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

Angiotensin Receptor Blockade In Patients After Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis With Left Ventricular Hypertrophy (ARBITAR) Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Left Ventricular Hypertrophy; Severe Aortic Stenosis; Transcatheter Aortic Valve Replacement (TAVR)
• Intervention / Treatment: Drug: Angiotensin Receptor Blocker (ARB)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 632
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jung-Kyu Han, MD, PhD; Phone Number: +82-2-2072-4870; Email: hpcrates@gmail.com

Study Locations

• South Korea
  • Seoul
    • Seoul, Seoul, South Korea, 03080
      • Seoul National University Hospital
      • Contact: Jung-Kyu Han, MD, PhD; Phone Number: +82-2-2072-4870; Email: hpcrates@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Angiotensin Receptor Blocker (ARB) Group; Participants in this group receive an angiotensin receptor blocker (candesartan, losartan, or valsartan) in addition to standard care after TAVR. As a principle, the ARB is up-titrated toward the target daily dose, but it may be initiated at a lower starting dose based on clinical need. Assigned treatment is continued for up to 24 months. ACE inhibitors, direct renin inhibitors, and angiotensin receptor/neprilysin inhibitors are prohibited.	Drug: Angiotensin Receptor Blocker (ARB); An oral angiotensin receptor blocker - candesartan, losartan, or valsartan - is administered to the experimental group and, as a principle, up-titrated toward the target daily dose, with initiation at a lower starting dose permitted based on clinical need. Doses are: candesartan 4-8 mg once daily titrated to 32 mg once daily; losartan 25-50 mg once daily titrated to 50-150 mg once daily; valsartan 20-40 mg once daily titrated to 160 mg twice daily. Treatment is continued for up to 24 months. Up-titration is considered when all of the following are met: standing systolic blood pressure ≥90 mmHg, no symptoms of hypotension, serum creatinine <2.0 mg/dL or <50% increase from baseline, and serum potassium <5.5 mmol/L. If serum potassium exceeds 6.0 mmol/L, the ARB is discontinued and resumed at a low dose once potassium returns below 5.5 mmol/L.
No Intervention: Control (No ARB) Group; Participants in this group receive standard care after TAVR without any angiotensin receptor blocker during the study period. ACE inhibitors, direct renin inhibitors, and angiotensin receptor/neprilysin inhibitors are also prohibited in this group. Participants are followed for up to 24 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of all-cause death or admission for heart failure	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.	From randomization to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause death	Time to death from any cause after randomization.	From randomization to 2 years
Cardiovascular death	Time to death from a cardiovascular cause as defined by VARC-3, including death due to heart failure, cardiogenic shock, prosthetic valve dysfunction, myocardial infarction, stroke, thromboembolism, bleeding, cardiac tamponade, vascular complication, arrhythmia or conduction disorder, or cardiovascular infection, as well as intraprocedural death, sudden death, and death of undetermined cause.	From randomization to 2 years
Any admission	Time to first hospitalization for any cause after randomization.	From randomization to 2 years
Admission for heart failure	Time to first hospitalization for new or worsening heart failure, defined per VARC-3 as an admission of at least 24 hours confirmed by signs and symptoms together with diagnostic testing and requiring intravenous pharmacologic therapy or mechanical heart failure therapies.	From randomization to 2 years
Myocardial infarction	Time to first myocardial infarction as defined by VARC-3 criteria.	From randomization to 2 years
Stroke (ischemic and/or hemorrhagic)	Time to first stroke, including ischemic and/or hemorrhagic stroke, as defined by VARC-3 criteria.	From randomization to 2 years
Redo aortic valve replacement (redo-AVR)	Time to first repeat aortic valve replacement procedure, by either transcatheter or surgical approach.	From randomization to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Echocardiographic measurements - LVEF	Left ventricular ejection fraction measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: percentage (%)	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Peak aortic velocity	Peak aortic jet velocity measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: m/s	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Peak transaortic gradient	Peak transaortic pressure gradient measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: mmHg	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Mean transaortic gradient	Mean transaortic pressure gradient measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: mmHg	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Aortic valve area	Aortic valve area measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: cm^2	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Aortic valve area index	Aortic valve area indexed to body surface area, measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: cm^2/m^2	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Aortic regurgitation	Aortic regurgitation (paravalvular and central) assessed by transthoracic echocardiography, assessed serially over the follow-up period.	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Mitral inflow E-wave velocity (E)	Peak early diastolic mitral inflow velocity (E) measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: m/s	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Mitral inflow A-wave velocity (A)	Peak late diastolic (atrial) mitral inflow velocity (A) measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: m/s	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Mitral annular early diastolic velocity (e')	Mitral annular early diastolic tissue Doppler velocity (e') measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: cm/s	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Left atrial volume	Left atrial volume measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: mL	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Left atrial volume index (LAVI)	Left atrial volume indexed to body surface area, measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: mL/m^2	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Tricuspid regurgitation peak velocity	Peak tricuspid regurgitation jet velocity measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: m/s	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Pulmonary artery systolic pressure (PASP)	Pulmonary artery systolic pressure estimated by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: mmHg	Baseline and 1, 6, 12, and 24 months
Echocardiographic measurement - Left ventricular mass index	Left ventricular mass indexed to body surface area, measured by transthoracic echocardiography, assessed serially over the follow-up period. Unit of Measure: g/m^2	Baseline and 1, 6, 12, and 24 months
NT-proBNP	Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, assessed serially over the follow-up period.	Baseline and 1, 3, 6, 12, and 24 months
New York Heart Association (NYHA) functional class	NYHA functional classification of heart failure symptoms, assessed serially over the follow-up period.	Baseline and 1, 3, 6, 12, and 24 months
Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) overall summary score	Patient-reported health status measured by the KCCQ-12 overall summary score (range 0-100, with higher scores indicating better health status), assessed serially over the follow-up period.	Baseline and 1, 6, 12, and 24 months

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: Samjin Pharmaceutical Co., Ltd.

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Estimated): August 15, 2026
• Primary Completion (Estimated): June 15, 2030
• Study Completion (Estimated): June 15, 2030

Study Registration Dates

• First Submitted: June 10, 2026
• First Submitted That Met QC Criteria: July 26, 2026
• First Posted (Actual): July 29, 2026

Study Record Updates

• Last Update Posted (Actual): July 29, 2026
• Last Update Submitted That Met QC Criteria: July 26, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Left ventricular hypertrophy; Transcatheter aortic valve replacement (TAVR); Angiotensin receptor blocker; Severe aortic stenosis; Renin-angiotensin system blockade
• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Pathological Conditions, Anatomical; Heart Diseases; Heart Valve Diseases; Ventricular Outflow Obstruction; Cardiomegaly; Hypertrophy; Pathological Conditions, Signs and Symptoms; Aortic Valve Stenosis; Hypertrophy, Left Ventricular; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Angiotensin Receptor Antagonists
• Other Study ID Numbers: H-2601-159-1713

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No