Effect of Dapagliflozin on Myocardial and Renal Function Following Aortic Valve Stenosis Intervention

Study Overview
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Brief Summary
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Randomized, double-blinded, placebo-controlled study in AS patients with subclinical or clinical heart failure undergoing treatment with TAVR.

Detailed Description
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This is a randomized, double-blinded, placebo-controlled study in AS patients with subclinical or clinical heart failure undergoing treatment with TAVR. It evaluates the effect of Dapagliflozin versus placebo, given once daily in addition to background standard medical therapy. Patients who are scheduled for TAVR at Aarhus University Hospital (AUH) will be informed about the project and invited to participate if they fulfill the inclusion criteria prior to the TAVR procedure. Patients will be randomized 1:1 in blocks of 6 patients to either Dapagliflozin 10 mg daily or placebo within 1 months prior to the scheduled TAVR therapy. The total treatment period is 13 months with 6 scheduled outpatient clinic visits at baseline (before TAVR) and at 1, 3, 6, 9, 12 months after TAVR. Cardiac magnetic resonance imaging (CMRI) is performed at baseline and 12 months follow-up. Echocardiography is performed at baseline, 1- and 12 months. 24-hour ambulatory blood pressure is measured at baseline and 12-months post-TAVR. Clinical status, HF questionnaire and blood samples will be performed at each visit. Drug accountability and adherence to the protocol is evaluated at each visit. A sub study in 40 of the included patients (20 treated with Dapagliflozin and 20 placebo) is planned. This will include additional endomyocardial biopsies taken at baseline and 12-months follow-up for high resolution respirometry (mitochondrial function) and electron microscopy (mitochondrial structure and interstitial fibrosis) supplemented by right heart catherization (RHC) for hemodynamic assessment.

Official Title
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Effect of Dapagliflozin on Myocardial and Renal Function Following Aortic Valve Stenosis Intervention

Conditions
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Aortic Stenosis, Left Ventricle Hypertrophied

Intervention / Treatment
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* Drug: SGLT2 inhibitor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Scheduled TAVR for significant symptomatic AS according to current guidelines Age ≥ 18 years and < 85 years. * LVEF ≥ 40% and ≤ 50 % or LVEF ≥ 50% with at least one of the following: LV GLS ≤ 15% by TTE LV septum or posterior wall thickness ≥ 12mm by TTE or LV mass index ≥108/131 g/m2 for females/males (mild LVH) LVEF ≥ 50 % and Nt-proBNP > 600/900 ng/l (sinus rhythm/atrial fibrillation) eGFR > 30 mL/min/1.73 m2 Exclusion Criteria: Medically treated type 1 or type 2 diabetes mellitus Ongoing treatment with an SGLT2-inhibitor or intolerance to SGLT2-inhibitors Life expectancy < 12 months Symptomatic hypotension or persistent SBP < 100 mmHg Contraindications to CMRI HF due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis or hypertrophic obstructive cardiomyopathy Additional other untreated severe valvular disease Liver failure Women who are pregnant or plan to be within the study period. Allergy to any substance in the project medicine, both placebo and active medicine. Previous renal transplantation. Chronic dialysis treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention group<br>10 mg (oral) SGLT-2 inhibitor once daily | Drug: SGLT2 inhibitor<br>* 10 mg orally once daily in addition to standard medical treatment.<br>|
| Placebo Comparator: Control group<br>Placebo tablet encapsulated as the active treatment. | Drug: Placebo<br>* Placebo tablets similar to active treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint of changes in LV mass, systolic function, eGFR, and serum Nt-proBNP | Changes from baseline to 12 months of follow-up in at least 2 out of 4 well-known parameters is required to reach the primary endpoint: LVMi (grams) reduction of 10 % point (by CMRI) LV GLS (percent) absolute increase of 2.0 % point (by TTE) A decrease in serum Nt-proBNP (ng/L) of more than 25% Relative increase of 10% in eGFR (ml/min/1.73m^2) If 2 or more of the 4 outcome measures are reached at 12-months follow-up, the patient has fulfilled the primary end-point. | Baseline assesment to 12-months follow-up post-TAVR | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the change in eGFR | Difference between active treatment and placebo at 12-months follow-up | baseline to 12-months | 
| Difference in eGFR | Difference between active treatment and placebo at 12-months follow-up | 12-months | 
| The number of patients with a relative difference of 10 % of myocardial interstitial fibrosis evaluated by the biomarker extracellular volume (ECV) by late enhancement gadolinium by CMR | Difference between active treatment and placebo. | Baseline to 12-months | 
| The number of patients with a >10% decrease in cardiac fibrosis when assessed by histology and quantified by stereology (sub study) | Difference between active treatment and placebo. | Baseline to 12-months | 
| The number of patients with an increase in the respiratory control ratio (RCR) by ≥10% measured by High Resolution Respirometry (HRR) (sub study) | Difference between active treatment and placebo. | Baseline to 12-months | 
| Composite endpoint of worsening HF with hospitalization or urgent outpatient clinical visit due to HF, and all-cause mortality. | Difference between active treatment and placebo in the incidence rate of hospitalization due to worsening heart failure or urgent clinical visit due to heart failure and all-cause mortality (using dates of the events to assess the incidence rates in the two groups: active treatment and placebo. | 12-months post-TAVR | 
| All-cause mortality | Difference between active treatment and placebo. | Baseline to 12-months post-TAVR | 
| Worsening HF with hospitalization or urgent outpatient clinical visit due to HF | Difference between active treatment and placebo. | 12-months post-TAVR | 
| Difference in the change in urinary albumin/creatinine ratio | Difference between active treatment and placebo. | Baseline to 12-months | 
| Difference in ACR at 12-months follow-up | Difference between active treatment and placebo. | 12-months follow-up | 
| 24-hour ambulatory blood pressure changes | Difference between active treatment and placebo in both systolic and diastolic blood pressure. | baseline to 12 months | 
| Change from baseline to 12-months follow-up in the Kansas City Cardiomyopathy questionnaire | Change from baseline in KCCQ will be reported. The KCCQ is a 23-item, self-administered questionnaire with score range of 0 to 100, and higher scores indicating better health. Difference in score for active treatment vs. placebo. | Baseline to 12-months | 
| Change from baseline to 12-months follow-up in New York Heart Association-class (NYHA) | The NYHA functional classification categorizes the extent of heart failure by placing subjects in one of four (I, II, III, IV) categories based on how much they are limited during physical activity and symptoms of shortness of breath and/or angina. Shift in NYHA-class between active treatment group and placebo. | baseline to 12-months. | 
| LVMi reduction of 10 % point (by CMRI) | Difference between active treatment and placebo. | baseline to 12-months. | 
| LV GLS absolute increase of 2.0 % point (by TTE) | Difference between active treatment and placebo. | Baseline to 12-months follow-up | 
| A decrease in serum Nt-proBNP of more than 25% follow-up | Difference between active treatment and placebo. | baseline to 12-months follow-up. | 
| Relative increase of 10% in eGFR | Difference between active treatment and placebo. | Baseline to 12-months follow-up |