Clinical trial NCT01275339: Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
Official title: Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Aortic Stenosis
LV Remodeling, Hypertrophy
Keywords: Aortic valve stenosis
Tadalafil
Phosphodiesterase inhibitors
Hypertension, pulmonary
Hypertrophy, left ventricular
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2011-01-12
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 phosphodiesterase type 5 (PDE5) inhibition influences nitric oxide (NO) - cyclic guanosine monophosphate (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 have a favorable impact on LV structure and function as well as pulmonary artery pressures. In this pilot study, the investigators anticipate that short-term administration of tadalafil to patients with AS will be safe and well-tolerated.

Detailed description: Subjects with moderately severe to severe aortic stenosis (AS), left ventricular hypertrophy (LVH), diastolic dysfunction, preserved ejection fraction, and no planned aortic valve replacement over the next 6 months will be eligible for this randomized, double-blind, placebo-controlled, pilot study. There will be a diabetic cohort (n=32) and non-diabetic cohort (n=24); each cohort will be randomized 1:1 to tadalafil vs. placebo. During a baseline study visit, the following will be obtained: clinical data, 6 minute walk, quality of life questionnaire, blood draw, and an echocardiogram. A 3-day run-in will occur to initially assess tolerability and compliance. If the drug is tolerated during this run-in period, participants will be randomized. An MRI will also be performed during this randomization visit. Follow-up study visits and testing will occur at 6 and 12 weeks and 6 months.

Eligibility criteria: Inclusion Criteria:

* Patients with moderate to severe aortic stenosis (AVA \< 1.5 cm2)
* Left ventricular hypertrophy
* Diastolic dysfunction as evidenced by tissue Doppler e' (average of septal and lateral) ≤ 7 cm/s
* EF ≥ 50%
* None or minimal symptoms related to aortic stenosis (NYHA ≤ 2)
* The subject and treating physician are not planning on a valve replacement procedure to occur during the next 6 months
* Ambulatory
* 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
* Contraindication to MRI
* Creatinine clearance \< 30 mL/min
* Cirrhosis
* Pulmonary fibrosis
* 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)
* 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

Primary outcomes:
measure: Diastolic Function as Measured by Tissue Doppler e'
timeFrame: Baseline, 12 weeks, and 6 months
Secondary outcomes:
measure: Change in Myocardial Fibrosis (ECV) on MRI
timeFrame: 6 months
measure: Change in Other Echocardiographic Indices of Diastolic Function
timeFrame: 12 weeks and 6 months
measure: Safety and Tolerability
timeFrame: 6 and 12 weeks and 6 months
measure: Change in Indices of Systolic Function
timeFrame: 12 weeks and 6 months
measure: Change in LV Hypertrophic Remodeling
timeFrame: 12 weeks and 6 months
measure: Change in Novel Echocardiographic Indices of Diastolic Function
timeFrame: 12 weeks and 6 months
measure: Change in 6 Minute Walk Distance
timeFrame: 6 and 12 weeks and 6 months
measure: Change in Circulating Neurohormonal Markers
timeFrame: 6 and 12 weeks and 6 months
measure: Change in Quality of Life
timeFrame: 6 and 12 weeks and 6 months
measure: Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo
timeFrame: 12 weeks and 6 months
measure: Change in Systemic Blood Pressure
timeFrame: 6 and 12 weeks and 6 months
measure: Change in RV Function
timeFrame: 12 weeks and 6 months
measure: Change in AS Severity
timeFrame: 12 weeks and 6 months
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Brian R. Lindman, MD, MSCI
role: PRINCIPAL_INVESTIGATOR
References: