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

University of Pennsylvania

Status and phase: Completed; Phase 2

Conditions: Aortic Valve Stenosis

Treatments: Drug: Potassium Nitrate; Drug: Potassium Chloride

Study type: Interventional

Funder types: Other

Identifiers

NCT03483051

828994

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 5 patients

Sex: All

Ages: 50 to 90 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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5 participants in 2 patient groups

Potassium Nitrate (KNO3)

Experimental group

Description:

Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks.

Treatment:

Drug: Potassium Nitrate

Potassium Chloride

Sham Comparator group

Description:

Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks.

Treatment:

Drug: Potassium Chloride