Angiotensin Receptor Blockade In Patients After Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis With Left Ventricular Hypertrophy (ARBITAR) Trial
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 632
- 试验地点
- 1
- 主要终点
- Composite of all-cause death or admission for heart failure
研究概览
简要总结
This is a multicenter, prospective, open-label, randomized, investigator-initiated trial evaluating whether angiotensin receptor blocker (ARB) therapy improves clinical outcomes in patients with severe aortic stenosis (AS) and left ventricular hypertrophy (LVH) who have undergone transcatheter aortic valve replacement (TAVR).
Severe AS imposes chronic pressure overload on the left ventricle, leading to LVH as a compensatory response. While initially adaptive, sustained LVH promotes myocardial fibrosis, reduced ventricular compliance, and impaired cardiac function. LVH that persists after valve replacement is associated with increased morbidity and mortality, including a higher risk of heart failure. Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEi) or ARBs has been proposed as a strategy to attenuate adverse left ventricular remodeling after valve replacement by inhibiting angiotensin II-mediated hypertrophic and fibrotic signaling. However, evidence in TAVR patients with LVH remains limited, and a small randomized trial of an ACEi reported drug discontinuation in approximately 10% of patients due to dry cough. The ARBITAR trial therefore evaluates the clinical efficacy of an ARB in this population.
A total of 632 patients with symptomatic severe AS and LVH who have successfully undergone TAVR within the prior 30 days will be randomized 1:1 to receive an ARB (experimental group) or no ARB (control group), stratified by site and sex. Assigned treatment is continued for up to 24 months, with follow-up visits at 1, 6, 12, and 24 months. In the experimental group, the ARB (candesartan, losartan, or valsartan) is up-titrated toward a target dose. ACE inhibitors, direct renin inhibitors, and angiotensin receptor/neprilysin inhibitors are prohibited in both groups.
The primary endpoint is the composite of all-cause death or admission for heart failure over 2 years. Secondary endpoints include the individual components of the primary endpoint and other clinical events, as well as echocardiographic measures, NT-proBNP, NYHA functional class, and KCCQ-12 score. The primary analysis follows the intention-to-treat principle.
详细描述
Background and Rationale Severe aortic stenosis (AS) imposes chronic pressure overload on the left ventricle. To compensate for the elevated afterload, the left ventricular myocardium thickens, producing left ventricular hypertrophy (LVH). Although LVH initially serves as an adaptive mechanism in early AS, when it persists over the long term it leads to myocardial fibrosis, reduced left ventricular compliance, and deterioration of cardiac function.
Patients with severe AS and concomitant LVH generally have a poor prognosis even after transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). LVH that persists after the procedure, and the resulting myocardial fibrosis, are closely associated with increased morbidity and mortality, including an increased risk of heart failure.
Blockade of the renin-angiotensin system (RAS), using ACE inhibitors (ACEi) or angiotensin receptor blockers (ARBs), has been proposed as a treatment strategy from which patients with severe AS may benefit after TAVR. By inhibiting angiotensin II, RAS blockade may attenuate adverse left ventricular remodeling after the procedure by blocking the hypertrophic signaling and fibrosis to which angiotensin II contributes in AS. Some preliminary studies have suggested favorable effects of RAS blockers on LVH regression and improvement of left ventricular function after valve replacement, but current evidence is insufficient, and data in TAVR patients with LVH are particularly limited. Among RAS blockers, an ACEi was recently studied in a small randomized trial in patients who had undergone TAVR, in which approximately 10% of patients discontinued the study drug because of dry cough. The ARBITAR trial therefore evaluates the clinical efficacy of an ARB used after TAVR in patients with severe AS and LVH.
Objective To evaluate whether an ARB improves clinical outcomes and patient symptoms, and reduces LVH, in patients with severe AS and LVH who have undergone TAVR.
Study Design ARBITAR is a multicenter, prospective, open-label, randomized, investigator-initiated trial. Patients with severe AS and LVH who have undergone TAVR are randomized 1:1 to an experimental group receiving an ARB and a control group receiving no ARB. The funding organization provides financial support only and does not participate in any aspect of the study, including study design, site selection, conduct, management, data collection, or statistical analysis. The study is conducted in accordance with the Declaration of Helsinki, and all participants provide written informed consent at enrollment.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female aged 40 years or older
- •Symptomatic severe aortic stenosis (AS) with left ventricular hypertrophy (LVH) who successfully underwent transcatheter aortic valve replacement (TAVR) within the prior 30 days, including native-valve or valve-in-valve TAVR
- •* Severe AS defined by at least one of the following: aortic valve area ≤1.0 cm²; aortic valve area index ≤0.6 cm²/m²; mean pressure gradient ≥40 mmHg; or maximal aortic valve velocity ≥4.0 m/sec
- •* LVH defined as left ventricular mass index >115 g/m² in men or >95 g/m² in women
- •Successful TAVR (technical success) meeting all VARC-3 criteria: survival; successful access, delivery, and retrieval of the device; correct positioning of a single prosthetic valve in the proper anatomic location; no additional surgery or procedure related to the device (excluding permanent pacemaker implantation) or to major vascular, access-site, or cardiac structural complications; and intended prosthetic valve performance (mean gradient <20 mmHg, peak velocity <3 m/s, Doppler velocity index ≥0.25, and less than moderate aortic regurgitation)
- •Left ventricular ejection fraction (LVEF) >40% before TAVR
- •Provided written informed consent to participate, either voluntarily or through a legal representative
排除标准
- •Hypotension (systolic blood pressure <90 mmHg) or hemodynamic instability defined as a need for continuous intravenous vasopressor support at screening
- •Hyperkalemia (serum potassium >5.5 mmol/L)
- •Bilateral renal artery stenosis without stent placement
- •Allergy, hypersensitivity, or prior intolerance to angiotensin receptor blockers
- •Pregnancy, breastfeeding, or planning to become pregnant
- •Estimated life expectancy of less than 2 years
- •Acute coronary syndrome diagnosed within the past 1 year
- •Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2 by the CKD-EPI equation, or currently undergoing renal replacement therapy
- •Any other medical condition that, in the investigator's judgment, makes participation in the trial inappropriate
结局指标
主要结局
Composite of all-cause death or admission for heart failure
时间窗: From randomization to 2 years
Time to the first occurrence of either all-cause death or admission for heart failure. Admission for heart failure is defined per VARC-3 criteria as hospitalization of at least 24 hours for new or worsening heart failure that is confirmed by signs and symptoms together with diagnostic testing and requires intravenous pharmacologic therapy or mechanical heart failure therapies.
次要结局
- All-cause death(From randomization to 2 years)
- Cardiovascular death(From randomization to 2 years)
- Any admission(From randomization to 2 years)
- Admission for heart failure(From randomization to 2 years)
- Myocardial infarction(From randomization to 2 years)
- Stroke (ischemic and/or hemorrhagic)(From randomization to 2 years)
- Redo aortic valve replacement (redo-AVR)(From randomization to 2 years)
研究者
Jung-Kyu Han
Principal Investigator
Seoul National University Hospital