Should N-acetylcysteine be used routinely to prevent contrast-induced acute kidney injury?
THE NEGATIVE TRIALS
Several studies found that NAC did not prevent contrast-induced acute kidney injury.1,2,9
The Acetylcysteine for Contrast-induced Nephropathy Trial (ACT), published in 2011,1 was the largest of these trials. It included 2,308 patients undergoing an angiographic procedure who had at least one risk factor for contrast-induced acute kidney injury (age > 70, renal failure, diabetes mellitus, heart failure, or hypotension). Patients were randomly assigned to receive the drug (1,200 mg by mouth) or placebo.
The incidence of contrast-induced acute kidney injury was 12.7% in the treated group and 12.7% in the control group (relative risk 1.00; 95% confidence interval 0.81–1.25; P = .97). The rate of a combined end point of death or need for dialysis at 30 days was also similar in both groups (2.2% with treatment vs 2.3% with placebo).
Importantly, only about 15% of patients had a baseline serum creatinine greater than 1.5 mg/dL. Of these, most had an estimated glomerular filtration rate between 45 and 60 mL/min. Indeed, most patients in the ACT were at low risk of contrast-induced acute kidney injury. As a result, there were low event rates and, not surprisingly, no differences between the control and treatment groups.
Subgroup analysis did not suggest a benefit of treatment in those with a baseline serum creatinine greater than 1.5 mg/dL. However, as the authors pointed out, this subgroup was small, so definitive statistically powered conclusions cannot be drawn. There was no significant difference in the primary end point among several other predefined subgroups (age > 70, female sex, diabetes).1
The ACT differed from the “positive” study by Marenzi et al8 in several ways. The ACT patients were at lower risk, the coronary catheterizations were being done mainly for diagnosis rather than intervention, a lower volume of contrast dye was used (100 mL in the ACT vs 250 mL in the Marenzi study), and patients with ST-elevation myocardial infarction were excluded. Other weaknesses of the ACT include use of a baseline serum creatinine within 3 months of study entry, variations in the hydration protocol, and the use of a high-osmolar contrast agent in some patients.
Webb et al2 found, in a large, randomized trial, that intravenous NAC did not prevent contrast-induced acute kidney injury. Patients with renal dysfunction (mean serum creatinine around 1.6 mg/dL) undergoing cardiac catheterization were randomly assigned to receive either NAC 500 mg or placebo immediately before the procedure. All patients first received isotonic saline 200 mL, then 1.5 mL/kg per hour for 6 hours, unless contraindicated. The study was terminated early because of a determination of futility.
Gurm et al9 found that a database of 90,578 consecutive patients undergoing nonemergency coronary angiography from 2006 to 2009 did not show differences in the rate of contrast-induced acute kidney injury between patients who received NAC and those who did not (5.5% vs 5.5%, P = .99). There was also no difference in the rate of death or the need for dialysis. These negative findings were consistent across many prespecified subgroups.
MIXED RESULTS IN META-ANALYSES
Results from meta-analyses have been mixed,10,11 mainly because of study heterogeneity (eg, baseline risk, end points, dose of the drug) and publication bias. None of the previous meta-analyses included the recent negative results from the ACT.
CURRENT GUIDELINES
After the publication of the ACT, the joint guidelines of the American College of Cardiology and the American Heart Association were updated, designating NAC as class III (no benefit) and level of evidence A.12
However, recently published guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Working Group recommend using the drug together with intravenous isotonic crystalloids in patients at high risk of contrast-induced acute kidney injury, although the level of evidence is 2D (2 = suggestion, D = quality of evidence very low).5
WHAT WE RECOMMEND
The routine use of NAC to prevent contrast-induced acute kidney injury is not supported by the current evidence. However, clarification of its efficacy in high-risk patients is needed, especially those with baseline renal dysfunction and diabetes mellitus.
The Prevention of Serious Adverse Events Following Angiography (PRESERVE) study (ClinTrials.gov identifier NCT01467466) may clarify the role of this drug in a high-risk cohort using the important clinical outcomes of death, need for acute dialysis, or persistent decline in kidney function after angiography. This important study was set to begin in July 2012, with an anticipated enrollment of more than 8,000 patients who have glomerular filtration rates of 15 to 59 mL/min/1.73 m2.
In the meantime, we recommend the following in patients at high risk of contrast-induced acute kidney injury:
- Clarify whether contrast is truly needed
- When possible, limit the volume of contrast, avoid repeated doses over a short time frame, and use an iso-osmolar or low-osmolar contrast agent
- Discontinue nephrotoxic agents
- Provide an evidence-based intravenous crystalloid regimen with isotonic sodium bicarbonate or saline
- Although it is not strictly evidence-based, use NAC in patients with significant baseline renal dysfunction (glomerular filtration rate < 45 mL/min/1.73 m2), multiple concurrent risk factors such as hypotension, diabetes, preexisting kidney injury, or congestive heart failure that limits the use of intravenous fluids, or who need a high volume of contrast dye
- Avoid using intravenous NAC, given its lack of benefit and risk of anaphylactoid reactions.7,13
We do not yet have clear evidence on the optimal dosing regimen. But based on the limited data, we recommend 600 to 1,200 mg twice a day for 1 day before and 1 day after the dye is given.
