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Mindstretcher: NAC and CIN in coronary angiography

Systematic review
Results
Trials
NAC effectiveness
Comment


Contrast-induced nephropathy (CIN) is a complication of coronary angiography, usually defined biochemically by increased serum creatinine in the 48 hours after angiography. The incidence of CIN tends to be higher in patients with more severe renal dysfunction and diabetes. CIN is associated with increased morbidity, longer hospital stay, dialysis, and even mortality. There are several proposed mechanisms, including oxidative stress and reduced renal perfusion. N-acetylcysteine (NAC) has been considered to reduce the incidence of CIN, with evidence mainly from a meta-analysis of small trials [1]. A newer meta-analysis [2] does not find a statistically reduced incidence.


There are problems with clinical heterogeneity, including definition of renal impairment, and the proportion of patients with diabetes. Others are dose of contrast medium, and the dose and dosing regimen of NAC, which has typically been a pre-loading for one or two days before the procedure. As problems are always good learning opportunities, Bandolier decided to examine the evidence from the meta-analysis [2].


Systematic review


The review sought randomised trials published to November 2003 in three electronic databases, as well as abstracts from a number of international meetings published over the previous five years. Included studies had to be randomised, compare NAC (any regimen) against placebo, in patients undergoing coronary angiography and receiving intravenous fluids and low osmolarity non-ionic contrast media. CIN was defined as an increase in serum creatinine of at least 0.5 mg/dL (44 μmol/L) or an increase of at least 25% from baseline over 48 hours.


Results


Trials


The review [2] found 13 trials with 1,874 patients. Six of these were published only as abstracts (five of which have subsequently been published in full). They varied in size, creatinine concentrations for inclusion, the volume of contrast medium, and particularly the dosing regimen of NAC. Eleven used only oral NAC, while two used intravenous NAC. Almost all used NAC both before and after the procedure.

A brief PubMed search (December 2006) identified an additional eight randomised trials with 1,343 patients. These additional trials used different NAC regimens, with three using intravenous NAC, with or without oral NAC.


NAC effectiveness


Results for all 21 trials are shown in Figure 1, which demonstrates a wide variation in trial size (38 to 477 patients), CIN incidence with placebo (0% to 45%), and NAC effectiveness. Only five of the 21 trials individually showed a significant reduction in CIN incidence with NAC.



Figure 1: Individual results from all 21 trials of NAC for CIN






Various sensitivity analyses are shown in Table 1. There was a statistically significant reduction in CIN incidence for all 21 trials combined, for the 13 in the meta-analysis, for the eight subsequent trials, and for those using only oral NAC or intravenous NAC (sometimes with oral NAC also).



Table 1: Analysis for all trials combined, and sensitivity analyses using different criteria



Number of
CIN rate (%) with
Types of trial
Trials
Patients
NAC
Placebo
Relative risk
(95% CI)
NNTp
(95% CI)
All trials combined
21
3202
11
16
0.7 (0.6 to 0.8)
23 (15 to 51)
In meta-analysis
13
1874
13
18
0.8 (0.6 to 0.9)
22 (13 to 82)
Since meta-analysis
8
1328
9
13
0.6 (0.5 to 0.8)
26 (14 to 220)
Oral only
16
2193
9
13
0.7 (0.6 to 0.9)
26 (15 to 77)
IV ± oral
5
1009
16
22
0.7 (0.6 to 0.9)
16 (9 to 66)
CER ≤12%
10
1409
8
7
1.1 (0.7 to 1.5)
not calculated
CER 12-24%
7
1184
16
19
0.9 (0.7 to 1.1)
not calculated
CER ≥25%
4
609
10
31
0.3 (0.2 to 0.4)
4.7 (3.6 to 6.8)
CER is the control event rate, in this case the CIN incidence with placebo



A sensitivity analysis was performed according to the CIN incidence with placebo. When the CIN incidence with placebo was below 25%, there was no significant reduction with NAC. When the CIN incidence with placebo was above 25% in four trials, there was a large reduction with NAC by about two thirds, producing a number needed to treat to prevent one case of CIN of 4.7 (95% CI 3.6 to 6.8).


Comment


There are many different lessons to be learned here:



The bottom line is that it is only worth doing a systematic review and meta-analysis if you are prepared to think.


References:

  1. R Birck et al. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet 2003 362: 598-603.
  2. A Zagler et al. N-acetylcysteine and contrast-induced nephropathy: a meta-analysis of 13 randomized trials. American Heart Journal 2006 151: 140-145.

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