Clinical trial NCT05241431: Effect of Dapagliflozin on Myocardial and Renal Function Following Aortic Valve Stenosis Intervention
Official title: Effect of Dapagliflozin on Myocardial and Renal Function Following Aortic Valve Stenosis Intervention
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Aortic Stenosis
Left Ventricle Hypertrophied
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
First posted: 2022-02-15
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent
2. Scheduled TAVR for significant symptomatic AS according to current guidelines
3. Age ≥ 18 years and \< 85 years.
4. \*

   * 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)
5. eGFR \> 30 mL/min/1.73 m2

Exclusion Criteria:

1. Medically treated type 1 or type 2 diabetes mellitus
2. Ongoing treatment with an SGLT2-inhibitor or intolerance to SGLT2-inhibitors
3. Life expectancy \< 12 months
4. Symptomatic hypotension or persistent SBP \< 100 mmHg
5. Contraindications to CMRI
6. HF due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis or hypertrophic obstructive cardiomyopathy
7. Additional other untreated severe valvular disease
8. Liver failure
9. Women who are pregnant or plan to be within the study period.
10. Allergy to any substance in the project medicine, both placebo and active medicine.
11. Previous renal transplantation.
12. Chronic dialysis treatment.

Primary outcomes:
measure: Composite endpoint of changes in LV mass, systolic function, eGFR, and serum Nt-proBNP
timeFrame: Baseline assesment to 12-months follow-up post-TAVR
Secondary outcomes:
measure: Difference in the change in eGFR
timeFrame: baseline to 12-months
measure: Difference in eGFR
timeFrame: 12-months
measure: 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
timeFrame: Baseline to 12-months
measure: The number of patients with a >10% decrease in cardiac fibrosis when assessed by histology and quantified by stereology (sub study)
timeFrame: Baseline to 12-months
measure: The number of patients with an increase in the respiratory control ratio (RCR) by ≥10% measured by High Resolution Respirometry (HRR) (sub study)
timeFrame: Baseline to 12-months
measure: Composite endpoint of worsening HF with hospitalization or urgent outpatient clinical visit due to HF, and all-cause mortality.
timeFrame: 12-months post-TAVR
measure: All-cause mortality
timeFrame: Baseline to 12-months post-TAVR
measure: Worsening HF with hospitalization or urgent outpatient clinical visit due to HF
timeFrame: 12-months post-TAVR
measure: Difference in the change in urinary albumin/creatinine ratio
timeFrame: Baseline to 12-months
measure: Difference in ACR at 12-months follow-up
timeFrame: 12-months follow-up
measure: 24-hour ambulatory blood pressure changes
timeFrame: baseline to 12 months
measure: Change from baseline to 12-months follow-up in the Kansas City Cardiomyopathy questionnaire
timeFrame: Baseline to 12-months
measure: Change from baseline to 12-months follow-up in New York Heart Association-class (NYHA)
timeFrame: baseline to 12-months.
measure: LVMi reduction of 10 % point (by CMRI)
timeFrame: baseline to 12-months.
measure: LV GLS absolute increase of 2.0 % point (by TTE)
timeFrame: Baseline to 12-months follow-up
measure: A decrease in serum Nt-proBNP of more than 25% follow-up
timeFrame: baseline to 12-months follow-up.
measure: Relative increase of 10% in eGFR
timeFrame: Baseline to 12-months follow-up
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
Study officials:
affiliation: Aarhus University Hospital
name: Steen Hvitfeldt Poulsen
role: PRINCIPAL_INVESTIGATOR
References: