Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode.

NCT02554890 | Completed Phase 4 Results DMC

• 1 other identifier: CLCZ696BUS01
• Study Type: interventional
• Target: 887
• Locations: 1 country
• Sites: 123

Brief Summary

The purpose of this study was to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%).

Conditions

Acute Heart Failure

Keywords

Acute; Heart Failure; reduced ejection fraction; NTproBNP; Heart failure with reduced ejection fraction (HFREF)

Outcome Measures

Primary Outcomes (1)

• N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline

  To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction \[LVEF\] ≤ 40%) between week 4 and 8. Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.

  Baseline, Week 4 and Week 8

Secondary Outcomes (8)

• Number of Patients With Incidences of Symptomatic Hypotension

  8 weeks of treatment

• Number of Patients With Incidences of Hyperkalemia

  8 weeks of treatment

• Number of Patients With Incidences of Angioedema

  8 weeks of treatment

• Change From Baseline in High Sensitivity Troponin (Hs-Troponin)

  Baseline, Week 4/Week 8

• Change From Baseline in Urinary cGMP

  Baseline, Week 4 and Week 8

Study Arms (2)

sacubitril/valsartan (LCZ696)

EXPERIMENTAL

Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Drug: sacubitril/valsartan (LCZ696); Drug: enalapril matching placebo

Enalapril

ACTIVE COMPARATOR

Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)

Drug: Enalapril; Drug: sacubitril/valsartan (LCZ696) matching placebo

Interventions

sacubitril/valsartan (LCZ696) DRUG

sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.

Also known as: LCZ696

sacubitril/valsartan (LCZ696)

Enalapril DRUG

Enalapril tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.

Enalapril

sacubitril/valsartan (LCZ696) matching placebo DRUG

matching placebo of sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.

Enalapril

enalapril matching placebo DRUG

enalapril matching placebo tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.

sacubitril/valsartan (LCZ696)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
• Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.
• Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:
• SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
• No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
• No i.v. inotropic drugs for 24 hours prior to randomization
• No i.v. vasodilators including nitrates within last 6 hours prior to randomization
• LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of \>40%.
• Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.

You may not qualify if:

• Currently taking sacubitril/valsartan tablets or any use within the past 30 days.
• Enrollment in any other clinical trial involving an investigational agent or investigational device.
• History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).
• Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
• Requirement of treatment with both ACE inhibitor and ARB.
• eGFR \< 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.
• Serum potassium \> 5.2 mEq/L at screening.
• Known hepatic impairment (as evidenced by total bilirubin \> 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices
• Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (123)

Novartis Investigative Site

Birmingham, Alabama, 35294, United States

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Fort Smith, Arkansas, 72901, United States

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Little Rock, Arkansas, 72205, United States

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Bakersfield, California, 93301, United States

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Fresno, California, 93701, United States

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Long Beach, California, 90806, United States

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Los Angeles, California, 90033, United States

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Los Angeles, California, 90073, United States

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Orange, California, 92868, United States

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Pasadena, California, 91105, United States

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Sacramento, California, 95817-1460, United States

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San Diego, California, 92123, United States

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San Marino, California, 91108, United States

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San Pablo, California, 94806, United States

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Stanford, California, 94305, United States

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Denver, Colorado, United States

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Littleton, Colorado, 80120, United States

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Bridgeport, Connecticut, 06610, United States

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Hartford, Connecticut, 06102, United States

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Hartford, Connecticut, 06105, United States

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West Haven, Connecticut, 06516, United States

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Washington D.C., District of Columbia, 20422, United States

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Atlantis, Florida, 33462, United States

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Daytona Beach, Florida, 32117, United States

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Fort Lauderdale, Florida, 33308, United States

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Gainesville, Florida, 32608, United States

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Gainesville, Florida, 32610, United States

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Hollywood, Florida, 33021, United States

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Jacksonville, Florida, 32209-6511, United States

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Jacksonville, Florida, 32216, United States

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Lakeland, Florida, 33805, United States

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Sarasota, Florida, 34239, United States

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Tampa, Florida, 33612, United States

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Tampa, Florida, 34667, United States

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Vero Beach, Florida, 32960, United States

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Winter Haven, Florida, 33881, United States

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Augusta, Georgia, 30901, United States

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Macon, Georgia, 31201, United States

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Marietta, Georgia, 30060, United States

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Boise, Idaho, 83702, United States

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Aurora, Illinois, 60504, United States

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Elk Grove Village, Illinois, 60007, United States

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Oakbrook Terrace, Illinois, 60181, United States

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Park Ridge, Illinois, 60068, United States

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Peoria, Illinois, 61606, United States

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Peoria, Illinois, 61614, United States

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Winfield, Illinois, 60190, United States

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Elkhart, Indiana, 46514, United States

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Indianapolis, Indiana, 46202, United States

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Indianapolis, Indiana, 46237, United States

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Muncie, Indiana, 47303-3400, United States

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Richmond, Indiana, 47374, United States

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Des Moines, Iowa, 50314, United States

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Kansas City, Kansas, 66103, United States

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Louisville, Kentucky, 40205, United States

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Louisville, Kentucky, 40245, United States

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Alexandria, Louisiana, 71301, United States

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Baton Rouge, Louisiana, 70808, United States

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Slidell, Louisiana, 70458, United States

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Bangor, Maine, 04401, United States

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Annapolis, Maryland, 21401, United States

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Baltimore, Maryland, 21215, United States

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Boston, Massachusetts, 02215, United States

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Boston, Massachusetts, United States

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Ann Arbor, Michigan, 48106, United States

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Bay City, Michigan, 48708, United States

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Detroit, Michigan, 48201, United States

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Maplewood, Minnesota, 55109, United States

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Minneapolis, Minnesota, 55417, United States

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Saint Paul, Minnesota, 55101, United States

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Saint Paul, Minnesota, 55102, United States

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Hattiesburg, Mississippi, 39401, United States

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Jackson, Mississippi, 39216, United States

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Kansas City, Missouri, 64108, United States

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Omaha, Nebraska, 68198, United States

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Reno, Nevada, 89502, United States

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Camden, New Jersey, 08103-3117, United States

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Elmer, New Jersey, 08318, United States

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Haddon Heights, New Jersey, 08035, United States

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Newark, New Jersey, 07102, United States

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Brooklyn, New York, 11215, United States

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Buffalo, New York, 14215, United States

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Johnson City, New York, 13790, United States

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Manhasset, New York, 11030, United States

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New York, New York, 10016, United States

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New York, New York, 10029, United States

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New York, New York, 10032, United States

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Poughkeepsie, New York, 12601, United States

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Rochester, New York, 14621, United States

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Staten Island, New York, 10310, United States

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The Bronx, New York, 10461, United States

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The Bronx, New York, 10467-2490, United States

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Chapel Hill, North Carolina, 27599, United States

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Greenville, North Carolina, 27834, United States

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Winston-Salem, North Carolina, 27157, United States

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Grand Forks, North Dakota, 58201, United States

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Cincinnati, Ohio, 45220, United States

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Toledo, Ohio, 43608, United States

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Oklahoma City, Oklahoma, 73122, United States

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Tulsa, Oklahoma, 74104, United States

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Abington, Pennsylvania, 19001, United States

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Camp Hill, Pennsylvania, 17011, United States

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Natrona Heights, Pennsylvania, 15065, United States

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Philadelphia, Pennsylvania, 19102 2293, United States

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Providence, Rhode Island, 02903, United States

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Charleston, South Carolina, 29403, United States

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Greenville, South Carolina, 29615, United States

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Rapid City, South Dakota, 57701, United States

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Nashville, Tennessee, 37203, United States

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Nashville, Tennessee, 37212, United States

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Dallas, Texas, 75204, United States

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Dallas, Texas, 75390, United States

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Houston, Texas, 77030, United States

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Plano, Texas, 75093, United States

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San Antonio, Texas, 78229, United States

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White River Junction, Vermont, 05009, United States

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Charlottesville, Virginia, 22908, United States

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Lynchburg, Virginia, 24501, United States

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Richmond, Virginia, 23298, United States

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Virginia Beach, Virginia, 23454, United States

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Clarksburg, West Virginia, 26301, United States

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Madison, Wisconsin, 53792-1615, United States

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Novartis Investigative Site

Wausau, Wisconsin, 54401, United States

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Related Publications (8)

• Velazquez EJ, Morrow DA, DeVore AD, Ambrosy AP, Duffy CI, McCague K, Hernandez AF, Rocha RA, Braunwald E. Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Am Heart J. 2018 Apr;198:145-151. doi: 10.1016/j.ahj.2018.01.004. Epub 2018 Jan 10.

  PMID: 29653636 BACKGROUND

• Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11.

  PMID: 30415601 BACKGROUND

• Morrow DA, Velazquez EJ, DeVore AD, Desai AS, Duffy CI, Ambrosy AP, Gurmu Y, McCague K, Rocha R, Braunwald E. Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial. Circulation. 2019 May 7;139(19):2285-2288. doi: 10.1161/CIRCULATIONAHA.118.039331. No abstract available.

  PMID: 30955360 BACKGROUND

• Morrow DA, Velazquez EJ, DeVore AD, Prescott MF, Duffy CI, Gurmu Y, McCague K, Rocha R, Braunwald E. Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial. Eur Heart J. 2019 Oct 21;40(40):3345-3352. doi: 10.1093/eurheartj/ehz240.

  PMID: 31093657 BACKGROUND

• Berardi C, Braunwald E, Morrow DA, Mulder HS, Duffy CI, O'Brien TX, Ambrosy AP, Chakraborty H, Velazquez EJ, DeVore AD; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Black Americans: Data From the PIONEER-HF Trial. JACC Heart Fail. 2020 Oct;8(10):859-866. doi: 10.1016/j.jchf.2020.06.019. Epub 2020 Sep 9.

  PMID: 32919915 DERIVED

• Ambrosy AP, Braunwald E, Morrow DA, DeVore AD, McCague K, Meng X, Duffy CI, Rocha R, Velazquez EJ; PIONEER-HF Investigators. Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists. J Am Coll Cardiol. 2020 Sep 1;76(9):1034-1048. doi: 10.1016/j.jacc.2020.06.073.

  PMID: 32854838 DERIVED

• Berg DD, Braunwald E, DeVore AD, Lala A, Pinney SP, Duffy CI, Gurmu Y, Velazquez EJ, Morrow DA. Efficacy and Safety of Sacubitril/Valsartan by Dose Level Achieved in the PIONEER-HF Trial. JACC Heart Fail. 2020 Oct;8(10):834-843. doi: 10.1016/j.jchf.2020.06.008. Epub 2020 Aug 12.

  PMID: 32800511 DERIVED

• DeVore AD, Braunwald E, Morrow DA, Duffy CI, Ambrosy AP, Chakraborty H, McCague K, Rocha R, Velazquez EJ; 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 Feb 1;5(2):202-207. doi: 10.1001/jamacardio.2019.4665.

  PMID: 31825471 DERIVED

Related Links

• A Plain Language Trial Summary is available on novartisclinicatrials.com

MeSH Terms

Conditions

Heart Failure

Interventions

sacubitril; Valsartan; sacubitril and valsartan sodium hydrate drug combination; Enalapril

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Dipeptides; Oligopeptides; Peptides

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 17, 2015
• First Posted: September 18, 2015
• Study Start: April 29, 2016
• Primary Completion: June 29, 2018
• Study Completion: July 24, 2018
• Last Updated: January 5, 2021
• Results First Posted: September 24, 2019

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will share

Locations

US (123)