We hypothesized that fimasartan, a new generation ARBs, would improve exercise capacity and decrease the rate of progression of AS by modifying hemodynamic factors and reducing adverse LV remodeling favorably in patients with asymptomatic moderate to severe AS.

Aortic stenosis (AS) is common valvular disorder, affecting 2% to 4% of adults older than 65 years. It is gradually but constantly progressive disease whit a long asymptomatic phase, but once symptoms develop, the prognosis is poor.

Currently, treatment strategy is focused mainly to watchful monitoring and judicious timing of aortic valve replacement (AVR). However, not all patients are proper candidate of corrective surgery and the needs of development of medical treatment are increasing. Various mechanisms have been suggested in progression of AS and recent observational studies suggested not only mechanical stress of "wear and tear" but also active inflammatory process likewise atherosclerosis may contribute the progression of AS. Through clinical descriptive studies, atherosclerotic risk factors, such as hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, and metabolic syndrome have been known to facilitate the progression of AS.

The renin-angiotensin system (RAS) is activated at an early stage of AS, promoting developemtnt of left ventricular hypertrophy (LVH), myocardial fibrosis, and diastolic dysfunction. Lipid lowering therapy and RAS blockade have emerged potential medical treatment to slow the progression of AS, however, many clinical trials did not show consistent beneficial effect of statins.8-10 RAS blockers are perceived as being relative contraindication due to concerns about increasing pressure gradient. However, patients with AS tolerate RAS blocker well on initiation and the use of angiotensin converting enzyme (ACE) inhibitors appears to confer long term survival benefit on patients considered to have a contraindication including AS.Pressure overload of LV, activation of RAS, and subsequent adverse LV remodeling, myocardial fibrosis, and LV dysfunction may potential therapeutic target to retard the progression of AS and to improve exercise capacity, and even long-term outcomes. RAS blocker including ACEI or angiotensin receptor blockers (ARBs) have been known to improve exercise capacity and long term outcome in patient with hypertension, congestive heart failure, or myocardial infarction.

We hypothesized that fimasartan, a new generation ARBs, would improve exercise capacity and decrease the rate of progression of AS by modifying hemodynamic factors and reducing adverse LV remodeling favorably in patients with asymptomatic moderate to severe AS.

Prospective, double-blinded, randomized clinical trial with enrollment of normotensive or hypertensive patients of age 20 to 75 who require echocardiography for a clinical indication, which typically consists of known aortic stenosis or presence of cardiac murmur. Moderate to severe aortic stenosis will be defined as a continuous wave Doppler determined peak aortic valve jet velocity of 3.0 - 4.5 m/s or mean pressure gradient of 25 - 49 mmHg, or aortic valve area of 0.76 - 1.5 cm2. Patients meeting inclusion criteria without any exclusion criteria will be randomized 1:1 to angiotensin receptor blocker, Fimasartan, or placebo. After 1-year enrollment period, all patients will be followed for 1 year. Cardiopulmonary exercise test will be performed at baseline enrollment period, and at the end of follow-up. Echocardiographic evaluation will be performed at regular interval of baseline and 6 months interval until the end of study.

Inclusion Criteria:

• Male or female
• Age: 20-75 years
• Moderate to severe aortic stenosis defined as a continuous wave Doppler determined peak aortic valve jet velocity of 3.0 - 4.5 m/s, mean pressure gradient of 25 - 49 mmHg, or aortic valve area of 0.76 - 1.5 cm2.
• Asymptomatic aortic stenosis patients, Stationary or minimum dyspnea on exertion (NYHA Fc ≤ I or II) will be included.
• Patients who were prescribed ACEI or ARBs for treatment of hypertension will be enrolled after 2 weeks wash-out period.
• SBP 120-140 mmHg with or without medication regardless of presence of hypertension or not.
• Patients with BP > 140/90 mmHg with or without medication will be included after their BP is controlled with anti-hypertensive medication other than ACEI/ARBs.
• Patients who are able to perform appropriate cardiopulmonary exercise test with treadmill.
• The patient agrees to the study protocol and the schedule of clinical, cardiopulmonary exercise test, and echocardiographic follow-up, and provides informed, written consent, as approved by the appropriate Institutional Review Board/Ethical Committee of the respective clinical site.

Exclusion Criteria:

• Symptomatic aortic stenosis: presence of exertional dyspnea (≥ NYHA Fc III), angina or syncope
• Very severe aortic stenosis regardless of presence of symptoms. It was defined as a critical stenosis in the aortic valve area ≤ 0.75 cm2 accompanied by a peak aortic jet velocity ≥4.5 m/s or a mean transaortic pressure gradient ≥50 mm Hg on Doppler echocardiography.
• Uncontrolled HTN (SBP > 160 or DBP >100) without ACEI or ARBs during 2-weeks wash out period in patients who were prescribed ACEI or ARBs for treatment of hypertension.
• Patients with known history of coronary artery disease including myocardial infarction, regardless of the treatment (medication only, percutaneous coronary intervention, or coronary artery bypass grafting).
• Planned cardiac surgery or planned major non-cardiac surgery within the study period.
• Stroke or resuscitated sudden death in the past 6 months.
• Chronic disease requiring treatment with oral, intravenous, or intra-articular corticosteroids (use of topical, or nasal corticosteroids is permissible).
• Untreated hyperthyroidism or hypothyroidism with TSH levels more than 2 times upper limit of normal.
• A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) in the past 3 years or current treatment for the active cancer.
• Female of child-bearing potential who do not use adequate contraception and women who are pregnant or breast-feeding.
• Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the Investigator, would preclude safe completion of the study.
• Evidence of congestive heart failure, or left ventricular ejection fraction < 50%.
• Significant renal disease manifested by serum creatinine > 2.0mg/dL
• Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (ALT or AST > 3 times upper limit of normal).
• Documented bilateral renal artery stenosis or known contraindication of ACEI or ARBs
• History of chronic obstructive pulmonary disease or asthma manifested by acute aggravation of COPD in the past 6 months, or currently taking bronchodilators including long-acting beta2 agonist, anticholinergics, or inhaled steroids.
• Other valvular disease : Moderate or severe mitral regurgitation or mitral stenosis, Moderate or severe aortic regurgitation
• Patients who are unable to perform cardiopulmonary exercise test.
• Unwillingness or inability to comply with the procedures described in this protocol.
• Patient who have been diagnosed with galactose intolerance, lactase deficiency, malabsorption of glucose or galactose which is main ingredient of placebo.