EMPagliflozin After Aortic Valve Replacement

Study Overview
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Brief Summary
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The study is a randomized, placebo-controlled, and double-blinded trial in patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR). After AVR, patients will be randomized 1:1 to empagliflozin (SGLT2i) or placebo to investigate whether empagliflozin is superior to placebo in reducing left ventricular mass and improve symptoms to 6 months.

Detailed Description
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In this randomized, placebo-controlled, and double-blinded trial we investigate whether empagliflozin (SGLT2i) is superior to placebo in reducing left ventricular mass and improve symptoms. All patients with AS who are referred to Rigshospitalet for AVR (both surgical and transcatheter approaches) will be screened for in- and exclusion criteria in the medical record based on the Danish Health Act §46 by the PI, co-PI, or a delegated study nurse. If the patient fulfills the inclusion criteria and none of the exclusions criteria, the patient is invited to participate in the study. Included patients will be randomized 1:1 in blocks of 2, 4, and 6 patients to either Empagliflozin 10 mg daily or placebo. Point of randomization will be in the hospital when the patients has undergone AVR. The total treatment period is 6 months with either 10 mg Empagliflozin or placebo. The trial participants will receive conventional treatment, which will be carried out irrespective of the inclusion in the trial in accordance with national guidelines. Routine clinical check-ups irrespective of the trial setup will be performed at 3 months after discharge, and study-outcomes will be assessed at discharge, 3 months, and 6 months (eg. echocardiography). Blood samples (including N-Terminal-proBNP, renal function and electrolytes, hemoglobin and HbA1c) will be part of such routine visits as well as a standardized symptom-scoring tool (KCCQ and NYHA classification). Compliance will be evaluated at 1-, 3- and 6-months. The assessment for 1-month will be per telephone and the assessment at 3- and 6-months will be at the routine clinical check-ups in the outpatient clinic. The CT scan performed in the planning of the procedure will be used for the baseline assessment (before AVR). An identical exam (CT scan) will be performed at 6 months to assess change in LV mass.

Official Title
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EMPagliflozin After Aortic Valve Replacement - The EMPAVR Study - A Randomized Clinical Trial

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe symptomatic aortic stenosis AND Surgical or transcatheter aortic valve replacement within 14 days Exclusion Criteria: Prior treatment with a SGLT2i Left ventricular ejection fraction < 45% Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min Hypersensitivity to empagliflozin or placebo tablet Type I Diabetes Patients who do not understand Danish or English Women who are pregnant or are nursing or plan to become pregnant during trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Empagliflozin<br>Empagliflozin 1 capsule of 10 mg, once daily for six months. | Drug: Empagliflozin<br>* 10 mg empagliflozin daily for six months<br>* Other names: Jardiance;|
| Placebo Comparator: Placebo<br>1 capsule of placebo, once daily for six months | Drug: Placebo<br>* Placebo capsule once daily for six months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular mass indexed to body surface area | Change in left ventricular mass indexed to body surface area (measured by CT) from pre-Aortic Valve Replacement to 6-months post-Aortic Valve Replacement | 6 months from discharge post-Aortic Valve Replacement | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LVESVi | Left ventricular end-systolic volume indexed to body surface (LVESVi) (measured by CT) | 6-months from discharge post-aortic valve replacement | 
| LV GLS (echo) | Left ventricular global longitudinal strain (LV GLS) (measured by echocardiography) | 3- and 6-months from discharge | 
| N-terminal pro B-type natriuretic peptide (NT-proBNP) change | NT-proBNP change from baseline to 6 months | 3- and 6-months from discharge | 
| Death and readmission for any non-planned cause | A composite outcome of death and readmission for any non-planned cause | 6 months from discharge date (after aortic valve replacement) | 
| Death | Death during follow-up, from discharge to 6-months after discharge | 6 months from discharge date (after aortic valve replacement) | 
| Readmission for any cause | Readmission for any cause to any hospital after discharge | 6 months from discharge date (after aortic valve replacement) | 
| Admission for heart failure | Admission for heart failure to any hospital | 6 months from discharge date (after aortic valve replacement) | 
| Kansas City Cardiomyopathy Questionaire (KCCQ) | Change in symptom score (KCCQ) at 6-months. KCCQ scores are scaled from 0 to 100, where scores represent health status as follows: 0-24: very poor to poor; 25-49: poor to fair; 50-74: fair to good; and 75-100: good to excellent. In this study a change of 5 points is considered a meaningful change. | 6 months from discharge date (after aortic valve replacement) | 
| Quality of Life (QoL) - The Minnesota Living with Heart Failure Questionnaire (MLHFQ) | Quality of life assessment at baseline and 6 months after discharge post-AVR using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). MLHFQ consist of 21 questions. The response format ranges from 0 (none or not applicable), to 1 (very little) to 5 (very much). The sum of responses ranges from 0 to 105. The score increases with adverse impact of the disease on the respondent's life. | 6 months from discharge date (after aortic valve replacement) | 
| New York Heart Association (NYHA) Functional Classification | Change in symptom score at 6 months (NYHA classification). The NYHA classification places patients in one of four categories based on limitations of physical activity. Class I: No limitation of physical activity; Class II: Slight limitation of physical activity; Class III: Marked limitation of physical activity; Class IV: Symptoms of heart failure at rest. | 3- and 6-months from discharge date (after aortic valve replacement) | 
| Six-minute walk test (6MWT) | Six-minute walk tests done at baseline and at 6-months after discharge (post-AVR) | 6 months from discharge date (after aortic valve replacement) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aortic Valve Stenosis, Aortic Valve Replacement, Transcatheter Aortic Valve Implantation, Aortic Valve, Sodium-Glucose Cotransporter-2 inhibitor, SGLT2i, Empagliflozin