Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Washington University School of Medicine
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests if taking potassium nitrate daily can help people with heart failure improve their muscle strength and exercise ability. The study involves an initial test followed by a period of daily doses. Potassium nitrate may work by improving blood flow in the body.
Is the drug KNO3 a promising treatment for heart failure?Yes, KNO3, which is a form of nitrate supplementation, shows promise as a treatment for heart failure. Studies suggest it can improve heart function during exercise and enhance muscle strength in patients with heart failure. It may also help reduce resistance in blood vessels, potentially improving overall heart health.34679
What safety data exists for nitrate supplementation in heart failure treatment?The provided research does not directly address the safety of nitrate supplementation (KNO3, Potassium Nitrate) for heart failure. It discusses potassium binders and dietary potassium, but not nitrate supplementation. Therefore, specific safety data for nitrate supplementation in heart failure is not available in the given research.28101113
Do I need to stop taking my current medications for the trial?The trial does not specify that you need to stop all current medications, but you must have stable medical therapy for heart failure medications like beta-blockers and ACE inhibitors for 60 days before joining. You cannot have taken nitrate therapy or phosphodiesterase inhibitors in the last 3 months, and you must be willing to stop taking phosphodiesterase inhibitors during the trial. If you take proton pump inhibitors or antacids, you may need to stop them if your doctor approves.
What data supports the idea that Nitrate Supplementation for Heart Failure is an effective treatment?The available research shows that nitrate supplementation can improve heart function during exercise in people with heart failure. In one study, participants with heart failure who took nitrate supplements showed better heart performance during exercise compared to those who took a placebo. This suggests that nitrate supplementation might help people with heart failure exercise more effectively. However, more research is needed to confirm these findings in larger groups.156912
Eligibility Criteria
This trial is for adults with heart failure where the heart's left ventricle doesn't pump well (ejection fraction <45%). They should be in a stable condition without recent changes to key medications and not involved in other studies. Excluded are pregnant women, those with severe liver disease, recent major cardiovascular procedures, or conditions that prevent exercise testing.Exclusion Criteria
I have severe heart valve disease.
I have an active collagen vascular disease.
I have severe liver disease with symptoms like confusion or bleeding from enlarged veins.
I have a specific heart condition like thickened heart muscle, amyloidosis, heart inflammation, or a complex congenital heart disease.
I am pregnant or a postmenopausal woman on hormone replacement therapy.
I have ongoing chest pain or heart issues due to blocked heart arteries.
My heart pumps well, with an ejection fraction of 45% or higher.
I need extra oxygen when I'm resting or moving.
I am not taking medication for gout.
I have a terminal illness and am expected to live less than one year.
I don't have any major health issues that would stop me from doing exercise tests.
My kidney function is reduced, with a filtration rate below 45 mL/min.
Treatment Details
The iNIX-HF study tests if KNO3 can improve muscle power and aerobic performance in heart failure patients compared to a placebo. Participants will receive either KNO3 or placebo over six weeks and undergo exercise tests to measure any improvements.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Potassium Nitrate (KNO3) treatment armExperimental Treatment1 Intervention
10 mmol of KNO3 via a single gel capsule to be consumed orally once per day for 6 weeks.
Group II: Placebo-controlled armPlacebo Group1 Intervention
10 mmol of placebo via a single gel capsule to be consumed orally once per day for 6 weeks.
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Research locations nearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
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Who is running the clinical trial?
Washington University School of MedicineLead Sponsor
References
Effect of isosorbide-5-mononitrate on exercise performance and clinical status in patients with congestive heart failure. Results of the Nitrates in Congestive Heart Failure (NICE) Study. [2017]Nitrate therapy improves hemodynamics in patients with heart failure, but the chronic effects of oral nitrates on exercise performance and clinical status have not been well studied.
Oral potassium supplement use and outcomes in chronic heart failure: a propensity-matched study. [2021]Hypokalemia is common in heart failure (HF) and is associated with increased mortality. Potassium supplements are commonly used to treat hypokalemia and maintain normokalemia. However, their long-term effects on outcomes in chronic HF are unknown. We used a public-use copy of the Digitalis Investigation Group (DIG) trial dataset to determine the associations of potassium supplement use with outcomes using a propensity-matched design.
Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. [2018]Inorganic nitrate (NO3(-)), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO3(-) supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise.
Acute Dietary Nitrate Intake Improves Muscle Contractile Function in Patients With Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Trial. [2018]Skeletal muscle strength, velocity, and power are markedly reduced in patients with heart failure, which contributes to their impaired exercise capacity and lower quality of life. This muscle dysfunction may be partially because of decreased nitric oxide (NO) bioavailability. We therefore sought to determine whether ingestion of inorganic nitrate (NO3 (-)) would increase NO production and improve muscle function in patients with heart failure because of systolic dysfunction.
Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction. [2017]Nitrates may be beneficial in heart failure with preserved ejection fraction (HFpEF) by enhancing cGMP signaling and improving hemodynamics, but real-world data on potential efficacy are lacking.
Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction. [2018]To assess the haemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF).
Inorganic nitrate as a treatment for acute heart failure: a protocol for a single center, randomized, double-blind, placebo-controlled pilot and feasibility study. [2018]Label="BACKGROUND">Acute heart failure (AHF) is a frequent reason for hospitalization worldwide and effective treatment options are limited. It is known that AHF is a condition characterized by impaired vasorelaxation, together with reduced nitric oxide (NO) bioavailability, an endogenous vasodilatory compound. Supplementation of inorganic sodium nitrate (NaNO3) is an indirect dietary source of NO, through bioconversion. It is proposed that oral sodium nitrate will favorably affect levels of circulating NO precursors (nitrate and nitrite) in AHF patients, resulting in reduced systemic vascular resistance, without significant hypotension.
Low- Versus Moderate-Sodium Diet in Patients With Recent Hospitalization for Heart Failure: The PROHIBIT (Prevent Adverse Outcomes in Heart Failure by Limiting Sodium) Pilot Study. [2021]We conducted a pilot study to assess feasibility, on-study retention, trends in natriuretic peptide levels, quality of life, and safety of a 12-week feeding trial with 1500- versus 3000-mg daily sodium meals in high-risk patients with heart failure.
The Effect of Dietary Inorganic Nitrate Supplementation on Cardiac Function during Submaximal Exercise in Men with Heart Failure with Reduced Ejection Fraction (HFrEF): A Pilot Study. [2021]Heart failure with reduced ejection fraction (HFrEF) is a common end point for patients with coronary artery disease and it is characterized by exercise intolerance due, in part, to a reduction in cardiac output. Nitric oxide (NO) plays a vital role in cardiac function and patients with HFrEF have been identified as having reduced vascular NO. This pilot study aimed to investigate if nitrate supplementation could improve cardiac measures during acute, submaximal exercise. Five male participants (61 ± 3 years) with HFrEF (EF 32 ± 2.2%) completed this pilot study. All participants supplemented with inorganic nitrate (beetroot juice) or a nitrate-depleted placebo for ~13 days prior to testing. Participants completed a three-stage submaximal exercise protocol on a recumbent cycle ergometer with simultaneous echocardiography for calculation of cardiac output (Q), stroke volume (SV), and total peripheral resistance (TPR). Heart rate and blood pressure were measured at rest and during each stage. Both plasma nitrate (mean = ~1028%, p = 0.004) and nitrite (mean = ~109%, p = 0.01) increased following supplementation. There were no differences between interventions at rest, but the percent change in SV and Q from rest to stage two and stage three of exercise was higher following nitrate supplementation (all p > 0.05, ES > 0.8). Both interventions showed decreases in TPR during exercise, but the percent reduction TPR in stages two and three was greater following nitrate supplementation (p = 0.09, ES = 0.98 and p = 0.14, ES = 0.82, respectively). There were clinically relevant increases in cardiac function during exercise following supplementation with nitrate. The findings from this pilot study warrant further investigation in larger clinical trials.
Effects of enriched-potassium diet on cardiorespiratory outcomes in experimental non-ischemic chronic heart failure. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">Chronic heart failure (CHF) is a global health problem. Increased sympathetic outflow, cardiac arrhythmogenesis and irregular breathing patterns have all been associated with poor outcomes in CHF. Several studies showed that activation of the renin-angiotensin system (RAS) play a key role in CHF pathophysiology. Interestingly, potassium (K+) supplemented diets showed promising results in normalizing RAS axis and autonomic dysfunction in vascular diseases, lowering cardiovascular risk. Whether subtle increases in dietary K+ consumption may exert similar effects in CHF has not been previously tested. Accordingly, we aimed to evaluate the effects of dietary K+ supplementation on cardiorespiratory alterations in rats with CHF.
Reduced dietary sodium did not reduce clinical events in heart failure. [2022]Label="SOURCE CITATION">Ezekowitz JA, Colin-Ramirez E, Ross H, et al. Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial. Lancet. 2022;399:1391-400. 35381194.
Inorganic nitrate supplementation may improve diastolic function and the O2 cost of exercise in cancer survivors: a pilot study. [2023]In non-cancer populations, inorganic dietary nitrate (NO3-) supplementation is associated with enhanced cardiorespiratory function but remains untested in patients with a history of cancer. Therefore, this pilot study sought to determine if oral NO3- supplementation, as a supportive care strategy, increases left ventricular (LV) function and exercise performance in survivors of cancer treated with anticancer therapy while simultaneously evaluating the feasibility of the methods and procedures required for future large-scale randomized trials. Two cohorts of patients with a history of cancer treated with anticancer chemotherapy were recruited. Patients in cohort 1 (n = 7) completed a randomized, double-blind, crossover study with 7 days of NO3- or placebo (PL) supplementation, with echocardiography. Similarly, patients in cohort 2 (n = 6) received a single, acute dose of NO3- supplementation or PL. Pulmonary oxygen uptake (VO2), arterial blood pressure, and stroke volume were assessed during exercise. In cohort 1, NO3- improved LV strain rate in early filling (mean difference (MD) [95% CI]: - 0.3 1/s [- 0.6 to 0.06]; P = 0.04) and early mitral septal wall annular velocity (MD [95% CI]: 0.1 m/s [- 0.01 to - 0.001]; P = 0.02) compared to placebo. In cohort 2, NO3- decreased the O2 cost of low-intensity steady-state exercise (MD [95% CI]: - 0.5 ml/kg/min [- 0.9 to - 0.09]; P = 0.01). Resting and steady-state arterial blood pressure and stroke volume were not different between conditions. No differences between conditions for peak VO2 (MD [95% CI]: - 0.7 ml/kg/min [- 3.0 to 1.6]; P = 0.23) were observed. The findings from this pilot study warrant further investigation in larger clinical trials targeting the use of long-term inorganic dietary NO3- supplementation as a possible integrative supportive care strategy in patients following anticancer therapy.
The efficacy and safety of new potassium binders on renin-angiotensin-aldosterone system inhibitor optimization in heart failure patients: a systematic review and meta-analysis. [2023]Guideline-directed medical therapy (GDMT) has improved outcomes in patients with heart failure, including the use of renin-angiotensin-aldosterone system inhibitors, which can hinder the excretion of potassium, resulting in hyperkalaemia. New potassium binders (NPBs) can prevent this adverse effect; however, the efficacy and safety of NPB for this indication have not been fully established. We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching PubMed, Web of Science, Scopus, and Cochrane through 26 April 2023. The risk of bias assessment was conducted, following Cochrane's updated Risk of Bias 2 assessment tool. We used the fixed-effects model to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD), with a 95% confidence interval (CI) (PROSPERO ID: CRD42023426113). We included six RCTs with a total of 1432 patients. NPB was significantly associated with successful mineralocorticoid receptor antagonist (MRA) optimization [RR: 1.13 with 95% CI (1.02-1.25), P = 0.02], decreased patients with MRA at less than the target dose [RR: 0.72 with 95% CI (0.57-0.90), P = 0.004], and decreased hyperkalaemic episodes [RR: 0.42 with 95% CI (0.24-0.72), P = 0.002]. However, there was no difference between NPB and placebo regarding angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB)/angiotensin receptor/neprilysin inhibitor (ANRi) optimization [RR: 1.02 with 95% CI (0.89-1.17), P = 0.76] and serum potassium change [MD: -0.31 with 95% CI (-0.61 to 0.00), P = 0.05], with an acceptable safety profile except for the increased incidence of hypokalaemia with NPB [RR: 1.57 with 95% CI (1.12-2.21), P = 0.009]. NPB has been shown to improve GDMT outcomes by enhancing MRA optimization and reducing hyperkalaemic episodes. However, there are limited data on the effects of NPB on ACEi/ARB/ANRi optimization. Future RCTs should investigate ACEi/ARB/ANRi optimization and conduct head-to-head comparisons of NPB (patiromer and sodium zirconium cyclosilicate).