Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (PULSE AS)

Study Overview
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Brief Summary
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The current trial is designed to assess the safety and efficacy of sustained oral administration of inorganic nitrate in patients with severe aortic stenosis and to assess the mechanisms by which inorganic nitrate enhances oxygen uptake and exercise capacity in this population.

Detailed Description
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This is a randomized double-blind crossover clinical trial, in which 22 subjects who underwent transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) three or more months prior to enrollment will receive the following 2 interventions, in randomized order: (1) Potassium nitrate (KNO3), at a dose of 12-18 mmol/d by mouth for 4 weeks, or; (2) Potassium chloride (KCl), at a dose of 12-18 mmol/d by mouth for 4 weeks. A 1-week washout period will be introduced between the 2 interventions. The purpose of the trial is to test the safety of KNO3 and its efficacy on a number of clinical and physiologic endpoints in subjects who underwent TAVR for severe AS.

Official Title
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Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (PULSE AS)

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Drug: Potassium Nitrate
* Drug: Potassium Chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged 50-90 years of age Diagnosis of severe aortic stenosis prior to aortic valve repair Successful trancatheter aortic valve repair via transfemoral procedural approach or successful surgical aortic valve repair at least three months prior to enrollment Stable medical therapy: no addition/removal/changes in anti-hypertensive medications, or beta-blockers in the preceding 30 days. Exclusion Criteria Supine systolic blood pressure (SBP) < 100 mmHg OR supine diastolic blood pressure (DBP) <60 mmHg Poorly controlled hypertension, as defined as SBP > 160 mmHg OR DBP > 100 mmHg Pregnancy. Women of childbearing potential will undergo a pregnancy test during the screening visit Atrial fibrillation within the prior 8 weeks before enrollment Inability/unwillingness to exercise Moderate or greater mitral regurgitation or aortic/peri-valvular regurgitation, any degree of mitral stenosis, severe right-sided valvular disease, or presence of a mitral prosthetic valve. Moderate or severe patient prosthesis mismatch, as defined by Effective Orifice Area Index < 0.85 cm2/m2 Hypertrophic, infiltrative, or inflammatory cardiomyopathy Pericardial disease Current angina Acute coronary syndrome or coronary intervention within the past 2 months Primary pulmonary arteriopathy Clinically significant lung disease as defined by: Chronic Obstructive pulmonary disease meeting Stage III or greater GOLD criteria, treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, or the use of daytime supplemental oxygen Ischemia on stress testing without subsequent revascularization (during the screening visit) Treatment with phosphodiesterase inhibitors that cannot be withheld Treatment with organic nitrates Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin <3.0 g/dL) eGFR < 30 mL/min/1.73 m2 G6PD deficiency. For males of African, Asian or Mediterranean decent, this will be evaluated prior to drug administration. A qualitative test positive for deficiency or a quantitative test with clinically significant G6PD deficiency (<60% of normal activity) will prompt exclusion from the trial (prior to drug administration). History of methemoglobinemia or methemoglobin level >5% at baseline visit Serum K>5.0 mEq/L Severe right ventricular dysfunction. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: In this phase IIb, double-blind, cross-over trial, we will assign 22 subjects who are post-TAVR for severe AS to: (A) Potassium nitrate administered by mouth at a dose of 6 mEq three times daily for 4 weeks, or (B) Potassium chloride (KCl) at identical doses. The order of the interventions (AB-BA design) will be randomized, with a 1-week washout period separating each intervention. A crossover design will enable each subject to receive both treatments.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Potassium Nitrate (KNO3)<br>Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks. | Drug: Potassium Nitrate<br>* Potassium nitrate capsules will consist of potassium nitrate (KNO3-) crystals [610 mg, corresponding to 6.03 mmoles of NO3-] with 190mg of lactose monohydrate, spray dried, NF. The dose for this trial will be 18 mmoles of NO3-per day, given as one capsule (6 mmoles) three times a day.<br>|
| Sham Comparator: Potassium Chloride<br>Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks. | Drug: Potassium Chloride<br>* Potassium chloride capsules will consist of potassium chloride (KCl), granular, USP (450mg) plus lactose monohydrate, spray dried, NF (300mg). The dose for this trial will be 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Work Performed During a Maximal-effort Exercise Test | The effect of KNO3 on exercise capacity, quantified as Total work performed during a maximal-effort exercise test; | 9 weeks | 
| Peak Oxygen Uptake (VO2) During a Maximal Effort Exercise Test | The effect of KNO3 on exercise capacity, quantified as: Peak oxygen consumption (VO2) during a symptom-limited maximal effort exercise test. | 9 weeks | 
| Quality of Life Score | The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire. | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic Vasodilator Response to Exercise | The effect of KNO3 on systemic vasodilator response, measured by change in systemic vascular resistance, during a symptom-limited maximal exercise test, | 9 weeks | 
| Left Ventricle Diastolic Function | The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise) | 9 weeks | 
| Myocardial Systolic Strain | The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography) | 9 weeks | 
| Late Systolic Left Ventricle Load | The effect of KNO3 on last systolic left ventricle load from wave reflections (assessed via comprehensive aortic pressure-flow regulations, using arterial tonometry and Doppler echocardiography) | 9 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aortic stenosis, aortic valve replacement