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PARADIGM-HF

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PARADIGM-HF

PIONEER-HF

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

In PARADIGM-HF, the largest HF trial ever conducted, ENTRESTO was proven superior to enalapril1-3

ARR=absolute risk reduction; CV=cardiovascular; NNT=number needed to treat; RRR=relative risk reduction.
*Versus 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 KM CURVE

PARADIGM-HF: Time to first occurrence of CV death or HF hospitalization1
PARADIGM-HF: Time to first occurrence of CV death or HF hospitalization

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
PARADIGM-HF study design
  • 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

§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 a post hoc analysis

PARADIGM-HF: Rapid and sustained reductions in NT-proBNP vs enalapril

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 limitations4,8
  • Biomarker measurements, including NT-proBNP were drawn and analyzed in a subgroup of the total PARADIGM-HF patient population and therefore might not represent the entire cohort of systolic HF patients studied

  • Biological variability may influence the accuracy of predictive value of a change in biomarkers. The change from baseline data should be interpreted in light of this influence

ACC/AHA/HFSA CLASS I RECOMMENDATION FOR ENTRESTO

Recommendation for chronic systolic HF patients was given 10 months after approval6
ACC/AHA/HFSA CLASS I RECOMMENDATION FOR ENTRESTO
  • In the guideline update, ENTRESTO, a fixed combination of an angiotensin receptor blocker and a neprilysin inhibitor, is referred to as an ARNI

ACC=American College of Cardiology; AHA=American Heart Association; B-R=Level of Evidence B, randomized clinical trial; C-EO=Level of Evidence C, consensus of expert opinion;
COR=Class of Recommendation; HFSA=Heart Failure Society of America; LOE=Level of Evidence; RAAS=renin-angiotensin-aldosterone system.
#In conjunction with evidence-based beta blockers and aldosterone antagonists in select patients. **NYHA Class II or III. ††Who are otherwise tolerating an ACEi or ARB.

ENTRESTO IS AN ESSENTIAL HF TREATMENT–A FIRST CHOICE

INSTEAD OF AN ACEi/ARB FOR YOUR PATIENTS WITH SYSTOLIC HF

VIEW FULL GUIDELINES

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 analysis10,11†

Double-Blind Period

Click here for PIONEER-HF Primary End Point

Double-Blind Period

ARR=absolute risk reduction; RRR=relative risk reduction.
*Vs enalapril.
Readmission was defined as the first hospitalization after inpatient initiation of study drug.8

Click here for PIONEER-HF Primary End Point

Double-Blind Period

Click here for PIONEER-HF Primary End Point

Double-Blind Period

ARR=absolute risk reduction; RRR=relative risk reduction.
*Vs enalapril. Readmission was defined as the first hospitalization after inpatient initiation of study drug.8

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 HF readmission vs enalapril in a post hoc analysis11‡§

Open-label extension

Open-label extension

ARR=absolute risk reduction; RRR=relative risk reduction.
Readmission was defined as the first hospitalization after inpatient initiation of study drug.8 §CV death and HF rehospitalizations (8-week, double-blind followed by 4-week, open-label period) events have been adjudicated as defined or probably. 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 design8,12

PIONEER-HF was a multicenter, US only, randomized, double-blind, active-controlled clinical trial

PIONEER-HF study design

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 HF and cause of death were adjudicated post hoc.
ACEi=ACE inhibitor; ADHF=acute decompensated heart failure; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor-neprilysin inhibitor; BID=twice daily; BNP=B-type natriuretic peptide; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; SBP=systolic blood pressure.

Patients randomized 1:1 to enalapril or ENTRESTO

  • Enalapril: Patients (in-hospital) randomized to the enalapril treatment group received enalapril from the first dose (n=441)

  • 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)

  • All patients had a 36-hour washout period prior to starting the open label extension

Cohort Description

  • 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

Study Outcomes

  • 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

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 HF and cause of death were adjudicated post hoc.
ACEi=ACE inhibitor; ADHF=acute decompensated heart failure; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor-neprilysin inhibitor; BID=twice daily; BNP=B-type natriuretic peptide; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; SBP=systolic blood pressure.

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 ENTRESTO8

The primary end point was the time-averaged proportional change in NT-proBNP at 4 and 8 weeks:
ENTRESTO 47%, enalapril 25%.

ENTRESTO delivered rapid and sustained reductions in NT-proBNP vs enalapril

A decrease in NT-proBNP of >30% has been shown to be associated with reduction risk of
CV death and HF hospitalization6,13

PIONEER-HF STUDY LIMITATIONS

PIONEER-HF: post hoc study limitations10
  • These were post hoc analyses of a composite of cardiovascular death or heart failure rehospitalization; the study was powered for changes in NT-proBNP

  • 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

  • These results should be interpreted with caution due to the short time frame and infrequency of events

PIONEER-HF: study limitations10,14
  • Biological variability may influence the accuracy of a predictive value of a change in biomarkers. The change from baseline data should be interpreted in light of this influence

  • 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

NT-proBNP=N-terminal pro–b-type natriuretic peptide.

EXPAND

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

COLLAPSE

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. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; October 2019. 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. 3. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation. 2017;136(17):1643-1658. 4. McMurray JJV, Packer M, Desai AS, et al; for the PARADIGM-HF Investigators and Committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 5. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310:452-454. 6. Zile MR, Claggett 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. 7. Data on file. LCZ696 Clinical Study Report (CLCZ696B2314). Novartis Pharmaceuticals Corp; 2014. 8. Velazquez EJ, Morrow DA, DeVore AD, et al; for the PIONEER-HF Investigators. Angiotensin–neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548. 9. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161. 10. 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. 11. 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. 12. Data on file. LCZ696 clinical trial protocol CLCZ696BUS01. Novartis Pharmaceuticals Corp; August 31, 2015. 13. 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. 14. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. November 11, 2018. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1812851/
supplfile/nejmoa1812851appendix.pdf.

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