Bicuspid Valve Aortopathy Randomized Trial Proposal Dept of Defense Grant 2014

Background Estimated 3,000,000 Americans with BAV and enlarged aorta Male predominance, likely prevalent within military NO data on pharmacotherapy

Pilot Research US AARCC Grant “BAV Feasibility Study” designed to measure screening eligibility, med compliance, and variation Canada CACHnet “BAV Pilot Study” randomized trial Study design modified after initial experience Established study logistics (data collection, Rx dispensing) First 90 patients already enrolled

Proposal

Inclusion/Exclusion Inclusion Criteria Age  18 years Bicuspid aortic valve as determined by referring providers Ascending aorta (any location) measuring ≥ 37mm at end diastole in any imaging modality previously reported. General Exclusion Criteria History of cardiac diseases, such as Severe aortic stenosis or aortic regurgitation referred or likely to be referred for surgical intervention based on current guidelines Other known aortopathy (Marfan syndrome, Turner syndrome, Loey’s-Dietz syndrome, Ehlers- Danlos syndrome) Ascending aorta measuring ≥ 50-55mm at any location by any modality prior to referral for participation, for which prophylactic ascending aorta surgery may be indicated. Prior surgery on ascending aorta or aortic root. Patients with prior valvular interventions (balloon valvuloplasty, aortic valvotomy, aortic valve replacement) or coarctation are acceptable. Systolic blood pressure < 100 mmHg, measured at baseline History of drug sensitivity, contraindication, or adverse reaction to both beta blocker (BB) and angiotensin receptor blocker (ARB). Need for both BB and ARB for treatment of concomitant medical conditions for which there are no other alternatives. Contraindication to magnetic resonance imaging (MRI) (claustrophobia, pacemaker, defibrillator, ferromagnetic objects in eye or brain) History of any illness or other condition which may limit the participants’ ability to complete the study (including desired pregnancy within the anticipated study period or women who are of childbearing age and are not on a reliable, accepted form of birth control)

Substudy Exclusions Exclusion Criteria for BB study Resting, awake heart rate <60 bpm Heart block (2nd and 3rd degree atrioventricular block), or sick sinus syndrome seen on baseline electrocardiogram. Asthma of sufficient severity to represent a contraindication to BB use in the judgment of the patient’s physician History of severe peripheral artery disorders History of pheochromocytoma without the use of alpha-adrenergic blockers History of metabolic acidosis Exclusion Criteria for ARB study Hyperkalemia (serum potassium > 5.5 mmol/L) on prior outpatient blood testing or risk of hyperkalemia (such as patient taking aldosterone or similar medication that can not be discontinued) Renal dysfunction (glomerular filtration rate <45% measured by MDRD) at baseline Patients being treated with an angiotensin converting enzyme (ACE) inhibitor that cannot be discontinued. (These patients may be randomized in the BB arm if no exclusion criteria are met.) History of bilateral renal artery stenosis or unilateral renal artery stenosis to a solitary kidney History of hepatic insufficiency and hepato-biliary obstruction History of fructose intolerance

Genetic Analysis Aim to identify potential genes involved in aortic enlargement Partnering with BAVCon group (Simon Body, Boston) GWAS analysis using previously gathered samples (with and without aortopathy) Focused analysis of target genes using the study population

Study Population Target Enrollment 420 (105 in each study arm) 100 Canadian (12 centers), 320 US (19 centers) Outside Sources of Patient Enrollment High rate of ineligibility from ACHD clinics (86%!!) Importance of Community Involvement Desire for Military Personnel enrollment

Proposal

MRI Protocol Designed to emphasize plane alignment from baseline to followup Accounts for both root enlargement or mid ascending enlargement Will measure change in AREA rather than diameter Also measure valve orientation, valve function, and PW velocity

Participation Get through IRB and grant/contract bureaucracy Screen BAV patients across your institution Enroll approx 1 patient/month for first year Visits heaviest in first year Every 6 months thereafter 5 year funding period

Budget Funding intended to cover: Limited startup costs Research coordinator time Small ancillary costs (sample collection, packaging, parking) MRI x 3 ~3,600/patient enrolled

Timeline Spring 2015 USAMRMC Human Research Protection Application Gather contract/grant personnel info from each center Begin IRB submission Summer 2015 Expedite IRB approvals and subcontract approvals Gather screening databases Fall 2015 Begin enrollment Fall 2016 Complete enrollment