Model-based Meta-Analysis on the Efficacy of Pharmacological Treatments for Idiopathic Pulmonary Fibrosis.

Recently, the US Food and Drug Administration (FDA) approved the first two drugs (pirfenidone and nintedanib) indicated for the treatment of idiopathic pulmonary fibrosis (IPF). The purpose of this analysis was to leverage publicly available data to quantify comparative efficacy of compounds that are approved or in development. An analysis-ready database was developed, and the analysis dataset is composed of summary-level data from 43 arms in 20 trials, with treatment durations ranging from 8-104 weeks. A hierarchical multivariable regression model with nonparametric placebo estimation was used to fit the longitudinal profile of change from baseline of percent predicted forced vital capacity (%predicted FVC) data. Pirfenidone and nintedanib were the only drugs identified to have significant estimated positive treatment effects. Model simulations were performed to further evaluate the covariate and time course of treatment effects on longitudinal change from baseline %predicted FVC to inform future trial designs and support decision making.

Exploratory Literature Meta-Analysis to Characterize the Relationship Between Early and Longer Term Body Weight Loss for Antiobesity Compounds.

The presented analysis was performed to characterize the relationship between treatment-related early (week 4) and longer term (3-6 months) weight loss to understand the potential utility of 4-week proof-of-mechanism studies in the early decision-making process during clinical development of new antiobesity compounds. A regression-based meta-analysis was performed leveraging publically available clinical outcomes data to (1) characterize the within-trial relationship between treatment-related early and longer term body weight loss and (2) identify and quantify key covariate effects on this relationship. Data from 89 randomized clinical trials with 209 treatment arms, representing observations from 54 461 patients and 9 treatments, were available for the meta-analysis. Results indicated that (1) there is a correlation between treatment-related early and longer term body weight loss (r > 0.9), (2) baseline body weight influences the relationship between early and longer term weight loss, whereas comorbidity such as type 2 diabetes mellitus, class of drugs including GLP-1 analogues and the antiobesity compounds lorcaserin or phentermine/topiramate showed no significant effects on this relationship. The model was externally evaluated with data from the investigational compound beloranib, for which longer term weight loss could be successfully predicted based on early response data. Based on these results, the identified strong relationship between treatment-related early and longer term weight loss appears to be independent of mechanism of action. Thus, findings from this analysis can optimize design of clinical studies and facilitate development of new anti-obesity compounds.

Under-reporting of venous and arterial thrombotic events in randomized clinical trials: a meta-analysis.

For the detection of unwanted outcomes of new interventions, physicians rely on adverse event reporting. We attempt to quantify the reported incidence of venous thromboembolism (VTE) and arterial thrombosis (AT) in randomized clinical trials (RCTs), and evaluate the extent of under-reporting. We selected all therapeutic RCTs published in the four highest-impact general medicine journals between January 2011 and July 2011. Patients were categorized according to VTE risk. The occurrences of VTE and AT, either as predefined outcome or adverse event, were assessed. We identified 131 RCTs. VTE and AT were not reported in 89 and 70 % of these studies, respectively. The raw-unweighted reported incidence in the 3 studies with predefined outcomes for VTE was 8.4 (7.8-9.1) per 1,000 person-years. In the 128 studies without predefined outcomes for VTE, (consisting of 322,029 individuals, including patients with cancer, inflammatory disease, cardiovascular disease, surgery, adding up to a follow-up >500,000 person-years), an incidence of 0.4 (0.4-0.5) per 1,000 person-years was found. The reported incidence of AT in 18 studies in which AT was part of predefined outcomes was 25.6 (24.9-26.3) per 1,000 person-years. In 92 studies without predefined outcomes for AT (231,638 individuals, follow-up >200,000 person-years,), the incidence was 2.5 (2.3-2.7) per 1,000 person-years. The incidence of VTE and AT in RCTs is highly under-reported. Uniform registration of adverse events, even when unlikely to be related to the intervention, is necessary to be able to inform physicians about the potential toxicities of new therapeutic strategies.

Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment.

Thrombomodulin alfa is a soluble recombinant human thrombomodulin that was reported to enhance the reversal of disseminated intravascular coagulation (DIC) in subjects with sepsis or hematologic malignancy and reduce mortality in subjects with sepsis and DIC. Population pharmacokinetic (PK) analysis of thrombomodulin alfa was performed based on rich samples collected in 24 healthy subjects (0.02 and 0.06 mg/kg) and sparse samples collected in 368 subjects with sepsis and DIC (0.06 mg/kg). Sources of variability (baseline characteristics, markers of renal/liver function, hematocrit, and disease severity) were explored using non-linear mixed effect modeling to support dosing rationale in patients with sepsis and DIC. Plasma concentrations of thrombomodulin alfa were best fitted with a one-compartment model. Body weight and creatinine clearance were important covariates describing the PK of thrombomodulin alfa. Typical CL values in patients with normal renal function, or mild, moderate and severe renal impairment were 0.158, 0.145, 0.128, and 0.105 L/h, respectively. Based on simulations, a 0.06 mg/kg dosing of thrombomodulin alfa is expected to result in drug exposure within the therapeutic range of the product (300-5,400 ng/mL), with minimum risks of bleeding in patient with normal and impaired renal functions.

Laparoscopy versus open distal gastrectomy by expert surgeons for early gastric cancer in Japanese patients: short-term clinical outcomes of a randomized clinical trial.

BACKGROUND: Short-term outcomes of laparoscopy-assisted distal gastrectomy (LADG) and open DG (ODG) have been investigated in previous clinical trials, but operative techniques and concomitant treatments have evolved, and up-to-date evidence produced by expert surgeons is required to provide an accurate image of the relative efficacies of the treatments. The purpose of this study was to compare laparoscopic versus ODG with respect to specific primary and secondary short-term outcomes. METHODS: From October 2005 to February 2008, a total of 64 patients with early gastric cancer were randomly assigned to the LADG or the ODG group. One patient was excluded due to concurrent illness unrelated to the intervention, so the data from 63 patients were analyzed. The primary short-term outcome was the 4-day postoperative use of analgesics. Secondary short-term outcomes were postoperative residual pain, complications, days hospitalized, blood data, days with fever, and days to first flatus. RESULTS: There was a significant difference in favor of LADG for postoperative use of analgesics (P = 0.022). Unexpectedly, there was no significant difference in degree of pain in the immediate postoperative period, putatively due to the optimal use of analgesics. Of the secondary outcomes, residual pain at postoperative day 7 (P = 0.003) and days to first flatus (P = 0.001) were significantly better with LADG. Postoperative complications, number of days hospitalized, and number of days with fever were also better with LADG, but the differences were not significant. Blood data representing inflammation (WBC and CRP) showed marked differences, especially on postoperative day 7 (P = 0.0016 and P = 0.0061, respectively). CONCLUSIONS: LADG performed by expert surgeons results in less postoperative pain accompanied by decreased surgical invasiveness and is associated with fewer postoperative inconveniences. No preliminary suggestions of changes in long-term curability were observed. LADG for early gastric cancer is a feasible and safe procedure with short-term clinical results superior to those of ODG.

Supervised walking therapy in patients with intermittent claudication.

OBJECTIVE: Exercise therapy is a common intervention for the management of intermittent claudication (IC). However, considerable uncertainty remains about the effect of different exercise components such as intensity, duration, or content of the exercise programs. The aim of this study was to assess the effectiveness of supervised walking therapy (SWT) as treatment in patients with IC and to update and identify the most important exercise components resulting in an optimal training protocol for patients with IC. METHODS: A systematic literature search using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases was performed. Randomized controlled trials (RCTs) published between January 1966 and February 2012 were included if they evaluated the effectiveness of SWT. Predefined exercise components were extracted, including treadmill use during training, claudication pain end point used during walking, length of the SWT program, and total training volume. A meta-analysis and meta-regression was performed to evaluate the weighted mean difference in maximum walking distance (MWD) and pain-free walking distance (PFWD) between SWT and noninterventional observation. RESULTS: Twenty-five RCTs (1054 patients) comparing SWT vs noninterventional observation showed a weighted mean difference of 180 meters (95% confidence interval, 130-230 meters) in MWD and 128 meters (95% confidence interval, 92-165 meters) in PFWD, both in favor of the SWT group. In multivariable meta-regression analysis, none of the predefined exercise components were independently associated with significant improvements in MWD or PFWD. CONCLUSIONS: SWT is effective in improving MWD and PFWD in patients with IC. However, pooled results from the RCTs did not identify any of the exercise components including intensity, duration, or content of the program as being independently associated with improvements in MWD or PFWD.

ST analysis of the fetal electrocardiogram in intrapartum fetal monitoring: a meta-analysis.

OBJECTIVE: To compare the effects of ST-waveform analysis in combination with cardiotocography with conventional cardiotocography for intrapartum fetal monitoring. DATA SOURCES: We searched MEDLINE, Embase, and PubMed for randomized controlled trials (RCTs) evaluating ST-waveform analysis for intrapartum fetal monitoring. METHODS OF STUDY SELECTION: We identified RCTs that compared ST-waveform analysis and conventional cardiotocography for intrapartum fetal monitoring of singleton pregnancies in cephalic presentation beyond 34 weeks of gestation and evaluating at least one of the following: metabolic acidosis, umbilical cord pH less than 7.15, umbilical cord pH less than 7.10, umbilical cord pH less than 7.05, umbilical cord pH less than 7.00, Apgar scores less than 7 at 5 minutes, admittance to the neonatal intensive care unit, need for intubation, presence of hypoxic ischemic encephalopathy, perinatal death, operative delivery, and number of fetal blood samplings. TABULATION, INTEGRATION, AND RESULTS: Five RCTs, which included 15,352 patients, met the selection criteria. Random-effects models were used to estimate the combined relative risks (RRs) of ST analysis compared with conventional cardiotocography. Compared with conventional cardiotocography, ST analysis showed a nonsignificant reduction in metabolic acidosis (RR 0.72, 95% confidence interval 0.43-1.19, number needed to treat [NNT] 357). ST analysis significantly reduced the incidence of additional fetal blood sampling (RR 0.59, 95% confidence interval 0.44-0.79, NNT 11), operative vaginal deliveries (RR 0.88, 95% confidence interval 0.80-0.97, NNT 64), and total operative deliveries (RR 0.94, 95% confidence interval 0.89-0.99, NNT 64). For other outcomes, no differences in effect were seen between ST analysis and conventional cardiotocography, or data were not suitable for meta-analysis. CONCLUSION: The additional use of ST analysis for intrapartum monitoring reduced the incidence of operative vaginal deliveries and the need for fetal blood sampling but did not reduce the incidence of metabolic acidosis at birth.

Beyond publication bias.

In drug development, clinical medicine, or health policy making, basing one's decisions on a selective part of the available evidence can pose a major threat to the health of patients and the society. If, for example, primarily positive research reports are taken into account, one could wrongfully conclude that a harmful drug is safe. The systematic error introduced by summarizing evidence that is not representative of the available evidence is commonly referred to as "publication bias." Some, however, prefer other terms to refer to the same concept. In this article, we explore the terminology and concepts relevant to this bias and propose a more systematic nomenclature than what is currently used.

Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery.

BACKGROUND: A combination of general anesthesia (GA) with thoracic epidural anesthesia (TEA) may have a beneficial effect on clinical outcomes after cardiac surgery. We have performed a meta-analysis to compare mortality and cardiac, respiratory, and neurologic complications in patients undergoing cardiac surgery with GA alone or a combination of GA with TEA. METHODS: Randomized studies comparing outcomes in patients undergoing cardiac surgery with either GA alone or GA in combination with TEA were retrieved from PubMed, Science Citation index, EMBASE, CINHAL, and Central Cochrane Controlled Trial Register databases. RESULTS: The search strategy yielded 1,390 studies; 28 studies that included 2,731 patients met the selection criteria. Compared with GA alone, the combined risk ratio for patients receiving GA with TEA was 0.81 (95% CI: 0.40-1.64) for mortality, 0.80 (95% CI: 0.52-1.24) for myocardial infarction, and 0.59 (95% CI: 0.24-1.46) for stroke. The risk ratios for the respiratory complications and supraventricular arrhythmias were 0.53 (95% CI: 0.40-0.69) and 0.68 (95% CI: 0.50-0.93), respectively. CONCLUSIONS: This meta-analysis showed that the use of TEA in patients undergoing cardiac surgery reduces the risk of postoperative supraventricular arrhythmias and respiratory complications. The sparsity of events precludes conclusions about mortality, myocardial infarction, and stroke, but the estimates suggest a reduced risk after TEA. The risk of side effects of TEA, including epidural hematoma, could not be assessed with the current dataset, and therefore TEA should be used with caution until its benefit-harm profile is further elucidated.

Detection of lymph node metastases by gadolinium-enhanced magnetic resonance imaging: systematic review and meta-analysis.

BACKGROUND: Gadolinium-based contrast agents are used with magnetic resonance imaging (MRI) to highlight tumor vascularity in organs. They are also widely used for primary tumor visualization. We conducted a systematic review and meta-analysis of the existing evidence of the accuracy of gadolinium-enhanced MRI for staging lymph node metastases. METHODS: We systematically searched the MEDLINE, Cochrane, CANCERLIT, and EMBASE databases for studies published in English or German from January 1, 1988, to January 1, 2008, that assessed the diagnostic accuracy of gadolinium-enhanced MRI in the evaluation of lymphatic metastases compared with histopathologic examination as the reference test. Based on a priori-defined clinical considerations, we studied three subgroups of studies: those that used a single malignancy criterion and those that used multiple malignancy criteria with or without contrast highlighting. Summaries of MRI sensitivity and specificity for detecting lymph node metastases were calculated using a bivariate regression model. All statistical tests were two-sided. RESULTS: The literature search yielded 43 full-text papers that were considered for inclusion in the meta-analysis. We performed quantitative pooled analyses on the 32 studies that provided data on patient-level diagnosis. The weighted estimates of sensitivity and specificity for all studies combined were 0.72 (95% confidence interval [CI] = 0.66 to 0.79) and 0.87 (95% CI = 0.82 to 0.91). Estimates of sensitivity and specificity were essentially unchanged for studies that used a single malignancy criterion (0.71 [95% CI = 0.61 to 0.79] and 0.88 [95% CI = 0.80 to 0.93], respectively; n = 11 studies) or multiple malignancy criteria without contrast enhancement (0.70 [95% CI = 0.58 to 0.79] and 0.86 [95% CI = 0.68 to 0.94], respectively; n = 6 studies). The sensitivity increased to 0.84 (95% CI = 0.70 to 0.92), with a specificity of 0.82 (95% CI = 0.72 to 0.89) for the nine studies that incorporated contrast enhancement in their multiple malignancy criteria. Six studies did not define the malignancy criteria they used. CONCLUSIONS: The overall accuracy of gadolinium-enhanced magnetic resonance imaging for the detection of nodal metastases is moderate. Incorporating contrast enhancement in the malignancy criteria substantially improves the accuracy of this diagnostic test.

Repeatability, reproducibility, and agreement characteristics of rotating Scheimpflug photography and scanning-slit corneal topography for corneal power measurement.

PURPOSE: To evaluate the repeatability, reproducibility, and agreement in anterior, posterior, and in particular the total corneal power of 2 topography devices, rotating Scheimpflug photography and scanning-slit topography. SETTING: Department of Ophthalmology and Visual Science, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan. METHODS: Seventeen eyes of 17 subjects (mean age 24.7 years +/- 4.1 [SD]) were included in the study. The corneal shapes within the central 3.0 mm were measured with rotating Scheimpflug photography (Pentacam) and scanning-slit corneal topography (Orbscan II). The within-rater repeatability and reproducibility of 2 raters and the overall between-instrument agreement of the measurements were evaluated using intraclass correlation coefficients (ICCs) and the Bland-Altman method. RESULTS: The repeatability of Scheimpflug photography and scanning-slit corneal topography was high (ICC, 0.70 to 0.99). Scheimpflug photography outperformed scanning-slit corneal topography for anterior power, posterior power, and total corneal power. The reproducibility results were similar, with limits of agreement (LoA) consistently narrower for Scheimpflug photography. The between-instrument agreement was moderate, with LoA around the mean value of total corneal power of 0.46 diopter ranging from 0.032 to 0.889. CONCLUSIONS: The results suggest that repeatability and reproducibility are higher in Scheimpflug photography than in scanning-slit topography. The agreement between rotating Scheimpflug photography and scanning-slit topography for total corneal power was moderate.

More than numbers: the power of graphs in meta-analysis.

In meta-analysis, the assessment of graphs is widely used in an attempt to identify or rule out heterogeneity and publication bias. A variety of graphs are available for this purpose. To date, however, there has been no comparative evaluation of the performance of these graphs. With the objective of assessing the reproducibility and validity of graph ratings, the authors simulated 100 meta-analyses from 4 scenarios that covered situations with and without heterogeneity and publication bias. From each meta-analysis, the authors produced 11 types of graphs (box plot, weighted box plot, standardized residual histogram, normal quantile plot, forest plot, 3 kinds of funnel plots, trim-and-fill plot, Galbraith plot, and L'Abbé plot), and 3 reviewers assessed the resulting 1,100 plots. The intraclass correlation coefficients (ICCs) for reproducibility of the graph ratings ranged from poor (ICC = 0.34) to high (ICC = 0.91). Ratings of the forest plot and the standardized residual histogram were best associated with parameter heterogeneity. Association between graph ratings and publication bias (censorship of studies) was poor. Meta-analysts should be selective in the graphs they choose for the exploration of their data.

A systematic comparison of software dedicated to meta-analysis of causal studies.

BACKGROUND: Our objective was to systematically assess the differences in features, results, and usability of currently available meta-analysis programs. METHODS: Systematic review of software. We did an extensive search on the internet (Google, Yahoo, Altavista, and MSN) for specialized meta-analysis software. We included six programs in our review: Comprehensive Meta-analysis (CMA), MetAnalysis, MetaWin, MIX, RevMan, and WEasyMA. Two investigators compared the features of the software and their results. Thirty independent researchers evaluated the programs on their usability while analyzing one data set. RESULTS: The programs differed substantially in features, ease-of-use, and price. Although most results from the programs were identical, we did find some minor numerical inconsistencies. CMA and MIX scored highest on usability and these programs also have the most complete set of analytical features. CONCLUSION: In consideration of differences in numerical results, we believe the user community would benefit from openly available and systematically updated information about the procedures and results of each program's validation. The most suitable program for a meta-analysis will depend on the user's needs and preferences and this report provides an overview that should be helpful in making a substantiated choice.

Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death.

A recent, widely publicized meta-analysis of 42 clinical trials concluded that rosiglitazone was associated with an approximately 43% increased risk for myocardial infarction and an approximately 64% increased risk for cardiovascular death. The sensitivity of these conclusions to several methodological choices was not assessed. The meta-analysis was not based on a comprehensive search for all studies that might yield evidence about rosiglitazone's cardiovascular effects. Studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in study design and outcome assessment. The meta-analytic approach that was used required the exclusion of studies with zero events in the treatment and control groups. Alternative meta-analytic approaches that use continuity corrections show lower odds ratios that are not statistically significant. We conclude that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain: Neither increased nor decreased risk is established.

Polychotomization of continuous variables in regression models based on the overall C index.

BACKGROUND: When developing multivariable regression models for diagnosis or prognosis, continuous independent variables can be categorized to make a prediction table instead of a prediction formula. Although many methods have been proposed to dichotomize prognostic variables, to date there has been no integrated method for polychotomization. The latter is necessary when dichotomization results in too much loss of information or when central values refer to normal states and more dispersed values refer to less preferable states, a situation that is not unusual in medical settings (e.g. body temperature, blood pressure). The goal of our study was to develop a theoretical and practical method for polychotomization. METHODS: We used the overall discrimination index C, introduced by Harrel, as a measure of the predictive ability of an independent regressor variable and derived a method for polychotomization mathematically. Since the naïve application of our method, like some existing methods, gives rise to positive bias, we developed a parametric method that minimizes this bias and assessed its performance by the use of Monte Carlo simulation. RESULTS: The overall C is closely related to the area under the ROC curve and the produced di(poly)chotomized variable's predictive performance is comparable to the original continuous variable. The simulation shows that the parametric method is essentially unbiased for both the estimates of performance and the cutoff points. Application of our method to the predictor variables of a previous study on rhabdomyolysis shows that it can be used to make probability profile tables that are applicable to the diagnosis or prognosis of individual patient status. CONCLUSION: We propose a polychotomization (including dichotomization) method for independent continuous variables in regression models based on the overall discrimination index C and clarified its meaning mathematically. To avoid positive bias in application, we have proposed and evaluated a parametric method. The proposed method for polychotomizing continuous regressor variables performed well and can be used to create probability profile tables.

Development and validation of MIX: comprehensive free software for meta-analysis of causal research data.

BACKGROUND: Meta-analysis has become a well-known method for synthesis of quantitative data from previously conducted research in applied health sciences. So far, meta-analysis has been particularly useful in evaluating and comparing therapies and in assessing causes of disease. Consequently, the number of software packages that can perform meta-analysis has increased over the years. Unfortunately, it can take a substantial amount of time to get acquainted with some of these programs and most contain little or no interactive educational material. We set out to create and validate an easy-to-use and comprehensive meta-analysis package that would be simple enough programming-wise to remain available as a free download. We specifically aimed at students and researchers who are new to meta-analysis, with important parts of the development oriented towards creating internal interactive tutoring tools and designing features that would facilitate usage of the software as a companion to existing books on meta-analysis. RESULTS: We took an unconventional approach and created a program that uses Excel as a calculation and programming platform. The main programming language was Visual Basic, as implemented in Visual Basic 6 and Visual Basic for Applications in Excel 2000 and higher. The development took approximately two years and resulted in the 'MIX' program, which can be downloaded from the program's website free of charge. Next, we set out to validate the MIX output with two major software packages as reference standards, namely STATA (metan, metabias, and metatrim) and Comprehensive Meta-Analysis Version 2. Eight meta-analyses that had been published in major journals were used as data sources. All numerical and graphical results from analyses with MIX were identical to their counterparts in STATA and CMA. The MIX program distinguishes itself from most other programs by the extensive graphical output, the click-and-go (Excel) interface, and the educational features. CONCLUSION: The MIX program is a valid tool for performing meta-analysis and may be particularly useful in educational environments. It can be downloaded free of charge via http://www.mix-for-meta-analysis.info or http://sourceforge.net/projects/meta-analysis.

Does neuromuscular electrical stimulation strengthen the quadriceps femoris? A systematic review of randomised controlled trials.

Devices for neuromuscular electrical stimulation (NMES) are increasingly used by individuals without specific injuries and are standard equipment in most physical therapy practices. The most often stimulated muscle group is the quadriceps femoris. We designed a systematic review and meta-analysis of randomised controlled trials to determine whether NMES is an effective modality for strength augmentation of the quadriceps femoris. A full content search for randomised controlled trials was performed in Medline, Embase, Cinahl, the Cochrane Controlled Trials Register and the Physical Therapy Evidence Database. Maximum volitional isometric or isokinetic muscle torque in Nm was used as main outcome measure.Thirty-five trials were included and evaluated. A fundamental distinction was made between the trials using subjects with unimpaired quadriceps femoris muscles and the trials using post-injury or post-operative subjects. In the unimpaired quadriceps subgroup, meta-analyses were performed for the comparisons 'NMES versus no exercises' and 'NMES versus volitional exercises'. All other comparisons were evaluated descriptively. The included trials were generally of poor quality and meta-analytic data indicate that publication bias may be present. The evaluated data suggest that, both for the unimpaired and impaired quadriceps, NMES makes sense compared with doing no exercises but volitional exercises appear to be more effective in most situations.Based on the available evidence, NMES may only be preferred over volitional training for within-cast muscle training and perhaps in specific situations where volitional training does not receive sufficient patient compliance. Further research should be directed toward identifying the clinical impact at activity and participation levels and the optimal stimulation parameters of this modality.