Empagliflozin Impact on Hemodynamics in Patients With Heart Failure (EMBRACE-HF)

• ClinicalTrials.gov Identifier: NCT03030222
• Recruitment Status: Completed
• First Posted: January 24, 2017
• Results First Posted: December 9, 2021
• Last Update Posted: December 9, 2021
• Sponsor: Saint Luke's Health System
• Information provided by (Responsible Party): Saint Luke's Health System

Study Description

Brief Summary:

The primary purpose of this trial is to evaluate the impact of empagliflozin, as compared with placebo, on hemodynamic parameters (pulmonary artery diastolic pressure) in patients with heart failure (reduced or preserved ejection fraction, ischemic or non-ischemic etiology) who already have a CardioMEMs device (a wireless hemodynamic monitoring system) implanted for non-study related clinical reasons.

Condition or disease	Intervention/treatment	Phase
Heart Failure	Drug: Empagliflozin 10 mg Tab; Drug: Placebo Oral Tablet	Phase 4

Detailed Description:

A 12-week randomized, double-blind, placebo-controlled trial to explore the effects of once-daily empagliflozin 10 mg on hemodynamic parameters (pulmonary artery pressures) in patients with heart failure (reduced or preserved ejection fraction, ischemic or non-ischemic etiology) who already have a CardioMEMs device implanted for non-study related clinical reasons.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure
• Actual Study Start Date: July 5, 2017
• Actual Primary Completion Date: March 10, 2020
• Actual Study Completion Date: March 10, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Empagliflozin; Empagliflozin 10 mg tab, once daily, for 12 weeks	Drug: Empagliflozin 10 mg Tab; Empagliflozin 10 mg Tab; Other Name: Jardiance
Placebo Comparator: Placebo; Empagliflozin matching placebo oral tablet, once daily for 12 weeks	Drug: Placebo Oral Tablet; Empagliflozin matching placebo; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change in Pulmonary Artery Diastolic Pressure From Baseline to End of Treatment Period (Defined as Average of Pulmonary Artery Diastolic Pressure Measurements Between Weeks 8-12) Between Empagliflozin and Placebo [ Time Frame: Baseline to average between Weeks 8-12 ]
   Change in pulmonary artery diastolic pressure from baseline to end of treatment period (defined as average of pulmonary artery diastolic pressure measurements between weeks 8-12) between empagliflozin and placebo

Secondary Outcome Measures :

1. Change From Baseline in Pulmonary Artery Diastolic Pressure at Each Interim Timepoint (Wks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Weeks 1-12 ]
   Change from baseline in pulmonary artery diastolic pressure at each interim timepoint (wks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12) between empagliflozin and placebo.
2. Change in Pulmonary Artery Systolic Pressure From Baseline to End of Treatment Period (Week 12) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 12 ]
   Change in pulmonary artery systolic pressure from baseline to end of treatment period (week 12) between empagliflozin and placebo.
3. Change From Baseline in Pulmonary Artery Systolic Pressure at Each Interim Time Point (Wks 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Weeks 1-12 ]
   Change from baseline in pulmonary artery systolic pressure at each interim time point (wks 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12) between empagliflozin and placebo.
4. Change in Mean Pulmonary Artery Pressure From Baseline to End of Treatment Period (Week 12) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 12 ]
   Change in mean pulmonary artery pressure from baseline to end of treatment period (week 12) between empagliflozin and placebo.
5. Change From Baseline in Mean Pulmonary Artery Pressure at Each Interim Time Point (Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Weeks 1-12 ]
   Change from baseline in mean pulmonary artery pressure at each interim time point (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) between empagliflozin and placebo.
6. Change in Heart Failure Related Quality of Life, Using the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS) From Baseline to Follow-up (Defines as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
   The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For the Kansas City Cardiomyopathy Questionnaire Overall Summary Score KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points.
7. Proportion of Patients With a ≥ 5 Point Increase From Baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS) at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
   The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For the Kansas City Cardiomyopathy Questionnaire Overall Summary Score KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points.
8. Change in 6 Minute Walk Test From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
   Change in 6 minute walk test from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo.
9. Change in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
   Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo.
10. Change in Brain Natriuretic Peptide (BNP) From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
    Change in brain natriuretic peptide (BNP) from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo.
11. Proportion of Patients With a ≥ 20% Decrease From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
    Proportion of patients with a ≥ 20% decrease from baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at either 6 weeks or 12 weeks of follow-up between empagliflozin and placebo.
12. Proportion of Patients With a ≥ 20% Decrease From Baseline in Brain Natriuretic Peptide (BNP) at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
    Proportion of patients with a ≥ 20% decrease from baseline in brain natriuretic peptide (BNP) at either 6 weeks or 12 weeks of follow-up between empagliflozin and placebo.
13. Proportion of Patients With Both a ≥ 5 Point Increase From Baseline in KCCQ-OS and a ≥ 20% Decrease From Baseline in NT-proBNP at Either 6 Weeks or 12 Weeks of Follow-up Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
    Proportion of patients with both a ≥ 5 point increase from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS) and a ≥ 20% decrease from baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) at either 6 weeks or 12 weeks of follow-up between empagliflozin and placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For the Kansas City Cardiomyopathy Questionnaire Overall Summary Score KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points.
14. Number of Participants With Diuretic Medication Adjustments During the Treatment Period Between Empagliflozin and Placebo [ Time Frame: Baseline to Week 12 ]
    Number of Participants with Diuretic Medication Adjustments During the Treatment Period Between Empagliflozin and Placebo
15. Change in Hemoglobin A1c From Baseline to Follow-up (Defined as Average of Measurements at 6 and 12 Weeks) Between Empagliflozin and Placebo. [ Time Frame: Baseline to Week 6 and Week 12 ]
    Change in Hemoglobin A1c from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) between empagliflozin and placebo.

Eligibility Criteria

• Ages Eligible for Study: 19 Years to 119 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Established diagnosis of heart failure (for at least 16 weeks prior to the screening visit) with either preserved (LVEF>40%) or reduced systolic function (LVEF≤40%), due to either ischemic or non-ischemic etiology, documented by an imaging modality (echocardiography, nuclear imaging, LV angiography, magnetic resonance imaging) within the past 24 months.
2. No major change in diuretic management for 48 hours prior to screening visit or 48 hours prior to randomization visit (major change defined by doubling of diuretic dose or addition of another diuretic medication)
3. New York Heart Association (NYHA) class II, III or IV heart failure symptoms at the screening and randomization visit
4. Presence of previously (≥ 2 weeks prior to screening visit) implanted CardioMEMs pulmonary artery pressure monitor for a clinical indication unrelated to the study.
5. Pulmonary artery diastolic pressure ≥ 12 mmHg at the time of the screening visit (last measurement available prior to the screening visit).
6. Ability to provide informed consent prior to initiating screening visit procedures

Exclusion Criteria:

1. Decompensated heart failure (hospitalization for heart failure within the 2 weeks prior to screening) or between screening and randomization
2. History of type 1 diabetes
3. Major change in diuretic management during 48 hours prior to screening visit or 48 hours prior to randomization visit. (major change defined by doubling of diuretic dose or addition of another diuretic medications)
4. Significant variability in baseline pulmonary artery diastolic pressures during screening period. Defined as changes greater than +/- 6 mmHg from average pulmonary artery diastolic pressure during week 1 of the screening phase and average pulmonary artery diastolic pressure during week 2 of the screening phase for those patients with an average baseline pulmonary artery diastolic pressure during week 1 of the screening phase of <30 mmHg. If the average baseline pulmonary artery diastolic pressure during week 1 of the screening phase is ≥30 mmHg, then ≥20% relative change in average pulmonary diastolic pressure between week 1 and week 2 of the screening phase will be used to define significant variability.
5. Initiation of hydralazine, long-acting nitrates, beta blockers, angiotensin-converting enzyme inhibitors (ACEIs) , angiotensin II receptor blockers (ARBs) or valsartan/sacubitril in the prior 4 weeks prior to screening
6. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 at the screening visit
7. Admission for an acute coronary syndrome (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina), percutaneous coronary intervention, or cardiac surgery within 30 days prior to the screening visit.
8. Implantation of cardiac resynchronization therapy (CRT) device within the previous 90 days.
9. Implantation of the CardioMEMs device within the past 2 weeks.
10. Planned cardiovascular revascularization (percutaneous intervention or surgical) or major cardiac surgery (coronary artery bypass grafting, valve replacement, ventricular assist device, cardiac transplantation, or any other surgery requiring thoracotomy), or planned implantation of cardiac resynchronization therapy (CRT) device within the 90 days after the screening visit.
11. Participation in any interventional clinical trial (with an investigational drug or device) that is not an observational registry within the 4 weeks prior to the screening visit.
12. History of hypersensitivity to empagliflozin
13. For women of child-bearing potential: Current or planned pregnancy or currently lactating
14. Life expectancy <1 year at the screening visit
15. Patients who are volume depleted based upon physical examination at the time of the screening or randomization visit
16. Pulmonary artery diastolic pressure < 12 mmHg at the time of the screening visit (average of last four measurements available prior to the screening visit).
17. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin) or having received treatment with any SGLT-2 inhibitor within the 8 weeks prior to the screening visit
18. Average supine systolic BP <90 mmHg at the screening or randomization visit
19. Current documented history of bladder cancer
20. Active Gross Hematuria
21. Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, severe stenotic valve disease, and hypertrophic obstructive cardiomyopathy (HOCM).
22. History of heart transplant.
23. Patients on heart transplant list as 1a and 1b status

Contacts and Locations

Locations

United States, California

University of Southern California

Los Angeles, California, United States, 90033

United States, Florida

First Coast Cardiovascular Institute

Jacksonville, Florida, United States, 32256

United States, Illinois

NorthShore University Health System Research Institute

Evanston, Illinois, United States, 60201

United States, Minnesota

CentraCare Heart and Vascular Center

Saint Cloud, Minnesota, United States, 56303

United States, New York

St. Francis Hospital

Roslyn, New York, United States, 11576

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43210

United States, South Dakota

Sanford Research

Sioux Falls, South Dakota, United States, 57104

United States, Texas

Austin Heart Clinical Research

Austin, Texas, United States, 78756

Baylor College of Medicine

Houston, Texas, United States, 77030

United States, Virginia

Sentara Cardiovascular Research Institute

Norfolk, Virginia, United States, 23507

Sponsors and Collaborators

Saint Luke's Health System

Investigators

• Study Chair: Mikhail Kosiborod, MD; Saint Luke's Mid America Heart Institute

  Study Documents (Full-Text)

Documents provided by Saint Luke's Health System:

Study Protocol  [PDF] September 24, 2018

Statistical Analysis Plan  [PDF] March 8, 2020

More Information

Additional Information:

Empagliflozin information 

Publications of Results:

Nassif ME, Qintar M, Windsor SL, Jermyn R, Shavelle DM, Tang F, Lamba S, Bhatt K, Brush J, Civitello A, Gordon R, Jonsson O, Lampert B, Pelzel J, Kosiborod MN. Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure: Results From the EMBRACE-HF Trial. Circulation. 2021 Apr 27;143(17):1673-1686. doi: 10.1161/CIRCULATIONAHA.120.052503. Epub 2021 Feb 8.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nassif ME, Spertus JA, Tang F, Windsor SL, Jones P, Thomas M, Khariton Y, Brush J, Gordon RA, Jermyn R, Jonsson O, Lamba S, Shavelle DM, Kosiborod MN. Association Between Change in Ambulatory Hemodynamic Pressures and Symptoms of Heart Failure. Circ Heart Fail. 2021 Nov;14(11):e008446. doi: 10.1161/CIRCHEARTFAILURE.121.008446. Epub 2021 Oct 26. No abstract available.

Nassif ME, Kosiborod M. Effects of sodium glucose cotransporter type 2 inhibitors on heart failure. Diabetes Obes Metab. 2019 Apr;21 Suppl 2:19-23. doi: 10.1111/dom.13678.

• Responsible Party: Saint Luke's Health System
• ClinicalTrials.gov Identifier: NCT03030222
• Other Study ID Numbers: 1245.129
• First Posted: January 24, 2017
• Results First Posted: December 9, 2021
• Last Update Posted: December 9, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Saint Luke's Health System:

heart failure; empagliflozin; Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Empagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs