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

Phase 2

Completed

• Conditions: Acute Kidney Injury; Contrast-induced Nephropathy; Acute Coronary Syndrome
• Interventions: Drug: Potassium Nitrate; Drug: Potassium Chloride

• Registration Number: NCT03627130
• Lead Sponsor: Barts & The London NHS Trust

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.

Study Timeline

• Study First Submitted: 2018-01-17
• Study First Submitted QC: 2018-08-10
• Study First Posted: 2018-08-13
• Study Start: 2018-11-29
• Primary Completion: 2022-05-30
• Study Completion: 2022-05-30
• Status Verified: 2022-12
• Last Update Submitted: 2022-12-15
• Last Update Posted: 2022-12-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 640

Inclusion Criteria

1. Patients undergoing coronary angiography+/-Percutaneous Coronary Intervention (PCI) for NSTE-ACS

2. 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)

3. Aged >18

4. Patients able and willing to give their written informed consent.

Exclusion Criteria

1. ST segment myocardial infarction undergoing Primary PCI.
2. Patients with eGFR<30ml/min or on renal replacement therapy
3. 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
4. Current life-threatening condition other than vascular disease that may prevent a subject completing the study.
5. 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.
6. 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).
7. Severe acute infection
8. Pregnancy
9. Breast-feeding mothers.
10. Any Inclusion Criteria not met

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Potassium Nitrate	Potassium Nitrate	Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days
Potassium Chloride	Potassium Chloride	Potassium Chloride

Primary Outcome Measures

Name	Time	Method
Contrast Induced Nephropathy	48-72 hours	Defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Barts Heart Centre; 🇬🇧 London, United Kingdom