Nitrate Supplementation for Heart Failure

(iNIX-HF Trial)

Recruiting at 1 trial location

Overseen By Lauren K Park, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must be taking: Beta-blockers, ACE inhibitors

Must not be taking: Nitrates, Phosphodiesterase inhibitors

Disqualifiers: Hypertrophic cardiomyopathy, Liver disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a potassium nitrate supplement (KNO3) can enhance muscle power and aerobic exercise performance in individuals with heart failure with reduced ejection fraction (HFrEF), a condition that impairs the heart's ability to pump blood effectively. Participants will take either a KNO3 supplement or a placebo daily for six weeks. The trial targets individuals diagnosed with HFrEF who have stable heart medication routines and experience symptoms such as shortness of breath or fatigue during activities. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you do not change your current heart failure medications like beta-blockers or ACE inhibitors for 60 days before joining. If you take proton pump inhibitors or antacids, you may need to stop them during the study if your doctor approves.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that potassium nitrate (KNO3) is usually well tolerated by people with heart failure. Studies have found that it can help these patients exercise longer and improve their quality of life. Previous patients using KNO3 did not report serious side effects, indicating that the treatment is quite safe. Since this trial is in an early stage, it focuses on ensuring the treatment's safety for humans. Any serious side effects would likely have been identified by now. Overall, KNO3 seems promising for helping those with heart failure, with minimal risk of negative effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Unlike standard heart failure treatments that often focus on managing symptoms with medications like ACE inhibitors or beta-blockers, potassium nitrate (KNO3) offers a novel approach by potentially enhancing nitric oxide levels in the body. Nitric oxide is crucial for blood vessel health, helping to improve blood flow and reduce heart strain. Researchers are excited about KNO3 because it provides a new way to support heart function by targeting vascular health directly, which could lead to better outcomes for patients with heart failure. Plus, it's delivered as a simple daily gel capsule, which might make it easier for patients to incorporate into their routine.

What evidence suggests that this trial's treatments could be effective for heart failure?

This trial will compare potassium nitrate (KNO3) with a placebo to evaluate its effects on exercise performance in heart failure patients. Research has shown that potassium nitrate might improve exercise capacity in these individuals. Studies have found that dietary nitrate can increase VO2peak, a measure of the body's oxygen use during exercise. This increase may enable longer and more effective exercise sessions. Additionally, KNO3 is generally well tolerated, making it a promising option for those seeking to enhance exercise ability. While more research is needed, these findings suggest that KNO3 could benefit heart failure patients aiming to improve their exercise performance. ^{1 2 3 5 6}

Who Is on the Research Team?

Linda R Peterson, MD

Principal Investigator

Washington University School of Medicine

Lauren K Park, PhD

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

My heart medication doses have been stable for the last 60 days.

I have heart failure with an ejection fraction under 45% and moderate symptoms.

Exclusion Criteria

Enrollment in another therapeutic trial during the period of the study

I have had heart surgery or a procedure to improve blood flow to the heart in the last 3 months.

I have severe heart valve disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Acute Dose Study

Participants receive a single dose of KNO3 or placebo and undergo various tests including blood sampling, exercise tests, and questionnaires

1 day

1 visit (in-person)

Chronic Treatment

Participants take a daily dose of KNO3 or placebo for 6 weeks and are instructed not to change their diet or exercise routine

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• KNO3
• Placebo

Trial Overview

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.

How Is the Trial Designed?

Group I: Potassium Nitrate (KNO3) treatment arm Experimental Treatment 1 Intervention

10 mmol of KNO3 via a single gel capsule to be consumed orally once per day for 6 weeks.

Group II: Placebo-controlled arm Placebo Group 1 Intervention

10 mmol of placebo via a single gel capsule to be consumed orally once per day for 6 weeks.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Published Research Related to This Trial

In a study of 7788 chronic heart failure patients, potassium supplement use did not significantly affect all-cause mortality, suggesting it may be safe in this regard.

However, potassium supplements were linked to a higher rate of hospitalizations for cardiovascular issues and worsening heart failure, indicating potential risks associated with their long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral potassium supplement use and outcomes in chronic heart failure: a propensity-matched study. Ekundayo, OJ., Adamopoulos, C., Ahmed, MI., et al.[2021]

In a study involving 17 subjects with heart failure, supplementation with inorganic nitrate from beetroot juice significantly improved exercise capacity, as indicated by increased peak VO2 and total work performed during exercise tests.

The nitrate supplementation enhanced cardiac output and reduced systemic vascular resistance, suggesting improved blood flow and vascular function, although it did not change exercise efficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Zamani, P., Rawat, D., Shiva-Kumar, P., et al.[2018]

A pilot trial is being conducted to evaluate the feasibility of using oral sodium nitrate as a treatment for acute heart failure (AHF), which is characterized by impaired vasorelaxation and reduced nitric oxide levels.

The study aims to determine if sodium nitrate can increase levels of nitric oxide precursors in the blood and improve vasorelaxation without causing significant drops in blood pressure, potentially offering a new treatment option for AHF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inorganic nitrate as a treatment for acute heart failure: a protocol for a single center, randomized, double-blind, placebo-controlled pilot and feasibility study. Falls, R., Seman, M., Braat, S., et al.[2018]

In a study of 136 heart failure patients, the addition of oral isosorbide-5-mononitrate (ISMN) to standard treatment showed a tendency to improve treadmill exercise duration, particularly in patients with an ejection fraction of 31-40%.

ISMN was well-tolerated with no serious side effects like hypotension, although 19% of patients experienced headaches, indicating it is a relatively safe option for enhancing exercise performance in heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Lewis, BS., Rabinowitz, B., Schlesinger, Z., et al.[2017]

In a pilot study involving 83 heart failure patients, a 12-week trial of 1500-mg sodium meals showed improved quality of life compared to 3000-mg meals, indicating that lower sodium intake may benefit patients' well-being.

Both sodium diets effectively reduced urinary sodium levels without significant adverse effects, suggesting that further research on dietary sodium in heart failure patients is warranted, despite challenges in participant compliance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Kalogeropoulos, A., Papadimitriou, L., Georgiopoulou, VV., et al.[2021]

In a study of 19,047 patients with heart failure and preserved ejection fraction (HFpEF), nitrates did not improve all-cause mortality or reduce heart failure hospitalizations, showing a hazard ratio of 1.06 when compared to untreated patients.

Despite initial expectations that nitrates could enhance heart function, the data indicated that their use was associated with worse outcomes, including a higher risk of hospitalization and lower event-free survival rates in the matched cohort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction. Lim, SL., Benson, L., Dahlström, U., et al.[2017]

In a pilot study involving 9 patients with heart failure, ingestion of inorganic nitrate (NO3 (-)) from beetroot juice significantly increased nitric oxide production and improved muscle power, particularly in knee extension.

The study found that dietary NO3 (-) led to a 9% to 11% increase in peak knee extensor power and maximal velocity, with no adverse effects reported, suggesting it could be a safe and effective intervention for enhancing muscle function in heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Dietary Nitrate Intake Improves Muscle Contractile Function in Patients With Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Trial. Coggan, AR., Leibowitz, JL., Spearie, CA., et al.[2018]

Nitroglycerin significantly lowers blood pressure and causes vasodilation in the carotid area, but its effects on wave reflections in the aorta are inconsistent, which may affect its overall efficacy in heart failure treatment.

Inorganic nitrate consistently reduces wave reflections without causing significant drops in blood pressure or vascular resistance, suggesting it may have a better safety profile and different effects on exercise capacity compared to nitroglycerin in patients with heart failure with preserved ejection fraction (HFpEF).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction. Chirinos, JA., Londono-Hoyos, F., Zamani, P., et al.[2018]

The SODIUM-HF trial, involving heart failure patients, demonstrated that reducing dietary sodium intake to less than 100 mmol per day can lead to significant improvements in heart failure symptoms and overall health outcomes.

This international, open-label, randomized controlled trial provides strong evidence supporting sodium reduction as a safe and effective dietary intervention for managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced dietary sodium did not reduce clinical events in heart failure. Alvarado, F., Borzak, S.[2022]

In a pilot study involving five male participants with heart failure and reduced ejection fraction (HFrEF), nitrate supplementation (from beetroot juice) significantly increased plasma nitrate and nitrite levels, indicating effective absorption and potential for improved cardiac function.

During submaximal exercise, nitrate supplementation led to clinically relevant increases in stroke volume and cardiac output, suggesting that it may enhance exercise capacity in patients with HFrEF, although further research with larger groups is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Woessner, MN., Levinger, I., Allen, JD., et al.[2021]

In a study involving rats with chronic heart failure (CHF), a potassium-supplemented diet significantly reduced the incidence of cardiac arrhythmias and improved cardiac sympathetic tone compared to a normal diet over a 6-week period.

The potassium supplementation also restored baroreflex function and improved irregular breathing patterns, indicating that increasing dietary potassium may help alleviate cardiorespiratory dysfunction in CHF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of enriched-potassium diet on cardiorespiratory outcomes in experimental non-ischemic chronic heart failure. Schwarz, KG., Pereyra, KV., Toledo, C., et al.[2022]

New potassium binders (NPBs) significantly improve the optimization of mineralocorticoid receptor antagonists (MRAs) in heart failure patients, reducing the occurrence of hyperkalaemia and allowing more patients to reach target doses of MRAs.

While NPBs show promise in enhancing MRA therapy, they do not significantly affect the optimization of other heart failure medications like ACE inhibitors or ARBs, and they may increase the risk of hypokalaemia, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Abuelazm, M., Badr, A., Turkmani, M., et al.[2023]

In a pilot study involving 13 cancer survivors, oral nitrate supplementation improved left ventricular function, specifically enhancing early filling and mitral wall velocity compared to a placebo.

Nitrate supplementation also reduced the oxygen cost during low-intensity exercise, suggesting potential benefits for exercise performance in cancer survivors, although no significant changes were observed in peak oxygen uptake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inorganic nitrate supplementation may improve diastolic function and the O2 cost of exercise in cancer survivors: a pilot study. Turpin, VG., Lovoy, GM., Parr, SK., et al.[2023]

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