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

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.

Study Overview

• Status: Terminated
• Conditions: Aortic Stenosis; LV Remodeling, Hypertrophy
• Intervention / Treatment: Drug: Tadalafil; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tadalafil in Diabetic Cohort	Drug: Tadalafil; Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.; Other Names: Cialis; Adcirca
Placebo Comparator: Placebo in Diabetic Cohort	Drug: Placebo; The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.
Active Comparator: Tadalafil in Non-Diabetic Cohort	Drug: Tadalafil; Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.; Other Names: Cialis; Adcirca
Placebo Comparator: Placebo in Non-Diabetic Cohort	Drug: Placebo; The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Myocardial Fibrosis (ECV) on MRI		6 months
Change in Other Echocardiographic Indices of Diastolic Function	E/e' and deceleration time	12 weeks and 6 months
Safety and Tolerability	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	6 and 12 weeks and 6 months
Change in Indices of Systolic Function	Stroke volume, EF, LV twist, and stress-corrected midwall shortening by echo and 3D multiparametric strain and EF by MRI	12 weeks and 6 months
Change in LV Hypertrophic Remodeling	Relative wall thickness, LV chamber dimensions, and wall thickness	12 weeks and 6 months
Change in Novel Echocardiographic Indices of Diastolic Function	LV stiffness, viscoelasticity, and a load independent index of diastolic filling	12 weeks and 6 months
Change in 6 Minute Walk Distance		6 and 12 weeks and 6 months
Change in Circulating Neurohormonal Markers	BNP and systemic markers of collagen turnover and oxidative stress	6 and 12 weeks and 6 months
Change in Quality of Life	Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)	6 and 12 weeks and 6 months
Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo		12 weeks and 6 months
Change in Systemic Blood Pressure		6 and 12 weeks and 6 months
Change in RV Function	TAPSE, s' tissue Doppler, and Tei index	12 weeks and 6 months
Change in AS Severity	Aortic valve area, transvalvular pressure gradients	12 weeks and 6 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Brian R. Lindman, MD, MSCI, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): April 14, 2017
• Study Completion (Actual): April 14, 2017

Study Registration Dates

• First Submitted: January 6, 2011
• First Submitted That Met QC Criteria: January 10, 2011
• First Posted (Estimate): January 12, 2011

Study Record Updates

• Last Update Posted (Actual): April 17, 2019
• Last Update Submitted That Met QC Criteria: April 8, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Tadalafil; Aortic valve stenosis; Phosphodiesterase inhibitors; Hypertension, pulmonary; Hypertrophy, left ventricular
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Hypertrophy; Constriction, Pathologic; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: 10-1334b

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No