DICE Study- Diastolic Improvement With Carvedilol & Empagliflozin in Patients With Cirrhosis

Официальное название

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

Обзор

1. 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. 2. 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. 3. 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.

Подробное описание

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.

Вмешательства

• Препарат Empagliflozin + Carvedilol
  Patient Recruitment: The study participants are all cirrhosis patients receiving treatment at PGIMER Chandigarh. Eligible participants meeting LVDD criteria per the CCM Consortium 2020 consensus. Carvedilol Dosing protocol in this study Patients will be given carvedilol in a starting dose of 3.125 mg twice daily. The dose will be titrated weekly to achieve a target heart rate of 50-60/ min taking care that side effects such as hypotension bronchospasm excessive bradycardia are not seen. The ma
• Препарат Carvedilol
  * Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate 10 mg placebo pill * Standard Medical Therapy

Первичные конечные точки

• Composite end point of decompensation event and/or death [Срок оценки: From enrolment through study completion, an average of 1 year]

Вторичные конечные точки (12)

• Improvement in Cardiac Diastolic Function [Срок оценки: From enrolment through study completion, an average of 1 year]
• Improvement in Cardiac Diastolic Function [Срок оценки: From enrolment through study completion, an average of 1 year]
• Improvement in Cardiac Diastolic Function [Срок оценки: From enrolment through study completion, an average of 1 year]
• Improvement in Cardiac Diastolic Function [Срок оценки: From enrolment through study completion, an average of 1 year]
• Improvement in Cardiac Systolic Function [Срок оценки: From enrolment through study completion, an average of 1 year]
• Improvement in Cardiac Systolic Function [Срок оценки: From enrolment through study completion, an average of 1 year]
• Improvement in Cardiac Systolic Function [Срок оценки: From enrolment through study completion, an average of 1 year]
• Hospitalization events [Срок оценки: From enrolment through study completion, an average of 1 year]
• • Serum level of NT-proBNP [Срок оценки: At enrolment]
• • Serum level of NT-proBNP [Срок оценки: At 6 months from enrolment]
• • Serum level of NT-proBNP [Срок оценки: At 12 months from enrolment]
• • Serum level of Galectin-3 [Срок оценки: At enrolment]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Индия · 1 центр

• PGIMER Chandigarh — Chandigarh

Идентификаторы

NCT: NCT07322237 · PGI/IEC/2025/SPL-865

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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