AMSTERDAM, Netherlands — A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.
In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.
The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.
Dr Dan Jones
The trial was presented here by Dan Jones, MD, Barts Health NHS Trust, London, England, on August 28 at the European Society of Cardiology (ESC) Congress 2023 held in Amsterdam, the Netherlands.
“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Jones concluded.
He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.
At this point, “the only way to get inorganic nitrate is in the diet — specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he told theheart.org | Medscape Cardiology.
However, Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a similar dose as that used in this study, starting the day before angiography.
“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he commented.
Dietary Nitrates “Make Sense”
Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York City, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”
On the main findings of a major significant 50% reduction in acute kidney injury, Mehran commented, “It is difficult to imagine such a reduction is possible.”
She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.
Dr Roxanna Mehran
“We’re all going to get on beet juice after this,” she quipped.
Still Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.
Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.
“From our pilot data we thought nitrate may be effective in preventing CIN,” he told theheart.org | Medscape Cardiology. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”
Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.
“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.
“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Jones added.
A larger trial is now being planned.
The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Jones said.
He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.
“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Jones commented.
Replacing Lost Nitric Oxide
In his presentation, Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.
The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients — older patients and/or those with heart failure, chronic kidney disease, or diabetes.
“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”
The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different to medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.
“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Jones added.
NITRATE-CIN Study
NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St Bartholomew’s Hospital in London, England, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.
To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.
Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.
The patient population had a mean age of 71 years, 73% were male, 75% were Caucasian, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow up, which was attributed to the COVID pandemic.
The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.
The primary endpoint was the incidence of CIN as defined by KDIGO criteria — a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.
Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.
Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.
The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on pre-existing organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.
As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Jones reported.
Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).
Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min/1.73 m2 (10%) in the nitrate group vs the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.
At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events — including all-cause mortality, recurrent MI, and recurrent revascularization — which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.
Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.
While Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.
“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”
In her comments, Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.
She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”
Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.
The NITRATE-CIN study was funded by Heart Research UK. Jones has disclosed no relevant financial relationships.
European Society of Cardiology (ESC) Congress 2023. Presented August 29, 2023.
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