Direct Pairwise Meta-analysis Research Articles

Pimecrolimus 1% cream for mild-to-moderate atopic dermatitis: a systematic review and meta-analysis with a focus on children and sensitive skin areas.

This systematic literature review (SLR) and meta-analysis assessed the efficacy and safety of pimecrolimus vs other topical treatments in patients with mild-to-moderate atopic dermatitis (AD), focusing on children and sensitive skin areas. An SLR was conducted in MEDLINE, Embase and Cochrane Library databases on January 15th, 2020, to identify randomized controlled trials (RCTs) with pimecrolimus as a study arm. Another SLR performed on October 5th, 2020 identified RCTs with a crisaborole study arm. Direct pair-wise meta-analysis was used to compare pimecrolimus with vehicle, tacrolimus or topical corticosteroids (TCS; n = 27 studies). Outcomes included Investigator's Global Assessment (IGA) score 0/1 up to week 6 and adverse events. Pimecrolimus was more efficacious than vehicle in achieving IGA 0/1 up to week 6 in children, and similar safety profiles were observed with pimecrolimus and vehicle in children and the mixed population, including on sensitive skin. No significant differences in efficacy and safety were observed between pimecrolimus and tacrolimus 0.03%. Efficacy and safety were similar for pimecrolimus and mild medium potency TCS; mildly potent steroids caused transient epidermal thinning in sensitive skin areas (not seen with pimecrolimus). Pimecrolimus can be considered as a first-line option for mild-to-moderate AD, particularly in children and sensitive skin areas.

Are acupuncture and dry needling effective in the management of masticatory muscle pain: A network meta-analysis of randomised clinical trials.

Several studies have shown that both acupuncture and dry needling are effective in the treatment of musculoskeletal pains. Therefore, the aim of this network meta-analysis (NMA) was to investigate the treatment outcome of acupuncture and dry-needling for masticatory muscle pain (TMD-M) and to compare with active and inactive placebo. An electronic search was performed to identify randomised controlled trials (RCTs) published until September 2019, comparing dry-needling, acupuncture, and inactive as well as active placebo in patients with TMD-M. Outcome variables were post-treatment pain intensity, pressure pain threshold (PPT), and maximum mouth opening (MMO). The quality of evidence was rated according to Cochrane's tool for assessing the risk of bias. Mean difference was used to analyse via frequentist NMA using STATA-software. Both NMA and direct pairwise meta-analysis have shown that there was no difference between active treatment with either acupuncture or dry-needling when compared to active and inactive placebo in patients with TMD-M with respect to pain intensity, and PPT (p > .05). However, there was a significant increase in MMO following dry-needling when compared to the placebo (very low-quality evidence). Despite the short-term positive effect of MMO by dry-needling, this NMA could not show any pain-reducing effect in patients with TMD-M by acupuncture or dry-needling when compared to an active or inactive placebo. Taken together, this NMA indicates that it is the placebo effect that accounts for the majority of the treatment effect of TMD-M, rather than a real therapeutic effect of acupuncture/dry-needling.

Efficacy of integrative medicine using Yinhua-based herbal granules on herpangina: A Bayesian network meta-analysis of randomized controlled trials

BackgroundDifferent Traditional Chinese Medicine (TCM) in the format of granules, such as Kanggan Granules (KangGs), Kouyanqing Granules (KouGs), Lianhua Qingwen Granules (LQGs), Qingkailing Granules (QGs) and Xiao'er Qingjie Granules (XQJGs), collectively named Yinhua-based herbal granules (YH-HGs) have been widely used in the management of pediatric outpatients with herpangina. Few head-to-head randomized controlled trials (RCTs) have compared the efficacy of these agents. This network meta-analysis (NMA) was conducted to indirectly compare the efficacy of YH-HGs. MethodsThis systematic review and fixed-effect NMA was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) extension statement for NMA. RCTs assessing the efficacy and safety of YH-HGs in children that were also receiving ribavirin as the conventional therapy were searched from eight databases and two trial registers up to Jan 13, 2022. The primary outcome was total effectiveness rate (TER). The secondary outcomes were total adverse events (TAEs) and the time to symptom improvement of fever, vesicles, pain and salivation. Relative risk (RR) and weighted mean difference with 95% confidence intervals (CIs) were estimated by direct pairwise meta-analysis (MA) and NMA. ResultsA total of 10 RCTs, enrolling 1 017 pediatric patients, were included. YH-HGs were better than no medication (NM) in TER (RR = 1.22, 95%CIs, 1.16 – 1.28) by direct pairwise MA, in which KangGs (RR = 1.24, 95%CIs, 1.05 – 1.47), KouGs (RR = 1.17, 95%CIs, 1.08 – 1.27), LQGs (RR = 1.24, 95%CIs, 1.14 – 1.35), QGs (RR = 1.33, 95%CIs, 1.11 – 1.58) and XQJGs (RR = 1.18, 95%CIs, 1.00 – 1.40) were also more efficient than NM. As for secondary outcomes, YH-HGs was associated with a 103% increased risk of TAEs compared to NM, but no significant differences were found. YH-HGs has a more positive symptom improvement effect than NM in fever, vesicles, pain and salivation. The ranking results showed that QGs (79.2%) had the highest probability ranking first in TER and KangGs (63.6%) ranked as the second, followed by LQGs (52.4%), XQJGs (50.3%), KouGs (49.7%), and NM (4.9%) at last. ConclusionsOur findings support the better efficacy of YH-HGs than NM as regards TER. QGs, KangGs, LQGs, XQJGs, KouGs remain superior to NM and their clinical choice should depend on the patient's conditions to improve symptoms better for the different effects. Given the limitations of NMA, head-to-head RCTs with high-quality are needed.

M12. Network Meta-Analysis about Cytokine Gene Functional Polymorphisms Towards the Susceptibility and Severity of Acute Rheumatic Fever and Rheumatic Heart Disease among Asian and Non-Asian People

Abstract Background Great diversity among public hereditary variants may play a role in the susceptibility and severity of acute rheumatic fever (ARF)/rheumatic heart disease (RHD). Cytokine gene polymorphisms may contribute to the disease-associated cytokine imbalance. However, to the best of our knowledge, there is no existing meta-analysis concerning an association of the cytokine gene functional polymorphisms with the susceptibility / severity of ARF/RHD. Aims To investigate the potential association between cytokine gene functional polymorphisms of TNF-α, TGF-β, IL-10, IL-6 and IL-1β and the susceptibility and severity of ARF/RHD. Methods Comprehensive and structured search on Pubmed/Medline, Embase, EBSCO, and Cochrane Central Register of Controlled Trials was performed. Statistical analyses were performed using STATA. First, we performed direct pairwise meta-analysis. Then, a network meta-analysis was performed with the consistency model to compare the genetic models of different cytokine gene polymorphisms. Results Evidence derived from the meta-analysis of 24 retrospective cohort and case-control studies identified that elevated serum levels of TNF-α have been observed in ARF cases, occurring as a result of a SNP (-308G>A) in the promoter site of the TNF-α gene. Our results also suggest that IL-1β (-511) C/T polymorphism, TGF-β1 [rs1800469], and IL-1β [rs2853550] single nucleotide polymorphisms (SNPs) contributed to the susceptibility of ARF/RHD. Egger’s test did not demonstrate significant asymmetry in the dominant. Conclusion In summary, the polymorphism model increased the risk of RHD in the dominant genetic model, recessive genetic model, homozygote model and allelic genetic model among non-Asians while, recessive genetic model and homozygote model among Asians.

Diagnostic Value of Seven Different Imaging Modalities for Patients with Neuroblastic Tumors: A Network Meta-Analysis.

Objective We performed a systematic review and network meta-analysis (NMA) to compare the diagnostic value of seven different imaging modalities for the detection of neuroblastic tumors in diverse clinical settings. Methods PubMed, Embase, Medline, and the Cochrane Library were searched to identify eligible studies from inception to Sep 29, 2020. Quality assessment of included studies was appraised with Quality Assessment of Diagnostic Accuracy Studies. Firstly, direct pairwise meta-analysis was conducted to calculate the pooled estimates of odds ratio (OR) and 95% confidence interval (CI) of the sensitivity, specificity, NPV, PPV, and DR. Next, NMA using Bayesian methods was performed. The superiority index was assessed to quantify the rank probability of a diagnostic test. The studies performed SPECT/CT or SPECT were analyzed separately from the ones only performed planar imaging. Results A total of 1135 patients from 32 studies, including 7 different imaging modalities, were eligible for this NMA. In the pairwise meta-analysis, 18F-FDOPA PET/CT had a relatively high value of all the outcomes (sensitivity: 10.195 [5.332–19.493]; specificity: 17.906 [5.950–53.884]; NPV: 16.819 [7.033–40.218]; PPV: 11.154 [4.216–29.512]; and DR 5.616 [3.609–8.739]). In the NMA, 18F-FDOPA PET/CT exhibited relatively high sensitivity in all subgroups (all data: 0.94 [0.87–0.98]; primary tumor: 0.89 [0.53–1]; bone/bone marrow metastases: 0.96 [0.83–1]; and primary tumor and metastases (P + M): 0.92 [0.80–0.97]), the highest specificity in the subgroup of P + M (0.85 [0.61–0.97]), and achieved the highest superiority index in the subgroups of all data (8.57 [1–15]) and P + M (7.25 [1–13]). Conclusion18F-FDOPA PET/CT exhibited the best diagnostic performance in the comprehensive detection of primary tumor and metastases for neuroblastic tumors, followed by 68Ga-somatostatin analogs, 123I-meta-iodobenzylguanidine (MIBG), 18F-FDG, and 131I-MIBG tomographic imaging.

Comparing Nonoperative Treatment, MPFL Repair, and MPFL Reconstruction for Patients With Patellar Dislocation: A Systematic Review and Network Meta-analysis.

Background:Medial patellofemoral ligament (MPFL) reconstruction, MPFL repair, and nonoperative treatment are important treatments for patients with patellar dislocation. However, it is unclear which treatment leads to better outcomes.Purpose:To determine the efficacy and safety of the 3 treatments in the treatment of patellar dislocation and compare the effect of MPFL reconstruction with MPFL repair, MPFL reconstruction with nonoperative treatment, and MPFL repair with nonoperative treatment.Study Design:Systematic review; Level of evidence, 3.Methods:The PubMed, Web of Science, Cochrane Library, Embase, CNKI (China National Knowledge Infrastructure), and Wanfang databases were searched from inception to December 2020. Included were clinical studies that described the efficacy and safety of 2 of the 3 treatments, studies directly comparing the clinical effects of the 2 operative techniques, or studies comparing the effects of reconstruction or repair with nonoperative treatment. Two reviewers independently extracted data and assessed the quality of the included studies with the Cochrane risk-of-bias tools. The outcomes evaluated were postoperative redislocation rate, revision rate, complications, and Kujala score. We used traditional direct pairwise meta-analysis as well as network meta-analysis for comprehensive efficacy of all 3 treatment measures.Results:Twelve studies were included: 5 compared MPFL reconstruction with MPFL repair, 2 compared MPFL reconstruction with nonoperative treatment, and 5 compared MPFL repair with nonoperative treatment. The risk of bias was serious in 4, moderate in 4 and low in 4 articles. MPFL reconstruction led to significantly reduced redislocation and improved Kujala scores compared with MPFL repair and nonoperative treatment. MPFL repair led to reduced redislocation rates compared with nonoperative treatment but did not show an obvious benefit in primary dislocations. There was no significant difference among the 3 treatments in terms of revision rate and incidence of complications, although we found that treatment-related complications were least likely to occur in nonoperative treatment.Conclusion:The results of this review indicate that MPFL reconstruction decreases recurrent dislocation compared with MPFL repair or nonoperative treatment, but it has a higher possibility of complications. MPFL repair resulted in less postoperative redislocation than nonoperative treatment but did not show an obvious benefit in primary dislocation.

Efficacy of Subcutaneous and Sublingual Immunotherapy for House Dust Mite Allergy: A Network Meta-Analysis–Based Comparison

Meta-analyses comparing the efficacy of sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) for house dust mite allergy are lacking. To compare the efficacy of SLIT drops, SLIT tablets, and SCIT in patients with perennial allergic rhinitis through network analysis. Frequentist network meta-analyses estimated the standardized mean difference (SMD) across the three immunotherapy modalities on allergic rhinitis symptom and medication score data from double-blind randomized clinical trials. Random effects models were investigated. We included 26 double-blind randomized clinical trials in this meta-analysis for the symptom score and 18 for the medication score. In the direct pairwise meta-analysis, a significant reduction of the symptom score was observed for all immunotherapy modalities compared with the placebo: pooled SMDs of -0.461 (95% confidence interval [CI], -0.795 to -0.127) for SLIT drop, -0.329 (95% CI, -0.426 to -0.231) for SLIT tablet, and -1.669 (95% CI, -2.753 to -0.585) for SCIT. For the medication score, a significant reduction was observed for all modalities. In network meta-analysis, the clinical efficacy of SCIT based on the symptom score was greater than for SLIT drop or SLIT tablet (SMD: -0.697, 95% CI, -1.105 to -0.288; and SMD: -0.819, 95% CI, -1.242 to -0.397). However, there was no significant difference in the symptom score between SLIT drop and SLIT tablet. This study demonstrated the clinical efficacy of all house dust mite immunotherapy modalities and suggests that SCIT may be more effective than SLIT drops or tablets in controlling symptoms of allergic rhinitis.

Adherence to Single-Pill Versus Free-Equivalent Combination Therapy in Hypertension: A Systematic Review and Meta-Analysis.

Poor adherence to antihypertensive therapy is a major cause of poor blood pressure (BP) control in patients with hypertension. Regimen simplification may improve adherence and BP control. This systematic review assessed whether single-pill combination (SPC) therapy led to improved adherence, persistence, and better BP control compared with free-equivalent combination (FEC) therapy in patients with hypertension. PubMed, Medline, Embase, and the Cochrane Library were searched until July 2020, in addition to manual searching of relevant congress abstracts from 2014 to 2020 for studies including adults with hypertension aged ≥18 years receiving SPC or FEC antihypertensive therapy measuring any of the following: adherence, persistence, and reductions in systolic BP and/or diastolic BP. Adherence and persistence were summarized in a narrative analysis; direct pair-wise meta-analysis was conducted to compare BP reductions with SPC therapy versus FEC therapy using fixed-effect and random-effects models. Following screening, 44 studies were included. The majority (18 of 23) of studies measuring adherence showed adherence was significantly improved in patients receiving SPCs versus FECs. Overall, 16 studies measured persistence, of which 14 showed that patients receiving SPCs had significantly improved persistence or were significantly less likely to discontinue therapy than patients receiving FECs. Systolic BP (mean difference, -3.99 [95% CI, -7.92 to -0.07]; P=0.05) and diastolic BP (-1.54 [95% CI, -2.67 to -0.41]; P=0.0076) were both significantly reduced with SPC therapy compared with FEC therapy at week 12. SPC therapy leads to improved adherence and persistence compared with FEC therapy and may lead to better BP control in patients with hypertension.

Intra-Articular Injections of Hyaluronic Acid or Steroids Associated With Better Outcomes Than Platelet-Rich Plasma, Adipose Mesenchymal Stromal Cells, or Placebo in Knee Osteoarthritis: A Network Meta-analysis

To evaluate the clinical effects of hyaluronic acid (HA), steroids, platelet-rich plasma (PRP), or adipose mesenchymal stromal cell (MSC) injections in the treatment of knee osteoarthritis (OA). Randomized controlled trials with OA of the knee that compared HA, steroids, PRP, adipose MSC, or their combination with placebo or in head-to-head combination were identified from the MEDLINE, EMBASE, Cochrane Library, Web of Science, and SCOPUS databases up to June 30, 2019. We performed a network meta-analysis of the relevant literature to determine whether there was benefit from HA, steroids, PRP, or adipose MSC treatment as compared with placebo. A total of 43 trials covering 5554 patients were included. Steroids were ranked most likely to be effective for the management of pain or function, with adipose MSC and multiple PRP appearing least likely to be effective. Although no significant difference was observed among the 6 interventions, except for single PRP with respect to adverse effects, steroids and HA exhibited a lower rate of AEs compared with the placebo. In view of severe adverse effects, only single PRP was superior to placebo. Direct pairwise meta-analysis for pain relief showed that HA was superior to placebo or single PRP, but steroids had a significantly worse effect than single PRP. In addition, direct pairwise meta-analysis for adverse effects favored steroids in comparison to HA. The ranking statistics like surface under the cumulative ranking curve values of our network meta-analysis support the use of steroids and HA for appropriate patients with knee OA. For pain relief and AEs, steroids are most likely the best treatment, followed by HA. Single PRP, multiple PRP, and adipose MSC interventions do not result in a relevant reduction of joint pain nor improvement of joint function compared with placebo. However, treatment effect differences were small and potentially not clinically meaningful, indicating that other factors, such as cost and patient preferences, may be more important in patients with knee OA. meta-analysis of non-homogenous randomized controlled trials, Level II.

Adjuvant treatment for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis.

Adjuvant chemotherapy has significantly improved outcomes following surgical resection for pancreatic adenocarcinoma; however, the optimal adjuvant strategy remains unclear. This systematic review and network meta-analysis was conducted to provide indirect comparative evidence across adjuvant chemotherapies. Electronic searches of EMBASE, MEDLINE, Cochrane and ASCO databases were conducted to identify eligible randomized controlled trials (RCT). Direct pairwise meta-analysis was conducted for disease-free survival (DFS), overall-survival (OS) and adverse events (AE). Network meta-analysis of DFS and OS was conducted to evaluate indirect comparisons. Ten publications of eleven RCT met eligibility criteria. Indirect DFS comparison demonstrated superiority of mFOLFIRINOX versus gemcitabine-capecitabine, gemcitabine-erlotinib and gemcitabine-nab-paclitaxel. S-1 demonstrated a DFS benefit versus gemcitabine-capecitabine, gemcitabine-erlotinib, gemcitabine-nab-paclitaxel. OS benefits were demonstrated for mFOLFIRINOX verus gemcitabine-erlotinib and for S-1 versus gemcitabine-based combination with erlotinib, capecitabine and nab-paclitaxel. In conclusion, mFOLFIRINOX is the preferred approach for adjuvant therapy. For mFOLFIRINOX-ineligible patients no additional benefit is seen with gemcitabine-nab-paclitaxel.

Comparative efficacy and tolerability of front-line treatments for newly diagnosed chronic-phase chronic myeloid leukemia: an update network meta-analysis

BackgroundRecent years have witnessed the rapid evolution of therapies in chronic-phase chronic myeloid leukemia (CP-CML). To assess the efficacy and tolerability of all reported front-line treatments for patients with newly diagnosed CML, a multiple-treatments meta-analysis was performed, which accounted for both direct and indirect comparisons among those treatments.MethodsPrimary outcomes were the percentage of patients achieving major molecular response (MMR) and complete cytogenetic response (CCyR) within 12 months. Secondary outcomes included the percentage of progression to accelerated phase (AP), serious adverse effects (AEs), overall discontinuation and discontinuation for drug-related AEs. Direct pairwise meta-analysis and indirect multi-comparison meta-analysis among those treatments in each outcome were both conducted. The surface under the cumulative ranking curve (SUCRA) was calculated for all treatments in each outcome. Cluster analysis demonstrated the division of treatments into distinct groupings according to efficacy and tolerability profiles.ResultsA total of 21 randomized controlled trials (RCTs, including 10,187 patients) comparing 15 different interventions for CP-CML patients were included in this study. SUCRA analysis suggested that all tyrosine kinase inhibitors (TKIs) are highly effective in newly diagnosed CP-CML when compared to traditional drugs. Newer TKIs and higher-dose imatinib generally resulted in faster cytogenetic and molecular responses when compared with standard-dose imatinib and traditional drugs. Furthermore, traditional drugs, higher-dose imatinib and newer TKIs demonstrated lower acceptability than standard-dose imatinib. One cluster of interventions, which included nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID), demonstrated higher efficacy and tolerability than other treatments.ConclusionsNilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID) prove to be the most recommended front-line treatments of the greatest efficacy and tolerability for CP-CML patients. High-dose therapies are recommended only for patients in accelerated phase/blast phase or with suboptimal CML-CP response, and management of adverse events should be carried out to avoid compromising the clinical efficacy.

The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials.

AimThe association between dipeptidyl peptidase-4 inhibitors (DPP-4is), a class of anti-diabetes, and bone fracture in patients with type 2 diabetes mellitus (T2DM) is unknown. This meta-analysis aimed to systematically evaluate the effects of DPP-4is on bone fracture in T2DM patients.MethodsWe searched the Cochrane Library, Embase, Medline and ClinicalTrials.gov from inception through April 28th, 2016 to identify randomized controlled trials (RCTs) that compared DPP-4is with placebo or other anti-diabetes in T2DM patients. RCTs lasting more than 12 weeks and having data on bone fracture were included. We conducted random-effects meta-analysis to estimate odds ratios (ORs) and their 95% confidence intervals (CIs), and network meta-analysis (NMA) to supplement direct comparisons. Predictive interval plot and node-splitting method were used to evaluate the heterogeneity and inconsistency for NMA, while the funnel plot was applied to explore publication bias. Besides, study quality was assessed according to Cochrane risk of bias tool.ResultsWe identified 75 RCTs with a total of 70,207 patients and 11 treatments: interventions included 5 DPP-4is (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin), while controls included placebo and 5 other anti-diabetes (sulfonylureas, glucagon-like peptide-1 receptor agonists, metformin, thiazolidinediones, sodium-glucose co-transporter 2 inhibitors). In the NMA, the risk of fracture for alogliptin tended to decrease when versus placebo (OR, 0.51; 95% CI, 0.29 to 0.88). Besides, aloglitpin had a lower risk compared with linagliptin (OR, 0.45; 95% CI, 0.20 to 0.99) and saxagliption (OR, 0.46; 95%CI, 0.25 to 0.84); the risk was higher with saxagliptin when versus sitagliptin (OR, 1.90; 95% CI, 1.04 to 3.47) and sulfonylureas (OR, 1.98; 95% CI, 1.06 to 3.71). In the direct pairwise meta-analysis, alogliptin was associated with a non-significant tendency to reduction of bone fracture compared with placebo (OR, 0.54; 95% CI, 0.29 to 1.01). Ranking probability analysis indicated alogliptin decreased the risk of bone fracture most with a probability of 76.3%.ConclusionAlogliptin may be associated with a lower risk of bone fracture compared with placebo, linagliptin, or saxagliptin, while other anti-diabetes did not seem to have an association with the risk of bone fracture.

Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and network meta-analysis of randomized clinical trials.

Although adjuvant chemotherapy (ACH) is widely used in clinical practice for the management of muscle-invasive bladder cancer (MIBC), a consensus has yet to be established on which ACH regimen is the most effective for improving postoperative survival. In this study, we aimed to systematically assess the optimal ACH regimen for improving survival outcomes in patients treated with radical cystectomy (RC) for MIBC. A comprehensive literature search was conducted in the PubMed, Embase, and the Cochrane Library databases for all articles published until December 2016 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The study end-points were progression-free survival (PFS) and overall survival (OS). A direct pairwise meta-analysis was conducted by pooling the studies that compared RC with ACH and RC alone, and the results are presented as a pooled hazard ratio (HR) with a 95% confidence interval (CI). A Bayesian network meta-analysis was adopted for indirect comparisons among various ACH regimens, and the outcomes are presented as HRs with 95% credible intervals (CrI). The eleven randomized controlled trials ultimately selected for the current analysis comprised of 1,546 patients with 49 to 327 subjects per study. Based on the pairwise meta-analysis, the use of ACH showed significantly better PFS (HR, 0.64; 95% CI, 0.49–0.85) and OS (HR, 0.79; 95% CI, 0.68–0.92) than RC alone. In the network meta-analysis, the gemcitabine/cisplatin/paclitaxel (GCP) combination was the only ACH regimen associated with significant improvement in both the PFS (HR, 0.38; 95% CrI, 0.25–0.58) and OS (HR, 0.38; 95% CrI 0.22–0.65). ACH following RC for MIBC may therefore contribute to improved PFS and OS. In particular, the GCP combination may be the optimal ACH regimen for improving postoperative survival outcomes. Additional well-designed, large scale, prospective, randomized trials are still required to establish the optimal ACH regimen in MIBC patients.

Pathological T0 Following Cisplatin-Based Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Network Meta-analysis.

To systematically assess and compare the relationship between various neoadjuvant chemotherapy regimens and pCR in patients with muscle-invasive bladder cancer. We performed a literature search of PubMed, Embase, and the Cochrane Library for all articles published before March 2015 and according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. There were 17 articles that met the study eligibility criteria and were selected for the final analysis. A direct pair-wise meta-analysis was performed for studies that compared the same regimen. Finally, a Bayesian network meta-analysis was used to indirectly compare the regimens. In a pair-wise meta-analysis, the methotrexate/vinblastine/Adriamycin/cisplatin [MVAC; OR, 4.36; 95% confidence interval (CI), 2.71-7.02] and gemcitabine/cisplatin (GC) regimens (OR, 4.92; 95% CI, 2.93-8.24) were significantly associated with a better pCR than RC alone. In a network meta-analysis, there was no significant difference in terms of pCR achievement between the GC and MVAC regimens (OR, 1.14; 95% CI; 0.85-1.70). However, in a subgroup network meta-analysis that only included prospective randomized trials, the MVAC regimen was significantly correlated with a higher rate of pCR (OR, 5.75; 95% CI, 1.96-24.18). The results of this meta-analysis suggest that a GC regimen was associated with a pCR rate that was similar to that of a MVAC regimen based on retrospective data, but only the MVAC regimen was proven to achieve pCR in prospective randomized trials. Additional prospective randomized trials comparing both regimens will be necessary to establish the optimal neoadjuvant chemotherapy regimen.

A systematic review of post first-line treatments for advanced gastrointestinal stromal tumor (GIST): Direct pairwise meta-analyses and indirect comparisons.

195 Background: Treatment for metatastatic or unresectable GIST is with imatinib. The majority of patients eventually acquire imatinib resistance, prompting the development of a growing number of agents as post-first-line treatment. Currently no studies directly compare these treatments. Methods: A systematic review was performed through MEDLINE, EMBASE, CENTRAL, and ASCO meeting abstracts up to July 2014 to identify randomized controlled trials that included GIST patients who were previously treated with a first-line chemotherapy for advanced disease. Progression-free survival (PFS) and overall survival (OS) with 95% credible regions were extracted using the Parmar method. Direct pairwise meta-analyses and indirect comparisons using the Bucher method were performed. Results: Four studies were identified for the systematic review. 1 study (n=312) showed that sunitinib in the second-line setting (vs. placebo) improved PFS but not OS. 3 studies (n=528) examined the third-line setting (imatinib resumption vs. placebo; regorafenib vs. placebo; nilotinib vs. best supportive care with or without imatinib or sunitinib). Of the 3 third-line studies, there was significant heterogeneity between placebo-controlled trials and the non-placebo controlled trial (I2= 98%). Direct pairwise meta-analysis using random-effects of the 2 placebo-controlled studies showed that the PFS hazard ratio (HR) was 0.63 (0.22-0.61, p=0.0001), whereas the PFS HR for the non-placebo controlled study was 0.90 (0.65-1.26, p=0.56). These 2 HRs are different statistically (interaction: p=0.002). Indirect comparisons of imatinib resumption vs. regorafenib suggested that the PFS HR was 0.59 (0.31-1.11, p=0.10), trending in favor of regorafenib. OS HRs were not significant for direct or indirect comparison in the third-line setting. Conclusions: The number and size of completed phase III studies and the lack of a standard comparator arm limit the use of direct and indirect comparison methods to determine the best therapeutic option for patients who have progressed on imatinib. At this time, clinicians should interpret the available evidence at an individual level.

The efficacy and safety of different anticoagulants on patients with severe sepsis and derangement of coagulation: a protocol for network meta-analysis of randomised controlled trials

IntroductionSepsis is the leading cause of mortality in non-cardiological critically ill patients. There are as many as 20 million cases of sepsis annually worldwide, with a mortality rate of around...

Prevention of type 2 diabetes - where is the evidence?

Diabetes is an “old disease”. The first description of diabetes written on papyrus about 3500 years ago is found in the Ebers papyrus, which was discovered in Egypt in 1873 by the German archeologist Georg Ebers. Humans, like most mammals, may develop diabetes, if sufficient environmental exposure to physical inactivity, unhealthy diet and obesity are present. Genetic effects are important for the individual risk of type 2 diabetes (T2D) but twin studies have shown that the genetic effects combined explain less than 50% of the risk of T2D (1). Today we know almost 100 susceptibility genes associated with T2D but the relative importance of each of these genes is low (2), and together they explain only a small part of the disease risk. Thus, genetic screening cannot be used for the prediction of T2D for individuals. On the other hand, healthy lifestyle can also prevent T2D in people who are genetically at high risk, e.g. those with positive family history (3). Thus, the importance of lifestyle factors for the development and prevention of T2D is overwhelming. The strongest evidence in medicine is considered to come from randomized controlled trials (RCTs). They are also important in providing the link to causal inference that in most observational studies cannot be derived. At the same time, observational studies are necessary for the identification of factors associated with an increased or decreased risk of a disease, and for generation of hypotheses on potential means for prevention based on modifiable risk factors. Observational studies have by now identified a large number of factors that are associated with the development of T2D or with the protection against it. Most of them are related to physical activity, diet and obesity. It has also been shown unequivocally that exposures (poor nutrition, infections, smoking, etc.) during fetal life and early infancy resulting in insufficient development (often shown as low birth weight) also predict T2D later in life (4). Traditionally, T2D has been considered to be a disease of the elderly. However, with increasing obesity and sedentary lifestyle in children, there are increasing numbers of cases of T2D already occurring at a young age in many populations (5). In the past two decades several innovative RCTs have repeatedly shown that interventions on modifiable risk factors can reduce the incidence of diabetes in high-risk groups. The evidence has been summarized in several systematic reviews and meta-analyses (6,7). There is compelling scientific evidence from RCTs that T2D can be prevented or its onset delayed. The key for prevention is a multimodal package of lifestyle changes that is a sum outcome of dietary and physical activity behaviours. The power of lifestyle was dramatically illustrated by the Finnish Diabetes Prevention Study (DPS) that explicitly showed that when the study participants with impaired glucose tolerance reached all five modest lifestyle intervention targets, none of them progressed to T2D (8). Importantly, lifestyle intervention lasting for 3–6 years has been shown to have a carry-over effect on T2D incidence that lasts for several years; up to 15 in the Finnish Diabetes Prevention Study (9) and 20 years in the China Da Qing Diabetes Prevention Study (10). The observed sustained risk reduction seems to be a result of sustained lifestyle changes, but the legacy effect of improved glycaemia during the early intervention may also have contributed to the long-term effect. The follow-up data from the Chinese study indicate moreover that vascular risks are also reduced by lifestyle management. Several prognostic questionnaires exist for detecting people at risk of T2D (11). One of the screening tools with an adequately high sensitivity and specificity is the Finnish Diabetes Risk Score (FINDRISC) developed in Finland (12). The FINDRISC has been successfully implemented in the Finnish primary health care system and used also in many other countries. The FINDRISC was also tested in the Omani population and as a result a slightly modified Omani Diabetes Risk Score was developed (13) which may be a suitable screening tool for the Arab populations in the Middle East. Lifestyle interventions aiming at translating evidence from efficacy RCTs on T2D prevention into “real world” intervention programmes have also been carried out in various populations. Such data were recently combined in a meta-analysis considering the relationship between intervention effectiveness and adherence to guidelines (14). The primary meta-analysis included 22 studies with outcome data for weight loss at 12 months. The pooled result of the direct pairwise meta-analysis shows that lifestyle

Diabetes Prevention in the Real World: Effectiveness of Pragmatic Lifestyle Interventions for the Prevention of Type 2 Diabetes and of the Impact of Adherence to Guideline Recommendations

OBJECTIVE To summarize the evidence on effectiveness of translational diabetes prevention programs, based on promoting lifestyle change to prevent type 2 diabetes in real-world settings and to examine whether adherence to international guideline recommendations is associated with effectiveness. RESEARCH DESIGN AND METHODS Bibliographic databases were searched up to July 2012. Included studies had a follow-up of ≥12 months and outcomes comparing change in body composition, glycemic control, or progression to diabetes. Lifestyle interventions aimed to translate evidence from previous efficacy trials of diabetes prevention into real-world intervention programs. Data were combined using random-effects meta-analysis and meta-regression considering the relationship between intervention effectiveness and adherence to guidelines. RESULTS Twenty-five studies met the inclusion criteria. The primary meta-analysis included 22 studies (24 study groups) with outcome data for weight loss at 12 months. The pooled result of the direct pairwise meta-analysis shows that lifestyle interventions resulted in a mean weight loss of 2.12 kg (95% CI -2.61 to -1.63; I(2) = 91.4%). Adherence to guidelines was significantly associated with a greater weight loss (an increase of 0.3 kg per point increase on a 12-point guideline-adherence scale). CONCLUSIONS Evidence suggests that pragmatic diabetes prevention programs are effective. Effectiveness varies substantially between programs but can be improved by maximizing guideline adherence. However, more research is needed to establish optimal strategies for maximizing both cost-effectiveness and longer-term maintenance of weight loss and diabetes prevention effects.

The Efficacy and Safety of Different Kinds of Laparoscopic Cholecystectomy: A Network Meta Analysis of 43 Randomized Controlled Trials

Background and ObjectiveWe conducted a network meta analysis (NMA) to compare different kinds of laparoscopic cholecystectomy [LC] (single port [SPLC], two ports [2PLC], three ports [3PLC], and four ports laparoscopic cholecystectomy [4PLC], and four ports mini-laparoscopic cholecystectomy [mini-4PLC]).MethodsPubMed, the Cochrane library, EMBASE, and ISI Web of Knowledge were searched to find randomized controlled trials [RCTs]. Direct pair-wise meta analysis (DMA), indirect treatment comparison meta analysis (ITC) and NMA were conducted to compare different kinds of LC.ResultsWe included 43 RCTs. The risk of bias of included studies was high. DMA showed that SPLC was associated with more postoperative complications, longer operative time, and higher cosmetic score than 4PLC, longer operative time and higher cosmetic score than 3PLC, more postoperative complications than mini-4PLC. Mini-4PLC was associated with longer operative time than 4PLC. ITC showed that 3PLC was associated with shorter operative time than mini-4PLC, and lower postoperative pain level than 2PLC. 2PLC was associated with fewer postoperative complications and longer hospital stay than SPLC. NMA showed that SPLC was associated with more postoperative complications than mini-4PLC, and longer operative time than 4PLC.ConclusionThe rank probability plot suggested 4PLC might be the worst due to the highest level of postoperative pain, longest hospital stay, and lowest level of cosmetic score. The best one might be mini-4PLC because of highest level of cosmetic score, and fewest postoperative complications, or SPLC because of lowest level of postoperative pain and shortest hospital stay. But more studies are needed to determine which will be better between mini-4PLC and SPLC.

A comparison of biologics in first-line advanced colorectal cancer: A Bayesian network meta-analysis of EGFR inhibitors and bevacizumab.

543 Background: Adding bevacizumab (B) or EGFR inhibitors (E) to chemotherapy have improved outcomes when compared to chemotherapy (chemo) alone in the first-line treatment of mCRC, however it is unclear which of these combinations is optimal. As the 2 RCTs presented to date were not powered to detect overall survival (OS) benefits and have shown conflicting OS results, a meta-analysis may be beneficial. Methods: We conducted a systematic review of RCTs comparing (1) E + chemo vs. B + chemo (2) E + chemo vs. chemo only, or (3) B + chemo vs. chemo only, using MEDLINE, Embase, Cochrane Central, and ASCO abstracts up to June 2013 with Cochrane methodology. Data on PFS and OS were extracted using the Parmar method. For RCTs involving E, only the K-ras WT data was included. The patient characteristics and outcomes of the reference arms of the RCTs were examined to assess for heterogeneity. Bayesian pairwise and network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios comparing E to B using WinBUGs. Results: Seventeen RCTs (8,048 patients) were identified; 15 of them contained extractable data for quantitative analysis. Direct pairwise meta-analyses (2 RCTs) comparing E vs. B showed that PFS HR=1.00 (95% credible regions (CR): 0.86-1.17) and OS HR=0.76 (95% CR: 0.63-0.92) in favour of E. Indirect comparisons of E vs. B (through the intermediate of chemo only: 5 RCTs comparing E + chemo vs. chemo only, 8 RCTs comparing B + chemo vs. chemo only) showed that PFS HR=1.31 (95% CR: 0.98-1.85) and OS HR=1.06 (95% CR: 0.93-1.22). Combining direct and indirect comparisons with NMA (15 RCTs) showed that the PFS HR=1.10 (95% CR: 1.00-1.21) (trend in favour of B) and OS HR=0.95 (95% CR: 0.85-1.06). Conclusions: The results of direct pairwise meta-analysis, dominated mostly by FIRE-3, suggested E improves OS without PFS benefits when compared to B. However, the results from indirect or combined NMA synthesizing all relevant data from the existing literature did not confirm those findings. The findings of FIRE-3 may be due to chance or trial specific reasons. The results of the upcoming CALGB 80405 will provide further direct evidence to help refine these estimates.