Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study

Phase 4

Terminated

Conditions: Aortic Stenosis
LV Remodeling, Hypertrophy

Interventions: Drug: Placebo
Drug: Tadalafil

Registration Number: NCT01275339

Lead Sponsor: Washington University School of Medicine

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 10

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo in Diabetic Cohort	Placebo	-
Placebo in Non-Diabetic Cohort	Placebo	-
Tadalafil in Diabetic Cohort	Tadalafil	-
Tadalafil in Non-Diabetic Cohort	Tadalafil	-

Primary Outcome Measures

Name	Time	Method
Diastolic Function as Measured by Tissue Doppler e'	Baseline, 12 weeks, and 6 months	Measurement of e' (average of septal and lateral) on echo at each of the time points specified.

Secondary Outcome Measures

Name	Time	Method
Change in LV Hypertrophic Remodeling	12 weeks and 6 months	Relative wall thickness, LV chamber dimensions, and wall thickness
Change in 6 Minute Walk Distance	6 and 12 weeks and 6 months
Safety and Tolerability	6 and 12 weeks and 6 months	The following with be reported - frequency of the following: hypotension (SBP \< 90 mmHg), symptomatic hypotension (symptoms of presyncope or syncope associated with SBP \<90), syncope, hospitalization for a cardiac reason, myocardial infarction, new onset or worsening heart failure, and new sustained arrhythmia requiring intervention
Change in Novel Echocardiographic Indices of Diastolic Function	12 weeks and 6 months	LV stiffness, viscoelasticity, and a load independent index of diastolic filling
Change in Other Echocardiographic Indices of Diastolic Function	12 weeks and 6 months	E/e' and deceleration time
Change in Indices of Systolic Function	12 weeks and 6 months	Stroke volume, EF, LV twist, and stress-corrected midwall shortening by echo and 3D multiparametric strain and EF by MRI
Change in Circulating Neurohormonal Markers	6 and 12 weeks and 6 months	BNP and systemic markers of collagen turnover and oxidative stress
Change in Quality of Life	6 and 12 weeks and 6 months	Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo	12 weeks and 6 months
Change in Myocardial Fibrosis (ECV) on MRI	6 months
Change in Systemic Blood Pressure	6 and 12 weeks and 6 months
Change in RV Function	12 weeks and 6 months	TAPSE, s' tissue Doppler, and Tei index
Change in AS Severity	12 weeks and 6 months	Aortic valve area, transvalvular pressure gradients