Inorganic Nitrate for Heart Failure

Overseen By Deb Koudelis

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must be taking: Beta-blockers, ACE inhibitors, ARBs

Must not be taking: Organic nitrates, Phosphodiesterase inhibitors

Disqualifiers: Atrial fibrillation, Severe liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

42 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to do the work that is necessary and sufficient for setting up an appropriate multi-center, randomized clinical trial (RCT) of a new therapy for heart failure: inorganic nitrate. The investigators will first determine the effects and palatability of \~12.8mmol KNO3 (an oral pill) as compared to the roughly equivalent amount of nitrate in 2 beetroot juice (BRJ) Sports Shots (by James White Drinks). Next, the investigators will determine the effects of inorganic nitrate (KNO3 in an oral pill format) on blood pressure, blood nitrate levels, breath nitric oxide (NO) levels, and exercise performance in a dose-response study. Third, the investigators will perform a small phase II chronic treatment study that will allow them to determine the best primary endpoint and the numbers of patients the investigators will need to study in the large, multi-center RCT to follow this project. In the small study and in the RCT to follow, the investigators will determine whether inorganic nitrate can improve aerobic exercise capacity, muscle power, and speed of muscle contraction, and lessen the effort of breathing during exercise.

Will I have to stop taking my current medications?

The trial requires that your current heart failure medications remain stable, meaning no major changes in dosage or type for 30 days before joining. If you're on phosphodiesterase inhibitors, you must stop them for the trial duration.

What data supports the effectiveness of the drug potassium nitrate (KNO3) for heart failure?

Research suggests that nitrates, like potassium nitrate, can help improve heart function by increasing nitric oxide levels, which relax blood vessels and improve blood flow. This can lead to better heart performance and reduced symptoms in heart failure patients. ^{1 2 3 4 5}

Is inorganic nitrate (KNO3, Potassium Nitrate) safe for use in humans?

The research does not provide specific safety data for inorganic nitrate (KNO3, Potassium Nitrate) in humans. ^{6 7 8 9 10}

How does the drug KNO3 differ from other treatments for heart failure?

KNO3 (Potassium Nitrate) is unique because it provides a source of nitric oxide (NO) through bioconversion, which helps improve blood flow by reducing vascular resistance without causing significant drops in blood pressure. This mechanism is different from traditional heart failure treatments that often focus on reducing heart workload or fluid retention. ^{1 11 12 13 14}

Research Team

Linda R Peterson, MD

Principal Investigator

Washington University School of Medicine

Andrew R Coggan, PhD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults aged 18-75 with heart failure characterized by reduced ejection fraction (NYHA II-IV) and stable on certain heart medications. Excluded are pregnant individuals, those with severe liver disease, recent other nitrate treatments, complex heart issues, or conditions affecting exercise test performance.

Inclusion Criteria

My heart medication doses haven't changed significantly in the last 30 days.

My heart's pumping ability is below 45%.

I have been diagnosed with heart failure where my heart doesn’t pump well.

Exclusion Criteria

I have inflammation of the heart muscle.

Pregnancy

My kidney function is reduced, with a filtration rate under 50 ml/min.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Visit 1

Participants receive 2 capsules containing either 10 or 20 mmol of potassium nitrate (KNO3) and undergo various assessments including blood pressure, plasma nitrite levels, and nitric oxide breath analysis

1 day

1 visit (in-person)

Washout Period

Participants undergo a 7-day washout period between dose visits

1 week

Dose Visit 2

Participants receive the alternate dose of potassium nitrate (KNO3) and repeat the same assessments as Dose Visit 1

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• KNO3

Trial Overview The study tests if potassium nitrate pills can improve blood pressure, blood nitrate levels, breath NO levels, and exercise performance in heart failure patients. It compares the effects of these pills to beetroot juice shots and looks at different doses.

Participant Groups

Group I: 20mmol KNO3 Experimental Treatment 1 Intervention

Intervention: Subjects with heart failure will receive a single oral dose of potassium nitrate (10 or 20 mmol KNO3) in 2 gelatin capsules during dose visit 1 and the other dose (10 or 20 mmol KNO3) during dose visit 2. The dose order will be randomized.

Group II: 10mmol KNO3 Experimental Treatment 1 Intervention

Intervention: Subjects with heart failure will receive a single oral dose of potassium nitrate (10 or 20 mmol KNO3) in 2 gelatin capsules during dose visit 1 and the other dose (10 or 20 mmol KNO3) during dose visit 2. The dose order will be randomized.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Findings from Research

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]

Nitrates, such as isosorbide dinitrate, can improve heart failure symptoms and exercise tolerance by reducing cardiac filling pressures and increasing cardiac output, as shown in studies combining them with digoxin and diuretics.

Long-term use of nitrates has been associated with improved survival rates and left ventricular ejection fraction, suggesting they may help prevent harmful changes in the heart's structure, although the best dosing strategies for heart failure patients are still being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of action and efficacy of nitrates in heart failure. Cohn, JN.[2019]

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]

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 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]

Nitroglycerin and its derivatives effectively treat severe heart failure by reducing the heart's preload and afterload, which improves cardiac output and alleviates symptoms for patients.

Intravenous nitrates are particularly useful in acute situations like myocardial infarction and worsening left ventricular failure, while oral and transdermal forms are prescribed for chronic heart failure in advanced stages (NYHA class III and IV).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of nitroglycerin in the treatment of congestive heart failure]. Curyło, AM.[2013]

References

1. 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]

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

Mechanisms of action and efficacy of nitrates in heart failure. [2019]

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. Spain pubmed.ncbi.nlm.nih.gov

Influence of Intravenous Nitrate Treatment on Early Mortality Among Patients With Acute Heart Failure. NITRO-EAHFE Study. [2016]

5. 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]

6. 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]

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

Effect of patiromer on serum potassium in hyperkalemic patients with heart failure: Pooled analysis of 3 randomized trials. [2021]

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

Characterization of Mineralocorticoid Receptor Antagonist Therapy Initiation in High-Risk Patients With Heart Failure. [2018]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. [2022]

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

Inorganic nitrate ingestion improves vascular compliance but does not alter flow-mediated dilatation in healthy volunteers. [2021]

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

Nitrates in the treatment of congestive heart failure. [2019]

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

Nitrates in congestive heart failure. [2019]

14. Poland pubmed.ncbi.nlm.nih.gov

[Use of nitroglycerin in the treatment of congestive heart failure]. [2013]