Empagliflozin + Carvedilol vs. Carvedilol Alone for Patients With Cirrhosis and Left Ventricular Diastolic Dysfunction and Impact on Hepatic Decompensation and Survival: A Double-Blind Placebo-Controlled Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 400
- 试验地点
- 1
- 主要终点
- Composite end point of decompensation event and/or death
研究概览
简要总结
- This proposed double-blind placebo controlled randomized controlled trial incorporates recent advances in management of heart failure and portal hypertension using the SGLT-2 inhibitor i.e. EMPAGLIFLOZIN. The drug has been found to be useful in large trials on heart failure with preserved ejection fraction in the general population with improvement in MASLD progression, with improvement in body weight and hepatic steatosis but no change in liver fibrosis.
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the development and progression of heart failure in patients with type 2 diabetes and in those with heart failure and a reduced and preserved ejection fraction. In patients with cirrhosis safety of empagliflozin in a dose of 10 mg has been demonstrated.
- Prevention of decompensation related events in cirrhosis is the key endpoint of any liver-directed therapy as the median survival in the compensated state exceeds 10 years but median survival in the decompensated state approximates 1.5 years. Previous data has demonstrated the risk of hepatic decompensation acute kidney injury and poor survival in patients with cirrhosis and heart failure with preserved ejection fraction (HFpEF) i.e. LVDD a large subset of whom meet criteria for CCM.
详细描述
New diagnostic criteria for cirrhotic cardiomyopathy For the diagnosis of cirrhotic cardiomyopathy (CCM) we will use criteria proposed by the CCM consortium in 2020 with modification to take septal e' and E/e' readings. In accordance with the recent CCM criteria 'systolic dysfunction is defined as an ejection fraction (EF) of 50% or less or an absolute value of GLS <18%. LVDD grade will be determined if 3 of the following 4 criteria are met: early diastolic trans mitral flow to early diastolic mitral annular velocity (E/e') ≥15 left atrial volume index (LAVI) >34 mL/m2 septal early diastolic mitral annular velocity (e') <7 cm/second or tricuspid regurgitation (TR) maximum velocity >2.8 m/second in the absence of pulmonary hypertension (HTN) and the presence of measurable early to late diastolic trans mitral flow velocity (E/A) ratio (E/A >2 = grade 3 E/A 0.8-2 = grade 2)'. LVDD will be classified as "of indeterminate grade" when only 2 of the 4 criteria are met. The supporting criteria for diagnosis of LVDD are changes in cardiac chamber sizes electrophysiological abnormalities increased biomarkers like N terminal pro-brain natriuretic peptide (NT-Pro BNP) and troponin I.
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)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age range of 18-65 years
- •Cirrhosis as diagnosed by histology or clinical laboratory and USG findings
- •LVDD (with EF>50%) on 2D echocardiography with TDI
- •Written informed consent.
排除标准
- •Age >65 years
- •Serum Creatinine>2 mg/dl
- •History of urinary tract /genital infections in last 3 months
- •Patient on treatment with statin (one month before the study)
- •Advanced Cirrhosis (MELD>20)
- •Coronary artery disease
- •Sick sinus syndrome/ Pacemaker valvular heart disease
- •Cardiac rhythm disorder Peripartum cardiomyopathy
- •Portopulmonary hypertension/ hepatopulmonary syndrome
- •Transjugular intrahepatic porto systemic shunt (TIPS) insertion
- •Hepatocellular carcinoma
- •Pregnancy or lactation
- •Patients with HIV or retroviral therapy
- •Anemia Hb < 8gm/dl in females and < 9 gm/dl in males
- •Acute variceal bleeding in last 6months.
研究组 & 干预措施
Experimental: Empagliflozin + Carvedilol-arm
Experimental: Empagliflozin + Carvedilol-arm
- Empagliflozin fixed dose of 10 mg per day in patients with or without diabetes for 1 year from randomization
- Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate
- Standard Medical Therapy for liver disease as per clinician decision
干预措施: Empagliflozin + Carvedilol (Drug)
Active Comparator: Carvedilol arm
- Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate 10 mg placebo administered once daily.
- Standard Medical Therapy prescribed as per clinician decision
干预措施: Carvedilol (Drug)
结局指标
主要结局
Composite end point of decompensation event and/or death
时间窗: From enrolment through study completion, an average of 1 year
The primary outcome measure is defined as a composite end point of acute decompensation event (acute variceal bleeding new ascites or recurrence of previously controlled ascites episode of hepatic encephalopathy or acute kidney injury) OR all-cause death in patients with cirrhosis and LVDD
次要结局
- Hospitalization events(From enrolment through study completion, an average of 1 year)
- • Serum level of Galectin 3(At 12 months from enrolment)
- • Serum level of NT-proBNP(At 12 months from enrolment)
- • Serum level of Galectin-3(At enrolment)
- • Serum level of Aldosterone(At 12 months from enrolment)
- Improvement in Cardiac Diastolic Function(From enrolment through study completion, an average of 1 year)
- Improvement in Cardiac Systolic Function(From enrolment through study completion, an average of 1 year)
- • Serum level of NT-proBNP(At enrolment)
- • Serum level of NT-proBNP(At 6 months from enrolment)
- • Serum level of Galectin 3(At 6 months from enrolment)
- • Serum level of Aldosterone(At enrolment)
- • Serum level of Aldosterone(At 6 months from enrolment)
研究者
Madhumita Premkumar
Additional Professor
Post Graduate Institute of Medical Education and Research, Chandigarh