Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study
Condition: Aortic Stenosis
MeSH terms: Aortic Valve Stenosis; Constriction, Pathologic
Intervention: Tadalafil; Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Tadalafil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Aortic valve stenosis; Tadalafil; Phosphodiesterase inhibitors; Hypertension, pulmonary; Hypertrophy, left ventricular

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 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.
    

Eligibility criteria:

        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