Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study
| Status: | Terminated |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 9/14/2018 |
| Start Date: | January 2011 |
| End Date: | April 2012 |
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.
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.
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.
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.
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
We found this trial at
1
site
660 S Euclid Ave
Saint Louis, Missouri 63110
Saint Louis, Missouri 63110
(314) 362-5000
Washington University School of Medicine Washington University Physicians is the clinical practice of the School...
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