This is a further meta-analysis to evaluate the effect of prophylactic antioxidant supplementation on the prevention of post-ERCP pancreatitis. The present meta-analysis of ten randomized controlled trials showed that antioxidant supplementation did not significantly decrease the incidence of post-ERCP pancreatitis. In addition, antioxidant supplementation also showed no beneficial effect on the severity of post-ERCP pancreatitis.
There have been two published meta-analyses of allopurinol (an inhibitor of oxygen-derived free-radicals) for post-ERCP pancreatitis prevention
[13, 14]. Both of them showed that the use of allopurinol was not associated with reduction in the incidence of post-ERCP pancreatitis. Our meta-analysis expands on these two earlier meta-analyses to provide a better characterization of the evidence base for antioxidant supplementation in preventing post-ERCP pancreatitis. First, in our analysis, there are more enlarged sample sizes than the previous analysis, giving greater power to evaluate this effect. Second, we were more capable of evaluating the effects of other antioxidants (such as N-acetylcysteine, β-carotene, and selenite) on post-ERCP pancreatitis prevention. Furthermore, we also were able to evaluate the effect of antioxidant supplementation on the severity of post-ERCP pancreatitis.
Based on the previous meta-analysis, we furthermore included other seven recent RCTs
[21, 23, 25, 27, 28, 30, 31]. With the added statistical power of having 2,970 cases, the present meta-analysis suggested that antioxidant supplementation did not significantly decrease the incidence of post-ERCP pancreatitis, which was in line with the previous meta-analysis. Moreover, exclusion of any single study and sensitivity analyses based on various exclusion criteria did not materially alter the pooled results, which adds robustness to our main finding. We also assessed the effect of antioxidant supplementation on the severity of post-ERCP pancreatitis, but failed to find significant alteration.
There was significant heterogeneity between studies in the overall analysis, which was not surprising given the differences in characteristics of populations, antioxidant supplementation, and definitions of pancreatitis. Our sensitivity analyses suggest that one trial conducted by Katsinelos et al. probably contributed to the heterogeneity
. For this study, only 43 patients in the allopurinol group underwent biliary sphincterotomy vs. 87 in the placebo group; thus, there was significant difference in the proportions of patients with biliary sphincterotomy between the two groups (P < 0.001). Besides, exclusion of the trial in our meta-analysis would not change our result; antioxidant supplementation still did not significantly decrease the incidence of post-ERCP pancreatitis (2,767 patients; fixed-effects model: RR, 1.08; 95% CI, 0.85–1.37; P = 0.531; data from nine trials)
Furthermore, antioxidant therapy failed to prevent the onset of post-ERCP pancreatitis in almost all trials. Only one clinical trial in which 600 mg of allopurinol was administered twice before ERCP showed a significant decrease in the rate of post-ERCP pancreatitis. The positive result may be attributed to the high doses of allopurinol. Wisner and Renner found that only high doses of allopurinol were effective in preventing pancreatic edema and an increase in serum amylase in caerulein-induced pancreatitis in rats
. Low doses of allopurinol were not effective in fully suppressing xanthine oxidase, causing a “leakage” of excessive radicals.
Most of the included RCTs did not reported adverse effects of antioxidant during the study period. We found that only 1 report indicated different adverse effects of N-acetylcysteine. In the report
, side effects most commonly attributable to N-acetylcysteine (i.e., skin rash, nausea, vomiting, and diarrhea) were observed with increased frequency in the N-acetylcysteine group (25% vs. 3.2%, N-acetylcysteine and placebo groups, respectively; P < 0.001).
The results of this meta-analysis must be interpreted cautiously in light of the strengths and limitations of the included trials. A major strength of this study is that all the included original studies used a randomized controlled design and most of them were well-performed, high-quality (Jadad score ≥ 3 in nine trials). In addition, with the enlarged sample size, we have enhanced statistical power to provide more precise and reliable effect estimates. Although the present analysis represents a complete summary of the current available evidence for antioxidant supplementation in preventing post-ERCP pancreatitis, it also serves to highlight limitations that remain. One potential limitation is the various types of antioxidant used and the lack of standard regimens of antioxidant applied in the randomized trials to date. These factors may result in the heterogeneity and have potential impact on our results. Furthermore, the variety of criteria was used to define pancreatitis. In the majority of the studies, the definition of post-ERCP pancreatitis and the grading of its severity were based on the Cotton consensus criteria
. Finally, exploration of the impact of antioxidant supplementation on other clinically meaningful endpoints including hyperamylasemia and length of the hospital stay has not been sufficient because of sparse and inconsistent reporting across the reviewed studies.