Article Identification

• Article Title: 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)
• Citation: ACT Investigators. Circulation. 2011;124(11):1250-1259. doi:10.1161/CIRCULATIONAHA.111.038943
• DOI: 10.1161/CIRCULATIONAHA.111.038943

Quick Reference Summary

• The ACT trial found that acetylcysteine administration did not reduce the incidence of contrast-induced acute kidney injury (CI-AKI), with CI-AKI rates being 12.7% in both the acetylcysteine and placebo groups (relative risk, 1.00; 95% CI, 0.81 to 1.25; P=0.97).
• Additionally, there was no significant difference in the combined endpoint of mortality or need for dialysis at 30 days between groups (2.2% vs. 2.3%; hazard ratio, 0.97; 95% CI, 0.56 to 1.69; P=0.92).

Core Clinical Question

Does oral acetylcysteine compared to placebo reduce the incidence of contrast-induced acute kidney injury in patients undergoing coronary or peripheral vascular angiography with at least one risk factor for CI-AKI?

Background

• Disease or Condition Overview:
  • Contrast-induced acute kidney injury (CI-AKI) is a significant complication following the administration of iodinated contrast media during angiographic procedures. CI-AKI is associated with increased mortality, need for dialysis, prolonged hospitalization, and higher healthcare costs.
• Prior Data on the Topic:
  • Early Studies: Initial smaller trials suggested a potential protective effect of acetylcysteine against CI-AKI, but these studies often suffered from small sample sizes and methodological limitations.
  • Systematic Reviews had identified high heterogeneity among trials, making it difficult to draw definitive conclusions.
• Guidelines and Consensus: Prior to the ACT trial, current guidelines had conflicting recommendations on the use of acetylcysteine for CI-AKI prevention, with some endorsing its use in high-risk patients and others calling for more robust evidence.
• Current Standard of Care: Hydration with isotonic saline remains the cornerstone for CI-AKI prevention, with pharmacological interventions like acetylcysteine being considered adjunctive but not universally recommended due to inconsistent evidence.
• Knowledge Gaps Addressed by the Study:
  • The efficacy of acetylcysteine in a large, well-powered, randomized controlled trial setting was unclear due to previous studies' limitations.
  • There was a need to clarify acetylcysteine's role in preventing CI-AKI among a broad high-risk population.
• Study Rationale: Given the inconsistent results from smaller trials and the lack of high-quality evidence, the ACT trial was designed to provide definitive answers regarding the benefit of acetylcysteine in preventing CI-AKI in patients with multiple risk factors undergoing angiography.

Methods Summary

• Study design: Multicenter, randomized, double-blind, placebo-controlled trial.
• Setting and time period: Conducted in 46 sites across Brazil between September 2008 and July 2010.
• Population characteristics: 2,308 patients undergoing coronary or peripheral arterial angiography with at least one risk factor for CI-AKI (age >70, renal failure, diabetes mellitus, heart failure, or hypotension).
• Inclusion/exclusion criteria:
  • Included: Patients ≥45 years (women), undergoing angiography with ≥1 CI-AKI risk factor.
  • Excluded: Patients on dialysis, pregnant or breastfeeding women, ST-segment elevation myocardial infarction patients undergoing primary angioplasty.
• Intervention details: Oral acetylcysteine 1200 mg administered twice daily for 2 doses before and 2 doses after the procedure.
• Control/comparison group details: Placebo administered identically to acetylcysteine.
• Primary and secondary outcomes:
  • Primary: Incidence of CI-AKI defined as a 25% elevation in serum creatinine above baseline within 48-96 hours post-angiography.
  • Secondary: Combined endpoint of mortality or need for dialysis at 30 days, individual components of the composite outcome, and other adverse events.
• Basic statistical analysis approach: Intention-to-treat analysis with chi-square tests for discrete variables, Wilcoxon rank-sum for continuous variables, and Cox proportional hazards regression for time-to-event outcomes.
• Sample size calculations: Designed to detect a 30% relative risk reduction with 90% power and α=0.05, enrolling 2,300 patients.
• Ethics and funding information: Approved by ethics boards of participating institutions; funding sources and conflicts of interest were not specified in the provided abstract.

Detailed Results

• Participant flow and demographics:
  • Total enrolled: 2,308 patients (1,172 acetylcysteine; 1,136 placebo).
  • Baseline characteristics: Well-balanced between groups with 60.4% having diabetes mellitus and 52.1% aged >70 years.
  • Renal function: Approximately 50.3% had creatinine clearance >60 mL/min.
• Primary outcome results:
  • CI-AKI incidence: 12.7% in both acetylcysteine and placebo groups (relative risk, 1.00; 95% CI, 0.81–1.25; P=0.97).
• Secondary outcome results:
  • Mortality or need for dialysis at 30 days: 2.2% vs 2.3% (hazard ratio, 0.97; 95% CI, 0.56–1.69; P=0.92).
  • Other secondary endpoints (e.g., doubling of creatinine, cardiovascular deaths) showed no significant differences between groups.
• Subgroup analyses:
  • Renal impairment subgroups: No effect of acetylcysteine in patients with baseline serum creatinine >1.5 mg/dL or eGFR <60 mL/min/1.73 m².
  • Other subgroups (e.g., diabetes status, age, contrast volume) also showed no significant interaction with treatment effect.
• Adverse events/safety data:
  • Serious adverse events: 1.3% vs 2.2% in acetylcysteine vs placebo (P=0.09).
  • Vomiting: Less common in acetylcysteine group (0.3% vs 1.2%; P=0.02).

Outcome	Acetylcysteine Group	Placebo Group	Difference (95% CI)	P-value
Primary Outcome
Contrast-induced acute kidney injury	147/1153 (12.7%)	142/1119 (12.7%)	1.00 (0.81–1.25)	0.97
Secondary Outcomes
Doubling of serum creatinine	13/1153 (1.1%)	17/1119 (1.5%)	0.74 (0.36–1.52)	0.41
Elevation ≥0.5 mg/dL in serum creatinine	45/1153 (3.9%)	42/1119 (3.8%)	1.04 (0.69–1.57)	0.85
Deaths or need for dialysis at 30 days	26/1171 (2.2%)	26/1135 (2.3%)	0.97 (0.56–1.69)	0.92
Deaths	23/1171 (2.0%)	24/1135 (2.1%)	0.97 (0.54–1.73)	0.92
Need for dialysis	3/1171 (0.3%)	3/1135 (0.3%)	0.87 (0.17–4.35)	0.86
Cardiovascular deaths	18/1171 (1.5%)	18/1135 (1.6%)	0.99 (0.51–1.90)	0.97

Authors’ Conclusions

• Primary conclusions:
  • Acetylcysteine does not reduce the risk of contrast-induced acute kidney injury in high-risk patients undergoing coronary and peripheral vascular angiography.
  • There was no significant benefit observed in secondary outcomes such as mortality and need for dialysis at 30 days.
• Clinical implications stated by authors:
  • Routine use of acetylcysteine for CI-AKI prevention is not recommended based on the findings.
  • The study results suggest that administering acetylcysteine may not confer additional protective benefits over standard hydration protocols.
• Future research recommendations:
  • Further investigation into alternative preventive strategies for CI-AKI.
  • Exploration of different dosing regimens or combinations with other interventions could be considered, although the neutral findings across multiple subgroups lessen the likelihood of efficacy.

Critical Analysis

A. Strengths

• Large Sample Size: With 2,308 participants, this is the largest trial to date evaluating acetylcysteine for CI-AKI prevention, providing adequate statistical power.
• Methodological Rigor:
  • Randomized and double-blind design minimizes selection and observer biases.
  • Centralized randomization and allocation concealment ensure internal validity.
  • Intention-to-treat analysis preserves randomization benefits and handles attrition appropriately.
• Comprehensive Subgroup Analyses: Evaluated various patient subgroups, including those with renal impairment, diabetes, and high contrast volumes, enhancing external validity.
• High Compliance and Follow-up: Over 95% adherence to study drugs and 99.9% complete follow-up, reducing information bias.

B. Limitations

• Event Rates for Secondary Outcomes: Low incidence of outcomes like mortality and need for dialysis limits the power to detect differences in these endpoints.
• Use of Serum Creatinine: Reliance on serum creatinine as the sole marker for CI-AKI may miss subtle or early kidney injuries; newer biomarkers like cystatin C could provide more sensitive assessments.
• Median Contrast Volume: Although the median was 100 mL, which is relatively low, the stratified analyses did not reveal any subgroup benefit even in those who received higher volumes (>140 mL).
• Duration of Acetylcysteine Therapy: Administered for only 2 doses before and after; however, authors argue that extending therapy is unlikely to alter outcomes significantly.
• Generalisability to Other Populations: Conducted in Brazil, and patient demographics or practice patterns may differ from other regions, potentially affecting external applicability.
• Other Interventions: Hydration protocols were strongly recommended but not strictly controlled, allowing for variability in concurrent preventive measures.

Literature Review

Introduction

The prevention of contrast-induced acute kidney injury (CI-AKI) remains a pivotal concern in patients undergoing angiographic procedures. The 2011 study by ACT Investigators published in Circulation evaluated the efficacy of acetylcysteine (NAC) in preventing CI-AKI among high-risk patients. This randomized controlled trial (RCT) administered 1200 mg of oral acetylcysteine twice daily before and after angiography, ultimately finding no significant reduction in CI-AKI incidence compared to placebo.

Comparison and Contrast with KDIGO 2023 Guidelines and Relevant Supporting Trials

Alignment with KDIGO 2023 Guidelines

The Kidney Disease: Improving Global Outcomes (KDIGO) 2023 Clinical Practice Guideline for Acute Kidney Injury (AKI) provides a comprehensive framework for prevention, diagnosis, and management of AKI, including CI-AKI. The result of the ACT trial aligns with KDIGO's evidence-based stance, which emphasizes hydration with isotonic saline as the primary preventive strategy and discourages the routine use of pharmacological interventions like acetylcysteine due to inconsistent evidence. KDIGO underscores the importance of individualized risk assessment and the use of alternative imaging modalities when appropriate, building upon the foundational evidence that pharmacological prophylaxis with antioxidants lacks robust support.

Additionally, KDIGO's 2023 guidelines incorporate advancements in diagnostic biomarkers and refined criteria for AKI classification, moving beyond serum creatinine alone. This progression reflects a broader shift towards personalized medicine and accurate risk stratification, areas not extensively covered in the ACT trial but critical for contemporary AKI management.

Comparison with Relevant Supporting Trials

• ACT Trial (2011):
  • Findings: No reduction in CI-AKI with acetylcysteine.
  • Significance: Reinforced the skepticism around acetylcysteine's efficacy due to robust methodology and large sample size.
• PRESERVE Trial (Thiele et al., JAMA 2018):
  • Design: Multicenter RCT with a 2x2 factorial design evaluating intravenous hydration, acetylcysteine, and other interventions.
  • Findings: Acetylcysteine showed no significant benefit in preventing CI-AKI, aligning with ACT's outcomes.
  • Implications: Further diminished the role of acetylcysteine in CI-AKI prevention.
• ENABLE Study (Kim et al., Int J Cardiol 2010):
  • Design: Prospective, randomized trial assessing cystatin C-based CI-AKI.
  • Findings: NAC reduced CI-AKI incidence based on cystatin C markers.
  • Contradiction: Suggested potential benefits absent in creatinine-based assessments.
• Additional Studies:
  • Intravenous vs Oral High-dose NAC (Erturk et al., Coron Artery Dis 2014): No benefit of either administration route in moderate-to-severe renal insufficiency.
  • Comparison of Supportive Treatments (Yeganehkhah et al., Saudi J Kidney Dis Transplant 2014): No significant difference in CI-AKI prevention among saline, NAC + saline, and bicarbonate groups.
  • Intrarenal Application of NAC (Aslanger et al., Coron Artery Dis 2012): No efficacy of intrarenal NAC compared to placebo.
  • Alpha-Tocopherol vs NAC (Samadi et al., Iranian J Kidney Dis 2020): No additive benefit of alpha-tocopherol over NAC and saline.
  • Biomarkers in PRESERVE Trial (Parikh et al., Am J Kidney Dis 2020): Introduction of biomarkers like KIM-1 and NGAL for better CI-AKI prediction, indicating a move towards personalized risk assessment.
  • NAC in Japanese Population (Kamiyama et al., Yakugaku Zasshi 2008): Dose-dependent trend toward prevention, though not statistically significant.

Analysis of Similarities, Differences, and Key Findings

Methodological Consistency:

• RCT Design: Most supporting trials, including ACT and PRESERVE, employ randomized, double-blind, placebo-controlled methodologies, ensuring high internal validity.
• Sample Size: Larger trials like ACT and PRESERVE provide more robust evidence, reducing the likelihood of type II errors seen in smaller studies like the ENABLE study.

Outcome Measures:

• Biomarker-based vs Creatinine-based: The ENABLE study's use of cystatin C suggested potential benefits of NAC, contrasting with creatinine-based outcomes in ACT and PRESERVE, which showed no efficacy.
• Diverse Endpoints: While some studies focused solely on CI-AKI incidence, others, like ACT, evaluated secondary outcomes such as mortality and dialysis needs, providing a more comprehensive safety and efficacy profile.

Population Differences:

• Geographical Variations: Studies conducted in different regions (e.g., Japan vs Brazil vs global trials) may have population-specific factors influencing outcomes, though ACT's large, diverse Brazilian cohort enhances generalizability.
• Baseline Renal Function: Variations in baseline renal impairment across studies affect CI-AKI risk, potentially influencing the detectability of NAC's effects.

Key Findings:

• Consistency Against NAC Efficacy: The majority of high-quality, large-scale RCTs, including ACT and PRESERVE, do not support the use of acetylcysteine for CI-AKI prevention, aligning with updated KDIGO 2023 guidelines.
• Biomarker Insights: Emerging studies highlight the potential role of biomarkers like cystatin C, KIM-1, and NGAL in early detection and risk stratification, suggesting a shift towards personalized preventive strategies over blanket pharmacological approaches.
• Alternative Strategies: Emphasis is increasingly on optimal hydration protocols and minimizing nephrotoxic exposures, supported by the lack of efficacy seen with NAC across multiple studies.

Conclusion

The ACT trial significantly contributes to the evolving landscape of CI-AKI prevention by demonstrating the ineffectiveness of acetylcysteine in a large, high-risk population undergoing angiography. This finding is corroborated by subsequent trials like PRESERVE, which further eliminate acetylcysteine as a viable prophylactic option. In contrast, studies employing biomarkers for CI-AKI detection offer innovative directions for personalized medicine but have yet to overcome the limitations of traditional markers like serum creatinine. The consolidated evidence aligns with KDIGO 2023 guidelines, which advocate for hydration and risk assessment over antioxidant therapies. Moving forward, clinical practice should prioritize evidence-based interventions and integrate novel biomarkers for more precise risk stratification and prevention of CI-AKI, thereby enhancing patient outcomes and optimizing resource utilization.

Clinical Application

• Findings Implications: The ACT trial demonstrates that acetylcysteine is ineffective in preventing CI-AKI among high-risk patients, aligning with current KDIGO 2023 guidelines that do not recommend routine use of this antioxidant therapy.
• Applicable Populations: These results are most relevant to clinicians managing high-risk patients (e.g., elderly, diabetic, renal impairment) undergoing coronary and peripheral angiographic procedures, emphasizing the need to focus on hydration strategies rather than pharmacological prophylaxis with acetylcysteine.
• Implementation Considerations: Feasibility of adhering to optimal hydration protocols is enhanced by the lack of need for additional pharmacological interventions, potentially reducing healthcare costs and patient burden.
• Integration with Guidelines: Clinicians should reinforce hydration protocols as per KDIGO 2023 recommendations, disregarding acetylcysteine unless future evidence suggests a beneficial role in specific subpopulations or when combined with other effective interventions.

How to Use This Info in Practice

Practical Utilization: Healthcare practitioners should prioritize evidence-based hydration protocols over acetylcysteine for preventing CI-AKI in high-risk patients, reinforcing current guidelines and optimizing patient care based on robust, up-to-date evidence.