Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (PULSE AS)
Condition: Aortic Valve Stenosis
MeSH terms: Aortic Valve Stenosis; Constriction, Pathologic
Intervention: Potassium Nitrate; Potassium Chloride
Intervention description: 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.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 5.0
Sex: All
Minimum age: 50 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: aortic stenosis, aortic valve replacement

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Adults aged 50-90 years of age

          2. Diagnosis of severe aortic stenosis prior to aortic valve repair

          3. Successful trancatheter aortic valve repair via transfemoral procedural approach or
             successful surgical aortic valve repair at least three months prior to enrollment

          4. Stable medical therapy: no addition/removal/changes in anti-hypertensive medications,
             or beta-blockers in the preceding 30 days.

        Exclusion Criteria

          1. Supine systolic blood pressure (SBP) < 100 mmHg OR supine diastolic blood pressure
             (DBP) <60 mmHg

          2. Poorly controlled hypertension, as defined as SBP > 160 mmHg OR DBP > 100 mmHg

          3. Pregnancy. Women of childbearing potential will undergo a pregnancy test during the
             screening visit

          4. Atrial fibrillation within the prior 8 weeks before enrollment

          5. Inability/unwillingness to exercise

          6. 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.

          7. Moderate or severe patient prosthesis mismatch, as defined by Effective Orifice Area
             Index < 0.85 cm2/m2

          8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy

          9. Pericardial disease

         10. Current angina

         11. Acute coronary syndrome or coronary intervention within the past 2 months

         12. Primary pulmonary arteriopathy

         13. 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

         14. Ischemia on stress testing without subsequent revascularization (during the screening
             visit)

         15. Treatment with phosphodiesterase inhibitors that cannot be withheld

         16. Treatment with organic nitrates

         17. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x
             ULN, Albumin <3.0 g/dL)

         18. eGFR < 30 mL/min/1.73 m2

         19. 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).

         20. History of methemoglobinemia or methemoglobin level >5% at baseline visit

         21. Serum K>5.0 mEq/L

         22. Severe right ventricular dysfunction.

         23. Any medical condition that, in the opinion of the investigator, will interfere with
             the safe completion of the study.