Clinical trial NCT02840799: Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)
Official title: Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Keywords: Heart Failure
Exercise Intolerance
Ejection Fraction
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Northwestern University
First posted: 2016-07-21
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This trial seeks to assess if potassium nitrate (KNO3) therapy improves exercise capacity and oxygen uptake in heart failure patients with preserved ejection fraction (HFpEF).

Detailed description: Approximately 50% of heart failure patients exhibit preserved left ventricular (LV) ejection fraction (EF), and therefore have HF with preserved EF (HFpEF). There are currently no proven effective pharmacologic interventions. Exercise intolerance with reduced aerobic capacity is the hallmark of HFpEF and greatly impairs quality of life (QOL). During exercise, blood vessels within active muscle vasodilator, increasing perfusion to the muscle bed. Nitric oxide is a chief mediator of this process. Inorganic nitrate can ultimately be converted to nitric oxide. This conversion occurs preferentially at the site of exercising muscle, allowing for vasodilation to occur, hence increasing blood flow to the working muscle. Preliminary data suggest that inorganic nitrate improves exercise tolerance in HFpEF. The investigator will aim to test this hypothesis in a larger group.

Eligibility criteria: Inclusion Criteria:

1. Adults aged 18-90 years of age
2. A diagnosis of heart failure with NYHA Class II-III symptoms
3. LV ejection fraction \>50% during baseline echocardiography
4. Stable medical therapy: no addition/removal/changes in antihypertensive medications, or beta-blockers in the preceding 30 days
5. Elevated filling pressures as evidenced by at least 1 of the following:

   1. Mitral E/e' ratio \> 8 (either lateral or septal), with low e' velocity (septal e'\<7 cm/sec or lateral e'\< 10 cm/sec), in addition to one of the following:

      i Enlarged left atrium (LA volume index \>34 ml/m2) ii Chronic loop diuretic use for control of symptoms iii Elevated natriuretic peptides (BNP levels \>100 ng/L or NT-proBNP levels \>300 ng/L)
   2. Mitral E/e' ratio \> 14 (either lateral or septal)
   3. Elevated invasively-determined filling pressures previously (resting LVEDP\>16 mmHg or mean pulmonary capillary wedge pressure \[PCWP\] \> 12 mmHg; or PCWP/LVEDP≥25 mmHg with exercise)
   4. Acute heart failure decompensation requiring IV diuretics

Exclusion Criteria:

1. Supine systolic blood pressure \<100 mm Hg
2. Pregnancy: Women of childbearing potential will undergo a pregnancy test during the screening visit
3. Orthostatic hypotension defined as \>20 mm Hg decrease in systolic blood pressure 3-5 minutes following the transition from the supine to standing position
4. Uncontrolled atrial fibrillation, as defined by a resting heart rate\>100 beats per minute
5. Hemoglobin \< 10 g/dL
6. Inability/unwillingness to exercise
7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), any degree of mitral stenosis, severe right-sided valvular disease, or presence of a prosthetic valve in the mitral position
8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy
9. Clinically significant pericardial disease, as per investigator judgement.
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 either (1) subsequent revascularization, or; (2) a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement.
15. Left ventricular ejection fraction \<45% in any prior echocardiogram or cardiac MRI, unless this was in the setting of uncontrolled atrial fibrillation.
16. Treatment with phosphodiesterase inhibitors that cannot be withheld
17. Treatment with organic nitrates
18. Significant liver disease impacting synthetic function or volume control (ALT/AST \> 3x ULN, Albumin \<3.0 g/dL)
19. eGFR \< 30 mL/min/1.73m2
20. G6PD deficiency. In males of African, Asian or Mediterranean decent, this will be formally evaluated by enzyme testing prior to drug administration. A negative screening test for G6PD will be required in these subjects for inclusion in the study. If a quantitative test is being performed, a clinically significant reduction in G6PD activity (\<60% of normal) will exclude subjects.
21. Methemoglobinemia - baseline methemoglobin level \>5%
22. Serum K\>5.0 mEq/L
23. Severe right ventricular dysfunction
24. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.
25. Contraindications to MRI (except as noted below), including the presence of a pacemaker, metal implants, claustrophobia, or that have known medical conditions which can be exacerbated by stress such as anxiety or panic attacks. Inability to lie flat in the MRI scanner for 90 minutes is also an exclusion criterion.

Primary outcomes:
measure: Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases
timeFrame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2
timeFrame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Secondary outcomes:
measure: Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL)
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of KNO3 on the Percent Change of Systemic Vasodilatory Response to Exercise: The Change in Systemic Vascular Resistance Reserve During Exercise During a Maximal Effort Exercise Test
timeFrame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Muscle Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol
timeFrame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: E/e' Ratio
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: Left Atrial Volume Index
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Longitudinal Strain
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Late Systolic Wall Stress as Assessed by the Arts Formula Using Echocardiographic and Tonometry Recordings
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Arterial Wave Reflections as Assessed by Wave Separation Analysis Using Tonometry and Doppler Flow Data
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Augmentation Index
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Muscle Blood Flow During Exercise: Muscle Blood Flow During Exercise, Measured With Arterial MRI Spin Labeling During a Standardized Plantar Flexion Exercise Test
timeFrame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
measure: Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Circumferential Strain
timeFrame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Other outcomes:
Locations:
city: Evanston
country: United States
facility: Northwestern Medical Center
state: Illinois
city: Philadelphia
country: United States
facility: Corporal Michael J Crescenz Veterans Affairs Medical Center (VA)
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Julio A Chirinos, MD, PhD
role: STUDY_CHAIR
affiliation: University of Pennsylvania
name: Payman Zamani, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Sanjiv Shah, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Corporal Michael J Crescenz Veterans Affairs Medical Center (VA)
name: Sujith Kuruvilla, MD
role: PRINCIPAL_INVESTIGATOR
References: