Effect on Clinical Status, Structural and Functional Cardiac Parameters and Myocardial Fibrosis of Triple Combination Therapy With a Sodium-glucose Cotransporter 2 Inhibitor, Angiotensin Receptor/Neprilysin Inhibitor and Mineralocorticoid Receptor Antagonist in Patients With Advanced HFpEF
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Change in myocardial extracellular volume (MRI)
研究概览
简要总结
Patients with advanced heart failure with preserved ejection fraction (HFpEF) will be randomly assigned in open-label multicenter study to receive triple combination therapy with [angiotensin receptor/neprilysin inhibitor [ARNI] + sodium-glucose cotransporter 2 inhibitor [SGLTi] + mineralocorticoid receptor antagonist [MRA]) or with individualized medical therapy [SGLTi + renin-angiotensin system inhibitor [RASi] [angiotensin receptor blocker [ARB] or angiotensin-converting enzyme inhibitor [ACE-I]), and will be treated for 52 weeks
详细描述
HFpEF has a significant morbidity and mortality, and the therapeutic options for HFpEF are limited. According to the results of clinical HFpEF trials, SGLTis and MRA can improve prognosis (EMPEROR-preserved, DELIVER, FINEARTS-HF trials); and ARNI can reduce the risk of hospitalization due to exacerbation of heart failure (PARAGON-HF trial). There is also clinical and experimental evidence of anti-inflammatory and antifibrotic effects in SGLTi, MRA and ARNI. However, there are currently no randomized clinical trials evaluating the efficacy of the combination therapy with all these drugs in HFpEF. The investigators suppose that triple combination therapy with [ARNI + SGLTi + AMR] in HFpEF will have a pronounced, rapid and safe positive clinical and haemodynamic effect primarily through its effect on fibrosis and inflammation in patients with HFpEF.
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
- None
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed and data informed consent;
- •Symptoms and signs of HF;
- •LV ejection fraction > 50%;
- •NT-proBNP > 300 pg/mL (for patients with atrial fibrillation NT-proBNP > 900 pg/mL)
- •LV diastolic dysfunction II-III grade OR
- •LV diastolic dysfunction I grade and at least 2 out of 4:
- •Е/е' > 14
- •LAVi > 34 ml/m2 (for those with persistent atrial fibrillation > 40 ml/m2)
- •PASP > 35 mm Hg or TR velocity > 2.8 m/sec
- •LV mass index > 95 g/m2 for women / > 115 g/m2 for men or LV interventricular septum or posterior wall thickness ≥ 1.1 sm OR
- •Chronic atrial fibrillation and at least 3 out of 4:
- •Е/е' > 11
- •E-wave velocity > 100 sm/s
- •TR velocity > 2.8 sm/s
- •DT ≤ 160 ms
排除标准
- •Evidence of myocardial ischemia during stress echocardiography;
- •Significant lesions of main coronary arteries;
- •Atrial fibrillation with resting HR > 110 beats/min;
- •Continuous (>90 days) treatment with ARNI, SGLTi and/or AMR within 12 months prior to screening. The last administration of these drugs must be at least 30 days prior to randomization. Treatment with these drugs should not be interrupted for the purpose of inclusion in the study.
- •Coronary bypass surgery, stroke or TIA within the last 3 months of screening;
- •Myocardial infarction or myocardial revascularization within the last 3 months of screening;
- •Systolic blood pressure < 90 mmHg or ≥ 180 mmHg at screening or randomization;
- •Genetic forms of HFpEF (HCM, amyloidosis, Fabry disease, glycogen storage diseases etc.);
- •Peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, viral myocarditis, isolated right-sided HF without left-sided structural disease, constrictive pericarditis, significant pericardial effusion;
- •Dyspnea due to non-cardiac causes such as pulmonary disease, anemia, severe obesity, primary valvular, or myocardial diseases;
- •Significant lung disease (severe lung disease requiring home oxygen or chronic oral steroid therapy);
- •Primary pulmonary artery hypertension;
- •Significant left sided structural valve disease;
- •Anemia (Hb < 100 g/L);
- •Obesity (body mass index > 50 kg/m2);
- •Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (CKD-EPI);
- •Impaired liver function (serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 × upper limit of normal);
- •Addison's disease;
- •Known hypersensitivity to medications used the in the study;
- •Non-cardiac conditions that complicate/exclude participation in the study;
- •Diseases associated with isolated LV insufficiency (idiopathic pulmonary hypertension, chronic thromboembolic pulmonary hypertension, etc.);
- •Serum/plasma potassium >5.0 mmol/L at screening or randomization or a history of hyperkalemia or acute renal failure during AMR treatment for >7 consecutive days leading to discontinuation of AMR treatment.
- •For patients with diabetes mellitus:
- •Type 1 diabetes mellitus;
- •Presence of more than 4 episodes of moderate hypoglycemia within the past month or at least one episode of severe hypoglycemia within the past year;
- •Glycated hemoglobin level > 9% or <6%
研究组 & 干预措施
[ARNI + SGLTi + AMR]
Patients will receive combination therapy with ARNI, gliflozin and AMR
干预措施: [ARNI + SGLTi + AMR] (Drug)
[SGLTi + previously taken RAAS blocker]
Patients will receive combination therapy with gliflozin and previously taken RAAS blocker
干预措施: [SGLTi + previously taken RAAS blocker] (Drug)
结局指标
主要结局
Change in myocardial extracellular volume (MRI)
时间窗: 52 weeks
Difference in myocardial extracellular volume assessed by MRI data between 52 weeks after baseline and at baseline
Change in 6-minute walking distance (6MWD)
时间窗: 52 weeks
Difference in distance walked during 6-minute walking test (6MWT) between 52 weeks after baseline and at baseline
Change in N-terminal pro b-type natriuretic peptide (NT-proBNP)
时间窗: 52 weeks
Difference in NT-proBNP plasma levels between 52 weeks after baseline and at baseline
Change in average E/e' ratio and tricuspid regurgitation velocity
时间窗: 52 weeks
Difference in E/e' ratio and tricuspid regurgitation velocity assessed by echocardiography both at rest and at peak exercise during diastolic stress test (DST) between 52 weeks after baseline and at baseline
Change in left atrial volume index (LAVi)
时间窗: 52 weeks
Difference in LAVi assessed by echocardiography between 52 weeks after baseline and at baseline
次要结局
- Change in left ventricular mass index (LVMi)(52 weeks)
- Change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score(52 weeks)
- Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score(52 weeks)
- Change in biomarkers of inflammation and fibrosis(52 weeks)
- Change in cardiac hemodynamic reserves - LV contractile(52 weeks)
- Change in cardiac hemodynamic reserves - LV diastolic(52 weeks)
- Change in cardiac hemodynamic reserves - LA reservoir(52 weeks)
- Change in cardiac hemodynamic reserves - cardiac chronotropic(52 weeks)
- Change in cardiac hemodynamic reserves - RV contractile(52 weeks)