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Inorganic nitrate improves safety of coronary angiography in patients at renal injury risk

NITRATE-CIN trial presented in a Hot Line session today at ESC Congress 2023


Amsterdam, Netherlands – 28 Aug 2023: Inorganic nitrate reduces contrast-induced nephropathy (CIN), improves renal outcomes and reduces cardiac events compared to placebo in patients at risk of renal injury undergoing coronary angiography for acute coronary syndrome, according to late breaking research presented in a Hot Line session today at ESC Congress 2023.1

CIN, also termed contrast associated-acute kidney injury, refers to a deterioration in renal function after contrast exposure and is a serious complication of coronary angiography.2-4 Older age, heart failure, chronic kidney disease and diabetes are independent predictors of CIN following coronary angiography for acute coronary syndromes.3,5 CIN is associated with longer hospital stays, an increased risk of myocardial infarction and higher mortality.5 ESC guidelines highlight that patients with chronic kidney disease have been excluded from randomised trials on myocardial revascularisation and that additional randomised evidence is needed on optimal strategies for CIN prevention.6

Research has suggested that nitric oxide is deficient in CIN; therefore, strategies to replace nitric oxide might be of benefit.7 Inorganic nitrate is metabolised in the body to deliver nitric oxide to areas of the body in need and has shown renoprotective effects in preclinical studies.8 The NITRATE-CIN trial examined the efficacy of inorganic nitrate for the prevention of CIN in patients with non-ST elevation acute coronary syndrome referred for invasive coronary angiography and at risk of CIN. Risk of CIN was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min or two of the following: diabetes, liver failure (cirrhosis), age >70 years, exposure to contrast in the last 7 days, heart failure (or left ventricular ejection fraction <40%), and concomitant renally active drugs.

NITRATE-CIN was a double-blind, randomised, placebo-controlled trial conducted at Queen Mary University of London and St Bartholomew's Hospital in London, UK. Patients were randomised in a 1:1 ratio to once daily potassium nitrate (12 mmol) or placebo (potassium chloride) capsules for 5 days.

The primary endpoint was the incidence of CIN (³0.3 mg/dl or ³26.5 mmol/L increase in creatinine within 48 hours or ³1.5 times within 1 week), as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury. Secondary outcomes included renal function (eGFR) at 3 months, rates of procedural myocardial infarction and major adverse cardiac events (MACE, a composite of death, non-fatal myocardial infarction and unscheduled revascularisation) at 12 months. Standard care for CIN prevention in both arms matched ESC recommendations (hydration before and after coronary angiography, use of low-osmolar contrast media).6

Over a 3-year period, a total of 640 patients were randomised: 319 received inorganic nitrate and 321 received placebo. The mean age of trial participants was 71.0 years, 73.3% were men, 75.2% were Caucasian. 45.9% had diabetes, 56.0% had chronic kidney disease (eGFR <60 ml/min) and the mean Mehran score was 10. The median follow up was 1.0 years.

Inorganic nitrate treatment significantly reduced CIN rates (9.1%) versus placebo (30.5%; p<0·001). This difference persisted after adjustment for baseline creatinine concentration and diabetes status (odds ratio [OR] 0.21; 95% confidence interval [CI] 0.13 to 0.34). Secondary outcomes were improved with inorganic nitrate, with lower rates of procedural myocardial infarction (2.7% vs. 12.5%; p=0.003), improved 3-month renal function (between group change in eGFR 5.17 [interquartile range 3.94-7.39]) and reduced 1-year MACE (9.1% vs. 18.1%; p=0.001) versus placebo.

Study author Dr. Dan Jones, representing the team at Queen Mary University of London said: “In patients at risk of renal injury undergoing coronary angiography for acute coronary syndrome, dietary inorganic nitrate reduced CIN compared to placebo. This corresponded to improved renal outcomes at three months and MACE at 12 months. These findings could have important implications for health systems by reducing the burden of CIN and the associated prolonged admissions, dialysis, and significant costs. Further studies powered for adverse cardiac events are needed to confirm these findings.”



Notes to editor

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This press release accompanies both a presentation and an ESC press conference at ESC Congress 2023. It does not necessarily reflect the opinion of the European Society of Cardiology.


Funding: The study was funded by Heart Research UK via the Translational Research Project RG2667


Disclosures: The Study CI (Prof Ahluwalia) is a Director of HeartBeet Ltd.


References and notes

1NITRATE-CIN will be discussed during Hot Line 8 on Monday 28 August at 14:00 to 15:20 CEST in room Amsterdam.

2Mehran R, Dangas GD, Weisbord SD. Contrast-associated acute kidney injury. N Engl J Med. 2019;380:2146-2155.

3Rear R, Bell RM, Hausenloy DJ. Contrast-induced nephropathy following angiography and cardiac interventions. Heart. 2016;102:638-648.

4McCullough PA, Choi JP, Feghali GA, et al. Contrast-induced acute kidney injury. J Am Coll Cardiol. 2016;68:1465-1473.

5Mohebi R, Karimi Galougahi K, Garcia JJ, et al. Long-term clinical impact of contrast-associated acute kidney injury following PCI: An ADAPT-DES substudy. JACC: Cardiovasc Interv. 2022;15:753-766.

6Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87–165.

7Beirne AM, Mitchelmore O, Palma S, et al. 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;26:303-309.

8Yang T, Zhang XM, Tarnawski L, et al. Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress. Redox Biol. 2017;13:320-330.


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