1. Pearls Presentation
Use of N-Acetylcysteine For prophylaxis of Radiocontrast Nephrotoxicity

2. The Patient 78 year-old male AMI
Radiocontrast for angiography prior to CABG
DM2
Requires insulin, poorly controlled
Kidney function
Creatinine clearance 40ml/min

3. The Controversy
Patient received prophylactic N- acetylcysteine during and after angiography
Student ‘Why is the N-acetylcysteine prescribed?’
Registrar ‘Prophylaxis for nephrotoxicity, but it doesn’t work. If you ever have an EBM assignment you should investigate this.’
Student ‘ Sure.’

4. The Theory Radiocontrast is potentially nephrotoxic
Risk factors
Pre-existing renal disease
Diabetes mellitus
N-acetylcysteine is prophylactic against acute kidney injury
Actions
An antioxidant
A vasodilator

5. Clinical question
P = Chronic kidney disease (CKD) receiving Radiocontrast
I = N-acetylcysteine (NAC)
C = Placebo
O = Radiation contrast nephrotoxicity (RCN)
In patients with chronic kidney disease receiving radiocontrast material, does the use of N- acetylcysteine decrease the incidence of nephroxicity?

6. Question of therapy Meta-analysis of all RCTs
Hierarchy of Evidence Regarding Therapy
Meta-analysis of all RCTs
Meta-analysis of all published RCTs
2 or more confirmatory RCTs
1 Randomised Controlled Trial (RCT)
Non-randomized controlled study
Uncontrolled experiences of
Geographically-defined populations 
Multiple treatment centres 
One treatment centre 
One clinician
 A patient

7. Search Strategy Cochrane database of systematic reviews Medline Pubmed
No meta-analysis, 1 protocol
Medline
No meta-analysis, 1 RCT
Pubmed
Clinical queries, systematic reviews -> 4 results

8. The article

9. Study Design
NAC for prevention of radiocontrast nephrotoxicity (RCN) in humans older than 18 years of age with CKD
Randomised controlled trials – blinded and unblinded
Full text studies or abstracts
Defined CKD = creatinine clearance of less than 70mL/min

10. Study Design
Search of
MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, HealthSTAR
Annual Scientific Meeting of several societies
References of published articles
HealthSTAR is part of PubMed, No EMBASE

11. Study Methods 6000 articles found and screened Exclusions on basis of
Duplications
Studies other than an RCT
Lack of information required for analyses
No mention of two independent reviewers

12. Study Methods 8 full text articles, 4 abstracts Analyses Heterogenous
Primary analysis = Full text articles only
Sensitivity analysis = Full text articles and abstracts
Subgroup analyses
Kidney function
Contrast volume
Clinically Heterogenous – different regimes of NAC (saline solutions, post-procedure doses,..), different reasons for radiocontrast materia (cardiac cath, CT, peripheral angiography), different definitions of RCN

13. Results Primary analyses NAC is beneficial 8 full text studies
885 patients
444 NAC-> 35 RCN
441 Placebo -> 82 RCN
Risk ratio (RR) = 0.41 (95% CI )
NNT = 8
NAC is beneficial
Risk Ratio is the ratio of risk in the treated group (EER) to the risk in the control group (CER): RR = EER/CER. RR is used in randomised trials and cohort studies.

14. Results Secondary analyses NAC is beneficial
8 full text studies + 4 abstracts
1312 patients
Risk ratio (RR) = 0.55 (95% CI )
NAC is beneficial

15. NAC is not beneficial if risk is low
Results
Subgroup analyses
Kidney function
Groups divided at creatinine of 1.9mg/dL
For levels greater, P = 0.36 Insignificant
Contrast volume
Groups divided at 140mL
For volumes lesser, P=0.14 Insignificant
NAC is not beneficial if risk is low

16. Appraisal Are the Results Valid?
Did this review address a focused clinical question? YES
Were the criteria for article inclusion appropriate? YES
Is it unlikely that relevant studies were missed? NO
Are the Results Valid?
Did this review address a focused clinical question? YES
Were the criteria for article inclusion appropriate? YES – unblinded studies were included but the measure was objective
Is it unlikely that relevant studies were missed? NO – only used american resources – no mention of EMBASE (expected in meta-analysis)

17. Appraisal Was the validity of the included studies appraised? NO
Was the assessments of studies reproducible? NO
Were the results similar from study to study? NO
Was the validity of the included studies appraised? NO – no jaddad
Was the assessments of studies reproducible? NO – probably only 1 extractor (unable to get a Kappa score)
Subject to both random error and bias
Were the results similar from study to study? NO
clinical, statistical differences
There were differences in populations (some for angiography, some for CT scans)
There were differences in interventions (different routes and regimes of acetylcysteine)
There were differences in outcome measures – defined radiocontrast nephrotoxicity different ways

18. Appraisal What Are the Results?
What are the overall results of the review?
NAC is beneficial
NNT = 8
How precise are the results?
Sufficient
CI =

19. Appraisal Will the Results Help Me in My Patient Care?
Can the results be applied to my patients?
YES
Were all clinically important outcomes considered?
Are the benefits worth the harms and costs?
In my patient – voume of radiocontrast, creatinine levels

20. Bias Search strategy bias Study selection bias EMBASE not searched
Only one reviewer (probably), no mention of independence

21. Strengths/Weaknesses
Attempts to elimination publication bias
No EMBASE
Inclusion of unblinded studies
Only 1 reviewer (probably)
No validity appraisal of individual RCTs
Heterogeneity
Strength & weakness ?
Heterogeneity
+ve Argue that differing patient populations and procedures perform strengthen the results and make it applicable for wide range of patients
-ve Differing definitions of RCN between studies
Inclusion of unblinded studies
Inclusion of abstracts to attempt to negate publication bias
1 reviewer – uncertain
No EMBASE

22. Level of evidence Meta-analysis is a strong level of evidence However
Study selection bias
No validity appraisal of individual RCTs
Heterogeniety of definition of outcome

23. Interpretation
The literature favours the use of NAC for prophylaxis of RCN in patients with CKD
BUT does not favour the use of NAC if there is
Good baseline kidney function
Small volumes of radiocontrast solution

24. Implications For individual For public health
Decreased risk of morbidity and mortality associated with RCN
For public health
Better use of hospital resources associated with a decreased incidence of RCN

25. Unanswered questions
What route of administration and regime is most beneficial?
How do these results compare to patients with CKD due to diabetes relative to those with non-diabetic causes?
Is N-acetylcysteine superior to other methods of prophylaxis?

26. Summary
N-acetylcysteine is useful in prevention of radiocontrast nephrotoxicity in selected cases
Correct decision was made for this patient

27. Thank You