Further systematic reviews and meta-analyses on these modalities of administrations are expected in future. mortality rate from acute pancreatitis. Results Seventeen trials were selected for analysis. Overall, protease inhibitors did not achieve a significant risk reduction in mortality (pooled risk difference [RD], -0.02; 95% Confidence Interval [CI], -0.05 to 0.01; number needed to treat [NNT], 74.8) with low heterogeneity. A subgroup analysis in moderate to severe pancreatitis (defined by control mortality rate [CMR] 0.10) did not show a significant effect of protease inhibitors to prevent death (pooled RD, -0.03; 95% CI, -0.07 to 0.01; NNT, 1603.9) with low heterogeneity. An additional subgroup analysis of two trials with CMR 0.20 (i.e., low quality) revealed a significant risk reduction. Conclusion The present meta-analysis re-confirmed that there is no solid evidence that supports the intravenous use of protease inhibitors to prevent death due to acute pancreatitis. risk in the control group, for the primary outcome of the trials. A negative RD indicated risk reduction due to intervention, and a positive RD, risk increase due to intervention (range, -1 to 1 1). Whether the treatment or control was favored was denoted by the signs + and -, respectively. Then, the weighted pooled estimates were calculated for binary data. A fixed-effect model weighted by the Mantel-Haenszel (M-H) method was used for pooling RD [19], followed by a test of homogeneity. Homogeneity among trials was assessed using the I2 test [20]. We defined I2 value 25% as low, 25 to 50% as moderate, and 50% as high heterogeneity. If the hypothesis of homogeneity was rejected, a random-effect model using the DerSimonian-Laird (D-L) method was employed [21]. The potential for publication bias was examined by the funnel plot method [22] using the Beggs [23] or Eggers test [24]. The number needed to treat (NNT, 1/RD) to prevent one adverse event was also used as a measure of treatment effect. We used the number needed to treat benefit (NNTB; the number of patients needed to be treated for one additional patient to benefit) for a positive NNT, and the number needed to treat harm (NNTH; the number of patients needed to be treated for one additional patient to be harmed) for a negative NNT. When the upper or lower limit of the 95% confidence interval (CI) was infinity, the NNT scale including infinity was used [25]. All statistical analyses were performed with Stata statistical software [26]. Results were expressed as means and 95% CIs, unless otherwise indicated. P? ?0.05 was considered statistically significant. Results Trial selection and features (Figure?1 and Additional file 1: Table S1) Open in a separate window Figure 1 Flow of randomized controlled trials through the process of retrieval and inclusion in the meta-analysis comparing protease inhibitors with placebo for acute pancreatitis. The numbers in parentheses are the Jadad scores of the individual trials. 95% CI, 95% confidence interval. ERCP, endoscopic retrograde cholangiopancreatography. Our database search yielded 96 articles, and handsearching of bibliographies of retrieved meta-analyses and clinical guidelines yielded additional three and two articles, respectively. There were no on-going trials in the registries. Of the 101 articles, 24 met the inclusion criteria [27-50]; no multiple publications were found. Reviewers selection of relevant articles was completely the same, and there was no unsuitable study for inclusion by authors consensus. The 77 excluded articles described ERCP studies (n?=?36), studies in which a protease inhibitor was administered to both intervention and control groups (n?=?8), arterial infusion studies (n?=?6), and other (n?=?27) (Figure?1). Next, all authors read the selected 24 articles, reaching a consensus to exclude seven more articles [27,38-40,45,48,50] including two in which a protease inhibitor was administered to both intervention and control groups [30,45], two that were published as comments [38,50], one in which glucagon was given to the control group [39], one published as an editorial (n?=?1) [40], and one reporting an ERCP study [48]. In the end, a total of 17 articles [27-29,31-37,41-44,46,47,49] were selected for analysis. The present meta-analysis of the retrieved competent studies included 15 RCTs from the handsearch [27,28,31-37,41-43,46,47,49], one [29] from a previous meta-analysis [51], and one [44] from guidelines [52], with the total sample size of 1 1,697 patients. Of the 15 articles manually looked, 10 [33,34,37,41-44,46,47,49] were used in our earlier meta-analysis [10]. All content articles evaluated death due to acute pancreatitis, in addition to other results such as pain relief (n?=?2) [31,49], pseudocyst formation (n?=?5) [29,37,41,43,46], intra-abdominal abscess formation (n?=?4) [37,41,43,46], surgical treatment (n?=?3) [44,47,49], paralytic small bowel obstruction.All authors read and authorized the final manuscript. Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-230X/14/102/prepub Supplementary Material Additional file 1: Table S1: Characteristics of main trials. Click here for file(367K, doc) Guarantor of the article Takeshi Seta, MD. Support This study was supported from the grant-in-aid from the Ministry of Health, Labour and Welfare, Japan.. review content articles and previously published meta-analyses were handsearched. The main end result of interest was the overall mortality rate from acute pancreatitis. Results Seventeen trials were selected for analysis. Overall, protease inhibitors did not achieve a significant risk reduction in mortality (pooled risk difference [RD], -0.02; 95% Confidence Interval [CI], -0.05 to 0.01; quantity needed to treat [NNT], 74.8) with low heterogeneity. A subgroup analysis in moderate to severe pancreatitis (defined by control mortality rate [CMR] 0.10) did not show a significant effect of protease inhibitors to prevent death (pooled RD, -0.03; 95% CI, -0.07 to 0.01; NNT, 1603.9) with low heterogeneity. An additional subgroup analysis of two tests with CMR 0.20 (i.e., low quality) revealed a significant risk reduction. Summary The present meta-analysis re-confirmed that there is no solid evidence that helps the intravenous use of protease inhibitors to prevent death due to acute pancreatitis. risk in the control group, for the primary outcome of the trials. A negative RD indicated risk reduction due to treatment, and a positive RD, risk increase due to treatment (range, -1 to 1 1). Whether the treatment or control was favored was denoted from the indications + and -, respectively. Then, the weighted pooled estimations were determined for binary data. A fixed-effect model weighted from the Mantel-Haenszel (M-H) method was utilized for pooling RD [19], followed by a test of homogeneity. Homogeneity among tests was assessed using the I2 test [20]. We defined I2 value 25% as low, 25 to 50% as moderate, and 50% as high heterogeneity. If the hypothesis Rabbit Polyclonal to HLA-DOB of homogeneity was declined, a random-effect model using the DerSimonian-Laird (D-L) method was used [21]. The potential for publication bias was examined from the funnel storyline method [22] using the Beggs [23] or Eggers test [24]. The number needed to treat (NNT, 1/RD) to prevent one adverse event was also used as a measure of treatment effect. We used the number needed to treat benefit (NNTB; the number of patients needed to be treated for one additional patient to benefit) for any positive NNT, and the number needed to treat harm (NNTH; the number of patients needed to be treated for one additional patient to be harmed) for a negative NNT. When NVP-QAV-572 the top or lower limit of the 95% confidence interval NVP-QAV-572 (CI) was infinity, the NNT level including infinity was used [25]. All statistical analyses were performed with Stata statistical software [26]. Results were indicated as means and 95% CIs, unless normally indicated. P? ?0.05 was considered statistically significant. Results Trial selection and features (Number?1 and Additional file 1: Table S1) Open in a separate window Number 1 Circulation of randomized controlled tests through the process of retrieval and inclusion in the meta-analysis comparing protease inhibitors with placebo for acute pancreatitis. The figures in parentheses are the Jadad scores of the individual tests. 95% CI, 95% confidence interval. ERCP, endoscopic retrograde cholangiopancreatography. Our database search yielded 96 content articles, and handsearching of bibliographies of retrieved meta-analyses and medical guidelines yielded additional three and two content articles, respectively. There were no on-going tests in the registries. Of the 101 content articles, 24 met the inclusion criteria [27-50]; no multiple publications were found. Reviewers selection of relevant content articles was completely the same, and there was no unsuitable study for inclusion by authors consensus. The 77 excluded content articles described ERCP studies (n?=?36), studies in which a protease inhibitor was given to both intervention and control organizations (n?=?8), arterial infusion studies (n?=?6), and other (n?=?27) (Number?1). Next, all authors read the selected 24 content articles, reaching a consensus to exclude seven more content articles [27,38-40,45,48,50] including two in which a protease inhibitor was given to both treatment and control organizations [30,45], two that were published as feedback [38,50], one in which glucagon was given to the control group [39], one published NVP-QAV-572 mainly because an editorial (n?=?1) [40], and one reporting an ERCP study [48]. In the end, a total of 17 content articles [27-29,31-37,41-44,46,47,49].