Vericiguat's Effects on Reverse Remodeling Indices: Pathophysiologic Approach to Treatment of Heart Failure With Reduced Ejection Fraction
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Change in right ventricular systolic function assessed by right ventricular fractional area change (RV FAC)
研究概览
简要总结
The goal of this clinical trial is to investigate how vericiguat benefits adults with stable heart failure with reduced ejection fraction (HFrEF) who are already receiving guideline-directed medical therapy.
The main questions are:
- Does vericiguat improve right ventricular systolic function, measured by tricuspid annular plane systolic excursion (TAPSE)?
- Does vericiguat favourably influence myocardial remodeling, fibrosis, angiogenesis, inflammation, metabolism, renal function, and hematologic balance?
- Do genetic and oxidative stress profiles modify treatment response? Researchers will compare a group receiving vericiguat plus usual care with a group receiving usual care alone to assess structural, functional, and biomarker changes over 12 months.
Participants will:
- Have blood drawn at baseline and follow-up visits for biomarker, metabolomic, genetic, transcriptomic, and hematologic analyses, including platelet function testing
- Perform oral glucose tolerance tests (OGTT) to assess insulin resistance
- Undergo echocardiography, cardiac magnetic resonance imaging, and cardiac scintigraphy to evaluate heart structure, function, and perfusion
- Attend follow-up visits at 1, 3, 6, and 12 months Open-label extension: After the 12-month randomized phase, participants originally assigned to usual care will be offered open-label vericiguat and followed for an additional 12 months. This exploratory extension will reassess study outcomes to evaluate the consistency and magnitude of response to vericiguat in the prior control cohort.
详细描述
Heart failure with reduced ejection fraction (HFrEF) involves pathologic processes that lead to maladaptive remodeling of the myocardium with ventricular dilation, wall thickening, and cellular and microvascular changes that progressively worsen cardiac function. Many established therapies for heart failure can promote reverse remodeling, improving symptoms and long-term outcomes.
Vericiguat is a soluble guanylate cyclase (sGC) stimulator that increases cyclic guanosine monophosphate (cGMP), a signaling molecule with vasodilatory and cardioprotective effects that is impaired in heart failure. Randomized trials show that vericiguat reduces the risk of worsening heart-failure events in HFrEF after recent decompensation, and emerging evidence indicates that these benefits extend to stable HFrEF. The mechanisms by which vericiguat may benefit patients with HFrEF remain incompletely understood.
Preclinical data suggest that augmenting cGMP signaling may confer antifibrotic, antihypertrophic, antiinflammatory, proangiogenic, and metabolic effects. These mechanisms could contribute to reverse remodeling and improved clinical status, but they require confirmation in a clinical setting.
This randomized, controlled study will evaluate the effects of vericiguat on right ventricular systolic function, assessed by tricuspid annular plane systolic excursion (TAPSE), and will characterize associated structural and biologic changes in adults with stable HFrEF on contemporary GDMT. Sixty participants will be randomized to vericiguat plus usual care or to usual care alone and followed for 12 months, with study visits at 1, 3, 6, and 12 months.
At each visit, blood samples will be collected for analysis of circulating biomarkers reflecting fibrosis, inflammation, angiogenesis, renal function, and metabolism, as well as transcriptomic profiling. Comprehensive metabolomic profiling will be performed, and insulin resistance will be evaluated by oral glucose tolerance testing (OGTT) at baseline and 12 months. Hematologic parameters will be measured at each visit, while platelet function will be assessed at baseline and 12 months.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent from an adult patient (≥ 18 years old) to participate in the clinical study,
- •Stable HFrEF defined as no heart failure worsening in the 6 months before randomization that required hospitalization or outpatient diuretic treatment,
- •Confirmed diagnosis of chronic heart failure with reduced ejection fraction (LVEF ≤ 40%, confirmed by echocardiography) within 12 months before randomization,
- •Stable GDMT for HFrEF for at least 3 months prior to randomisation.
排除标准
- •Systolic blood pressure < 100 mmHg or symptomatic hypotension,
- •Current or planned use of long-acting nitrates, soluble guanylate cyclase stimulators, or phosphodiesterase type V inhibitors,
- •Known allergy/hypersensitivity to soluble guanylate cyclase stimulators,
- •Awaiting heart transplantation or dependence on continuous inotropic therapy
- •Cardiac amyloidosis, sarcoidosis, myocarditis, stress cardiomyopathy, or tachycardic cardiomyopathy,
- •Acute coronary syndrome, coronary artery bypass grafting, or percutaneous coronary intervention in the past three months before randomisation,
- •Long-term mechanical circulatory support of the left ventricle,
- •Active infection,
- •Chronic kidney disease stage 4 or 5, and
- •Advanced liver failure classified as Child-Pugh B or C.
研究组 & 干预措施
Vericiguat + GDMT
Participants will receive vericiguat added to guideline-directed medical therapy (GDMT) for heart failure. Vericiguat will be initiated at 2.5 mg once daily and up-titrated in approximately 2-week intervals to 5 mg and then a target dose of 10 mg once daily, as tolerated, over the 12-month randomized phase.
干预措施: Vericiguat (Drug)
Vericiguat + GDMT
Participants will receive vericiguat added to guideline-directed medical therapy (GDMT) for heart failure. Vericiguat will be initiated at 2.5 mg once daily and up-titrated in approximately 2-week intervals to 5 mg and then a target dose of 10 mg once daily, as tolerated, over the 12-month randomized phase.
干预措施: Guideline Directed Medical Therapy for Heart Failure (GDMT) (Drug)
GDMT
Participants will continue to receive guideline-directed medical therapy (GDMT) for heart failure without vericiguat during the 12-month randomized phase (vericiguat offered during exploratory extension).
干预措施: Guideline Directed Medical Therapy for Heart Failure (GDMT) (Drug)
结局指标
主要结局
Change in right ventricular systolic function assessed by right ventricular fractional area change (RV FAC)
时间窗: Baseline to 6 months and 12 months
Change in RV FAC (%), measured by transthoracic echocardiography (TTE) in the apical four-chamber view.
次要结局
- Change in left ventricular systolic function assessed by left ventricular ejection fraction (LVEF)(Baseline to 6 months and 12 months)
- Change in left ventricular systolic function assessed by left ventricular global longitudinal strain (GLS)(Baseline to 6 months and 12 months)
- Change in left ventricular structure assessed by left ventricular mass index (LVMI)(Baseline to 6 months and 12 months)
- Change in right ventricular systolic function assessed by tricuspid annular plane systolic excursion (TAPSE)(Baseline to 6 months and 12 months)
- Change in circulating serum fibrosis biomarkers assessed by Galectin-3 (Gal-3) and soluble ST2 (sST2)(Baseline, 1 month, 3 months, 6 months, and 12 months)
- Change in serum angiogenetic biomarkers assessed by angiogenesis-related biomarker panel composite score(Baseline, 1 month, 3 months, 6 months, and 12 months)
- Change in systemic inflammation assessed by serum inflammatory biomarker panel composite score(Baseline, 1 month, 3 months, 6 months, and 12 months)
- Change in cardiac fibrosis assessed by the extent of late gadolinium enhancement (LGE)(Baseline to 12 months)
- Change in myocardial microvascular dysfunction assessed by quantitative myocardial perfusion scintigraphy(Baseline to 12 months)
- Change in insulin sensitivity assessed by the Matsuda index(Baseline and 12 months)
- Change in kidney function assessed by urine albumin-to-creatinine ratio (UACR)(Baseline, 1 month, 3 months, 6 months, and 12 months)
研究者
Gregor Poglajen
Associate Professor
University Medical Centre Ljubljana