Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event (HFpEF Decompensation) Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation (PARAGLIDE-HF)
PARAGLIDE-HF
A Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Valsartan on Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event (HFpEF Decompensation) Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation (PARAGLIDE-HF)
1 other identifier
interventional
467
2 countries
97
Brief Summary
The effect of sacubitril/valsartan vs. valsartan on changes in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event (HFpEF decompensation) who had been stabilized and initiated at the time of or within 30 days post-decompensation.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Jun 2019
Typical duration for phase_3
97 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 13, 2019
CompletedFirst Posted
Study publicly available on registry
June 17, 2019
CompletedStudy Start
First participant enrolled
June 29, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 14, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
December 14, 2022
CompletedResults Posted
Study results publicly available
July 29, 2024
CompletedMarch 6, 2025
March 1, 2025
3.5 years
June 13, 2019
November 22, 2023
March 4, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8
To demonstrate the effect of sacubitril/valsartan vs. valsartan on time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to weeks 4 and 8 in heart failure with preserved ejection fraction (HFpEF) patients with a worsening heart failure event (HFpEF decompensation) who have been stabilized for and initiated at the time of or within 30 days post-decompensation. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. The change from baseline to average of Week 4 and Week 8 was expressed as the geometric mean of the ratio: Week - 8/Baseline. NT-proBNP is a protein produced in large amounts by the heart when it is not working properly, as in heart failure. Baseline value was the last non-missing assessment of plasma NT-proBNP before the first administration of study drug.
Baseline, Average of Week 4 and Week 8
Secondary Outcomes (7)
Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome
Up to 84 weeks
EAC Adjudicated Recurrent Composite Events
Up to Week 84
Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function
Up to Week 84
Proportional Change in NT-proBNP From Baseline to Week 8
Baseline and Week 8
Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8
Baseline, Week 4 and Week 8
- +2 more secondary outcomes
Study Arms (2)
sacubitril/valsartan (LCZ696)
EXPERIMENTALStudy treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg twice daily (Dose Level 3). Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan , and one tablet of valsartan matching placebo)
valsartan
ACTIVE COMPARATORStudy treatment was titrated to the target dose of valsartan 160 mg twice daily (Dose Level 3). Patients were required to take a total of two tablets twice daily (one tablet of active valsartan, and one tablet of sacubitril and valsartan matching placebo)
Interventions
Sacubitril/valsartan (LCZ696) was available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily
Valsartan was available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily
Sacubitril/valsartan (LCZ696) matching placebo was available as tablet form to be taken orally, twice daily
Valsartan matching placebo was available as tablet form to be taken orally, twice daily
Eligibility Criteria
You may qualify if:
- Signed informed consent must be obtained prior to participation in the study
- Patients \>=18 years of age, male or female
- Current hospitalization for Worsening Heart Failure (WHF) (HFpEF decompensation), or within 30 days of discharge following a WHF event (defined as hospitalization, emergency department (ED) visit or out-of-hospital urgent HF visit, all requiring IV diuretics). 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). Eligible patients were randomized after IV diuresis for HFpEF is given (and no earlier than 36 hours from their last ACEi dose if applicable) and within 30 days post-decompensation after presentation with acute HFpEF decompensation and meeting the following definitions of hemodynamic stability:
- Randomized patients were hemodynamically stable defined in this study as:
- SBP \>=100mmHg for the preceding 6 hours prior to randomization; no symptomatic hypotension
- No increase (intensification) in IV diuretic dose within last 6 hours prior to randomization
- No IV inotropic drugs for 24 hours prior to randomization
- No IV vasodilators including nitrates within last 6 hours prior to randomization
- HFpEF with most recent LVEF \> 40% (within past 3 months)
- Elevated NT-proBNP or BNP at the time of acute HFpEF decompensation or post-decompensation screening (and within 72 hours for out-of-hospital randomization, if applicable):
- Patients not in Atrial Fibrillation(AF) at the time of biomarker assessment: NT-proBNP \>= 500pg/mL or BNP \>= 150 pg/mL; patients in AF at the time of biomarker assessment: NT-proBNP \>= 1000pg/mL or BNP \>= 300 pg/mL
- Patients recruited in-hospital were randomized based on the qualifying local lab value in-hospital NT-proBNP or BNP value.
- Patients enrolled post-decompensation can be randomized based on their NT-proBNP or BNP value in the following way:
- i. if enrolling in post-decompensation setting then need eligible screening/local NTproBNP/BNP within 72 hours of randomization. The test value could be from recent hospitalization if within 72 hours or ii. would require (re)drawing NT-proBNP or BNP labs in post-decompensation setting if the lab value is not already available within the last 72 hours).
- \) Has not taken an ACEi for 36 hours prior to randomization
You may not qualify if:
- Any clinical event within the 90 days prior to randomization that could have reduced the LVEF (i.e., myocardial infarction (MI), coronary artery bypass graft (CABG), unless an echo measurement was performed after the event confirming the LVEF to be \> 40%
- Entresto™ (sacubitril/valsartan) usage within the past 60 days
- eGFR \< 20ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at most recent assessment prior to randomization and within 24 hours prior to inpatient randomization or 72 hours prior to outpatient randomization
- Serum potassium \> 5.2 mEq/L at most recent assessment prior to randomization and within 24 hours prior to inpatient randomization or 72 hours prior to outpatient randomization
- Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within 30 days prior to randomization
- Probable alternative diagnoses that in the opinion of the investigator could account for the patient's HF symptoms (i.e. dyspnea, fatigue) such as significant pulmonary disease (including primary pulmonary HTN), anemia or obesity.
- Isolated right HF in the absence of left-sided structural heart disease
- History of hypersensitivity (i.e. including angioedema), known or suspected contraindications, or intolerance to any of the study drugs including ARNIs (i.e. sacubitril/valsartan), and/or ARBs
- Patients with a known history of angioedema due to any etiology
- Patients with a history of heart transplant or LVAD, currently on the transplant list, or with planned intent to implant LVAD or CRT device within the initial three months of enrollment during the trial
- A cardiac or non-cardiac medical condition other than HF with an estimated life expectancy of \< 6 months
- Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy including suspected or confirmed amyloid heart disease (amyloidosis)
- Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate \> 110 bpm
- Clinically significant congenital heart disease felt to be the cause of the patient's symptoms and signs of HF
- Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention within the duration of the trial
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (97)
University of Calif Irvine Med Cntr
Irvine, California, 92660, United States
Memorial Care Health System Memorialcare Long Beach
Long Beach, California, 90806, United States
University Of Southern California .
Los Angeles, California, 90033-4605, United States
University Of Southern California
Los Angeles, California, 90033-4605, United States
San Diego Cardiac Center
San Diego, California, 92123, United States
Zuckerberg General W84 Research .
San Francisco, California, 94110, United States
Sutter Health Network .
San Pablo, California, 94806, United States
Helping Hands Medical Associates INC
Santa Ana, California, 92704, United States
St Francis Medical Center
Colorado Springs, Colorado, 80923, United States
Colorado Heart and Vascular .
Lakewood, Colorado, 80228, United States
South Denver Cardiology Associates PC
Littleton, Colorado, 80120, United States
Hartford Healthcare Headache Center
West Hartford, Connecticut, 06109, United States
VA Connecticut Healthcare System
West Haven, Connecticut, 06516, United States
Cardiology Physicians PA .
Newark, Delaware, 19713, United States
University of Florida Health .
Gainesville, Florida, 32610, United States
New Generation of Medical Research Avera Health N Central Heart
Hialeah, Florida, 33016, United States
University of Florida Health Science Center
Jacksonville, Florida, 32209, United States
Intercoastal Medical Group
Sarasota, Florida, 34239, United States
Morehouse School Of Medicine
Atlanta, Georgia, 30310, United States
Emory University School of Medicine/Winship Cancer Institute
Atlanta, Georgia, 30322, United States
University Cardiology Associates
Augusta, Georgia, 30901, United States
St Lukes Idaho Cardiology Associates CLCZ696BUS13
Boise, Idaho, 83702, United States
University of Chicago .
Chicago, Illinois, 60637, United States
Amita Health
Elk Grove Village, Illinois, 60007, United States
Midwest Cardiovascular Institute .
Oakbrook Terrace, Illinois, 60181, United States
Advocate Medical Group .
Park Ridge, Illinois, 60068, United States
Unity Point Health Methodist
Peoria, Illinois, 61606, United States
OSF HealthCare
Peoria, Illinois, 61614, United States
Northwestern Medicine Northwestern University
Winfield, Illinois, 60190, United States
Midwest Cardiovascular Research and Education Foundation .
Elkhart, Indiana, 46514, United States
Indiana University Health
Indianapolis, Indiana, 46202, United States
Franciscan Health Services Research Center .
Indianapolis, Indiana, 46237, United States
Indiana University Health
Muncie, Indiana, 47303, United States
Reid Hosp And Hlth Care Services
Richmond, Indiana, 47374, United States
The Uni of Kansas Medical Center
Kansas City, Kansas, 66160, United States
Alexandria Cardiology Clinic
Alexandria, Louisiana, 71301, United States
The Franciscan Missionaries
Baton Rouge, Louisiana, 70808, United States
Northern Light Easter Maine Medical Center .
Bangor, Maine, 04401, United States
Johns Hopkins Univ School of Med
Baltimore, Maryland, 21287, United States
Tidal Health Peninsula Regional Inc .
Salisbury, Maryland, 21804, United States
Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
Boston Univeristy Medical Center .
Boston, Massachusetts, 02118, United States
Beth Israel Deaconess Med Ctr CLCZ696D2301
Boston, Massachusetts, 02215, United States
University of Michigan Hs
Ann Arbor, Michigan, 48109, United States
Detroit Medical Center Cardiovascular Clinical Trial .
Detroit, Michigan, 48201, United States
Henry Ford Hospital Cardiovascular Medicine
Detroit, Michigan, 48202, United States
Trinity Health Michigan Heart .
Ypsilanti, Michigan, 48197, United States
Novartis Investigative Site
Saint Paul, Minnesota, 55101, United States
Jackson Heart Clinic
Jackson, Mississippi, 39216, United States
Nebraska Heart Institute CHI Health Nebraska
Lincoln, Nebraska, 68510, United States
University of Nebraska Medical Center
Omaha, Nebraska, 68198, United States
Univ Medical Center Las Vegas
Las Vegas, Nevada, 89201, United States
R Ins For Heart And Vascular Health
Reno, Nevada, 89502, United States
Inspira Health Network
Elmer, New Jersey, 08318, United States
Cooper University Health Care
Haddon Heights, New Jersey, 08035, United States
Saint Michael Medical Center
Newark, New Jersey, 07102, United States
Cedar Multi-Specialty Clinic
Albuquerque, New Mexico, 87106, United States
Albany Associates In Cardiology
Albany, New York, 12205, United States
New York Presbyterian Queens .
Flushing, New York, 11355, United States
United Health Services Office Of Clinical Trails CLCZ696BUS01
Johnson, New York, 13790, United States
Northwell Health .
Manhasset, New York, 11030, United States
Mount Sinai Hospital .
New York, New York, 10029, United States
HealthQuest
Poughkeepsie, New York, 12601, United States
Catholic Hlth Svcs of Long Island
Roslyn, New York, 11576, United States
Mount Sinai Health System
Staten Island, New York, 10310, United States
Stony Brook University Medical Center CLCZ696G2301
Stony Brook, New York, 11794, United States
Montefiore Medical Center .
The Bronx, New York, 10461, United States
University Of North Carolina At Chapel Hill CRLX030A2209
Chapel Hill, North Carolina, 27599-7075, United States
Duke Health
Durham, North Carolina, 27710, United States
Cleveland Clinic Foundation .
Cleveland, Ohio, 44195, United States
St. Vincent Mercy Medical Center
Toledo, Ohio, 43608, United States
St John Health System
Bartlesville, Oklahoma, 74006, United States
Regional Medical Labaratory
Tulsa, Oklahoma, 74104, United States
Jefferson Abington .
Abington, Pennsylvania, 19001, United States
Allegheny Valley Hospital .
Natrona Heights, Pennsylvania, 15065, United States
Capital Area Research LLC CACZ885M2301
Newport, Pennsylvania, 17074, United States
Thomas Jefferson Univ Hospital .
Philadelphia, Pennsylvania, 19107, United States
Regional Health Clinic Research .
Rapid City, South Dakota, 57701, United States
North Central Heart .
Sioux Falls, South Dakota, 57105, United States
VA Tennessee Valley Healthcare System
Nashville, Tennessee, 37212, United States
Pharma Tex Research .
Amarillo, Texas, 79106, United States
Baylor University Medical Center .
Dallas, Texas, 75246, United States
The University of Texas Medical Branch
Galveston, Texas, 77555-1062, United States
The University of Vermont Medical Center CRLX030A2301
Burlington, Vermont, 05401, United States
Centra Health
Lynchburg, Virginia, 24501, United States
Swedish Medical Ctr Cardiovascular Re
Seattle, Washington, 98122, United States
University of Wisconsin School of Medicine and Public Health CLCZ696BUS01
Madison, Wisconsin, 53792-1615, United States
Novartis Investigative Site
Victoria, British Columbia, V8R4R2, Canada
Novartis Investigative Site
Winnipeg, Manitoba, R2H 2A6, Canada
Novartis Investigative Site
Hamilton, Ontario, L8L 2X2, Canada
Novartis Investigative Site
Montreal, Quebec, H1T 1C8, Canada
Novartis Investigative Site
Montreal, Quebec, H2X 0A9, Canada
Novartis Investigative Site
Montreal, Quebec, H3G 1A4, Canada
Novartis Investigative Site
Québec, Quebec, G1R 2J6, Canada
Novartis Investigative Site
Saguenay, Quebec, G7H 5H6, Canada
Novartis Investigative Site
Sherbrooke, Quebec, J1H 5N4, Canada
Novartis Investigative Site
Terrebonne, Quebec, J6V 2H2, Canada
Related Publications (6)
Peters AE, Li S, Cyr D, Williamson KM, Zieroth S, Fudim M, Ward JH, Mentz RJ. Influence of ejection fraction on outcomes with sacubitril/valsartan in patients with worsening heart failure with EF>40%: The PARAGLIDE-HF Trial. Am Heart J. 2025 Nov;289:158-167. doi: 10.1016/j.ahj.2025.04.023. Epub 2025 Apr 21.
PMID: 40268180DERIVEDRambarat P, Erickson T, Cyr D, Ward J, Hernandez A, Morrow D, Starling R, Velazquez E, Zieroth S, Williamson K, Solomon S, Mentz R. Effects of angiotensin-neprilysin inhibition in women vs men: Insights from PARAGLIDE-HF. Am Heart J. 2025 Oct;288:41-51. doi: 10.1016/j.ahj.2025.03.017. Epub 2025 Mar 31.
PMID: 40174692DERIVEDShoji S, Cyr DD, Hernandez AF, Velazquez EJ, Ward JH, Williamson KM, Sarwat S, Starling RC, Desai AS, Zieroth S, Solomon SD, Mentz RJ. Win Ratio Analyses Using a Modified Hierarchical Composite Outcome: Insights From PARAGLIDE-HF. Am Heart J. 2025 Feb;280:70-78. doi: 10.1016/j.ahj.2024.10.020. Epub 2024 Nov 4.
PMID: 39505123DERIVEDFudim M, Cyr DD, Ward JH, Hernandez AF, Lepage S, Morrow DA, Sharma K, Claggett BL, Starling RC, Velazquez EJ, Williamson KM, Desai AS, Zieroth S, Solomon SD, Braunwald E, Mentz RJ; PARAGLIDE-HF investigators. Association of Sacubitril/Valsartan vs Valsartan With Blood Pressure Changes and Symptomatic Hypotension: the PARAGLIDE-HF Trial. J Card Fail. 2024 Dec;30(12):1568-1577. doi: 10.1016/j.cardfail.2024.04.030. Epub 2024 May 26.
PMID: 38802053DERIVEDMorrow DA, Velazquez EJ, Desai AS, DeVore AD, Lepage S, Park JG, Sharma K, Solomon SD, Starling RC, Ward JH, Williamson KM, Zieroth S, Hernandez AF, Mentz RJ, Braunwald E. Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure. J Am Coll Cardiol. 2024 Mar 26;83(12):1123-1132. doi: 10.1016/j.jacc.2024.01.027.
PMID: 38508844DERIVEDMentz RJ, Ward JH, Hernandez AF, Lepage S, Morrow DA, Sarwat S, Sharma K, Starling RC, Velazquez EJ, Williamson KM, Desai AS, Zieroth S, Solomon SD, Braunwald E; PARAGLIDE-HF Investigators. Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure. J Am Coll Cardiol. 2023 Jul 4;82(1):1-12. doi: 10.1016/j.jacc.2023.04.019. Epub 2023 May 21.
PMID: 37212758DERIVED
Related Links
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Limitations and Caveats
No efficacy analyses include "OPEN LABEL' data. After Protocol Amendment 01, the open-label option was removed from the study, only the 233 patients randomized in the Double-blind Phase Sacubitril+ Valsartan (LCZ696) and the 233 patients randomized in the Double-blind Phase Valsartan arms were included in the efficacy analysis.
Results Point of Contact
- Title
- Study Director
- Organization
- Novartis Pharmaceuticals
Study Officials
- STUDY DIRECTOR
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 13, 2019
First Posted
June 17, 2019
Study Start
June 29, 2019
Primary Completion
December 14, 2022
Study Completion
December 14, 2022
Last Updated
March 6, 2025
Results First Posted
July 29, 2024
Record last verified: 2025-03
Data Sharing
- IPD Sharing
- Will share
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of the patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to criteria and process described on www.clinicalstudydatarequest.com