ACT Published: Definitive Results Nix NAC for Preventing Kidney Damage

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N-acetylcysteine (NAC) does nothing to reduce the risk of contrast-induced acute kidney injury (AKI) in at-risk patients undergoing angiography, according to a large randomized trial published online August 22, 2011, ahead of print in Circulation. Nor does the therapy affect other clinically relevant outcomes such as death and need for dialysis at 30 days.

Results from the Acetylcysteine for Contrast-induced nephropathy Trial (ACT) were presented last November at the American Heart Association Scientific Sessions 2010 in Chicago, IL.

To resolve what had been conflicting results in the literature about NAC’s efficacy, Otavio Berwanger, MD, PhD, of Hospital do Coração (São Paulo, Brazil), and colleagues performed a large multicenter study that enrolled 2,308 patients who were undergoing either coronary or peripheral vascular angiography. Subjects were randomized to 1,200 mg NAC (n = 1,172) or placebo (n = 1,136) given orally every 12 hours for 2 doses before and 2 doses after the procedure. All had at least 1 of the following risk factors for contrast-induced AKI:

  • Age greater than 70 years
  • Renal failure
  • Diabetes
  • Heart failure
  • Hypotension

Treatment allocation was concealed, and all outcomes were analyzed according to intention to treat.

At 48 to 96 hours after angiography, patients had exactly the same likelihood of developing contrast-induced AKI (primary endpoint; defined as 25% elevation in serum creatinine [SCr]), regardless of whether they received NAC or placebo. The proportions of those who experienced elevations of at least 0.5 mg/dL SCr or a doubling of SCr also were similar between groups (table 1).

Table 1. Outcomes at 48 to 96 Hours

 

NAC

Placebo

P Value

Contrast-Induced AKI

12.7%

12.7%

0.97

SCr Elevation ≥ 0.5 mg/dL

3.9%

3.8%

0.85

Doubling of SCr

1.1%

1.5%

0.41


At 30 days, clinical outcomes were equivalent in both study arms (table 2).

Table 2. Outcomes at 30 Days

 

NAC

Placebo

P Value

Mortality

2.0%

2.1%

0.92

CV Mortality

1.5%

1.6%

0.97

Need for Dialysis

0.3%

0.3%

0.86

Mortality/Dialysis

2.2%

2.3%

0.92


The lack of benefit from NAC was consistent across numerous subgroup analyses including patients aged above or below 70 years, male vs. female, those with or without diabetes, and those with baseline SCr greater than or less than 1.5 mg/dL.

“On the basis of our results, we do not recommend routine use of acetylcysteine for patients undergoing angiography,” the authors conclude. “These findings may have important implications for clinical practice and may prevent unnecessary procedure delays and health expenditures associated with the administration of acetylcysteine.”

ACT Provides Convincing Data

Richard J. Solomon, MD, of the University of Vermont (Burlington, VT), told TCTMD in a telephone interview that ACT is notable for being large and well-designed. “The criticism has been that they’re not high-risk patients,” he said, but pointed out that this appears irrelevant, since ACT found no benefit from NAC even in patients with renal insufficiency or diabetes. Most importantly, the study observed no effect on hard outcomes at 30 days, he stressed.

In a telephone interview with TCTMD, Hitinder S. Gurm, MD, of the University of Michigan Medical Center (Ann Arbor, MI), described the history of literature on NAC to prevent AKI. “A consistent message was that trials that use good methodology do not suggest there’s a benefit or at least are neutral, while trials with somewhat weak methodology are strongly positive,” he said, commending the ACT investigators for pursing such a high-quality study given the lack of financial incentive for researching NAC.

But Will Findings Be Adopted?

Dr. Solomon was not convinced, however, that the findings would immediately alter clinical practice.

“There’s an understanding that acute kidney injury is a bad thing. We don’t have a clear and definitive strategy for prevention. N-acetylcysteine has essentially no downside, and while the evidence doesn’t support its efficacy, my giving it at least indicates that I’m doing something and paying attention,” he commented. “I don’t know that people are going out of their way to change their protocols. They might stick with it, saying, ‘There’s no harm. Yes, it looks like this is not efficacious, but who knows. I’ll just keep doing what I’m doing because I’m happy.’”

Instead, the change is likely to be gradual as NAC use tapers off over time, he predicted.

Dr. Gurm—whose own research has found that approximately 13% of patients in Michigan received NAC during angiography until very recently—has already seen a decline in its use. “At the University of Michigan, although we recognized that the data were soft, based on the assumption that it was a low-cost drug and doesn’t have many side effects, we had this as part of our standard order for patient with abnormal renal function. But when this trial was presented at AHA, after that we changed our order. So it’s not part of our [protocol] anymore,” he said, adding that he was unsure whether there had been any change on a national scale.

In addition, Dr. Gurm emphasized that the therapy is not without problems. “It’s a pretty nasty smelling drug, and in occasional patients it causes a fair amount of nausea and vomiting. I’ve had patients who’ve developed dehydration and worsening of renal function from taking N-acetylcysteine,” he noted. “The other thing is . . . while the drug itself costs pennies, the pharmacy costs and everything add up. For the patient, there is a cost. And for the health care system, when 10% or maybe more of patients having [angiography] are getting this drug, that adds up.”

For now, the best ways to avoid contrast-induced nephropathy are simply hydration and minimization of contrast, Dr. Gurm advised.

Other options for preventing AKI are currently being investigated, Dr. Solomon noted. RenalGuard (PLC Medical Systems, Franklin, MA), a closed-loop hydration monitoring and infusion system, has shown promise in 2 Italian trials, REMEDIAL II and MYTHOS. In addition, he reported that the technology will soon be evaluated in a US-based registry. The BOSS study, meanwhile, “will end up being the definitive bicarbonate trial,” said Dr. Solomon, who is serving as one of the trial’s investigators.

Iron chelating agents, as well as pharmacologic agents that enhance the endogenous atrial natriuretic peptide effects, also are being studied, he added.

“Because we haven’t eliminated [AKI], there are still a lot of players out there trying to come up with some novel approaches,” Dr. Solomon concluded. “And there’s an increasing amount of concern about this kidney injury because it does seem to predict long-term adverse effects and may actually be a contributor to some of those adverse events, so there is still good reason to try to prevent it.”

Study Details

Hydration was strongly recommended. Patients were given 0.9% saline at 1 mL/kg/hour between 6 to 12 hours before and 6 to 12 hours after angiography. However, changes in total volume or speed of hydration were allowed.

 


Source:
ACT investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: Main results from the randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT). Circulation. 2011;Epub ahead of print.

 

 

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Disclosures
  • ACT was funded by the Brazilian Ministry of Health.
  • Drs. Berwanger, Solomon, and Gurm report no relevant conflicts of interest.

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