Angiotensin Receptor Blocker After TAVR in Severe Aortic Stenosis With Left Ventricular Hypertrophy (ARBITAR)

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.

Randomization and Blinding Patients who provide written informed consent and meet all inclusion and exclusion criteria are randomized 1:1 to the experimental or control group. Randomization is stratified by participating site and sex and is managed independently through a web-based interactive web response service (IWRS) to ensure balanced allocation. As an open-label study, no blinding of treatment assignment is performed. Approximately 632 patients will be enrolled at multicenter TAVR centers in Korea, and the assigned treatment is continued for up to 24 months of follow-up.

Intervention and Dosing

In the experimental group, one of the following ARBs is administered and up-titrated toward the target daily dose as a principle; treatment may be initiated at the lower starting dose based on clinical need:

Candesartan: starting dose 4-8 mg once daily; target dose 32 mg once daily Losartan: starting dose 25-50 mg once daily; target dose 50-150 mg once daily Valsartan: starting dose 20-40 mg once daily; target dose 160 mg twice daily

The control group does not receive any ARB during the study period. In both groups, concomitant use of ACE inhibitors, direct renin inhibitors, and angiotensin receptor/neprilysin inhibitors (ARNI) is prohibited throughout the study.

Study Assessments and Schedule Follow-up visits are scheduled at 1 month (±15 days), 6 months (±30 days), 12 months (±90 days), and 24 months (±90 days) after enrollment, with additional visits permitted at the investigator's discretion. At screening/baseline, eligibility assessment, informed consent, medical history, demographics, vital signs and physical examination, laboratory tests, procedural data, medication history, NYHA functional class, KCCQ-12, and transthoracic echocardiography are collected. At each follow-up visit, vital signs, laboratory tests (including NT-proBNP), medication review, NYHA class, KCCQ-12, transthoracic echocardiography, clinical outcomes, and adverse events are assessed. Investigators are encouraged to maintain follow-up through in-person visits or telephone contact and to contact patients who miss scheduled visits to minimize underreporting of clinical events.

Endpoints The primary endpoint is the composite of all-cause death or admission for heart failure. Secondary endpoints comprise all-cause death, cardiovascular death, any admission, admission for heart failure, myocardial infarction, stroke (ischemic and/or hemorrhagic), and redo aortic valve replacement (TAVR or surgical AVR). Other secondary endpoints include echocardiographic measurements (LVEF, peak aortic velocity, peak transaortic gradient, mean transaortic gradient, aortic valve area, aortic valve area index, and aortic regurgitation), NT-proBNP, NYHA functional class, and KCCQ-12 overall summary score.

Endpoint Definitions Endpoint definitions are based on the Valve Academic Research Consortium-3 (VARC-3) criteria. Cardiovascular death is defined as death due to a clear cardiovascular cause (e.g., heart failure, cardiogenic shock, prosthetic valve dysfunction, myocardial infarction, stroke, thromboembolism, bleeding, cardiac tamponade, vascular complication, arrhythmia or conduction disorder, or cardiovascular infection such as mediastinitis or endocarditis), intraprocedural death, sudden death, or death of undetermined cause. Admission for heart failure is defined 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. All endpoints are first evaluated by the investigator and subsequently adjudicated by an independent adjudicator before final determination.

Statistical Analysis The primary efficacy analysis is performed on the full analysis set according to the intention-to-treat principle; safety analysis is performed on the safety set. For the primary endpoint, time-to-event data are estimated and visualized with the Kaplan-Meier method, between-group differences are tested with a stratified log-rank test adjusted for stratification factors, and the treatment effect is expressed as a hazard ratio with 95% confidence interval from a Cox proportional hazards model, with verification of the proportional hazards assumption. Secondary endpoints are analyzed using the same principles while accounting for competing risk: for endpoints other than all-cause death, all-cause death is treated as a competing-risk event, cumulative incidence is compared using the cumulative incidence function, and a Fine and Gray model is used to estimate subdistribution hazard ratios with 95% confidence intervals. Other secondary endpoints (echocardiographic measurements, NT-proBNP, NYHA class, KCCQ-12) are summarized at baseline and follow-up time points and compared between and within groups using appropriate parametric or nonparametric tests. Safety is evaluated through adverse events of special interest.

Study Oversight The study is overseen by an Executive Committee, an independent Data Safety and Monitoring Board (DSMB), and a Clinical Event Adjudication Committee (CEAC) composed of independent cardiologists who adjudicate protocol-defined clinical events in a blinded manner. Data are collected through a web-based electronic case report form (eCRF) system, and clinical research associates conduct site monitoring, including source data verification.

• All-cause death [Срок оценки: From randomization to 2 years]
• Cardiovascular death [Срок оценки: From randomization to 2 years]
• Any admission [Срок оценки: From randomization to 2 years]
• Admission for heart failure [Срок оценки: From randomization to 2 years]
• Myocardial infarction [Срок оценки: From randomization to 2 years]
• Stroke (ischemic and/or hemorrhagic) [Срок оценки: From randomization to 2 years]
• Redo aortic valve replacement (redo-AVR) [Срок оценки: From randomization to 2 years]