Effect of Dapagliflozin on Myocardial and Renal Function Following Aortic Valve Stenosis Intervention
试验速览
- 阶段
- 2 期
- 入组人数
- 106
- 试验地点
- 1
- 主要终点
- Composite endpoint of changes in LV mass, systolic function, eGFR, and serum Nt-proBNP
研究概览
简要总结
Randomized, double-blinded, placebo-controlled study in AS patients with subclinical or clinical heart failure undergoing treatment with TAVR.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The medicine will be blinded by encapsulation of both active medicine and placebo in gelatine capsules, in order to blind treatment to both investigators and patients.
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Intervention group
10 mg (oral) SGLT-2 inhibitor once daily
干预措施: SGLT2 inhibitor (Drug)
Control group
Placebo tablet encapsulated as the active treatment.
干预措施: Placebo (Drug)
结局指标
主要结局
Composite endpoint of changes in LV mass, systolic function, eGFR, and serum Nt-proBNP
时间窗: Baseline assesment to 12-months follow-up post-TAVR
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.
次要结局
- Difference in the change in eGFR(baseline to 12-months)
- Difference in eGFR(12-months)
- The number of patients with a >10% decrease in cardiac fibrosis when assessed by histology and quantified by stereology (sub study)(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)(Baseline to 12-months)
- Composite endpoint of worsening HF with hospitalization or urgent outpatient clinical visit due to HF, and all-cause mortality.(12-months post-TAVR)
- All-cause mortality(Baseline to 12-months post-TAVR)
- Worsening HF with hospitalization or urgent outpatient clinical visit due to HF(12-months post-TAVR)
- Difference in the change in urinary albumin/creatinine ratio(Baseline to 12-months)
- Difference in ACR at 12-months follow-up(12-months follow-up)
- 24-hour ambulatory blood pressure changes(baseline to 12 months)
- Change from baseline to 12-months follow-up in the Kansas City Cardiomyopathy questionnaire(Baseline to 12-months)
- Change from baseline to 12-months follow-up in New York Heart Association-class (NYHA)(baseline to 12-months.)
- LVMi reduction of 10 % point (by CMRI)(baseline to 12-months.)
- LV GLS absolute increase of 2.0 % point (by TTE)(Baseline to 12-months follow-up)
- A decrease in serum Nt-proBNP of more than 25% follow-up(baseline to 12-months follow-up.)
- Relative increase of 10% in eGFR(Baseline to 12-months follow-up)
- 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(Baseline to 12-months)