Multicenter, Randomized, 2 x 2 Factorial, Phase 3 Study to Assess the Efficacy of Carvedilol and Empagliflozin on Improvement of Right Ventricular Remodeling in Patients With Severe Functional Tricuspid Regurgitation
Overview
- Phase
- Phase 3
- Intervention
- Carvedilol+Empagliflozin
- Conditions
- Tricuspid Regurgitation
- Sponsor
- Asan Medical Center
- Enrollment
- 56
- Locations
- 3
- Primary Endpoint
- Change of RV end-systolic volume index
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
Functional tricuspid regurgitation (TR) has been regarded as a secondary phenomenon of heart failure (HF), mitral valve (MV) disease or atrial fibrillation. Regardless of left ventricular (LV) function or pulmonary artery pressure, presence of moderate or greater functional TR is associated with poor prognosis. When a patient develops functional TR, it causes RV dilation and tricuspid annular enlargement, which also lead to deterioration of TR. A vicious cycle of significant TR, RV volume overload, tricuspid annular dilation and consequent aggravation of TR is accepted as a main determinant of the poor clinical outcome of patients with TR. Therefore, therapies that induce reverse remodeling of the RV and consequently reduce TR, may improve clinical outcomes. However, there have been no proven medical therapies for TR. The investigators hypothesize that carvedilol or empagliflozin is effective on improving RV remodeling in patients with functional severe TR and try to examine this hypothesis in a multicenter, 2x2 factorial, and randomized comparison study using cardiac MRI.
Detailed Description
Functional tricuspid regurgitation (TR) has been regarded as a secondary phenomenon of heart failure (HF), mitral valve (MV) disease or atrial fibrillation. The prevalence of functional TR was reported to be 25-64% in patients with either ischemic or non-ischemic cardiomyopathy. Regardless of left ventricular (LV) function or pulmonary artery pressure, presence of moderate or greater functional TR is associated with poor prognosis. When a patient develops functional TR, it causes RV dilation and tricuspid annular enlargement, which also lead to deterioration of TR. A vicious cycle of significant TR, RV volume overload, tricuspid annular dilation and consequent aggravation of TR is accepted as a main determinant of the poor clinical outcome of patients with TR. Because the quantitative assessment of RV size and function using echocardiography is often limited due to the complex geometry of RV, cardiac magnetic resonance imaging (MRI) has emerged as a gold standard for evaluating RV volume and function with excellent accuracy and reproducibility. The investigators previously reported that RV end-systolic volume index (ESVI) and RV end-diastolic volume index (EDVI) measured by MRI were significantly larger in severe TR patients, and also found that preoperative RV ESVI and RV ejection fraction (EF) on MRI were independent predictors of cardiac death and postoperative adverse events in patients who underwent TV surgery for severe functional TR. Therefore, therapies that induce reverse remodeling of the RV and consequently reduce TR, may improve clinical outcomes. However, there have been no proven medical therapies for TR. The morbidity and mortality of patients with functional TR remain high and novel therapeutic agents are needed to improve the prognosis of patients with functional TR. The investigators hypothesize that carvedilol or empagliflozin is effective on improving RV remodeling in patients with functional severe TR and try to examine this hypothesis in a multicenter, 2x2 factorial, and randomized comparison study using cardiac MRI.
Investigators
Duk-Hyun Kang
Professor
Asan Medical Center
Eligibility Criteria
Inclusion Criteria
- •Patients must agree to the study protocol and provide written informed consent
- •Outpatients ≥ 20 years of age, male or female
- •Patients with severe functional tricuspid regurgitation
- •TR whose vena contracta ≥0.7cm or central jet area \> 10 square cm and which lasted \> 6 months under medical treatment
- •LV ejection fraction ≥ 50%
- •Dyspnea of NYHA functional class II or III
Exclusion Criteria
- •History of hypersensitivity or allergy to the study drugs, drugs of similar chemical classes, as well as known or suspected contraindications to the study drug
- •Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor
- •Significant left-sided valve disease
- •Left ventricular ejection fraction \<40%
- •Marked bradycardia (\<50 beats/min) or 2nd or 3rd degree AVB, sinus node dysfunction
- •Severe pulmonary hypertension: TR Vmax \>4m/s at screening (including Cor pulmonale)
- •Medical history of hospitalization within 6 weeks
- •Current acute decompensated heart failure or dyspnea of NYHA functional class IV
- •Symptomatic hypotension and/or a SBP \< 90 mmHg at screening Estimated GFR \< 30 mL/min/1.73 square m
- •History of ketoacidosis, Type 1 diabetes
Arms & Interventions
carvedilol+empagliflozin
Patients will receive carvedilol SR 16mg and empagliflozin 10mg qd.
Intervention: Carvedilol+Empagliflozin
carvedilol alone
Patients will receive carvedilol SR 16mg alone.
Intervention: Carvedilol
empagliflozin alone
Patients will receive empagliflozin 10mg and matching placebo of carvedilol.
Intervention: Empagliflozin
placebo
Patients will receive matching placebo of carvedilol.
Intervention: Placebo
Outcomes
Primary Outcomes
Change of RV end-systolic volume index
Time Frame: from baseline to 12 months follow-up
Change of RV end-systolic volume index by cardiac MRI
Secondary Outcomes
- Occurrences of death from any causes(the entire follow-up period (continuing until 12 months after the last patient was enrolled))
- Change of RV end-diastolic volume index(from baseline to 12 months follow-up)
- Change of RV ejection fraction(from baseline to 12 months follow-up)
- Change of vena contract width of TR(from baseline to 12 months follow-up)
- Occurrences of death from cardiovascular causes or hospitalization for heart failure(the entire follow-up period (continuing until 12 months after the last patient was enrolled))