ACT

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ACT Investigators. "Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Angiography". Circulation. 2011. 124:1250-1259.
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Clinical Question

Among patients undergoing coronary and peripheral vascular angiography, does acetylcysteine reduce the risk of contrast-induced acute kidney injury?

Bottom Line

Acetylcysteine does not prevent contrast-induced acute kidney injury in patients undergoing angiography.

Major Points

Acetylcysteine reduces oxidative stress[1] and may improve renal perfusion.[2] Numerous small or otherwise low-quality trials have been published investigating whether acetylcysteine reduced the incidence of contrast-induced acute kidney injury (CI-AKI) in patients undergoing angiography.

Published in 2011, the multi-centered Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT) was aimed to address these deficiencies in previous studies. The study was triple-blinded with proper allocation concealment, and enrolled a total of 2,308 patients with one risk factor for CI-AKI to acetylcysteine 1200mg orally every 12 hours for two doses before and after angiography. The primary endpoint of CI-AKI, defined as 25% elevation of serum creatinine above baseline at 48-96 post-angiography, did not differ between groups.

This publication provided a meta-analyses of high-quality data, which found no benefit in prevention of CI-AKI when acetylcysteine was given with IV contrast (RR 1.05; 95% CI 0.73-1.53). (Including low-quality data found benefit, however.) Similarly, a 2013 NICE evidence summary deemed that overall there is low- to very-low quality evidence for benefit of NAC in prevention of CI-AKI.[3] The corresponding guidelines do not make recommendations on the use of NAC for prevention of CI-AKI.

Guidelines

ACCF/AHA/SCAI PCI (2011, adapted)[4]

  • Patients should be assessed for risk of CI-AKI before PCI (class I, level of evidence C)
  • Adequately hydrate patients before they undergo cardiac catheterization with contrast (class I, level of evidence C)
  • Minimize the volume of contrast media if CKD (CrCl <60 mL/min) (class I, level of evidence B)
  • Acetylcysteine is not useful in the prevention of CI-AKI (class III, level of evidence A)

Design

  • Multicenter, randomized, triple-blinded, randomized control trial
  • N=2308
    • Acetylcysteine (n=1172)
    • Placebo (n=1136)
  • Setting: 46 sites in Brazil
  • Enrollment: 2008-2010
  • Follow-up: 30 days (up to 96 hours for the primary outcome)
  • Analysis: Intention-to-treat
  • Primary outcome: Contrast-induced acute kidney injury 48-96h post-angiography

Population

Inclusion Criteria

  • Undergoing coronary or peripheral arterial diagnostic intravascular angiography or PCI
  • ≥1 risk factor for CI-AKI:
    • Age >70 years
    • CKD, defined by creatinine >132.6 umol/L (1.5 mg/dL)
    • DM
    • Clinical evidence of HF or LVEF <45%
    • Hypotension (not further defined)

Exclusion Criteria

  • Patients on dialysis
  • STEMI undergoing PCI (could not receive hydration procedure 6h pre-procedure)
  • Women who were pregnant, breastfeeding, <45 years without use of contraception

Baseline Characteristics

From the acetylcysteine group

  • Demographics: Age 68y, 38% female
  • Vitals: Weight 73 kg
  • Laboratory results: Creatinine 1.2 mg/dL
  • Diagnosis: ACS 36%, HTN 86%
  • Medications: NSAIDs 5%, ACE-inhibitor 60%, diuretics 38%, metformin 31%
  • Inclusion Criteria:
    • Serum Cr > 1.5mg/dL: 15%
    • Diabetes mellitus: 61%
    • Known heart failure: 10%
    • Hypotension: <1%
    • Age > 70y: 51%
  • Estimated GFR: 69 ml/min/1.73 m2
    • <30: 5%
    • 30-60: 36%
    • >60: 58%
  • Procedure Type: Peripheral vascular angiography 3%, coronary diagnostic angiography 66%, percutaneous coronary intervention 30%, none because of cancellation 1%
  • Hydration Before Procedure
    • NaCl 0.9%, any scheme: 93%
    • NaCl 0.9%, 1mL/kg/h for 6h: 47%
    • Bicarbonate 0.9%: 5%
  • Hydration After Procedure
    • NaCl 0.9%, any scheme: 98%
    • NaCl 0.9%, 1mL/kg/h for 6h: 69%
    • Bicarbonate 0.9%: 6%
  • Contrast Type: High osmolarity 22%, low osmolarity 75%, iso-osmolarity 3%
  • Contrast Volume: 100mL

Interventions

  • All groups received hydration 6-12 hours pre and post angiography
    • 0.9% saline at 1 mL/kg/h was recommended but could be substituted
  • Acetylcysteine arm received:
    • 1200mg acetylcysteine q12h for 2 doses before and after the procedure
  • Placebo arm received:
    • powder that had the same appearance, taste, and smell as acetylcysteine powder

Outcomes

Presented as acetylcysteine vs. placebo.

Primary Outcome

Contrast Induced Acute Kidney Injury
Defined as a rise in creatinine ≥25% above baseline at 48-96h.
12.7% vs. 12.7% (RR 1.00; 95% CI 0.81-1.25; P=0.97)

Secondary Outcomes

Doubling in serum creatinine at 48-96 hours
1.1% vs. 1.5% (RR 0.74; 95% CI 0.36-1.52; P=0.41)
Elevation in creatinine at 48-96 hours
≥0.5 mg/dL (≥44.2 umol/L): 3.9% vs. 3.8% (RR 1.04; 95% CI 0.69-1.57; P=0.85)
≥0.3 mg/dL (≥13.3 umol/L): 12.1% vs. 11.0% (RR 1.10; 95% CI 0.88-1.39; P=0.39)
All-cause mortality at 30 days
2.0% vs. 2.1% (HR 0.97; 95% CI 0.54-1.73; P=0.92)
Or need for HD: 2.2% vs. 2.3% (HR 0.97; 95% CI 0.56-1.69; P=0.92)
Or doubling of creatinine: 3.2% vs. 3.6% (HR 0.90; 95% CI 0.58-1.39; P=0.63)
Need for HD
0.3% vs. 0.3% (HR 0.87; 95% CI 0.17-4.35; P=0.86)
CV mortality
1.5% vs. 1.6% (HR 0.99; 95% CI 0.51-1.90; P=0.97)

Subgroup Analysis

There was no difference in the primary outcome for age, sex, baseline creatinine, diabetes, volume of contrast agent, ACS, type of contrast, timing of post-angiography serum creatinine, eGFR level, or CKD with diabetes.

Adverse Events

Serious
1.3% vs. 2.2% (P=0.09)
Vomiting
0.3% vs. 1.2% (P=0.02)

No other adverse events reached statistical significance.

Criticisms

  • Lower proportion of the primary outcome than expected
  • The average volume of contrast used was low (100mL) and may have prevented CI-AKI
  • Relatively short duration of acetylcysteine use[5]

Funding

  • Brazilian Ministry of Health

Further Reading

  1. Drager LF, et al. "Renal effects of N-acetylcysteine in patients at risk for contrast nephropathy: decrease in oxidant stress-mediated renal tubular injury." Nephrol Dial Transplant. 2004;19(7):1803-1807.
  2. Lopez BL, et al. "N-acetylcysteine enhances endothelium-dependent vasorelaxation in the isolated rat mesenteric artery." Annals of Emergency Medicine. 1998;32(4):405-410.
  3. NICE authors. "Acute Kidney Injury: Prevention, detection, and management up to the point of renal replacement therapy." NICE Clinical Guidelines. 2013;No. 169.
  4. Levine GN, et al. "2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention." Circulation. 2011;124:e574-e651.
  5. McCullough PA, et al. "Minimizing the renal toxicity of iodinated contrast." Circulation. 2011;124(11):1210-1211.