The Use of Inorganic Nitrate for the Prevention of Contrast-induced Nephropathy (NITRATE-CIN)

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Coronary Syndrome; Acute Kidney Injury; Contrast-induced Nephropathy
• Intervention / Treatment: Drug: Potassium Nitrate; Drug: Potassium Chloride

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 Type: Interventional
• Enrollment (Actual): 640
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • Barts Heart Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Potassium Nitrate; Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days	Drug: Potassium Nitrate; Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days
PLACEBO_COMPARATOR: Potassium Chloride	Drug: Potassium Chloride; Potassium Chloride capsules for 5 days

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

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust

Publications and helpful links

General Publications

• Beirne AM, Mitchelmore O, Palma S, Andiapen M, Rathod KS, Hammond V, Bellin A, Cooper J, Wright P, Antoniou S, Yaqoob MM, Naci H, Mathur A, Ahluwalia A, Jones DA. NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes. J Cardiovasc Pharmacol Ther. 2021 Jul;26(4):303-309. doi: 10.1177/1074248421000520. Epub 2021 Mar 25.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 29, 2018
• Primary Completion (ACTUAL): May 30, 2022
• Study Completion (ACTUAL): May 30, 2022

Study Registration Dates

• First Submitted: January 17, 2018
• First Submitted That Met QC Criteria: August 10, 2018
• First Posted (ACTUAL): August 13, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 16, 2022
• Last Update Submitted That Met QC Criteria: December 15, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Percutaneous Coronary Intervention; Acute Coronary Syndrome; Acute Kidney Injury; Nitric Oxide; Nitrite
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Urologic Diseases; Disease; Renal Insufficiency; Syndrome; Kidney Diseases; Acute Kidney Injury; Acute Coronary Syndrome
• Other Study ID Numbers: 18/1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The trial protocol will be published prior to the commencement of the study
• IPD Sharing Time Frame: Mid-late 2018
• IPD Sharing Access Criteria: Freely available via journal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No