Clinical trial NCT02554890: Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode.
Official title: A Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Enalapril on Changes in NT-proBNP and Safety and Tolerability of In-hospital Initiation of LCZ696 Compared to Enalapril in HFrEF Patients Who Have Been Stabilized Following Hospitalization for Acute Decompensated Heart Failure (ADHF).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Acute Heart Failure
Keywords: Acute
Heart Failure
reduced ejection fraction
NTproBNP
Heart failure with reduced ejection fraction (HFREF)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-09-18
Enrollment: 887
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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%).


Eligibility criteria: Key Inclusion Criteria:

1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
2. 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.
3. 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
4. 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%.
5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.

Key Exclusion Criteria:

1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days.
2. Enrollment in any other clinical trial involving an investigational agent or investigational device.
3. History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).
4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
5. Requirement of treatment with both ACE inhibitor and ARB.
6. eGFR \< 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.
7. Serum potassium \> 5.2 mEq/L at screening.
8. 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
9. 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.
10. 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.
11. 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.

Primary outcomes:
measure: N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline
timeFrame: Baseline, Week 4 and Week 8
Secondary outcomes:
measure: Number of Patients With Incidences of Symptomatic Hypotension
timeFrame: 8 weeks of treatment
measure: Number of Patients With Incidences of Hyperkalemia
timeFrame: 8 weeks of treatment
measure: Number of Patients With Incidences of Angioedema
timeFrame: 8 weeks of treatment
measure: Change From Baseline in High Sensitivity Troponin (Hs-Troponin)
timeFrame: Baseline, Week 4/Week 8
measure: Change From Baseline in Urinary cGMP
timeFrame: Baseline, Week 4 and Week 8
measure: Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio
timeFrame: Baseline, Week 4 and Week 8
measure: Change From Baseline in BNP to NTproBNP Ratio
timeFrame: baseline, Week 4 and Week 8
measure: N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8
timeFrame: Baseline, Week 8
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Fort Smith
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Little Rock
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Bakersfield
country: United States
facility: Novartis Investigative Site
state: California
city: Fresno
country: United States
facility: Novartis Investigative Site
state: California
city: Long Beach
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facility: Novartis Investigative Site
state: California
city: Los Angeles
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facility: Novartis Investigative Site
state: California
city: Los Angeles
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facility: Novartis Investigative Site
state: California
city: Orange
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facility: Novartis Investigative Site
state: California
city: Pasadena
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facility: Novartis Investigative Site
state: California
city: Sacramento
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facility: Novartis Investigative Site
state: California
city: San Diego
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state: California
city: San Marino
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city: San Pablo
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city: Stanford
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city: Denver
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facility: Novartis Investigative Site
state: Colorado
city: Littleton
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state: Colorado
city: Bridgeport
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facility: Novartis Investigative Site
state: Connecticut
city: Hartford
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facility: Novartis Investigative Site
state: Connecticut
city: Hartford
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facility: Novartis Investigative Site
state: Connecticut
city: West Haven
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facility: Novartis Investigative Site
state: Connecticut
city: Washington
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facility: Novartis Investigative Site
state: District of Columbia
city: Atlantis
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facility: Novartis Investigative Site
state: Florida
city: Daytona Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Fort Lauderdale
country: United States
facility: Novartis Investigative Site
state: Florida
city: Gainesville
country: United States
facility: Novartis Investigative Site
state: Florida
city: Gainesville
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state: Florida
city: Hollywood
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state: Florida
city: Jacksonville
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facility: Novartis Investigative Site
state: Florida
city: Jacksonville
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state: Florida
city: Lakeland
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state: Florida
city: Sarasota
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facility: Novartis Investigative Site
state: Florida
city: Tampa
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facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Vero Beach
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facility: Novartis Investigative Site
state: Florida
city: Winter Haven
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facility: Novartis Investigative Site
state: Florida
city: Augusta
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facility: Novartis Investigative Site
state: Georgia
city: Macon
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facility: Novartis Investigative Site
state: Georgia
city: Marietta
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state: Georgia
city: Boise
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state: Idaho
city: Aurora
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facility: Novartis Investigative Site
state: Illinois
city: Elk Grove Village
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facility: Novartis Investigative Site
state: Illinois
city: Oakbrook Terrace
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state: Illinois
city: Park Ridge
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city: Peoria
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city: Peoria
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city: Winfield
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state: Illinois
city: Elkhart
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facility: Novartis Investigative Site
state: Indiana
city: Indianapolis
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facility: Novartis Investigative Site
state: Indiana
city: Indianapolis
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facility: Novartis Investigative Site
state: Indiana
city: Muncie
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state: Indiana
city: Richmond
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state: Indiana
city: Des Moines
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state: Iowa
city: Kansas City
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state: Kansas
city: Louisville
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state: Kentucky
city: Louisville
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state: Kentucky
city: Alexandria
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state: Louisiana
city: Baton Rouge
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state: Louisiana
city: Slidell
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state: Louisiana
city: Bangor
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facility: Novartis Investigative Site
state: Maine
city: Annapolis
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facility: Novartis Investigative Site
state: Maryland
city: Baltimore
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facility: Novartis Investigative Site
state: Maryland
city: Boston
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facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Ann Arbor
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facility: Novartis Investigative Site
state: Michigan
city: Bay City
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facility: Novartis Investigative Site
state: Michigan
city: Detroit
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facility: Novartis Investigative Site
state: Michigan
city: Maplewood
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facility: Novartis Investigative Site
state: Minnesota
city: Minneapolis
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facility: Novartis Investigative Site
state: Minnesota
city: Saint Paul
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Saint Paul
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Hattiesburg
country: United States
facility: Novartis Investigative Site
state: Mississippi
city: Jackson
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facility: Novartis Investigative Site
state: Mississippi
city: Kansas City
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facility: Novartis Investigative Site
state: Missouri
city: Omaha
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facility: Novartis Investigative Site
state: Nebraska
city: Reno
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facility: Novartis Investigative Site
state: Nevada
city: Camden
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state: New Jersey
city: Elmer
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state: New Jersey
city: Haddon Heights
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state: New Jersey
city: Newark
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state: New Jersey
city: Bronx
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state: New York
city: Bronx
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state: New York
city: Brooklyn
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state: New York
city: Buffalo
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city: Johnson City
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state: New York
city: Manhasset
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state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Poughkeepsie
country: United States
facility: Novartis Investigative Site
state: New York
city: Rochester
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facility: Novartis Investigative Site
state: New York
city: Staten Island
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facility: Novartis Investigative Site
state: New York
city: Chapel Hill
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facility: Novartis Investigative Site
state: North Carolina
city: Greenville
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facility: Novartis Investigative Site
state: North Carolina
city: Winston-Salem
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facility: Novartis Investigative Site
state: North Carolina
city: Grand Forks
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facility: Novartis Investigative Site
state: North Dakota
city: Cincinnati
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facility: Novartis Investigative Site
state: Ohio
city: Toledo
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facility: Novartis Investigative Site
state: Ohio
city: Oklahoma City
country: United States
facility: Novartis Investigative Site
state: Oklahoma
city: Tulsa
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state: Oklahoma
city: Abington
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state: Pennsylvania
city: Camp Hill
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state: Pennsylvania
city: Natrona Heights
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facility: Novartis Investigative Site
state: Pennsylvania
city: Philadelphia
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state: Pennsylvania
city: Providence
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facility: Novartis Investigative Site
state: Rhode Island
city: Charleston
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facility: Novartis Investigative Site
state: South Carolina
city: Greenville
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facility: Novartis Investigative Site
state: South Carolina
city: Rapid City
country: United States
facility: Novartis Investigative Site
state: South Dakota
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Nashville
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facility: Novartis Investigative Site
state: Tennessee
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Plano
country: United States
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state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: White River Junction
country: United States
facility: Novartis Investigative Site
state: Vermont
city: Charlottesville
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Lynchburg
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Virginia Beach
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Clarksburg
country: United States
facility: Novartis Investigative Site
state: West Virginia
city: Madison
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Wausau
country: United States
facility: Novartis Investigative Site
state: Wisconsin
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.