Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Diastolic Function as Measured by Tissue Doppler e'
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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
研究组 & 干预措施
Tadalafil in Diabetic Cohort
干预措施: Tadalafil (Drug)
Placebo in Diabetic Cohort
干预措施: Placebo (Drug)
Tadalafil in Non-Diabetic Cohort
干预措施: Tadalafil (Drug)
Placebo in Non-Diabetic Cohort
干预措施: Placebo (Drug)
结局指标
主要结局
Diastolic Function as Measured by Tissue Doppler e'
时间窗: Baseline, 12 weeks, and 6 months
Measurement of e' (average of septal and lateral) on echo at each of the time points specified.
次要结局
- Safety and Tolerability(6 and 12 weeks and 6 months)
- Change in Novel Echocardiographic Indices of Diastolic Function(12 weeks and 6 months)
- Change in LV Hypertrophic Remodeling(12 weeks and 6 months)
- Change in 6 Minute Walk Distance(6 and 12 weeks and 6 months)
- Change in Other Echocardiographic Indices of Diastolic Function(12 weeks and 6 months)
- Change in Indices of Systolic Function(12 weeks and 6 months)
- Change in Circulating Neurohormonal Markers(6 and 12 weeks and 6 months)
- Change in Quality of Life(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 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)
- Change in AS Severity(12 weeks and 6 months)