Clinical trial NCT02874794: Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction
Official title: A Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group, Active-controlled, Forced-titration, 12-week Comparison of Combined Angiotensin-neprilysin Inhibition With Sacubitril and Valsartan Versus Enalapril on Changes in Central Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction (HFrEF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure and Reduced Ejection Fraction
Keywords: Heart Failure
Reduced Ejection Fraction
Central Aortic Stiffness
Vascular
Echocardiogram
Aortic Stiffness
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-08-22
Enrollment: 465
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To determine whether treatment with sacubitril/valsartan provides a superior effect on aortic characteristic impedance compared to enalapril in patients with heart failure and reduced ejection fraction (left ventricular ejection fraction \[LVEF\] ≤ 40%) after 12 weeks of treatment. The primary endpoint is the change in aortic characteristic impedance (Zc = dP/dQ in early systole) between baseline and Week 12.


Eligibility criteria: Inclusion Criteria:

* History of HTN and one of the following at BOTH screening and pre-randomization:

  1. SBP \>105 mm Hg on antihypertensive medication.
  2. SBP \>/= 140 mm Hg and NOT on antihypertensive medication.
* NYHA class I-III heart failure and with reduced ejection fraction \</= 40%, as determined by any local measurement made within the past 12 months using echocardiography, MUGA, CT scanning, MRI, ventricular angiography or single-photon emission computed tomography (SPECT), provided no subsequent measurement above 40%. Patients who have had an intervening medical event (e.g. myocardial infarction) or procedure (e.g. revascularization, cardiac resynchronization), must have a reassessment of EF ≥ 3 months following the event to ensure that eligibility criteria are still met.
* On stable doses of treatment with guideline-directed therapy, other than ACEis and ARBs prior to randomization.

  1. If the patient is currently taking an ACEi, a 36-hour washout is required prior to randomization (Visit 2).
  2. If the patient is currently taking an ARB, they must discontinue the ARB before initiation of study treatment however washout is not required.
* On an optimal medical regiment of diuretics and background medications to effectively treat co-morbidities such as HTN, DM, and coronary artery disease.

Key Exclusion Criteria:

* History of hypersensitivity to any of the study drigs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to ACEis, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs.
* Previous history of intolerance to sacubitril and valsartan, ACEi or ARB standard of care doses despite appropriate and gradual up-titration.
* History of angioedema, drug-related or otherwise.
* Requirement of treatment with both ACE inhibitor and ARB.
* Current or prior treatment with sacubitril and valsartan.

Primary outcomes:
measure: Change From Baseline in Aortic Characteristic Impedance at Week 12
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4
timeFrame: Pre-dose and 4 hours post dose at week 4
measure: Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4
timeFrame: pre-dose and 4 hours post dose at week 4
measure: Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
timeFrame: Baseline, Week 12
measure: Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain
timeFrame: Baseline, Week 12
measure: Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)
timeFrame: Baseline, Week 12
measure: Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)
timeFrame: Baseline, Week 12
measure: Change From Basekine in Echocardiographic Measure: Mitral E/E'
timeFrame: Baseline, Week 12
measure: Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)
timeFrame: Baseline, Week 12
measure: Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)
timeFrame: Baseline, Week 12
measure: Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)
timeFrame: Baseline, Week 12
measure: Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)
timeFrame: Baseline, Week 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Little Rock
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Beverly Hills
country: United States
facility: Novartis Investigative Site
state: California
city: Huntington Beach
country: United States
facility: Novartis Investigative Site
state: California
city: Newport Beach
country: United States
facility: Novartis Investigative Site
state: California
city: Northridge
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Ana
country: United States
facility: Novartis Investigative Site
state: California
city: Van Nuys
country: United States
facility: Novartis Investigative Site
state: California
city: Greenwich
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Norwalk
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Stamford
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Trumbull
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Newark
country: United States
facility: Novartis Investigative Site
state: Delaware
city: Atlantis
country: United States
facility: Novartis Investigative Site
state: Florida
city: Aventura
country: United States
facility: Novartis Investigative Site
state: Florida
city: Bradenton
country: United States
facility: Novartis Investigative Site
state: Florida
city: Coral Gables
country: United States
facility: Novartis Investigative Site
state: Florida
city: Daytona Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Doral
country: United States
facility: Novartis Investigative Site
state: Florida
city: Fort Lauderdale
country: United States
facility: Novartis Investigative Site
state: Florida
city: Hialeah
country: United States
facility: Novartis Investigative Site
state: Florida
city: Inverness
country: United States
facility: Novartis Investigative Site
state: Florida
city: Jacksonville
country: United States
facility: Novartis Investigative Site
state: Florida
city: Jupiter
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Naples
country: United States
facility: Novartis Investigative Site
state: Florida
city: Saint Augustine
country: United States
facility: Novartis Investigative Site
state: Florida
city: Athens
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Augusta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Blue Ridge
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Eatonton
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Macon
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Coeur d'Alene
country: United States
facility: Novartis Investigative Site
state: Idaho
city: Fairview Heights
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Gurnee
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Overland Park
country: United States
facility: Novartis Investigative Site
state: Kansas
city: Owensboro
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Baton Rouge
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Eunice
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Minden
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Monroe
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Slidell
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Alpena
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Owosso
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Saginaw
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Lincoln
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Omaha
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Las Vegas
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Hillsborough
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Linden
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Manalapan
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Mountain Lakes
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Bronx
country: United States
facility: Novartis Investigative Site
state: New York
city: Buffalo
country: United States
facility: Novartis Investigative Site
state: New York
city: Lake Success
country: United States
facility: Novartis Investigative Site
state: New York
city: Rosedale
country: United States
facility: Novartis Investigative Site
state: New York
city: Charlotte
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Greenville
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Lenoir
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Yardley
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Jackson
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Amarillo
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: McKinney
country: United States
facility: Novartis Investigative Site
state: Texas
city: McKinney
country: United States
facility: Novartis Investigative Site
state: Texas
city: Sherman
country: United States
facility: Novartis Investigative Site
state: Texas
city: Tomball
country: United States
facility: Novartis Investigative Site
state: Texas
city: Webster
country: United States
facility: Novartis Investigative Site
state: Texas
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Richland
country: United States
facility: Novartis Investigative Site
state: Washington
city: Spokane
country: United States
facility: Novartis Investigative Site
state: Washington
city: Manitowoc
country: United States
facility: Novartis Investigative Site
state: Wisconsin
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Myhre PL, Claggett BL, Shah AM, Prescott MF, Ward JH, Fang JC, Mitchell GF, Solomon SD, Desai AS. Changes in cardiac biomarkers in association with alterations in cardiac structure and function, and health status in heart failure with reduced ejection fraction: the EVALUATE-HF trial. Eur J Heart Fail. 2022 Jul;24(7):1200-1208. doi: 10.1002/ejhf.2541. Epub 2022 May 30.
citation: Myhre PL, Prescott MF, Murphy SP, Fang JC, Mitchell GF, Ward JH, Claggett B, Desai AS, Solomon SD, Januzzi JL. Early B-Type Natriuretic Peptide Change in HFrEF Patients Treated With Sacubitril/Valsartan: A Pooled Analysis of EVALUATE-HF and PROVE-HF. JACC Heart Fail. 2022 Feb;10(2):119-128. doi: 10.1016/j.jchf.2021.09.007. Epub 2022 Jan 12.
citation: Mitchell GF, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J, Abbas CA, Desai AS; EVALUATE-HF Investigators*. Hemodynamic Effects of Sacubitril-Valsartan Versus Enalapril in Patients With Heart Failure in the EVALUATE-HF Study: Effect Modification by Left Ventricular Ejection Fraction and Sex. Circ Heart Fail. 2021 Mar;14(3):e007891. doi: 10.1161/CIRCHEARTFAILURE.120.007891. Epub 2021 Mar 5.
citation: Desai AS, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J, McCague K, Abbas CA, Rocha R, Mitchell GF; EVALUATE-HF Investigators. Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2019 Sep 17;322(11):1077-1084. doi: 10.1001/jama.2019.12843.