The Use of Inorganic Nitrate for the Prevention of Contrast-induced Nephropathy

Study Overview
=================
Brief Summary
-----------------
Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is an important cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for an effective intervention. Dietary inorganic nitrate therapy, which through its chemical reduction in the body delivers nitric oxide has shown promise in attenuating CIN, but its effectiveness in preserving long-term renal function is unknown.

Detailed Description
-----------------
The NITRATE-CIN trial is a single-centre, randomised double-blinded placebo-controlled trial, which plans to recruit, over a period of 2 years, 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN. Patients will be randomised to either dietary inorganic nitrate therapy or placebo. The primary endpoint will be the development of CIN (KDIGO criteria). A key secondary endpoint will be whether nitrate therapy impacts upon persistent renal impairment over a 3-month follow-up period. Additional secondary endpoints include the measurement of serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) and urinary albumin at 6, 48 h and 3 months following administration of contrast. Findings from NITRATE-CIN will potentially demonstrate that nitrate attenuates contrast-induced acute and chronic kidney injury and influence future clinical practice guidelines in at-risk patients undergoing coronary angiographic procedures.

Official Title
-----------------
Effect of Inorganic Nitrate on Contrast-induced Nephropathy in Patients Undergoing Coronary Angiography/Percutaneous Coronary Intervention for Acute Coronary Syndrome (ACS): A Randomised Single-centre, Double-blind Placebo-controlled Trial

Conditions
-----------------
Contrast-induced Nephropathy, Acute Kidney Injury, Acute Coronary Syndrome

Intervention / Treatment
-----------------
* Drug: Potassium Nitrate
* Drug: Potassium Chloride


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients undergoing coronary angiography+/-Percutaneous Coronary Intervention (PCI) for NSTE-ACS Requirement for CIN prophylaxis as per Barts Heart Centre Criteria for CIN prophylaxis: eGFR<60ml/min OR 2 of the following: diabetes, liver failure (cirrhosis), age > 70yr, exposure to contrast in last 7 days, heart failure (or LVEF<40%), concomitant renally active drugs (ACEi, ARB, NSAIDs, aminoglycosides, diuretics) Aged >18 Patients able and willing to give their written informed consent. Exclusion Criteria: ST segment myocardial infarction undergoing Primary PCI. Patients with eGFR<30ml/min or on renal replacement therapy Subjects presenting with cardiogenic shock (systolic blood pressure <80 mmHg for >30 minutes, or requiring inotropes or emergency intra aortic balloon pump for hypotension treatment) or cardiopulmonary resuscitation Current life-threatening condition other than vascular disease that may prevent a subject completing the study. Use of an investigational device or investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication. Patients considered unsuitable to participate by the research team (e.g., due to medical reasons, laboratory abnormalities, or subject's unwillingness to comply with all study related procedures). Severe acute infection Pregnancy Breast-feeding mothers. Any Inclusion Criteria not met

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Potassium Nitrate<br>Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days | Drug: Potassium Nitrate<br>* Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days<br>|
| Placebo Comparator: Potassium Chloride<br>Potassium Chloride | Drug: Potassium Chloride<br>* Potassium Chloride capsules for 5 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contrast Induced Nephropathy | Defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria | 48-72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstration of a persistent benefit of dietary inorganic nitrate against long-term renal impairment | Difference in real function as measured by eGFR (estimated glomerular filtration rate) at 3 months post-contrast exposure | 3 months | 
| Measurement of Circulating Nitrite and Nitrate levels | Plasma Nitrite/Nitrate levels | Baseline, and at 6 hours, 48 hours and 3 months following treatment. | 
| Major Adverse Cardiac Events | Defined as death, non-fatal myocardial infarction, revascularisation, acute heart failure, non-fatal stroke | 3 and 12 months follow-up | 
| Cost effectiveness of dietary inorganic Nitrate | Incremental Cost Effectiveness Ratio (ICER) | 1 year | 
| To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by urinary renal biomarkers | Measurement of urinary IGFB7/TIMP-2 | 4-6 hours | 
| To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by serum biomarkers | Measurement of serum Neutrophil gelatinase-associated lipocalin (NGAL) | 4-6 hours | 
| To determine if dietary inorganic nitrate decreases rates of post-procedural Myocardial Infarction | Definition as per Society for Cardiovascular Angiography and Interventions (SCAI) | 6-12 hrs | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Percutaneous Coronary Intervention, Nitric Oxide, Nitrite, Acute Kidney Injury, Acute Coronary Syndrome