Now, 2 landmark studies, PARADIGM-HF and PIONEER-HF, join a growing body of evidence that ENTRESTO is a first-choice treatment for appropriate systolic HF patients1,2

The PIONEER-HF trial generated new evidence for in-hospital initiation of ENTRESTO

PIONEER-HF

ComParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode

PIONEER-HF Study Aim1

The PIONEER-HF trial, sponsored by Novartis Pharmaceuticals Corporation, sought to assess the NT-proBNP reduction and safety of in-hospital initiation of ENTRESTO compared with enalapril among HF patients with reduced EF [left ventricular ejection fraction (LVEF) ≤40%] who had been stabilized following admission for ADHF.

Study Outcomes1

  • Primary End Point: The time-averaged proportional change in NT-proBNP from baseline through weeks 4 and 8
  • Key Safety: The incidence of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema
  • Select Prespecified Exploratory: The incidence of rehospitalization* for heart failure by 8 weeks

Study Design1

PIONEER-HF was a multicenter, US only, randomized, double-blind, head-to-head clinical trial

Study_Design Study_Design_MOB
*Defined as first hospitalization after inpatient initiation of study drug.
Patients randomized to ENTRESTO received 2 doses of placebo to ensure a minimum 36-hour washout period prior to initiation of ARNI therapy.

Initial dose of study drug was determined by SBP at randomization:

SBP 100 to <120 mm Hg  Dose Level 1    ENTRESTO 24/26 mg BID or enalapril 2.5 mg BID

SBP ≥120 mm Hg        Dose Level 2    ENTRESTO 49/51 mg BID or enalapril 5 mg BID

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.

Initial dose of study drug was determined by SBP at randomization:

SBP 100 to <120 mm Hg

Dose Level 1 ENTRESTO 24/26 mg BID or enalapril 2.5 mg BID

SBP ≥120 mm Hg

Dose Level 2 ENTRESTO 49/51 mg BID or enalapril 5 mg BID

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.

Cohort Description1

  • 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
  • LVEF ≤40%
  • NYHA class II-IV
  • NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL

Hospitalized patients were determined to be stabilized when they met all of the following criteria:

  • SBP ≥100 mm Hg for 6 hours prior to randomization, no symptomatic hypotension
  • No increase (intensification) in intravenous (IV) diuretic dose within 6 hours prior to randomization
  • No IV vasodilators including nitrates within last 6 hours prior to randomization
  • No IV inotropic drugs for 24 hours prior to randomization

The median time for patients to meet the stabilization criteria was less than 3 days after initial presentation to the hospital.

Selected Baseline Demographics1


Study_Design Study_Design_MOB
*Defined as not receiving either medication at the time of index hospitalization.

Primary End Point Outcome1


Inpatient initiation of ENTRESTO resulted in a superior reduction in NT-proBNP from baseline to week 4/8

  • Subgroup analyses (e.g., age, race, HF history, treatment history) reflected a consistently beneficial effect of ENTRESTO compared to enalapril on the change in NT-proBNP
Study_Design Study_Design_MOB
  • Plasma NT-proBNP (pg/mL) values were averages from Week 4 and Week 8 visits
  • P-value and treatment comparison were evaluated using an ANCOVA model for a log-scaled response with treatment group as a class variable and the baseline value in logarithmic scale as a continuous covariate
  • Hazard ratios and confidence intervals for differences in clinical outcomes were calculated using a Cox Proportional Hazards model
  • Analytic variability (imprecision of the test) and the biological variability (expected variability within the subject over time) may influence the accuracy of a predictive value of a change in biomarkers. The change from baseline data should therefore be interpreted in light of the influence of the biological variability known to be present in systolic HF patients
  • Safety data were collected for only 8 weeks; therefore, adverse events that take longer to transpire may not have appeared in this study. Safety information should be interpreted in the context of prior trials with longer duration

ENTRESTO can help your patients with systolic HF stay alive and out of the hospital longer1*


ENTRESTO reduced the risk of CV death and HF readmission vs enalapril in a post hoc analysis1,8†

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

Study_Design Study_Design_MOB
*Vs enalapril.
Readmission was defined as the first hospitalization after inpatient initiation of study drug. 2
  • The study was powered for changes in NT-proBNP and secondary and exploratory end points should be interpreted with caution
  • This was a post hoc analysis of a composite of cardiovascular death or heart failure rehospitalization
  • The open-label portion of the study (weeks 8-12) could have an unknown impact on clinical and self-care decisions once providers and patients were unblinded to treatment
  • Blinded adjudication of CV death and HF hospitalization was performed by the clinical events committee post hoc
  • These results should be interpreted with caution due to the short time frame of the post hoc analyses of the CV death and HF hospitalization end point and infrequency of events
  • Adjudication of death and rehospitalization for HF was performed by a clinical events committee blinded to treatment arm
  • Cumulative event rates were calculated according to the Kaplan–Meier method and compared between randomized treatment groups using logrank test
  • Hazard ratios with associated Cls were calculated by using a Cox proportional hazards model. Tests for proportional hazards were met

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

Study_Design Study_Design_MOB
*Vs enalapril.
Readmission was defined as the first hospitalization after inpatient initiation of study drug. 2
CV death and HF 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.
  • The study was powered for changes in NT-proBNP and secondary and exploratory end points should be interpreted with caution
  • This was a post hoc analysis of a composite of cardiovascular death or heart failure rehospitalization
  • The open-label portion of the study (weeks 8-12) could have an unknown impact on clinical and self-care decisions once providers and patients were unblinded to treatment
  • Blinded adjudication of CV death and HF hospitalization was performed by the clinical events committee post hoc
  • These results should be interpreted with caution due to the short time frame of the post hoc analyses of the CV death and HF hospitalization end point and infrequency of events
  • Cumulative event rates were calculated according to the Kaplan–Meier method and compared between randomized treatment groups using logrank test
  • Hazard ratios with associated Cls were calculated by using a Cox proportional hazards model. Tests for proportional hazards were met

Adverse event profile was comparable to that in the PARADIGM-HF trial1,3,7


No new safety signals were observed

Study_Design Study_Design_MOB
  • There were no significant differences seen between the ENTRESTO group and the enalapril group with regard to rates of worsening renal function, hyperkalemia, symptomatic hypotension, or angioedema1
  • Angioedema events were adjudicated and confirmed in 6 cases of enalapril and 1 case of ENTRESTO (not statistically significant)1
Worsening renal function was defined by an increase in the serum creatinine concentration of O.5 mg/dL or more and a decrease in the estimated glomerular filtration rate of 25% or more.

In PARADIGM-HF, ENTRESTO was proven superior to enalapril (ACEi) in reducing CV death and HF hospitalization


The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial previously demonstrated that the use of ENTRESTO resulted in a lower risk of cardiovascular (CV) death or HF hospitalization than the use of enalapril in ambulatory outpatients who had received established high doses of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB).2

The CV effects of ENTRESTO are due to increased peptides and decreased angiotensin II effects, which result in decreased N-terminal pro-B-type natriuretic peptide (NT-proBNP).3 A decrease in NT-proBNP of >30% has been shown to be associated with reduced risk of CV death and HF hospitalization.4,5

ACEi=angiotensin-converting enzyme inhibitor.

PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic (NYHA Class II-IV) adult systolic HF patients (LVEF ≤40%). After discontinuing their existing ACEi or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice daily, followed by ENTRESTO 100 mg (49/51 mg) twice daily, increasing to 200 mg (97/103 mg) twice daily. Patients who successfully completed the run-in periods were then randomized to receive either ENTRESTO 200 mg (97/103 mg) (n=4209) twice daily or enalapril 10 mg (n=4233) twice daily. The median follow-up duration was 27 months, and patients were treated for up to 4.3 years.3 For the primary end point, composite of CV death or first HF hospitalization, ENTRESTO was superior to enalapril (P<0.0001). There was a reduction in each component: CV death 20% RRR, 3.2% ARR; HF hospitalization 21% RRR, 2.8% ARR.

NYHA=New York Heart Association.

levels of NT-proBNT
  • ENTRESTO resulted in a 26% greater reduction in NT-proBNP from the start of the enalapril run-in period to 4 weeks after randomization compared to enalapril
  • ENTRESTO CV effects are due to increased peptides and decreased angiotensin II effects, which results in decreased NT-proBNP3
  • A decrease in NT-proBNP of >30% has been shown to be associated with reduced heart failure hospitalization and cardiovascular death4,5
levels of NT-proBNT
  • ENTRESTO resulted in a 26% greater reduction in NT-proBNP from the start of the enalapril run-in period to 4 weeks after randomization compared to enalapril
  • ENTRESTO CV effects are due to increased peptides and decreased angiotensin II effects, which results in decreased NT-proBNP3
  • A decrease in NT-proBNP of >30% has been shown to be associated with reduced heart failure hospitalization and cardiovascular death4,5
  • Plasma NT-proBNP (pg/mL) values at the start of the enalapril run-in period were compared to values at the end of the enalapril run-in, at randomization, and at 4 weeks and 8 months after randomization
  • Changes in NT-proBNP were calculated using geometric means, and statistical comparisons were performed via an analysis of covariance in a log scale
  • Biomarker measurements, including NT-proBNP, were drawn and analyzed in a sub-group of the total PARADIGM-HF patient population and therefore might not represent the entire cohort of systolic HF patients studied
  • Analytic variability (imprecision of the test) and biological variability (expected variability within the subject over time) may influence the accuracy of a predictive value of a change in biomarkers. The change from baseline data should therefore be interpreted in light of the influence of the biological variability known to be present in systolic HF patients

See the Class I recommendation for ENTRESTO.

Discover the demonstrated safety and tolerability profile of ENTRESTO vs enalapril.

PARADIGM-HF trial was the largest clinical trial ever conducted in HF.

References: 1. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2018; Nov 11. doi: 10.1056/NEJMoa1812851. 2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 3. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; October 2019. 4. 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. 5. 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. 6. Data on file. LCZ696B2314 Clinical Study Report. Novartis Pharmaceuticals Corp; 2009. 7. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Eng/ J Med. 2018; Nov 11. doi: 10.1056/NEJMoa1812851. Supplementary protocol accessed at https://www.nejm.org/doisuppl/10.1056/NEJMoa1812851/suppl_file/nejmoa1812851_protocol.pdf. Accessed November 19, 2018. 8. DeVore AD, Braunwald E, Morrow AD, 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 [published online ahead of print December 11, 2019]. JAMA Cardiol. doi: 10.1001/jamacardio.2019.4665. Supplementary material accessed at https://jamanetwork.com/journals/jamacardiology/article-abstract/2756356. Accessed December 12, 2019.

ENTRESTO and the ENTRESTO logo are registered trademarks of Novartis AG.

INDICATION

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 ACE inhibitor or other ARB.

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, 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%).

Click here for full Prescribing Information, including Boxed WARNING.

References: 1. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2018; Nov 11. doi: 10.1056/NEJMoa1812851. 2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 3. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; October 2019. 4. 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. 5. 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. 6. Data on file. LCZ696B2314 Clinical Study Report. Novartis Pharmaceuticals Corp; 2009. 7. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Eng/ J Med. 2018; Nov 11. doi: 10.1056/NEJMoa1812851. Supplementary protocol accessed at https://www.nejm.org/doisuppl/10.1056/NEJMoa1812851/suppl_file/nejmoa1812851_protocol.pdf. Accessed November 19, 2018. 8. DeVore AD, Braunwald E, Morrow AD, 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 [published online ahead of print December 11, 2019]. JAMA Cardiol. doi: 10.1001/jamacardio.2019.4665. Supplementary material accessed at https://jamanetwork.com/journals/jamacardiology/article-abstract/2756356. Accessed December 12, 2019.

ENTRESTO and the ENTRESTO logo are registered trademarks of Novartis AG.
INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION

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.

INDICATION

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 ACE inhibitor or other ARB.

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, 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%).

Tap here for full Prescribing Information, including Boxed WARNING.