To examine consistency across varying study designs with different potential biases, we stratified data into subgroups on the basis of study design. In the subgroup meta-analysis of case–control studies, NSAIDs use significantly decreased the risk of melanoma on the basis of a fixed-effects model without evidence of heterogeneity (RR=0.86; 95% CI, 0.80–0.93). However, no evidence among the cohort studies was observed (fixed-effects model, RR=1.03; 95% CI, 0.95–1.13) (Table 2). There was no evidence of publication bias in either of the above subgroups.
Our findings were stable and robust in subgroup analyses. The results were similar for the use of aspirin and NA-NASIDs, and a null association was found in subgroup analyses of high-intensity and long-term NASIDs use. This also reinforced the confidence in the validity of our conclusion that NASID use is not associated with the risk of melanoma. We found that the meta-analysis of five case–control studies showed overall NSAID use to be significantly associated with a slight reduction in the risk of melanoma (RR=0.86; 95% CI, 0.80–0.93), whereas the subgroup analysis of cohort studies was not significant (RR=1.03; 95% CI, 0.95–1.13). This could be attributable to recall and inherent selection bias in case–control studies, which may distort the true exposure effect.
The possibility of publication bias is always a concern in meta-analyses of published studies. This could bias the results of this review if negative studies were less likely to be published in indexed journals. In our meta-analysis, no evidence for such a bias was found. Actually, most of the studies included reported a nonsignificant association.
There are some potential limitations that should be considered when interpreting the results of this meta-analysis. First, as our meta-analysis is mainly based on observational studies, we cannot rule out the possibility that the lack of an association between NSAID/aspirin use and the risk of melanoma is because of inherent confounding factors such as intake of other drugs in the original studies. Second, high heterogeneity was observed in the meta-analysis of overall NSAID use. Thus, a random-effects model was used, which provides a more conservative estimate of the pooled effect size (DerSimonian and Laird, 1986). Third, all the studies included were carried out among Whites; generalizability to other ethnicities requires caution. Finally, it has been determined that there is a long latency period before development of a clinically apparent melanoma (Whiteman et al., 2001), and the onset, duration, and dose intensity of chemopreventive drug use are very important factors in the relevant study design. However, in our meta-analysis, the dose and duration of NSAID use varied according to the definition of each study. We used the highest dosage and longest duration of NSAID use among the various categories in each study for subgroup analysis because no more detailed information could be obtained. This could have led to heterogeneity, and our results should be interpreted with caution.
There are no conflicts of interest.
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