Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)

Phase 2

Completed

• Conditions: Heart Failure
• Interventions: Drug: Potassium Nitrate (KNO3); Drug: Potassium Chloride (KCl)

• Registration Number: NCT02840799
• Lead Sponsor: University of Pennsylvania

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.

Study Timeline

• Study First Submitted: 2016-06-13
• Study First Submitted QC: 2016-07-18
• Study First Posted: 2016-07-21
• Study Start: 2016-08
• Primary Completion: 2022-08
• Study Completion: 2022-08
• Results First Submitted: 2023-07-27
• Status Verified: 2023-12
• Results First Submitted QC: 2023-12-14
• Last Update Submitted: 2023-12-14
• Results First Posted: 2023-12-18
• Last Update Posted: 2023-12-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 84

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Potassium Nitrate (KNO3)	Potassium Nitrate (KNO3)	Potassium nitrate (KNO3) capsules, providing 6 millimoles of inorganic nitrate per capsule, to be taken three times daily for 6 weeks.
Potassium Chloride (KCl)	Potassium Chloride (KCl)	Potassium Chloride (KCl) is the placebo (control drug) in this trial. Potassium Chloride (KCl) capsules administered at a dose of 6 millimoles (1 capsule) three times daily for 6 weeks.

Primary Outcome Measures

Name	Time	Method
Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases	6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)	Subjects will perform a maximal-effort peak oxygen consumption test using a supine bicycle exercise test with expired gas analysis.
Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2	6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)	Subjects will perform a maximal-effort supine bicycle exercise test.

Secondary Outcome Measures

Name	Time	Method
Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL)	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)	QOL will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). The overall summary score from the KCCQ ranges from 0-100, where higher scores indicate a better quality of life.
Effect of Potassium Nitrate (KNO3) on Arterial Wave Reflections as Assessed by Wave Separation Analysis Using Tonometry and Doppler Flow Data	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)	Arterial Wave reflections were assessed via wave separation analysis, using arterial tonometry and Doppler echocardiography.; The pulse wave generated by the left ventricle travels forward in arteries and is partially reflected at sites of impedance mismatch (i.e., bifurcations, points of change in arterial size or wall stiffness, predominantly in middle-sized conduit arteries). Wave reflections travel back to the heart, merging into a discrete reflected wave and arrive while the LV is still ejecting blood in mid-to-late systole. Wave reflections increase the late systolic workload of the LV and profoundly impact the LV loading sequence (late relative to early systolic load).
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	6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)	We measured the Systematic vasodilatory response at rest and peak maximal exercise using corresponding echo parameters and blood pressures for each visit. This measure depicts the change from rest and exercise.
Effect of Potassium Nitrate (KNO3) on Muscle Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol	6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)	Muscle PCr recovery kinetics were measured using MRI and a standardized plantar flexor exercise protocol with a high resolution spatial mapping of creatine in muscle to analyze creatine chemical exchange saturation transfer and quantify the recovery kinetics of creatine levels. Exercise induces increases in the rate of O2 consumption, which upon cessation of exercise, declines towards baseline in a mono-exponential fashion. This is characterized by a time constant (τ, tau) that corresponds to the time constant of PCr recovery kinetics. Muscle PCr is a marker of oxidative capacity. This outcome measure relates to the half-time derived from linear regression, where a lower value depicts a faster PCr recovery.
Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: E/e' Ratio	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)	E/e' ratio is a standard echo parameter that was measured at rest during each visit and calculated using the mitral E, septal e', and lateral e'. This index is parameter for noninvasive left ventricular diastolic function assessment, where an E/e' ratio \< 8 is considered to be normal, and a ratio \> 15 is considered to reflect an increase in the LV filling pressure.
Effect of Potassium Nitrate (KNO3) on Augmentation Index	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)	Aortic augmentation index was assessed via comprehensive aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography. It is an indirect measure of arterial stiffness, where a higher value would indicate greater arterial stiffness risk.
Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Circumferential Strain	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)
Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: Left Atrial Volume Index	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)	Left atrial volume index is a standard echo parameter that was measured at rest during each visit and calculated the body surface area (Dubois and Dubois equation) and left atrial volume from both the two chamber and four chamber views.
Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Longitudinal Strain	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)	Peak global systolic myocardial longitudinal strain was evaluated with resting echocardiograms at each visit. Strain was analyzed at the four chamber, two chamber, and three chamber views of the left ventricle and averaged.
Effect of Potassium Nitrate (KNO3) on Late Systolic Wall Stress as Assessed by the Arts Formula Using Echocardiographic and Tonometry Recordings	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)	Late systolic wall stress is assessed via comprehensive aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography. Myocardial wall stress was calculated with the following formula =: Stress = P / \[1/3 In (1 + VW/VLV)\], where ln is the natural logarithm, P is aortic pressure obtained with arterial tonometry, VW is the volume of the LV wall obtained with echocardiography and VLV is the cavity volume obtained with echocardiography
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	6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)	MRI studies will be performed at rest and immediately after a standardized plantar flexion exercise. Arterial spin labeling using the flow-sensitive alternating inversion recovery (FAIR) technique will be used to image muscle perfusion with high temporal resolution.

Trial Locations

Locations (3)

Northwestern Medical Center; 🇺🇸 Evanston, Illinois, United States

Corporal Michael J Crescenz Veterans Affairs Medical Center (VA); 🇺🇸 Philadelphia, Pennsylvania, United States

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States