A Meta-Analysis of Randomized Controlled Trials

Pioglitazone may have potential benefits in the treatment of cutaneous and metabolic derangements of psoriasis, but its role in the treatment of psoriasis remains in debate. We therefore conducted a meta-analysis to evaluate the clinical efficacy and safety of pioglitazone in psoriasis vulgaris (PsV). We performed a comprehensive search in database of PubMed, Web of Science, Cochrane library, Embase and China National Knowledge Infrastructure (CNKI), and Wan fang database through March 2019 to identify eligible studies. Randomized controlled trials that have evaluated the effect and safety of pioglitazone in PsV were included. Treatment success was defined as ≥75% reduction in psoriasis area and severity index (PASI) score after treatment. Weightedmean differences (WMD), relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were pooled to compare the clinical efficacy and safety between different groups. Six randomized controlled trials (n=270) were included. Meta-analysis showed that pioglitazone was associated with a remarkable reduction in PASI score in patients with PsV (weight mean difference: 2.68, 95%CI 1.41–3.94, P< .001). The treatment success rate in the pioglitazone group was higher than in the control group (RR 3.60, 95 CI 1.61–8.01, P< .001). Compared with control group, pioglitazone was not related to a pronounced increase in total adverse events (RR 1.180, 95 CI 0.85–1.63, P= .33). Moreover, the risk of common adverse events in the 2 groups were similar, such as elevated liver enzyme, fatigue, nausea, weight gain. This meta-analysis suggested pioglitazone is an effective and safe drug in the treatment of patients with PsV. Abbreviations: CIs = confidence intervals, PPARs = proliferator-activated receptors, PRISMA = Preferred Reporting Items for Systematic Review and Meta-analysis, PsV = psoriasis vulgaris, RRs = relative risks, TZDs = thiazolidinedoniones.


Introduction
With dramatic improvement in operative mortality, pancreaticoduodenectomy (PD) has become increasingly accepted as a safe and appropriate operation for selected patients with periampullary tumors, pancreatic head cancer, benign neoplasms, and other non-neoplastic conditions such as chronic pancreatitis [1].With advances in treatment techniques, the mortality rate of PD has decreased to below 5% in many institutions around the world in recent years [1][2][3][4][5].However, even with these advancements in operative technique and postoperative management, postoperative morbidity of intra-abdominal complications remains high even in large series [4].The most common complications after PD are pancreatic fistula, delayed gastric emptying, biliary fistula, and wound infection [6][7][8].They often contribute significantly to prolonged hospitalization and mortality [6].Leakage from the pancreatic anastomosis remains the single most important cause of morbidity and sometimes mortality [1].
Recently, considerable attention has been focused on refinements in operative technique for PD, especially on the management of the pancreatic remnant, with the intent to decrease the incidence of pancreatic fistula.These efforts include technical modifications such as the pancreatojejunal anastomosis technique, the pancreatogastric anastomosis, and external drainage of the pancreatic duct [5].Pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ) have been the most commonly used method of restoring pancreatioenteric continuity after PD.Some retrospective studies [9][10][11] and one RCT [12] have reported lower pancreatic fistula rate with PG instead of PJ, and a recent metaanalysis [13] suggested that the safer means of pancreatic reconstruction after PD was PG.However, 3 RCTs [14][15][16] showed PG and PJ to be similar in regards to pancreatic fistula rates, and a recent meta-analysis concluded [17] that PG and PJ were not different in terms of pancreatic fistula rate or overall morbidity rate.
Thus, in order to establish which is the best technique for pancreatoenteric anastomosis, it is important to identify the definition of pancreatic fistula used, before any series of patients can be compared [1].To evaluate and compare the results of PG and PJ after PD, we performed an up-todate meta-analysis to PG versus PJ including all RCTs, and when appropriate and possible, to establish the sources of heterogeneity in the results.

2.
1. Data Sources.We performed a systematic review of the literature published between 1990 and July 2011.To identify studies published from 1990 to July 2011, we performed a comprehensive search of abstracts in the MEDLINE database, OVID database, Springer database, the Science Citation Index, and the Cochrane Library database with use of the following search terms: "pancreaticoduodenectomy," "pancreaticogastrostomy," "pancreaticojejunostomy," with limitations to Randomized Controlled Trial, Humans.Reports in any language were eligible for inclusion.To avoid double counting, two data extractors compared the articles for participating institutions and inclusion criteria.Unpublished research was not included.

Inclusion and Exclusion
Criteria.Only RCTs were included.Any etiology for PD was eligible, and there was no limitation because of race, gender, or age.Comparator intervention was considered PG, while control intervention was considered PJ.

Statistical Analysis.
Two independent reviewers extracted data by using a specially developed form and entered it into the freeware program Review Manager (Version 5.0 for Windows, Cochrane Collaboration, Oxford, UK, 2008), respectively.The odds ratio (OR) for each trial was calculated from the number of evaluable patients, and ORs with their two-sided 95% CIs were used for dichotomous outcomes as the confirmatory effect size estimate and test criterion.For continuous variables, weighted mean difference (WMD) was calculated with 95% confidence intervals.In the course of data combination, heterogeneity was evaluated with the Cochran Q test.The fixed-effects model and random-effects model were applied.The hypothesis tests were based on the 95% CIs, and P values were used for illustration.All P values were two-sided, and P < 0.05 was considered statistically significant.To determine the potential risk bias in the overall results from the inclusion of studies that violated some of the eligibility criteria, sensitivity analysis and publication bias analysis were performed.

Trial and Patient Characteristics.
A total of 398 studies were retrieved, and the process of identifying relevant trials is shown in Figure 1.Among these 398 studies, 369 were excluded because of trial design, 29 studies were potentially appropriate clinical trials to be included in the meta-analysis, 15 were excluded because of absence of randomization, and 9 were excluded RCTs for other reasons.Finally, five RCTs were included [12,[14][15][16], which were all published as full articles; clinically relevant outcomes for our study could not be extracted from one of these five, thus leaving four RCTs for meta-analysis.Among these 4 studies, there were a total of 276 patients that underwent PJ and 277 patients that underwent PJ.The main characteristics of the four included studies are reported in Table 1.

Biliary Fistula.
Biliary fistula was defined as bile in the drain fluid from the subhepatic drain (or an operatively placed drain or a subsequently placed percutaneous drain) with the level of total bilirubin exceeding the upper limit of normal.7).

Sensitivity Analysis and Publication
Bias.Sensitivity analysis and publication bias estimates were performed to determine statistically significant results.For intraabdominal complications (IACs) between PG group and PJ group, combined ORs were calculated with a fixed-effects model and a random-effects model, and the results were compared.The OR with a fixed-effects model was 0.34 (95% CI, 0.23-0.49;P < 0.00001); moreover, because statistically significant data are more likely to be published and the findings of the present review were mostly positive, our meta-analysis was likely influenced very little by publication bias.However, because of the small numbers of randomized controlled trials available, more detailed stratification comparisons could not make, which could have influenced the validity of our study to some extent.

Discussion
To reduce the incidence of postoperative complications, a variety of techniques [18] as well as pharmacologic prophylactic approaches [19,20] have been used and evaluated over the years in the management of the pancreatic remnant following PD.Pancreatic anastomosis leakage remains a major  cause of postoperative morbidity after PD, and it contributes significantly to operative mortality.Pancreatoenteric anastomotic failure is one of the major causes of morbidity because of delayed gastric emptying, pancreatic fistula, and wound infection; pancreatic fistula can also lead to hemorrhage (intra-abdominal and/or into the digestive tract), leakage (biliary and/or digestive tract), intra-abdominal infection, wound disruption (infected or no), and even death.The most common techniques for reconstruction of pancreatic gastrointestinal continuity after PD involve a pancreaticoenteric anastomosis, usually either PJ or PG.The best technique for pancreatic anastomosis is still a challenge for the pancreatic surgeon.The pancreatojejunal anastomosis is carried out either as an end-to-end anastomosis with invagination of the pancreatic stump into the jejunum or as an end-to-side anastomosis with or without duct-tomucosa suturing [21].The pancreatogastric anastomosis is performed to the gastric lumen through either the gastric stump or through an anterior wall gastrostomy (in the case of pylorus-preserving PD).The present meta-analysis showed that PG is better than PJ for pancreatic reconstruction after PD, because PG has lower morbidity of intra-abdominal complications than PJ (P < 0.00001), while the two techniques of anastomosis were not different in terms of pancreatic fistula rate (P = 0.13), mortality (P = 0.87), recovery with no complications rate (P = 0.18), biliary fistula rate (P = 0.19), and delayed gastric emptying rate (P = 0.06).
The technique of PG has several potential advantages over PJ.First, the PG anastomosis can be performed easily, because the posterior wall of the stomach lies immediately anterior to the mobilized pancreatic remnant and is usually wider than the transected pancreas.Second, with PG, the pancreatic exocrine secretions enter the potentially acidic gastric environment, precluding digestive damage of the pancreatoenteric anastomosis by activated proteolytic enzymes.In contrast with PJ, the activation of pancreatic exocrine secretions can occur more easily in the presence of intestinal enterokinase and bile.Third, PG avoids the long jejunal loop where pancreatobiliary secretions accumulate during the early postoperative period.Fourth, postoperative gastric decompression can provide constant removal of pancreatic and gastric secretions avoiding accumulation and thus tension on the anastomosis.Fifth, PG anastomosis reduces the number of anastomoses in a single loop of retained jejunum, which potentially decreases the likelihood of loop kinking.The decreased morbidity of intra-abdominal complications for PG may be the result of the aforementioned theoretical advantages.Published studies have favored PG over PJ [12,22] although these studies are limited by their small patient populations.
It is generally accepted that compared to a fibrotic pancreatic remnant, a soft and fragile pancreatic remnant frequently results in a high pancreatic anastomosis leakage rate [23].There are many factors which can lead to pancreatic anastomosis leakage (pancreatic fistula), including pancreatic factors (pancreatic texture, original pathology, blood supply to the pancreas remnant, pancreatic juice output, pancreatic duct size), patient factors (age, gender, level of preoperative jaundice, comorbid illness), and operative factors (operation time, blood loss, type of anastomosis, stenting of pancreatic duct) [1,[24][25][26][27].Among these factors, the main factors include pancreatic texture [1,[27][28][29], pancreatic stump blood supply, pancreatic duct size [1,29], and pancreatic juice output [27,30].All RCTs which were included in our study reported diverse factors (pancreatic factors, patient factors, and operation factors) which were different between the PG group and the PJ group.For pancreatic fistula, the present study showed no significant difference in two groups (P = 0.13).Although there is heterogeneity between the analyzed RCTs, all RCTs were conducted in specialized centers by highly experienced surgeons, and the surgical care is likely to be similar among studies.Regarding methodological quality, we consider our analyses to be relevant [31].
The results of this meta-analysis are in line with research from McKay et al. [13] and are partly similar with Wente et al. [17].However, our meta-analysis has some limitations.First, due to the lack of specific information in the original papers, we cannot perform a subgroup analysis according to patient age and the etiology of PD; thus, it is unclear whether the advantage of PG is potentially applicable to all subgroups of patients.Second, the reported technique for PD in each RCT was variable with conventional PD, PPPD, or PD plus extended resection (Figure 1).Different operative procedures could lead to different complications.Third, other factors, such as presenting symptoms, preoperative blood parameters, the presence of comorbid illness, and preoperative biliary drainage, could influence the frequency or type of morbidity.Fourth, the definition for pancreatic fistula also varied between RCT, with only one [14], utilizing the ISGPF criteria [24], which could influence our study.Fifth, this meta-analysis included only 553 patients and 4 RCTs, and a type II error may be possible.
In conclusion, the evidence from this formal metaanalysis suggests that PG is better than PJ for pancreatic reconstruction after PD.PG can provide an adequate reconstruction for pancreaticoenteric continuity following PD.Future large-scale, high-quality, multicenter trials are still required to clarify the issues of PG reconstruction following PD.For future experiment on PD, the question for the management of the pancreatic remnant must be addressed in the future.

Table 1 :
Characteristics of RCTs Included in the study.
Figure 1: QUOROM flow diagram of included and excluded studies.