NITRATE-OCT-CIN (Sub-Study of NITRATE-OCT)
Condition: Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Interventional

Summary: 
      The NITRATE-OCT:- Contrast Nephropathy Sub-study is a proof-of concept single center,
      randomized, clinical trial designed to ascertain whether a dietary NO3- approach might prove
      useful adjunctive therapy improving renal function and reducing CIN in patients with stable
      angina undergoing elective angioplasty.

      Objectives: To determine whether dietary NO3- ingestion exerts any effect on the glomerular
      filtration rate (GFR) after the exposure to contrast media.

      To determine if dietary NO3- ingestion will decrease the incidence of contrast induced
      nephropathy.

      Setting: The patients will be recruited from an on-going clinical trial NITRATE-OCT. This is
      a study assessing whether the use of dietary NO3- may reduce the incidence of restenosis
      following elective angioplasty. This study is recruiting patients with stable angina and
      single/multiple coronary artery stenosis undergoing elective PCI who are haemodynamically
      stable (systolic BP>100 mmHg). These patients will be recruited at The Barts Heart Centre at
      St Bartholomew's Hospital. This is one of the biggest centres in the UK, serving a population
      of almost two million people from The City of London and The North East up to the M25 and is
      a 24/7 centre performing approximately 3000 angioplasties a year.

      The study will take place in the Clinical Trials Unit, William Harvey Heart Centre.

      Target population: A total of 246 patients (male and female, age 18-85) with stable angina as
      per requirements indicated above. Follow-up will take place in the Clinical Trials Unit,
      William Harvey Research Institute.

      Treatment: Patients will be randomised (using an on line randomisation database) to receive
      70 ml of a beetroot juice concentrate containing 4-5 mmol nitrate or nitrate-depleted placebo
      juice concentrate. This intervention will be taken by the patient daily from one day prior to
      re-establishment of flow with PCI and stent implantation.
    

Detailed description: 
      Contrast induced nephropathy (CIN) refers to a form of acute kidney injury (AKI) that occurs
      after parenteral administration of radio-contrast agent in the absence of other identifiable
      causes. It is the third most common cause of hospital-acquired renal failure, after decreased
      renal perfusion and use of nephrotoxic medications. It is generally defined as an increase in
      serum creatinine concentration of 44 mol/L (0.5 mg/dl) or 25% above baseline within 48 hours
      after contrast administration. More than 70 years after the first description of a fatal
      renal function impairment following the use of radiographic contrast media, CIN still
      represents a major and unmet clinical challenge, as this potential complication is associated
      with a prolonged hospital stay, a higher hospitalization cost, and a significant increase in
      morbidity and mortality.

      Data suggest that CIN is due to an acute tubular dysfunction, however mechanisms underlying
      such acute tubular dysfunction in the context of CIN are rather poorly understood. Acute
      tubular dysfunction seen in settings of CIN is generally less severe and tends to recover
      more quickly when compared with other forms of acute tubular necrosis. Previous studies have
      suggested that CIN may be caused by either renal vasoconstriction resulting in medullary
      hypoxemia or direct cytotoxic injury caused by the contrast agents. Both mechanisms are known
      to decrease nitric oxide (NO) synthesis and, therefore, may contribute to renal injury.
      Importantly studies in animal models of contrast induced nephropathy have suggested that
      decreased levels of NO contributes to this renal injury. Thus the replacement of this 'lost'
      NO represents an approach that might offer therapeutic benefit.

      Patients with chronic renal failure, diabetes mellitus, and heart failure all have a common
      phenotype of reduced bioavailability of NO, and it is possible that this state accounts for
      their increased susceptibility to develop contrast media nephrotoxicity. There have been
      several approaches taken in an attempt to restore NO biovailability in order to prevent
      development of CIN. N-acetylcysteine has been the most studied, and the most promising
      compound in this regard. The proposed mechanism of action of N-acetylcysteine is stimulation
      of NO synthase and increased production of NO. However, in patients with already impaired NO
      bioavailability due in part to dysfunction of the NO synthase pathways, activation of NO
      synthase may not generate amounts of sufficient for kidney protection.

      A potential solution for elevating endogenous NO levels lies in the chemical reduction of
      inorganic nitrite (NO2-) to NO. For several decades, NO2- was considered primarily an
      oxidative product of NO metabolism and possibly a deleterious substance with reputed
      carcinogenic properties. However, evidence indicates that NO2-, which is abundant in blood
      and tissues, represents a significant stable intravascular endocrine reservoir and tissue
      storage form of NO that exerts a number of beneficial effects. Indeed, NO2--derived NO
      protects against myocardial ischaemia/reperfusion injury in pre-clinical models, protects
      against experimentally-induced endothelial dysfunction and attenuates platelet reactivity in
      healthy volunteers and improves endothelial function in hypertensive patients with
      endothelial dysfunction. In addition, of specific relevance to this project, NO2--derived NO
      has been shown to be reno-protective in pre-clinical models of renal injury. Since the
      ingestion of dietary inorganic nitrate (NO3- ) increases endogenous NO levels, the
      investigators suggest that potential therapeutic benefit could be derived from the use of
      dietary NO3- in the prevention of CIN.

      There is no data assessing the impact of inorganic nitrite/nitrate treatment on CIN in
      patients undergoing PCI. However, in one small study, post-procedural renal function was
      compared between 112 patients who received organic nitrates prior to coronary intervention
      and 87 who did not. Baseline characteristics were similar between the 2 groups. Overall, 43
      (21.6%) patients developed CIN post-PCI. Of the patients who received organic nitrates, 15.2%
      developed renal impairment when compared to 29.9% in those who did not (odds ratio [OR] =
      0.42, 95% confidence interval [CI] 0.21-0.84, P = .014). Multivariate logistic regression
      analysis demonstrated that nitrate use was independently correlated with a reduction in the
      development of contrast nephropathy (OR = 0.334, 95% CI 0.157-0.709, P = .004). Importantly
      this study used a single dose of organic nitrate, in part it is likely that this approach was
      taken due to the major complications with the organic nitrates of the development of
      tolerance. Indeed, it is this characteristic of these drugs that has profoundly limited their
      clinical utility. Inorganic dietary nitrate, in contrast, is superior in this respect in that
      there is no evidence of tolerance with prolonged administration and it possesses a much
      longer half life (~8 hours) as opposed to minutes with the organic nitrates. The
      investigators therefore propose to evaluate the effects of dietary NO3- administration on the
      incidence of CIN in patients undergoing percutaneous coronary intervention.

      Specifically with respect to the study of NO2- and CIN; preliminary data from the NITRITE-AMI
      study performed by the investigators showed that a single bolus of intracoronary NO2- given
      during primary PCI for ST-elevation MI lead to a significant rise in circulating NO2- levels
      which lead to a suggestion of reduced CIN. During the first 48 hours after reperfusion, 12.5%
      of patients in the control group developed CIN, compared to 2.5% patients in the nitrite
      group (p=0.108). With respect to change in eGFR, from baseline to 48 hours, there was a
      reduction in eGFR in the placebo group with a trend to an increase in the nitrite group with
      a significant difference between the change in eGFR over time between the 2 groups (Nitrite
      group: 5.98 ± 1.99 vs Placebo: -10.15 ±3.69, p=0.002).

      Thus, together all of the above issues coupled with preliminary data support the rationale
      for further exploration of potential approaches based upon elevation of circulating NO2-
      levels that might reduce the burden of CIN on the NHS.
    

Intervention name(s): Beetroot Juice; Beetroot Juice
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 70 ml of beetroot juice containing ~5 mmol of inorganic nitrate; 70 ml of beetroot juice which is nitrate-depleted
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Stable Angina; Nitrate; Contrast Induced Nephropathy