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

Phase 2

Completed

Conditions: Aortic Valve Stenosis

Interventions: Drug: Potassium Nitrate
Drug: Potassium Chloride

Registration Number: NCT03483051

Lead Sponsor: University of Pennsylvania

Brief 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.

Detailed 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 5

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.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Potassium Nitrate (KNO3)	Potassium Nitrate	Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks.
Potassium Chloride	Potassium Chloride	Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Myocardial Systolic Strain	9 weeks	The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography)
Systemic Vasodilator Response to Exercise	9 weeks	The effect of KNO3 on systemic vasodilator response, measured by change in systemic vascular resistance, during a symptom-limited maximal exercise test,
Left Ventricle Diastolic Function	9 weeks	The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise)
Late Systolic Left Ventricle Load	9 weeks	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)