What is the evidence for using N-acetylcysteine (NAC) to prevent contrast-induced nephropathy in patients with impaired renal function or other risk factors such as diabetes or heart failure?

Evidence on NAC for Contrast-Induced Nephropathy Prevention

N-acetylcysteine (NAC) should NOT be used for prevention of contrast-induced nephropathy, as major guidelines explicitly recommend against its use based on high-quality evidence showing no benefit. 1, 2

Guideline Consensus Against NAC

The evidence against NAC is remarkably consistent across major cardiology and nephrology societies:

• The American College of Cardiology Foundation/American Heart Association explicitly states that NAC administration is not useful for prevention of contrast-induced AKI (Level of Evidence: A). 1

• The European Society of Cardiology classifies NAC as Class III (not indicated) based on Level A evidence, meaning it should not be used. 1, 2

• The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend against using NAC for prevention of postsurgical AKI in patients with impaired kidney function (Grade 1A recommendation). 2

The Pivotal ACT Trial Evidence

The shift away from NAC is based primarily on the Acetylcysteine for Contrast Nephropathy Trial (ACT), which remains the largest and highest-quality study on this topic:

• The ACT trial enrolled 2,308 patients undergoing intravascular angiography with at least one risk factor (age, CKD, diabetes, heart failure, or hypotension) and found identical rates of contrast-induced AKI in both groups: 12.7% in the NAC group versus 12.7% in the placebo group. 3, 2

• No difference was detected in the combined secondary endpoint of mortality or need for dialysis (hazard ratio 0.97; 95% CI 0.56-1.69). 3, 2

• Approximately 50% of enrolled participants had estimated creatinine clearance <60 mL/min, and there was no evidence of benefit in any prespecified subgroup, including those with diabetes or severe renal dysfunction. 3

Meta-Analysis Reveals Quality-Dependent Bias

An accompanying meta-analysis to the ACT trial revealed a critical insight about why earlier studies showed benefit:

• When trials were stratified by methodological quality, low-quality studies showed apparent benefit (RR 0.63; 95% CI 0.47-0.85), while high-quality trials meeting all three methodological criteria (allocation concealment, double blinding, intention-to-treat analysis) showed no effect (RR 1.05; 95% CI 0.73-1.53). 3, 1

• This demonstrates that the benefits reported in prior NAC studies were confined to trials with high risk of bias and do not support continuing recommendations for NAC use. 3

Additional Supporting Evidence

Other high-quality randomized trials corroborate the lack of NAC efficacy:

• A 2004 randomized controlled trial of 487 patients with renal dysfunction (median creatinine clearance 44 mL/min) receiving intravenous NAC found no difference in the primary endpoint: 23.3% in the NAC group versus 20.7% in placebo (P=0.57). 4

• This study was terminated early due to futility determination by the Data Safety Monitoring Committee. 4

What SHOULD Be Done Instead

The guidelines are clear about proven strategies that actually work:

• Hydration with isotonic saline (1.0-1.5 mL/kg/hour) for 3-12 hours before and 6-24 hours after contrast exposure is the cornerstone of prevention (Class I recommendation). 1, 2, 5

• Minimize contrast volume to <350 mL or <4 mL/kg, or maintain contrast volume/creatinine clearance ratio <3.7 (Class I recommendation). 1, 2

• Use low-osmolar or iso-osmolar contrast media (Class I recommendation). 1, 2

• Consider short-term high-dose statin therapy (rosuvastatin 40/20 mg, atorvastatin 80 mg, or simvastatin 80 mg) for a short period (Class IIa recommendation). 1, 2

• Sodium bicarbonate hydration (154 mEq/L in dextrose and water at 3 mL/kg for 1 hour before contrast, followed by 1 mL/kg/hour for 6 hours after) may be considered as an alternative to normal saline (Class IIa recommendation), though the European Society of Cardiology now classifies bicarbonate as Class III. 1, 5

Critical Caveat About NAC as Substitute for Hydration

• The American Journal of Kidney Diseases specifically advises against using oral acetylcysteine instead of intravenous hydration with isotonic solution in high-risk patients. 1

• Intravenous acetylcysteine may cause severe adverse effects and should not be administered routinely. 1

Canadian Nephrology Society Position

• The Canadian Society of Nephrology work group concluded that the updated evidence base does not support a recommendation to use NAC for prophylaxis of contrast-induced AKI in Canada, based on the ACT trial results and meta-analysis findings. 3

• They recommend that intravenous volume expansion with either isotonic sodium chloride or sodium bicarbonate solution is appropriate for prevention, with normal saline being preferred given its broad availability and lower cost. 3