Nitrate Supplementation for Heart Failure

(iNIX-HF Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Linda R Peterson, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

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.

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.

What data supports the effectiveness of the drug KNO3 (Potassium Nitrate) for heart failure?

Research suggests that nitrate supplementation, like KNO3, may improve heart function during exercise in people with heart failure by increasing blood flow and reducing resistance in blood vessels. This is based on studies showing improved cardiac measures and exercise performance with nitrate use. ^{1 2 3 4 5}

Is nitrate supplementation safe for heart failure patients?

The research does not provide specific safety data on nitrate supplementation for heart failure, but potassium supplements, which are sometimes used in heart failure, have been studied for safety. Potassium supplements are generally safe but can cause hypokalemia (low potassium levels) in some cases. ^{6 7 8 9 10}

How does nitrate supplementation differ from other heart failure treatments?

Nitrate supplementation for heart failure is unique because it increases nitric oxide (NO) levels, which helps improve heart and muscle function during exercise by enhancing blood flow and reducing resistance in blood vessels. This approach is different from standard heart failure treatments that may not specifically target NO levels or focus on exercise capacity improvements. ^{1 5 11 12 13}

Research Team

Linda R Peterson, MD

Principal Investigator

Washington University School of Medicine

Lauren K Park, PhD

Principal Investigator

Washington University School of Medicine

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.

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.

Trial Timeline

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

Treatment Details

Interventions

• KNO3 (Inorganic Nitrate)
• Placebo (Other)

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.

Participant Groups

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+

David H. Perlmutter

Washington University School of Medicine

Chief Executive Officer since 2015

MD from Washington University School of Medicine

Paul Scheel

Washington University School of Medicine

Chief Medical Officer since 2022

MD from Washington University School of Medicine

Findings from Research

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 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 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]

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]

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 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 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 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]

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]

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]

References

1. Switzerland 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. [2021]

2. Switzerland 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. [2017]

3. United States pubmed.ncbi.nlm.nih.gov

Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction. [2017]

4. Germany pubmed.ncbi.nlm.nih.gov

Inorganic nitrate supplementation may improve diastolic function and the O2 cost of exercise in cancer survivors: a pilot study. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Effects of enriched-potassium diet on cardiorespiratory outcomes in experimental non-ischemic chronic heart failure. [2022]

7. England 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. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Reduced dietary sodium did not reduce clinical events in heart failure. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Oral potassium supplement use and outcomes in chronic heart failure: a propensity-matched study. [2021]

10. United States 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. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. [2018]

12. United States 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. [2018]

13. England 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. [2018]