior to the run-in period.1
¶Patients were treated for up to 4.3 years.1
PARADIGM-HF: Rapid and sustained reductions in NT-proBNP vs enalapril6,7
Reductions in NT-proBNP were sustained through 8 months with ENTRESTO in an exploratory analysis

NT-proBNP=N-terminal prohormone of brain natriuretic peptide.
NT-proBNP=N-terminal prohormone of brain natriuretic peptide.
RR=relative reduction.
#From the start of enalapril run-in period to 4 weeks after randomization,
compared to enalapril.
ENTRESTO CV effects are attributed to increased levels of peptides and decreased angiotensin II effects, which resulted in decreased NT-proBNP.1
PARADIGM-HF STUDY NT-proBNP ANALYSIS LIMITATIONS
PARADIGM-HF: NT-proBNP analysis study limitations2,7
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This was a prespecified exploratory end point
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NT-proBNP was analyzed in a subgroup and may not represent the full population
NT-proBNP=N-terminal prohormone of brain natriuretic peptide.

Learn how ENTRESTO affected the risk of CV death and HF readmission vs enalapril in a post hoc analysis**
**Readmission was defined as the first hospitalization after inpatient initiation of study drug.8
*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
ENTRESTO® can help your patients with HFrEF stay alive and out of the hospital longer1†
ENTRESTO reduced the risk of CV death and heart failure readmission vs enalapril in a post hoc analysis8,9‡
Double-blind period
Click here for PIONEER-HF Primary End Point

ARR=absolute risk reduction; RRR=relative risk reduction.
†Versus enalapril.
‡Readmission was defined as the first hospitalization after
inpatient initiation of study drug.6
Click here for PIONEER-HF Primary End Point
Double-blind period
Click here for PIONEER-HF Primary End Point

ARR=absolute risk reduction; CV=cardiovascular; HR=hazard ratio; RRR=relative risk reduction.
†Vs enalapril.
‡Readmission was defined as the first hospitalization after
inpatient initiation of study drug.6
Click here for PIONEER-HF Primary End Point
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 analysis9§∥
Open-label extension

ARR=absolute risk reduction; CV=cardiovascular; HR=hazard ratio; RRR=relative risk reduction.
§Readmission was defined as the first hospitalization after
inpatient initiation of study drug.10
∥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 STUDY DESIGN
PIONEER-HF study design10,11
PIONEER-HF was a multicenter, US only, randomized, double-blind, active-controlled clinical trial

Patients taking low dose or no ACEi/ARB at randomization were initiated on ENTRESTO 49/51 mg if their SBP was ≥120 mm Hg. Patients were up-titrated as early as week 1 and again at weeks 2, 4, and 6 up to ENTRESTO 97/103 mg BID or enalapril 10 mg BID, as tolerated, based on their blood pressure. Follow labeled dosing recommendations.
¶Entering the open-label phase, regardless of prior drug or dose, all patients were administered ENTRESTO 49/51 mg BID and were titrated as early as week 1 to the target dose 97/103 mg BID. Follow labeled dosing recommendations.
Readmission (rehospitalization) was defined as the first hospitalization after inpatient initiation of study drug. Adjudication of readmission for Heart Failure and cause of death were adjudicated post hoc.
ACEi=angiotensin-converting enzyme inhibitor; ADHF=acute decompensated heart failure; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor-neprilysin inhibitor; BID=twice daily; BNP=brain natriuretic peptide; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; SBP=systolic blood pressure.
Patients randomized 1:1 to enalapril or ENTRESTO
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Enalapril: Patients (in-hospital) randomized to the enalapril treatment group received enalapril from the first dose (n=441)
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ENTRESTO: Patients (in-hospital) randomized to the ENTRESTO treatment group received 2 doses of placebo before receiving any dose of ENTRESTO to ensure the minimum 36-hour washout period prior to initiation of ARNI (n=440)
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All patients had a 36-hour washout period prior to starting the open label extension
Cohort Description
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This study included 881 patients ≥18 years of age who had been hemodynamically stabilized following hospitalization for a primary diagnosis of ADHF, including signs and symptoms of fluid overload
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LVEF ≤40%
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NYHA class II-IV
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NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL
Study Outcomes
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Primary end point: the time-averaged proportional change in NT-proBNP from baseline through weeks 4 and 8
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Key safety: the incidence of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema
Patients taking low dose or no ACEi/ARB at randomization were initiated on ENTRESTO 49/51 mg if their SBP was ≥120 mm Hg. Patients were up-titrated as early as week 1 and again at weeks 2, 4, and 6 up to ENTRESTO 97/103 mg BID or enalapril 10 mg BID, as tolerated, based on their blood pressure. Follow labeled dosing recommendations.
¶Entering the open-label phase, regardless of prior drug or dose, all patients were administered ENTRESTO 49/51 mg BID and were titrated as early as week 1 to the target dose 97/103 mg BID. Follow labeled dosing recommendations.
Readmission (rehospitalization) was defined as the first hospitalization after inpatient initiation of study drug. Adjudication of readmission for Heart Failure and cause of death were adjudicated post hoc.
ACEi=angiotensin-converting enzyme inhibitor; ADHF=acute decompensated heart failure; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor-neprilysin inhibitor; BID=twice daily; BNP=brain natriuretic peptide; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; SBP=systolic blood pressure.
PIONEER-HF: CV DEATH OR HEART FAILURE
REHOSPITALIZATION ANALYSES LIMITATIONS
PIONEER-HF: CV death or heart failure rehospitalization analyses limitations8
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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
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Weeks 8-12, being open-label, could have an unknowable influence on observed outcomes
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Results should be interpreted with caution due to the short time frame and infrequency of events
NT-proBNP=N-terminal prohormone of brain natriuretic peptide.
ENTRESTO delivered rapid and sustained reductions in NT-proBNP vs enalapril6,7
When started in the hospital in stabilized patients, reduction in NT-proBNP was shown as early as Week 1 with ENTRESTO10
The
primary end point
was the
time-averaged proportional change in
NT-proBNP
at 4 and 8 weeks:
ENTRESTO 47%, enalapril 25%.

NT-proBNP=N-terminal prohormone of brain natriuretic peptide;
RoC=Ratio of Change; RR=relative reduction.
A decrease in NT-proBNP of >30% has been associated with reduced risk of
CV death and heart failure hospitalization7,12

See biomarker and echocardiographic data in HFrEF patients taking ENTRESTO
HFrEF=heart failure with reduced ejection fraction.
*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