Role of Sacubitril/Valsartan in the Improvement of Heart Failure With Reduced Ejection Fraction

May 26, 2020 updated by: Frank Lloyd Dini, MD, Italian Society of Cardiology

Reverse Remodeling is Associated With Hemodynamic Improvement and Stabilization in Outpatients With Heart Failure With Reduced Ejection Fraction Treated With Sacubitril/Valsartan: an Echocardiographic Study

This prospective study evaluates the mechanisms of benefit of sacubitril/valsartan in a population of outpatients with heart failure with reduced ejection fraction, to investigate the relationship between the effects on left ventricular ejection fraction and volumes and noninvasively hemodynamic echo-derived parameters, as cardiac output and left ventricular filling pressure.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Therapeutic interventions were made according to a titration protocol in stable optimal medical therapy. Therapy with sacubitril/valsartan was introduced after a 48-hour wash-out of an ACE inhibitor or after a 24-hour wash-out of an angiotensin receptor antagonist. Doses of sacubitril/valsartan were optimized to individual tolerability.

Echocardiography was performed at baseline and after 12 months. LV end-diastolic and end-systolic volumes were calculated according to the biplane Simpson's method according to the recommendations of the American Society of Echocardiography and European Association of Cardiovascular Imaging. Doppler examinations included assessment of early diastolic filling velocity and early diastolic mitral annular velocity, an averaged E/e' ≥ 13 was considered a surrogate marker of increased filling pressure.

The LV stroke volume was calculated as the product of the LV outflow tract area and the time-velocity integral of the aortic flow velocity or was evaluated as the difference between LVEDV and LVESV. The LVSV index was estimated as LVSV divided by body surface area. Cardiac output (CO) was measured as stroke volume times heart rate, and the cardiac index was estimated by dividing CO by body surface area.

Patients who presented reverse remodeling were considered those exhibiting a ≥ 10% increase in ejection fraction and ≥15% reduction in end-systolic volume compared to baseline.

The accuracy of the sources data was verified by using in-hospital medical records, computerized or paper, by checking data from ultrasound images, laboratory reports or ambulatory cardiological tests.

Detailed information on patients' medical history, including medications and loop diuretic doses, was recorded for each patient. Patients' functional status was determined according to the classification of the New York Heart Association. Creatinine, B-type natriuretic peptide and amino-terminal pro-type B-natriuretic peptide levels were measured using standard laboratory methods. The estimated glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula.

Patients were removed from therapy with sacubitril/valsartan or assessment for non-adherence to treatment or persistent drug-related adverse event with his/her willingness to discontinue treatment.

Continuous measures were expressed as the mean value ± SD or median and interquartile range (IRQ) for normally and non-normally distributed variables, respectively. Continuous data were compared using paired and independent samples Student t-test or ANOVA when appropriate. Categorical variables were presented as percentages and were compared using Chi-square or McNemar test. Mann-Whitney, Kruskal-Wallis and Wilcoxon tests were used to analyze non-normally distributed variables. All differences were considered significant at the p = 0.05 level. Data were analyzed with SPSS version 23.0 (IBM Corp., Armonk, NY).

Study Type

Observational

Enrollment (Actual)

652

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Pisa, Italy, 56124
        • Frank Lloyd Dini

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

The participants were recruited from a population of ambulatory patients with heart failure and reduced LV ejection fraction, being treated by Units of Cardiology in 12 Italian University hospitals.

Description

INCLUSION CRITERIA

  • Ambulatory patients on stable optimal medical therapy
  • History of HF and LVEF ≤ 40%
  • II-III NYHA class

EXCLUSION CRITERIA

  • History of congenital heart disease
  • Severe valvular disease or valvular surgery
  • Recent acute coronary syndromes or stroke
  • Poor acoustic windows or missing data.
  • Death or uncompleted follow-up evaluation
  • Cardiac surgery interventions
  • Cardiac resynchronization therapy
  • Coronary or mitral interventions

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in Cardiac Output after 12 months of treatment
Time Frame: March, 16 th 2019 - March,16th 2020
Cardiac Output (in L/min) is a variable measured by echocardiography as the product of LV stroke volume (in mL/beat) and heart rate (in bpm).
March, 16 th 2019 - March,16th 2020

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in Left Ventricular Filling Pressure after 12 months of treatment
Time Frame: March, 16th 2019 - March,16th 2020
Left ventricular filling pressure is calculated by Doppler Echocardiography as the ratio of early diastolic filling velocity (E wave, m/s) and early diastolic mitral annular velocity (e', m/s). The increase of this ratio is indicative of higher LV filling pressure.
March, 16th 2019 - March,16th 2020

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in Left Ventricular Stroke Volume after 12 months of treatment
Time Frame: March, 16th 2019 - March,16th 2020
The LV stroke volume (in mL/beat) is obtained at echocardiography, as the product of the LV outflow tract area (cm2) and the time-velocity integral (cm) of the aortic flow velocity.
March, 16th 2019 - March,16th 2020
Change from baseline in Left Ventricular End-systolic Volume after 12 months of treatment
Time Frame: March, 16th 2019 - March,16th 2020
The LV End-systolic volume (in mL) is calculated according to the biplane Simpson's method according to the recommendations of the American Society of Echocardiography and European Association of Cardiovascular Imaging.
March, 16th 2019 - March,16th 2020

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Italian Society of Cardiology

Collaborators

Federico II University
University Of Perugia
University of Messina
Azienda Ospedaliero-Universitaria di Parma
Monaldi Hospital
Università degli Studi di Brescia
University of Salerno
University of Siena
Azienda Unità Sanitaria Locale di Piacenza
Fondazione IRCCS Policlinico San Matteo di Pavia
Ospedali Riuniti di Foggia

Investigators

  • Principal Investigator: Frank L Dini, MD, Italian Society of Cardiology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 13, 2019

Primary Completion (Actual)

March 16, 2020

Study Completion (Actual)

March 16, 2020

Study Registration Dates

First Submitted

May 4, 2020

First Submitted That Met QC Criteria

May 17, 2020

First Posted (Actual)

May 21, 2020

Study Record Updates

Last Update Posted (Actual)

May 28, 2020

Last Update Submitted That Met QC Criteria

May 26, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20190015213

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

IPD Plan Description

It is not yet known if there will be a plan to make IPD available.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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