Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study

The Washington University

Status and phase

Terminated

Phase 4

Conditions

Aortic Stenosis

Treatments

Drug: Tadalafil

Drug: Placebo

Study type

Interventional

Funder types

Other

Identifiers

NCT01272388

10-1334a

Details and patient eligibility

About

Currently, aortic stenosis (AS) is considered a "surgical disease" with no medical therapy available to improve any clinical outcomes, including symptoms, time to surgery, or long-term survival. Thus far, randomized studies involving statins have not been promising with respect to slowing progressive valve stenosis. Beyond the valve, two common consequences of aortic stenosis are hypertrophic remodeling of the left ventricle (LV) and pulmonary venous hypertension; each of these has been associated with worse heart failure symptoms, increased operative mortality, and worse long-term outcomes. Whether altering LV structural abnormalities, improving LV function, and/or reducing pulmonary artery pressures with medical therapy would improve clinical outcomes in patients with AS has not been tested. Animal models of pressure overload have demonstrated that PDE5 inhibition influences NO-cGMP signaling in the LV and favorably impacts LV structure and function, but this has not been tested in humans with AS. Studies in humans with left-sided heart failure and pulmonary venous hypertension have shown that PDE5 inhibition improves functional capacity and quality of life, but patients with AS were not included in those studies. The investigators hypothesize that PDE5 inhibition with tadalafil will upregulate NO-cGMP signaling, reduce oxidative stress, and have a favorable impact on LV structure and function as well as pulmonary artery pressures and quality of life. In this pilot study, the investigators anticipate that short-term administration of tadalafil to patients with AS will be safe and well-tolerated.

Full description

Patients with severe symptomatic AS who will undergo elective aortic valve replacement will be eligible for this randomized, double-blind, placebo-controlled, pilot study. Prior to randomization, subjects will have testing including: 6 minute walk, quality of life questionnaire, blood draw, and an echocardiogram. If an initial monitored dose of tadalafil is tolerated, participants will be randomized 2:1 to tadalafil vs. placebo. After 4 weeks on drug or placebo, subjects will have the same baseline testing repeated. At the time of aortic valve replacement surgery, the aortic valve and a small piece of LV myocardium will be taken for several analyses.

Enrollment

1 patient

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients with severe aortic stenosis (AVA < 1.0 cm2)
Left ventricular hypertrophy
EF ≥ 45%
NYHA functional class ≥ 2
Ambulatory (able to perform a 6 minute walk test)
Normal sinus rhythm
18 years of age and older
Able and willing to comply with all the requirements for the study

Exclusion criteria

Need for ongoing nitrate medications
SBP < 110mmHg or MAP < 75mmHg
Moderately severe or severe mitral regurgitation
Moderately severe or severe aortic regurgitation
Creatinine clearance < 30 mL/min
Increased risk of priapism
Retinal or optic nerve problems or unexplained visual disturbance
If a subject requires ongoing use of an alpha antagonist typically used for benign prostatic hyperplasia (BPH) (prazosin, terazosin, doxazosin, or tamsulosin), SBP < 120 mmHg or MAP < 80 mmHg is excluded
Need for ongoing use of a potent CYP3A inhibitor or inducer (ritonavir, ketoconazole, itraconazole, rifampin)
Cirrhosis
Pulmonary fibrosis
Current or recent (≤ 30 days) acute coronary syndrome
O2 sat < 90% on room air
Females that are pregnant or believe they may be pregnant
Any condition which the PI determines will place the subject at increased risk or is likely to yield unreliable data
Unwilling to provide informed consent