Aortic Stenosis, LV Remodeling, Hypertrophy
Conditions
Keywords
Aortic valve stenosis, Tadalafil, Phosphodiesterase inhibitors, Hypertension, pulmonary, Hypertrophy, left ventricular
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.
Interventions
DRUGTadalafil
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.
DRUGPlacebo
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.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Other Echocardiographic Indices of Diastolic Function | 12 weeks and 6 months | E/e' and deceleration time |
| 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 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 LV Hypertrophic Remodeling | 12 weeks and 6 months | Relative wall thickness, LV chamber dimensions, and wall thickness |
| 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 6 Minute Walk Distance | 6 and 12 weeks and 6 months | — |
| Change in Myocardial Fibrosis (ECV) on MRI | 6 months | — |
| 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 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 |
| Change in Circulating Neurohormonal Markers | 6 and 12 weeks and 6 months | BNP and systemic markers of collagen turnover and oxidative stress |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tadalafil in Diabetic Cohort 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. | 2 |
| Placebo in Diabetic Cohort 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. | 0 |
| Tadalafil in Non-Diabetic Cohort 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. | 4 |
| Placebo in Non-Diabetic Cohort 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. | 4 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Referred for surgery for AS symptoms | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Tadalafil in Diabetic Cohort | Tadalafil in Non-Diabetic Cohort | Placebo in Non-Diabetic Cohort | Total | Placebo in Diabetic Cohort |
|---|---|---|---|---|---|
| Age, Continuous | 65 years | 81.25 years | 75.5 years | 75.7 years | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 4 Participants | 8 Participants | — |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 3 Participants | 8 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 0 | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 1 / 2 | 0 / 0 | 2 / 4 | 2 / 4 |
| serious Total, serious adverse events | 0 / 2 | 0 / 0 | 0 / 4 | 0 / 4 |
Outcome results
Primary
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.
Time frame: Baseline, 12 weeks, and 6 months
Population: There were 0 enrolled that were randomized to placebo in the diabetic cohort; the total number enrolled in the study was small, so this happened randomly.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Tadalafil in Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | Baseline | 4.59 cm/sec |
| Tadalafil in Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | 12 weeks | 3.75 cm/sec |
| Tadalafil in Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | 6 months | 4.63 cm/sec |
| Tadalafil in Non-Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | 12 weeks | 6.44 cm/sec |
| Tadalafil in Non-Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | Baseline | 5.97 cm/sec |
| Tadalafil in Non-Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | 6 months | 6.16 cm/sec |
| Placebo in Non-Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | 12 weeks | 4.88 cm/sec |
| Placebo in Non-Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | 6 months | 5.33 cm/sec |
| Placebo in Non-Diabetic Cohort | Diastolic Function as Measured by Tissue Doppler e' | Baseline | 5.28 cm/sec |
Secondary
Change in 6 Minute Walk Distance
Time frame: 6 and 12 weeks and 6 months
Secondary
Change in AS Severity
Aortic valve area, transvalvular pressure gradients
Time frame: 12 weeks and 6 months
Secondary
Change in Circulating Neurohormonal Markers
BNP and systemic markers of collagen turnover and oxidative stress
Time frame: 6 and 12 weeks and 6 months
Secondary
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
Time frame: 12 weeks and 6 months
Secondary
Change in LV Hypertrophic Remodeling
Relative wall thickness, LV chamber dimensions, and wall thickness
Time frame: 12 weeks and 6 months
Secondary
Change in Myocardial Fibrosis (ECV) on MRI
Time frame: 6 months
Secondary
Change in Novel Echocardiographic Indices of Diastolic Function
LV stiffness, viscoelasticity, and a load independent index of diastolic filling
Time frame: 12 weeks and 6 months
Secondary
Change in Other Echocardiographic Indices of Diastolic Function
E/e' and deceleration time
Time frame: 12 weeks and 6 months
Secondary
Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo
Time frame: 12 weeks and 6 months
Secondary
Change in Quality of Life
Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
Time frame: 6 and 12 weeks and 6 months
Secondary
Change in RV Function
TAPSE, s' tissue Doppler, and Tei index
Time frame: 12 weeks and 6 months
Secondary
Change in Systemic Blood Pressure
Time frame: 6 and 12 weeks and 6 months
Secondary
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
Time frame: 6 and 12 weeks and 6 months