Improvement of survival after surgical resection of pancreatic cancer independent of adjuvant chemotherapy in the past two decades – A meta-regression

IntroductionSurgical resection improves survival in pancreatic ductal adenocarcinoma (PDAC) and adjuvant chemotherapy adds an additional survival-benefit. While surgical technique has improved in recent years, it remains unclear whether these improvements translate into a survival benefit independent of adjuvant chemotherapy. Thus, we aimed to clarify whether survival of patients who were treated with either Gemcitabine (GEM) or who were observed only in randomized controlled trials on adjuvant chemotherapy of PDAC improved over time.MethodsA systematic search of MEDLINE/PubMed was performed to identify randomized controlled trials on adjuvant chemotherapy of PDAC. The search was limited to studies with arms on GEM monotherapy or postoperative observation and studies were grouped by the median year of enrolment and the use of GEM. Subsequently, a meta-regression on the effect of the median year of enrolment on patient survival was performed.ResultsA total of 13 studies with 2469 patients was included, with median years of enrollment ranging from 1996 to 2015. While disease-free survival decreased in patients with postoperative observation (18.0 vs. 5.0 months, p = 0.001), median survival improved over time in patients with postoperative observation (15.8 vs. 18.4 months, p = 0.01) and in patients treated with adjuvant GEM (22.8 vs. 35.0 months, p < 0.001). One- (p ≤ 0.01) and two-year survival (p = 0.056) improved in both patients treated with adjuvant GEM and those observed only.ConclusionSurvival after surgical resection of PDAC has improved since 1996, even in patients who did not receive adjuvant chemotherapy. Improved surgical technique and postoperative management are likely to be causative factors.     

Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease: an updated meta-analysis

The objective of this study was to provide an updated meta-analysis of the efficacy and safety of huperzine A (HupA) in Alzheimer’s disease (AD). We searched for randomized trials comparing HupA with placebo in the treatment of AD. The primary outcome measures were mini-mental state examination (MMSE) and activities of daily living scale (ADL). Data were extracted from four randomized clinical trials and analyzed using standard meta-analysis and meta-regression methods. Oral administration of HupA for 8–24 weeks (300–500 μg daily) led to significant improvements in MMSE and ADL. The results of meta-regression showed that the estimated effect size of MMSE and ADL was increased over the treatment time. Most adverse events were cholinergic in nature and no serious adverse events occurred. Huperzine A is a well-tolerated drug that could significantly improve cognitive performance and ADL in patients with AD. B.-s. Wang and H. Wang contributed equally to this work.     

Effects of treatment with fluoride on bone mineral density and fracture risk - a meta-analysis

Summary Fluoride has fallen into discredit due to the absence of an anti-fracture effect. However, in this meta-analysis, a fracture reducing potential was seen at low fluoride doses [≤20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride)]: OR = 0.3, 95% CI: 0.1–0.9 for vertebral and OR = 0.5, 95% CI: 0.3–0.8 for non-vertebral fractures. Introduction Fluoride is incorporated into bone mineral and has an anabolic effect. However, the biomechanical competence of the newly formed bone may be reduced. Methods A systematic search of PubMed, Embase, and ISI web of science yielded 2,028 references. Results Twenty-five eligible studies were identified. Spine BMD increased 7.9%, 95% CI: 5.4–10.5%, and hip BMD 2.1%, 95% CI: 0.9–3.4%. A meta-regression showed increasing spine BMD with increasing treatment duration (5.04 ± 2.16%/year of treatment). Overall there was no significant effect on the risk of vertebral (OR = 0.8, 95% CI: 0.5–1.5) or non-vertebral fracture (OR = 0.8, 95% CI: 0.5–1.4). With a daily dose of ≤20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride), there was a statistically significant reduction in vertebral (OR = 0.3, 95% CI: 0.1–0.9) and non-vertebral (OR = 0.5, 95% CI: 0.3–0.8) fracture risk. With a daily dose >20 mg fluoride equivalents, there was no significant reduction in vertebral (OR = 1.3, 95% CI: 0.8–2.0) and non-vertebral (OR = 1.5, 95% CI: 0.8–2.8) fracture risk. Conclusions Fluoride treatment increases spine and hip BMD, depending on treatment duration. Overall there was no effect on hip or spine fracture risk. However, in subgroup analyses a low fluoride dose (≤20 mg/day of fluoride equivalents) was associated with a significant reduction in fracture risk.     

Using meta-regression in performing indirect-comparisons: comparing escitalopram with venlafaxine XR

ABSTRACT

Background: In the absence of well-powered, randomised, direct-comparison trials, indirect comparisons are the only option for comparing treatment strategies. Several methodologies have been developed and each has sparked criticism. Using direct comparisons of escitalopram versus venlafaxine extended release (XR), we explore the differences between the two compounds through indirect comparisons.

Methods: The CENTRAL, Medline and Embase databases were interrogated, focusing on randomized placebo-controlled clinical trials involving adult patients treated for major depressive disorder in the acute phase. Corresponding authors were contacted to reduce missing data. Effect sizes were derived from each study's primary outcome. For indirect comparisons, a global effect size was computed through meta-regression. For direct comparisons, the studies were considered separately due to missing data. Non-inferiority assessments were employed. The conclusion of the meta-regression was then compared with the conclusions made in direct comparison trials.

Results: Ten placebo-controlled studies – six assessing escitalopram and four assessing venlafaxine XR – and two direct comparison studies were retrieved. Escitalopram was found to be non-inferior to venlafaxine XR in both indirect and direct comparisons with results of mean –0.02 (unilateral 95% confidence interval [CI] –0.16 to ∞) and 0.23 (95% CI –0.01 to ∞), respectively. Results obtained by both indirect and direct comparisons were similar. Investigating the influence of age, gender repartition and severity at baseline suggests that results are consistent. Results were also considered robust against publication bias.

Conclusions: This empirical finding suggests that escitalopram is non-inferior to venlafaxine XR. This reinforces the evidence found in direct comparisons trials. Indirect comparisons through meta-regression may be suitable to support decision-making. To fully assess its potential, further evaluation of this methodology, using other examples, is needed.     

Association between difference in blood pressure reduction and risk of cardiovascular events in a type 2 diabetes population: A meta-regression analysis

AimRecent US recommendations indicate a target blood pressure (BP) of 130/80 mmHg for patients with type 2 diabetes (T2D). Our aim was to characterize the association between risk of cardiovascular events and differences in BP decreases in randomized trials of a T2D population.MethodsA systematic search was made for randomized clinical trials assessing the effects of antihypertensive treatments in T2D patients on mortality, and fatal and non-fatal cardiovascular events, using a meta-regression technique to explore the influence of BP decreases on treatment effects.ResultsA total of 88,503 patients from 44 randomized trials were included. There was no significant association between BP decreases and risk of all-cause or cardiovascular mortality, cardiovascular events or myocardial infarction. However, stroke risk was influenced by BP decreases: compared with no reduction, a 10-mmHg reduction in systolic BP was associated with a relative odds ratio (OR) decrease of 33% (OR: 0.67, 95% CI: 0.54–0.82), and a 5-mmHg diastolic BP reduction was associated with a relative OR decrease of 38% (OR: 0.62, 95% CI: 0.50–0.76). Restricting the analysis to double-blind studies did not change the results for diastolic BP.ConclusionA reduction in BP lowers the risk of stroke, but does not appear to affect the risk of other cardiovascular events in a T2D population.     

Meta回归与亚组分析在异质性处理中的应用

探讨Meta回归与亚组分析在异质性的识别与处理中的应用及意义.利用文献提供的二次数据建立Meta回归模型,筛选出异质性的影响因素,根据该因素做亚组分析,并比较亚组分析前后异质性的变化.Meta分析资料经异质性检验,Q=44.71,df=27,P=0.017,认为存在异质性.经Meta回归分析,从可能导致异质性的因素(研究时间、地区、样本量、病例对照比值等)中筛选出样本含量为异质性因素(P=0.012)、地区为可能的异质性因素(P=0.091).然后进行亚组分析,异质性明显减小(∑Q 由44.71减小至32.11).结论 :Meta回归法对筛选异质性影响因素比较简便可靠,据此进行的亚组分析能明显降低亚组内的异质性.故存在统计学异质性又要计算合并效应时推荐二者结合使用,可正确识别并降低异质性,从而使Meta分析结果更为稳健与合理.     

The mortality benefit seen with the newer more potent oral P2Y12 inhibitors prasugrel and ticagrelor over clopidogrel is dependent on the underlying risk: A class effect as suggested by a meta-regression analysis

BackgroundThe two newer oral P2Y₁₂ inhibitors prasugrel and ticagrelor have proven superior to clopidogrel in the treatment of acute coronary syndrome (ACS). The extent to which the reduction in mortality seen with ticagrelor is confined to this particular agent is hard to judge by simply looking at the overall study results as the study populations were composed of different cohorts at substantially different risk of death.MethodsA meta-regression technique was applied to 12 distinctive patient cohorts, six for each of prasugrel and ticagrelor, to investigate differential effects on mortality of P2Y₁₂ inhibitors.ResultsData for the analysis cohorts, totalling 37,372 patients, were extracted from publications and cover a widely comparable spectrum of patient types, defined by the type of ACS and treatment strategy. The meta-regression lines for cardiovascular mortality with prasugrel or ticagrelor (each versus clopidogrel), as well as for both agents pooled, indicate a linear relationship with increasing benefit seen with higher underlying risk (p = 0.007, 0.021 and 0.003, and R² = 0.87, 0.77 and 0.62, respectively).ConclusionsIn the ACS patients studied, we found a mortality benefit with the two newer oral P2Y₁₂ inhibitors prasugrel and ticagrelor when compared with clopidogrel, which increases progressively as the underlying risk of death increases. This appears to be a class effect for these two newer agents.     

Statins and risk of thromboembolism: A meta-regression to disentangle the efficacy-to-effectiveness gap using observational and trial evidence

Background and aimsMeta-analyses of randomised controlled trials (RCTs) and observational studies indicate a lower risk of venous thromboembolism (VTE) associated with statin treatment. We aimed to compare the effect of statin therapy in these two settings and to identify and quantify potential factors to explain statin efficacy and effectiveness.Methods and resultsWe electronically searched on December 11th, 2018, articles reporting on first VTE events in RCTs (statin vs placebo) and in observational studies (participants exposed vs non-exposed to statin). We performed Knapp-Hartung random-effect meta-analyses to calculate pooled relative risks (RRs) of VTE events associated with statin treatment, separately for RCTs and observational studies; and estimated the ratio of the relative risk (RRR) comparing RCTs and observational studies using meta-regressions, progressively adjusted for study-level characteristics. Twenty-one RCTs (115,107 participants; 959 events) and 8 observational studies (2,898,096 participants; 19,671 events) were included. Pooled RRs for RCTs and observational studies were 0.82 (95% confidence interval (CI): 0.67–1.00; I² 19.2%) and 0.60 (95% CI: 0.42–0.86; I² 86.3%), respectively. In meta-regressions, the unadjusted RRR indicated a nonsignificant 23% smaller benefit in RCTs (RRR 0.77; 95% CI: 0.52–1.13); accounting for age, sex, geographical region, and duration of follow-up, there was a sensible change of the RRR which resulted 0.30 (95% CI: 0.13–0.68).ConclusionDifferences in the characteristics between patients included in RCTs and those in observational studies may account for the differential effect of statins in preventing VTE in the two settings.     

饮水氟含量与龋齿率的剂量-效应关系的Meta回归分析

目的 研究饮水氟含量与龋齿率的剂量-效应关系,以确定预防龋齿的适宜水氟范围.方法 对检索国内外数据库得到的19篇关于我国饮水氟含量与龋齿率关系的文献进行Meta回归分析.采用分式多项式(fractional polynomial,FP)结合Logistic回归建立模型,同时考虑到数据质量差异,采取加权回归.结果 最优模型为最佳二阶FP模型,其拟合效果显著优于一般Logistic回归和最佳一阶FP模型.饮水氟含量与龋齿率呈U型剂量-效应关系,最低点的龋齿率为13.9％.饮水氟＞1.1 mg/L时,随着饮水氟含量的升高,龋齿率下降的速率减慢,因此,将此值定为氟的防龋上限值.结合饮水氟含量在0.6～1.1 mg/L区间内的龋齿率计算值,确定控制龋齿率为35％、30％时的适宜饮水氟含量范围分别为0.7～1.1mg/L和0.9～1.1 mg/L.结论 氟表现为低浓度防龋齿、中浓度无明显作用、高浓度加重龋齿,且其防龋齿作用有限.     

Meta-analysis of controlled trials of ventilator therapy in acute lung injury and acute respiratory distress syndrome: an alternative perspective

Objective The role of protective ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is controversial. Evidence was sought from published randomised trials for a consistent treatment effect of protective ventilation and any covariate modification.Design Meta-analysis of protective ventilation trials in ALI/ARDS and meta-regression of covariates on treatment effect (log odds ratio), with respect to 28-day mortality. Heterogeneity impact on the meta-analysis was assessed by the H statistic (substantial impact, >1.5) and graphical analysis. Five trials with a total of 1,202 patients were considered.Measurements and results Average 28-day mortality was 0.40 in the treatment group (protective ventilation, n=605) vs. 0.46 in the control group (control ventilation, n=597). The treatment effect (odds ratio) was: fixed-effects, 0.71 (95% CI 0.56–0.91, p=0.006; heterogeneity, p=0.06) and random effects: 0.80 (95% CI 0.49–1.31, p=0.37). Heterogeneity impact (H statistic=1.50) was adjudged as modest. The treatment effect was significant and (a) favoured protective ventilation for a tidal volume less than 7.7 ml/kg predicted (treatment group) and a mean plateau pressure of 30 cmH₂O or higher (control group) but was not influenced by plateau pressure 21–30 cmH₂O (treatment group) and (b) depended upon plateau pressure difference greater than 5–7 cmH₂O between protective ventilation and standard ventilation.Conclusions Overall treatment effect estimate favoured protective ventilation but did not achieve statistical significance. Protective ventilation depended upon threshold levels of tidal volume, plateau pressure, and plateau pressure difference.Electronic Supplementary Material Electronic supplementary material to this paper can be obtained by using the Springer Link server located at .