In high‑risk adults (eGFR < 60 mL/min/1.73 m² with diabetes, heart failure, or nephrotoxic drug use) undergoing coronary or peripheral vascular angiography, what were the findings of the PRESERVE trial regarding prophylaxis with oral N‑acetylcysteine and intravenous sodium bicarbonate for contrast‑induced acute kidney injury?

What Happened During the PRESERVE Trial for Contrast-Induced Nephropathy

The PRESERVE trial definitively demonstrated that neither intravenous sodium bicarbonate nor oral N-acetylcysteine provides any benefit over standard isotonic saline hydration for preventing death, dialysis, persistent kidney injury, or contrast-associated acute kidney injury in high-risk patients undergoing angiography. 1

Trial Design and Population

The PRESERVE (Prevention of Serious Adverse Events Following Angiography) trial was the largest randomized controlled trial ever conducted on contrast-induced nephropathy prevention, enrolling 5,177 high-risk patients using a 2×2 factorial design. 1 Patients were randomized to receive:

• Intravenous 1.26% sodium bicarbonate versus 0.9% sodium chloride
• Oral acetylcysteine (1,200 mg twice daily for 5 days) versus placebo 1

The trial specifically targeted patients at high risk for renal complications—those with stage III or IV chronic kidney disease (eGFR < 60 mL/min/1.73 m²) who also had diabetes, heart failure, or were taking nephrotoxic medications. 2 The median eGFR was approximately 50.7 mL/min/1.73 m², and 82% of patients had diabetes mellitus. 2

Primary Findings: No Benefit from Either Intervention

Sodium Bicarbonate Results

The primary composite endpoint (death, need for dialysis, or persistent ≥50% increase in serum creatinine at 90 days) occurred in:

• 4.4% (110/2,511) in the sodium bicarbonate group
• 4.7% (116/2,482) in the sodium chloride group
• Odds ratio: 0.93 (95% CI 0.72–1.22; P=0.62) 1

This represents no statistically significant difference and no clinically meaningful benefit. 1

N-Acetylcysteine Results

The same primary endpoint occurred in:

• 4.6% (114/2,495) in the acetylcysteine group
• 4.5% (112/2,498) in the placebo group
• Odds ratio: 1.02 (95% CI 0.78–1.33; P=0.88) 1

Again, no benefit whatsoever was demonstrated. 1

Contrast-Associated Acute Kidney Injury

There were no significant between-group differences in the rates of contrast-associated acute kidney injury for either sodium bicarbonate versus sodium chloride or acetylcysteine versus placebo. 1 This secondary endpoint reinforced the primary findings.

Subgroup Analysis in PCI Patients

A dedicated subgroup analysis examined 1,161 patients who underwent percutaneous coronary intervention during the study. 2 Even in this higher-risk population:

• Sodium bicarbonate showed no benefit: Primary endpoint occurred in 2.6% versus 4.0% (OR 0.64; 95% CI 0.33–1.24; P for interaction = 0.41) 2
• Acetylcysteine showed no benefit: Primary endpoint occurred in 3.8% versus 2.8% (OR 1.37; 95% CI 0.71–2.62; P for interaction = 0.29) 2

Trial Termination

The trial sponsor stopped enrollment after a prespecified interim analysis, ultimately including 4,993 patients in the modified intention-to-treat analysis rather than the originally planned 8,680 patients. 1 3 This early termination occurred because the futility of the interventions became apparent—continuing would not change the conclusions. 1

Why PRESERVE Matters: Methodological Superiority

PRESERVE addressed critical design flaws that plagued earlier trials:

1. Adequate Sample Size

Previous trials enrolled small numbers of patients, creating risk for both type I and type II statistical errors. 3 PRESERVE enrolled over 5,000 patients, providing definitive statistical power. 1

2. Patient-Centered Outcomes

Earlier studies used surrogate endpoints (small serum creatinine increments) that are associated with but not causally related to serious adverse outcomes. 3 PRESERVE used hard clinical endpoints: death, dialysis requirement, and persistent kidney function decline. 1

3. High-Risk Population

Many prior trials included low-risk patients with intact baseline kidney function, yielding low event rates and poor generalizability. 3 PRESERVE exclusively enrolled high-risk patients (eGFR < 60 mL/min/1.73 m² with comorbidities), making results directly applicable to the population most likely to benefit from prophylaxis. 1

4. Rigorous Methodology

The trial was randomized, double-blind, and multicenter with prespecified endpoints and interim analyses. 1 This design eliminated the methodological biases that characterized earlier positive studies. 4

Impact on Clinical Guidelines

Current guidelines now explicitly recommend against using N-acetylcysteine for contrast-induced nephropathy prevention based on PRESERVE trial results:

• The American College of Cardiology assigns Class III, Level A evidence (not useful) for NAC administration. 5 6
• The European Society of Cardiology classifies NAC as Class III (not indicated) based on Level A evidence. 5 6
• KDIGO guidelines recommend against NAC for prevention of contrast-induced AKI. 6

Regarding sodium bicarbonate, the evidence remains mixed in guidelines, with some maintaining Class IIa (reasonable alternative) while others now classify it as Class III (not indicated). 5 However, PRESERVE provides the highest-quality evidence showing no benefit. 1

What Actually Works: Evidence-Based Prevention

The cornerstone of contrast-induced nephropathy prevention remains intravenous isotonic saline hydration at 1.0–1.5 mL/kg/hour for 3–12 hours before and 6–24 hours after contrast exposure (Class I recommendation). 5 7 Additional proven strategies include:

• Minimizing contrast volume to <350 mL or <4 mL/kg 5
• Using low-osmolar or iso-osmolar contrast media 5
• Discontinuing nephrotoxic medications 24–48 hours before the procedure 5
• Considering short-term high-dose statin therapy (Class IIa) 5

Critical Pitfall to Avoid

Do not continue prescribing N-acetylcysteine or preferentially using sodium bicarbonate based on outdated evidence. 8 The PRESERVE trial represents the definitive answer to this question, and meta-analyses stratified by methodological quality show that only low-quality trials with high risk of bias demonstrated NAC benefit (RR 0.63), while high-quality trials showed no effect (RR 1.05; 95% CI 0.73–1.53). 4