Early Aortic Valve Lipoprotein(a) Lowering Trial
Early Aortic Valve Lipoprotein(a) Lowering Trial
Aortic valve disease is the most common form of heart valve disease and is a major burden to
 society. Aortic valve disease is also expected to become more prevalent with the aging of the
 Canadian population. Currently, over 1 million individuals in North America have aortic
 stenosis, which is a narrowing of the aortic valve, and leads to symptoms of heart failure
 and sometimes death. Valve replacement with its potential costs and complications remains the
 only avenue for treatment, once symptoms develop. Despite the major importance of this
 disease, there are currently no medical treatments to prevent the development of aortic
 stenosis.The lack of preventative treatments stems in large part to a poor understanding of
 the causes of this disease.

 Using cutting-edge genetic technologies, the investigators have recently identified that
 individuals with a genetic predisposition to elevations in a type of cholesterol not normally
 screened, called lipoprotein(a), have a much higher risk of developing aortic valve disease.
 The investigators have also shown that lipoprotein(a) causes hardening of the valve, a very
 early sign of valve narrowing. The investigators plan to evaluate in a randomized controlled
 trial whether lowering this unusual form of cholesterol at an early stage of this disease
 could slow or stop the development of aortic valve narrowing

 The investigators are currently proposing a pilot project to evaluate the feasibility of this
 type of study. If successful, our proposed treatment would be notable in two ways. First, it
 would represent the first medical treatment to prevent valve disease, which could lead to
 major reductions in the societal burden of this important disease. And second, it would
 herald a major success for genomic medicine as it would represent one of the first treatments
 borne from recent genetic studies. In these ways, our proposal could significantly impact the
 health of many Canadians while also highlighting the innovative research performed in Canada.

 Recruitment (n=238) for this project will be from the echocardiography laboratories of McGill
 University affiliated hospitals. Individuals with aortic sclerosis or mild aortic stenosis
 (aortic valve area [AVA] >1.5 cm2, mean gradient [MG] < 25 mmHG) and high Lp(a) will be
 eligible for inclusion into this proposed study.
Screening: Potentially eligible participants from the echocardiography laboratory will be
 screened by a member of the research team for inclusion and exclusion criteria and will be
 asked to review and sign a consent form that explains the study.

 Run-in: Participants with elevated Lp(a) and normal liver and renal indices, that meet all
 other inclusion and exclusion criteria will be started on low dose niacin (500 mg/d) for a 6
 week run-in phase prior to randomization to assess tolerability and compliance to the
 intervention. The niacin dose will be increased by 500 mg increments weekly, as tolerated, to
 a maximum of 1500 mg/day (Participants who remain compliant >85% (by pill count and
 self-report) and who tolerate at least 1500 mg/d of niacin for at least 2 weeks will then
 undergo randomization to 1500 mg/d of immediate release niacin or matching placebo.

 Randomization: will be performed via an Internet website where each participant will be given
 a unique identifier that matches the allocated drug kit.Blocking using random blocks of 2 and
 4 will ensure that similar numbers of patients are randomized to the two arms of the study at
 each of the study centers.

 The study will be double blind - neither patients, physicians, nor study personnel will know
 which participants are receiving active treatment.

 After a 6-week run-in phase, participants able to tolerate the intervention will be
 randomized 1:1 to niacin extended release or placebo. After randomization, the treatment
 phase will be for 2 years (104 weeks). Data will be collected during 5 visits: (i)
 Randomization visit; (ii) 6-month follow-up visit; (iii) 12-month follow-up visit; (iv)
 18-month follow-up visit; (v)Final visit (24-month).

 (i) Randomization visit (baseline)

 (1) Data Collected: A. Clinical and Biochemical Data B. Echocardiogram C. Blood Collection D.
 Cardiac CT

 (ii) Follow-up visits (at 6, 12 and 18 months from randomization) Collection of clinical data
 (re: side-effects), compliance to therapy and blood.

 (iii) Final visit (24 months) At the final visit, all usual data collected during the above
 follow-up visits will be obtained (including compliance, side-effects, etc). An
 echocardiogram, cardiac CT and a final blood test will also be obtained

 1. Primary Endpoints

 a) Relative reduction in rates of calcium score progression by cardiac CT in individuals
 randomized to niacin as compared to those randomized to placebo.

 2. Secondary Endpoints

 1. Number needed to screen to identify eligible participants

 2. Difference in mean change in Lp(a) levels between treatment arms

 3. Rates of progression in each arm by echocardiography at 1 and 2 years (Change in
 peak velocity (in m/s); Change in mean gradient (in mm Hg); Change in AVA (in cm2)

 3. Tertiary Endpoints

 1. Compliance (as a proportion of pills taken/pills prescribed) with niacin treatment

 2. Rates of side-effects and other adverse events
Inclusion Criteria:

 1. Age >50 years and < 85 years

 2. Aortic sclerosis OR mild AS

 -  Aortic sclerosis: diffuse of focal (at least 2 areas) thickening or calcification
 (highly echodense lesions) on aortic leaflets seen in at least 2 contiguous views
 with normal leaflet excursion and peak aortic jet velocity < 2 m/s.

 -  Mild AS: peak aortic jet velocity 2-3 cm/s, AVA >1.5cm2, mean gradient <25 m

 -  Elevated Lp(a) > 50 mg/dL (>80th percentile).

 Exclusion Criteria:

 1. Current use or documented indication for niacin therapy or known niacin
 allergy/intolerance

 2. Bicuspid valve, unicuspid valve or other congenital cardiac anomaly (except patent
 foramen ovale)

 3. Known renal disease or more than mild renal dysfunction (Creatinine > 150 mmol/L or
 Creatinine clearance < 60).

 4. Major comorbidities limiting life expectancy to < 2 years

 5. Unable or unwilling to complete follow-up visits to 2 year

 6. Diagnosed hepatic failure, cirrhosis, hepatitis or history of hepatic impairment (AST
 or ALT levels ³ 2 times upper limit of normal)

 7. Newly diagnosed (< 2 months) or poorly controlled diabetes

 8. Gout or use of anti-hyperuricemic medications