NCT02840799已完成2 期
Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 84
- 试验地点
- 3
- 主要终点
- Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults aged 18-90 years of age
- •A diagnosis of heart failure with NYHA Class II-III symptoms
- •LV ejection fraction >50% during baseline echocardiography
- •Stable medical therapy: no addition/removal/changes in antihypertensive medications, or beta-blockers in the preceding 30 days
- •Elevated filling pressures as evidenced by at least 1 of the following:
- •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)
- •Mitral E/e' ratio > 14 (either lateral or septal)
- •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)
- •Acute heart failure decompensation requiring IV diuretics
排除标准
- •Supine systolic blood pressure <100 mm Hg
- •Pregnancy: Women of childbearing potential will undergo a pregnancy test during the screening visit
- •Orthostatic hypotension defined as >20 mm Hg decrease in systolic blood pressure 3-5 minutes following the transition from the supine to standing position
- •Uncontrolled atrial fibrillation, as defined by a resting heart rate>100 beats per minute
- •Hemoglobin < 10 g/dL
- •Inability/unwillingness to exercise
- •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
- •Hypertrophic, infiltrative, or inflammatory cardiomyopathy
- •Clinically significant pericardial disease, as per investigator judgement.
- •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 either (1) subsequent revascularization, or; (2) a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement.
- •Left ventricular ejection fraction <45% in any prior echocardiogram or cardiac MRI, unless this was in the setting of uncontrolled atrial fibrillation.
- •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/1.73m2
- •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.
- •Methemoglobinemia - baseline methemoglobin level >5%
- •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.
- •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.
研究组 & 干预措施
Potassium Nitrate (KNO3)
Experimental
Potassium nitrate (KNO3) capsules, providing 6 millimoles of inorganic nitrate per capsule, to be taken three times daily for 6 weeks.
干预措施: Potassium Nitrate (KNO3) (Drug)
Potassium Chloride (KCl)
Placebo Comparator
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.
干预措施: Potassium Chloride (KCl) (Drug)
结局指标
主要结局
Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases
时间窗: 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
时间窗: 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.
次要结局
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
研究者
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