ACT: No Benefit of N-Acetylcysteine to Reduce Contrast-Induced Nephropathy

November 17, 2010

November 17, 2010 (Chicago, Illinois) — The addition of N-acetylcysteine failed to reduce the risk of contrast-induced nephropathy in patients undergoing coronary and vascular angiography. The findings, from the Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT), the largest randomized study to date, provide solid evidence that N-acetylcysteine is not effective in this setting and should no longer be used for the prevention of contrast-induced nephropathy, according to investigators.

Dr Otavio Berwanger

"I would be comfortable saying that this is a definitive trial, and I'd be comfortable saying that because if you look at the other high-quality trials, we reached exactly the same result," Dr Otavio Berwanger (Hospital do Coração, São Paulo, Brazil) told heartwire . "It would be extremely unlikely that another trial would be conducted, say a larger 20 000-patient trial, and would find a different result. One thing that is interesting with negative trials is that there is often a subgroup, maybe sicker patients, the elderly, that might have a different result. But here, it was very consistent."

Presenting the results of the study today during the late-breaking clinical-trials session here at the American Heart Association (AHA) 2010 Scientific Sessions, Berwanger explained that N-acetylcysteine, an antioxidant, has been used as adjunctive therapy for about 10 years to reduce kidney injury caused by contrast used in coronary and vascular angiography. Despite its use, however, the evidence accumulated to date is conflicting, leaving questions about its role in clinical practice.

I remember . . . patients . . . coming in with N-acetylcysteine, and I remember thinking, 'What the heck is this drug?'

In ACT, investigators randomized 2308 patients undergoing an angiographic procedure to 1200 mg of N-acetylcysteine, prescribed orally twice daily, with two doses given before the procedure and two doses after the procedure, or to placebo.

Despite treatment with N-acetylcysteine, they observed "absolutely no difference" in the primary end point of contrast-induced nephropathy and no difference in the secondary end point of serum creatinine elevations. Similarly, 30-day clinical end points, including mortality, the need for dialysis, or cardiovascular mortality, were no different between placebo- and N-acetylcysteine–treated patients. A subgroup analysis revealed no benefit in any patient population, including patients stratified by age, the presence of diabetes mellitus, sex, serum creatinine levels, or type of contrast used prior to angiography.

Berwanger and colleagues also performed their own meta-analysis, looking only at other high-quality studies, and observed no reduction in risk with N-acetylcysteine. Those results, Berwanger told heartwire , are in line with the lack of benefit observed in ACT.

A Decade of Debate

Dr Brahmajee Nallamothu

Dr Brahmajee Nallamothu (University of Michigan, Ann Arbor), the scheduled discussant during the late-breaking clinical-trials session, told heartwire that N-acetylcysteine is used in approximately 10% of all patients undergoing angiography and in about 30% of patients with chronic renal insufficiency. He said that since the first study showed a benefit of N-acetylcysteine in the prevention of contrast-induced nephropathy--published in the New England Journal of Medicine in 2000 by Dr Martin Tepel (Freie Universität Berlin, Germany)--more than 40 studies have been performed, including approximately 15 meta-analyses.

"I think this is a classic example where a very prominent clinical trial had a dramatic effect size, about a 90% reduction in the original Tepel study, and this changed practice almost overnight," Nallamothu told heartwire . "I remember being in the cath lab as a cardiology fellow and patients were coming in with N-acetylcysteine, and I remember thinking, 'What the heck is this drug?' How quickly it was adopted into practice was remarkable."

After the publication of the Tepel study, trials were published supporting its use, but others not showing any benefit also emerged. Nearly all of the trials were small, with as few as 25 patients in one study, said Nallamothu. After much back-and-forth over the questionable benefit of N-acetylcysteine and the publication of numerous meta-analyses, many of which combined heterogeneous trials, a large trial, such as ACT, was put off for almost 10 years.

"At least in some way, what was happening was a false sense of security that we already knew the answer," said Nallamothu. Like Berwanger, he said the results are "very definitive," showing no benefit on N-acetylcysteine in the broad spectrum of patients included in ACT, such as those with diabetes and chronic renal failure.

The American College of Cardiology (ACC)/AHA have been "consistently conservative" in their assessment of N-acetylcysteine and make no recommendation about its use in clinical practice, added Nallamothu. The European Society of Cardiology (ESC) gives N-acetylcysteine a class IIb recommendation in patients with chronic renal insufficiency.

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