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

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.

Study Overview

• Status: Terminated
• Conditions: Aortic Stenosis
• Intervention / Treatment: Drug: Tadalafil; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 1
• 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: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	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 the surgical date (~4 weeks). 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 daily is not tolerated, then the dose will be decreased back to 1 pill daily.
Active Comparator: Tadalafil	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 the surgical date (~4 weeks). 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life as Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)	KCCQ overall summary score is reported. Scale is 0-100 (higher value is better).	Baseline and 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 Minute Walk Distance	How far the subject walked in 6 minutes.	Baseline and 4 weeks

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: January 6, 2011
• First Submitted That Met QC Criteria: January 6, 2011
• First Posted (Estimate): January 7, 2011

Study Record Updates

• Last Update Posted (Actual): September 12, 2018
• Last Update Submitted That Met QC Criteria: September 10, 2018
• Last Verified: September 1, 2018

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; Constriction, Pathologic; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: 10-1334a