Replacing lost nitric oxide
In his presentation, Dr. 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 from 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,” Dr. 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, 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 per 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 White, 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 preexisting 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, Dr. 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 per 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 Dr. 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, Dr. 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.”
Dr. 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. Dr. Jones has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.