A Randomized Trial of Angiotensin Receptor bLocker,Fimasartan, in Aortic Stenosis (ALFA Trial)
A Randomized Trial of Angiotensin Receptor bLocker,Fimasartan, in Aortic Stenosis (ALFA Trial)
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.