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Abstract Introduction Given the chronic nature of psoriasis (PsO), more studies are needed that directly compare the effectiveness of different biologics over long observation periods. This study compares the effectiveness and durability through 12 months of anti-interleukin (IL)-17A biologics relative to other approved biologics in patients with moderate-to-severe psoriasis in a real-world setting. Methods The Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of 1981 adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. The study compares the effectiveness of anti-IL-17A biologics with other approved biologics and provides pairwise comparisons of seven individual biologics versus ixekizumab. The primary outcome was defined as the proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA). Secondary objective comparisons included the proportion of patients who achieved PASI90, PASI100, a Dermatology Life Quality Index (DLQI) score of 0 or 1, and three different measures of durability of treatment response. Unadjusted response rates are presented alongside the primary analysis, which uses frequentist model averaging (FMA) to evaluate the adjusted comparative effectiveness. Results Compared to the other biologics cohort, the anti-IL-17A cohort had a higher response rate (68.0% vs. 65.1%) and significantly higher odds of achieving the primary outcome at month 12. The two cohorts had similar response rates for PASI100 (40.5% and 37.1%) and PASI90 (53.9% and 51.7%) at month 12, with no significant differences between the cohorts in the adjusted analyses. At month 12, the response rates across the individual biologics were 53.5–72.6% for the primary outcome, 27.6–48.3% for PASI100, and 41.7–61.4% for PASI90. Conclusions These results show the comparative effectiveness of biologics at 6 and 12 months in the real-world setting.

Objective To compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic (bDMARD)-naïve RA patients using matching-adjusted indirect comparisons (MAICs).Methods Data were from Phase III trials on patients receiving monotherapy baricitinib, tocilizumab, adalimumab, tofacitinib or MTX. Pain was assessed using a visual analogue scale (0–100 mm) and physical function using the Health Assessment Questionnaire-Disability Index (HAQ-DI). An MAIC based on treatment-arm matching, an MAIC with study-level matching and Bucher’s method without matching compared change in outcomes between therapies. Matching variables included age, gender, baseline disease activity and baseline value of outcome measure.Results With all methods, greater improvements were observed in pain and HAQ-DI at 6 months for baricitinib compared with adalimumab and tocilizumab (p

Despite the abundance of data concerning biologic treatments for patients with psoriasis, clinicians are often challenged with discerning the optimal treatment for each patient. To inform this selection, this study explored whether a patient's baseline characteristics or disease profile could predict the likelihood of achieving complete skin clearance with biologic treatment. Machine-learning and other statistical methods were applied to the substantial data collected from patients with moderate-to-severe psoriasis in the ongoing, international, prospective, observational Psoriasis Study of Health Outcomes (PSoHO). The 3 measures of complete skin clearance were a psoriasis area and severity index (PASI)100 response at (a) week 12, (b) month 12, and (c) week 12 and maintain ed at month 6 and month 12 (PASI100 durability). From these real-world data, the absence of nail psoriasis emerged  as the most consistent feature that may be used by clinicians to predict high-level treatment responses with biologic treatment. Other significant predictors of skin clearance with biologic treatments were the absence of hypertension and a lower body surface area affected by psoriasis. Overall, this study evidences the substantial challenge of identifying reliable clinical markers of treatment response for patients with psoriasis and highlights the importance of regular screening for psoriatic nail involvement.

Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies-which was statistically significant for the comparison with teriflunomide-this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis., Competing Interests: This work was funded by Eli Lilly and Company and all authors are employees of Eli Lilly and Company. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Alan J.M. Brnabic was involved with the conceptualization, methodology, investigation and formal analysis of the data for the work and contributed to the original draft preparation, review and editing of the manuscript. Sarah E. Curtis was involved with the conceptualization, methodology, investigation and formal analysis of the data for the work and contributed to the review and editing of the manuscript. Joseph A. Johnston was involved with the conceptualization, methodology and investigation of the data for the work, and contributed to the original draft preparation, review and editing of the manuscript. Albert contributed to the review and editing of the manuscript. Anthony J. Zagar was involved with the methodology and investigation of the data for the work and contributed to the original draft preparation of the manuscript. Ilya Lipkovich was involved with the methodology and validation of the data for the work and contributed to the original draft preparation of the manuscript. Zbigniew Kadziola was involved with the formal analysis of the data for the work and contributed to the review and editing of the manuscript. Megan H. Murray was involved with the investigation, methodology and formal analysis of the data for the work and contributed to the original draft preparation of the manuscript. Timothy Ryan was involved with the conceptualization and investigation of the data for the work and contributed to the original draft preparation, review and editing of the manuscript. All authors have participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors give final approval of the manuscript to be published., (Copyright: © 2024 Brnabic et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Medication use trends among patients with type 2 diabetes from 2015 to 2019 were investigated in relation to the clinical group-specific recommendations from the 2018 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus report. Data were drawn from a large health insurance claims database representing Commercial (total patient-year count: 2,379,704) and Medicare (total patient-year count: 845,823) insurance programmes (IBM® MarketScan®). The utilization of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists increased over time but was lower in the Medicare cohort in every year evaluated. Patients diagnosed with obesity received recommended therapies at higher rates than those without obesity. Differences were more modest between those with versus without atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease, with greater treatment adoption in those without ASCVD in the Medicare cohort. Utilization of recommended treatments was paradoxically lower in those with versus without heart failure, and worse in the Medicare than in the Commercial cohort. Utilization of sulphonylureas was not different in those with versus without severe hypoglycaemia history. In conclusion, utilization of therapies recommended in the guidelines is increasing overall, which is not preferentially guided by ADA/EASD-defined clinical groups, and there exists a persistent gap in utilization between Commercial and Medicare populations., (© 2022 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Unlike in randomized clinical trials (RCTs), confounding control is critical for estimating the causal effects from observational studies due to the lack of treatment randomization. Under the unconfoundedness assumption, matching methods are popular because they can be used to emulate an RCT that is hidden in the observational study. To ensure the key assumption hold, the effort is often made to collect a large number of possible confounders, rendering dimension reduction imperative in matching. Three matching schemes based on the propensity score (PSM), prognostic score (PGM), and double score (DSM, ie, the collection of the first two scores) have been proposed in the literature. However, a comprehensive comparison is lacking among the three matching schemes and has not made inroads into the best practices including variable selection, choice of caliper, and replacement. In this article, we explore the statistical and numerical properties of PSM, PGM, and DSM via extensive simulations. Our study supports that DSM performs favorably with, if not better than, the two single score matching in terms of bias and variance. In particular, DSM is doubly robust in the sense that the matching estimator is consistent requiring either the propensity score model or the prognostic score model is correctly specified. Variable selection on the propensity score model and matching with replacement is suggested for DSM, and we illustrate the recommendations with comprehensive simulation studies. An R package is available at https://github.com/Yunshu7/dsmatch., (© 2021 John Wiley & Sons Ltd.)

Estimating a treatment effect from observational data requires modeling treatment and outcome subject to uncertainty/misspecification. A previous research has shown that it is not possible to find a uniformly best strategy. In this article we propose a novel Frequentist Model Averaging (FMA) framework encompassing any estimation strategy and accounting for model uncertainty by computing a cross-validated estimate of Mean Squared Prediction Error (MSPE). We present a simulation study with data mimicking an observational database. Model averaging over 15+ strategies was compared with individual strategies as well as the best strategy selected by minimum MSPE. FMA showed robust performance (Bias, Mean Squared Error (MSE), and Confidence Interval (CI) coverage). Other strategies, such as linear regression, did well in simple scenarios but were inferior to the FMA in a scenario with complex confounding.

Aim: To predict optimal treatments maximizing overall survival (OS) and time to treatment discontinuation (TTD) for patients with metastatic breast cancer (MBC) using machine learning methods on electronic health records. Patients/methods: Adult females with HR+/HER2- MBC on first- or second-line systemic therapy were eligible. Random survival forest (RSF) models were used to predict optimal regimen classes for individual patients and each line of therapy based on baseline characteristics. Results: RSF models suggested greater use of CDK4 & 6 inhibitor-based therapies may maximize OS and TTD. RSF-predicted optimal treatments demonstrated longer OS and TTD compared with nonoptimal treatments across line of therapy (hazard ratios = 0.44∼0.79). Conclusion: RSF may help inform optimal treatment choices and improve outcomes for patients with HR+/HER2- MBC.

In health technology assessment (HTA), beside network meta-analysis (NMA), indirect comparisons (IC) have become an important tool used to provide evidence between two treatments when no head-to-head data are available. Researchers may use the adjusted indirect comparison based on the Bucher method (AIC) or the matching-adjusted indirect comparison (MAIC). While the Bucher method may provide biased results when included trials differ in baseline characteristics that influence the treatment outcome (treatment effect modifier), this issue may be addressed by applying the MAIC method if individual patient data (IPD) for at least one part of the AIC is available. Here, IPD is reweighted to match baseline characteristics and/or treatment effect modifiers of published data. However, the MAIC method does not provide a solution for situations when several common comparators are available. In these situations, assuming that the indirect comparison via the different common comparators is homogeneous, we propose merging these results by using meta-analysis methodology to provide a single, potentially more precise, treatment effect estimate. This paper introduces the method to combine several MAIC networks using classic meta-analysis techniques, it discusses the advantages and limitations of this approach, as well as demonstrates a practical application to combine several (M)AIC networks using data from Phase III psoriasis randomized control trials (RCT)., (© 2020 John Wiley & Sons Ltd.)

Standard network meta-analysis (NMA) and indirect comparisons combine aggregate data from multiple studies on treatments of interest, assuming that any effect modifiers are balanced across populations. Population adjustment methods relax this assumption using individual patient data from one or more studies. However, current matching-adjusted indirect comparison and simulated treatment comparison methods are limited to pairwise indirect comparisons and cannot predict into a specified target population. Existing meta-regression approaches incur aggregation bias. We propose a new method extending the standard NMA framework. An individual level regression model is defined, and aggregate data are fitted by integrating over the covariate distribution to form the likelihood. Motivated by the complexity of the closed form integration, we propose a general numerical approach using quasi-Monte-Carlo integration. Covariate correlation structures are accounted for by using copulas. Crucially for decision making, comparisons may be provided in any target population with a given covariate distribution. We illustrate the method with a network of plaque psoriasis treatments. Estimated population-average treatment effects are similar across study populations, as differences in the distributions of effect modifiers are small. A better fit is achieved than a random effects NMA, uncertainty is substantially reduced by explaining within- and between-study variation, and estimates are more interpretable., (© 2020 The Authors, Journal of the Royal Statistical Society: Series A (Statistics in Society) Published by John Wiley & Sons Ltd on behalf of the Royal Statistical Society.)

Background: Pharmacogenetic (PGx) testing identifies pharmacotherapeutic risks to permit personalized therapy. Identifying the genetic profile of patients with acute coronary syndrome (ACS) who are considered for therapy with clopidogrel (P2Y 12 receptor blockers) and acetylsalicylic acid (ASA) contributes to the treatment paradigm. Patient preferences would inform a collaborative framework and by extension inform healthcare policy formulation., Purpose: To quantify stated preferences (willingness to pay) for attributes of a novel point-of-care PGx ( CYP2C19 ) test using a discrete choice experiment (DCE) from the general public in Ontario, Canada, and to identify starting point bias of the cost attribute., Methods: A web survey was created and included a questionnaire, decision board, and a DCE. DCE choice sets include the following attributes (levels): sample collection (blood, finger prick, and cheek swab), turnaround time for results (1 hr, 3 days, and 1 week), and cost in additional insurance premiums. The presence of starting point bias (cost attribute levels of $0, $1, $5 or $0, $2, $10) in the estimation of willingness to pay (WTP) was tested., Results: Estimates for turnaround time and cost attributes were statistically significant. Coefficients related to the starting point bias were also significant. Approximately 67% of survey participants chose the PGx test compared to status quo treatment options. WTP for a 1 hr turnaround time compared to a 1-week turnaround time was $10.77 (95% CI 9.58 -12.25)., Conclusion: This translational study shows preference for a point of care PGx test., Competing Interests: Dr. So has received unrestricted grant support (physician-initiated grant) from Eli Lilly Canada; is a member of the advisory board and has received honoraria from AstraZeneca Canada; is a member of the advisory board for Bayer Canada; has received unrestricted grant support (physician-initiated grant) from Spartan Biosciences; has received unrestricted grant support (physician-initiated grant) from Aggredyne; has received unrestricted grant support (physician-initiated grant) from Diapharma/Roche Diagnostics; and has received honoraria from Abbott Vascular, Canada. Dr. Emmanuel Papadimitropoulos is an employee of Eli Lilly Canada Inc, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Bereza et al.)

Background: Adjusted indirect comparisons (anchored via a common comparator) are an integral part of health technology assessment. These methods are challenged when differences between studies exist, including inclusion/exclusion criteria, outcome definitions, patient characteristics, as well as ensuring the choice of a common comparator., Objectives: Matching-adjusted indirect comparison (MAIC) can address these challenges, but the appropriate application of MAICs is uncertain. Examples include whether to match between individual-level data and aggregate-level data studies separately for treatment arms or to combine the arms, which matching algorithm should be used, and whether to include the control treatment outcome and/or covariates present in individual-level data., Results: Results from seven matching approaches applied to a continuous outcome in six simulated scenarios demonstrated that when no effect modifiers were present, the matching methods were equivalent to the unmatched Bucher approach. When effect modifiers were present, matching methods (regardless of approach) outperformed the Bucher method. Matching on arms separately produced more precise estimates compared with matching on total moments, and for certain scenarios, matching including the control treatment outcome did not produce the expected effect size. The entropy balancing approach was used to determine whether there were any notable advantages over the method proposed by Signorovitch et al. When unmeasured effect modifiers were present, no approach was able to estimate the true treatment effect., Conclusions: Compared with the Bucher approach (no matching), the MAICs examined demonstrated more accurate estimates, but further research is required to understand these methods across an array of situations., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Since the introduction of the propensity score (PS), methods for estimating treatment effects with observational data have received growing attention in the literature. Recent research has added substantially to the number of available statistical approaches for controlling confounding in such analyses. However, researchers need guidance to decide on the optimal analytic strategy for any given scenario. To address this gap, we conducted simulations evaluating both well-established methods (regression, PS weighting, stratification, and matching) and more recently proposed approaches (tree-based methods, local control, entropy balancing, genetic matching, prognostic scoring). The simulation scenarios included tree-based and smooth regression models as true data-generation mechanisms. We evaluated an extensive number of analysis strategies combining different treatment choices and outcome models. Key findings include 1) the lack of a single best strategy across all potential scenarios; 2) the importance of appropriately addressing interactions in the treatment choice model and/or outcome model; and 3) a tree-structured treatment choice model and a polynomial outcome model with second-order interactions performed well. One limitation to this initial assessment is the lack of heterogeneous simulation scenarios allowing treatment effects to vary by patient.

In this article, we develop new methods for estimating average treatment effects in observational studies, in settings with more than two treatment levels, assuming unconfoundedness given pretreatment variables. We emphasize propensity score subclassification and matching methods which have been among the most popular methods in the binary treatment literature. Whereas the literature has suggested that these particular propensity-based methods do not naturally extend to the multi-level treatment case, we show, using the concept of weak unconfoundedness and the notion of the generalized propensity score, that adjusting for a scalar function of the pretreatment variables removes all biases associated with observed pretreatment variables. We apply the proposed methods to an analysis of the effect of treatments for fibromyalgia. We also carry out a simulation study to assess the finite sample performance of the methods relative to previously proposed methods., (© 2016, The International Biometric Society.)

Purpose: The objectives of this study were to estimate the incidence, cumulative incidence, and economic burden of Alzheimer's disease (AD) in Taiwan, using data from the National Health Insurance Research Database (NHIRD)., Materials and Methods: This was a retrospective, longitudinal, observational study using data from the Longitudinal Health Insurance Database of the NHIRD. Patients were included in this study if they were 50 years of age or older and their records included a primary or secondary diagnosis of AD. New patients who met inclusion criteria were followed up longitudinally from 2005 to 2010. Costs were calculated for the first year following the diagnosis of AD., Results: Overall, a higher percentage of women than men were diagnosed with AD (54% vs 46%, respectively). The first AD diagnosis occurred most frequently in the age of 75-84 years. The person-year incidence rate increased from 5.63/1,000 persons (95% CI, 5.32-5.94) in 2005 to 8.17/1,000 persons (95% CI, 7.78-8.57) in 2010. The cumulative incidence rate was 33.54/1,000 persons (95% CI, 32.76-34.33) in 2005-2010. The total mean inflated annual costs per patient in new Taiwan dollars (NT$) in the first year of diagnosis ranged from NT$205,413 (2009) to NT$227,110 (2005), with hospitalization representing the largest component., Conclusion: AD represents a substantial burden in Taiwan, and based on the observed increase in incidence rate over time, it is likely that this burden will continue to increase. The findings reported here are consistent with previous research. The NHIRD contains extensive real-world information that can be used to conduct research, allowing us to expand our understanding of the incidence, prevalence, and burden of disease in Taiwan.

Aims: Association between body mass index (BMI) and glycemic control, comorbidities/complications, and health-related quality of life (HRQoL) was assessed in Chinese patients with type 2 diabetes mellitus (T2DM) enrolled in the Diabetes Disease Specific Programme., Methods: Surveys of 200 physicians and 2052 patients with T2DM captured demographic, clinical, and HRQoL information. Adjusted and unadjusted analyses were conducted across 3 BMI groups; normal (18.5-<24.0, n=998), overweight (24.0-<28.0, n=822), and obese (≥28.0, n=212)., Results: There were no between group differences in the achievement of glycated hemoglobin (HbA1c) <7.0% (48mmol/mol); however, compared with the normal BMI group, more obese patients had an HbA1c >9.0% (75mmol/mol; 4.3% vs 10.2%, P=0.002). More obese patients compared with normal BMI patients had hypertension (48.6% vs 35.3%, P<0.001), dyslipidemia (35.4% vs 18.8%, P<0.001), or both hypertension and dyslipidemia (24.1% vs 13.9%, P<0.001). Patients in the obese group reported worse HRQoL and greater effects of diabetes on their daily living., Conclusions: Obesity in Chinese patients with T2DM results in poor glycemic control, more comorbidities, and worse HRQoL. Management of these patients should include efforts to reduce weight. Selection of weight-neutral or weight-reducing anti-diabetic medications maybe useful in these patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate the correlation between changes in symptoms and changes in self-reported quality of life among Chinese patients with schizophrenia who were switched from a typical antipsychotic to olanzapine during usual outpatient care., Patients and Methods: This post hoc analysis was conducted using data from the Chinese subgroup (n=475) of a multicountry, 12-month, prospective, noninterventional, observational study. The primary publication previously reported the efficacy, safety, and quality of life among patients who switched from a typical antipsychotic to olanzapine. Patients with schizophrenia were included if their symptoms were inadequately controlled with a typical antipsychotic and they were switched to olanzapine. Symptom severity was measured using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impressions-Severity scale (CGI-S). Health-Related Quality of Life (HRQOL) was assessed using the World Health Organization Quality of Life-Abbreviated (WHOQOL-BREF). Paired t-tests were performed to assess changes from baseline to endpoint. Pearson's correlation coefficients (r) were used to assess the correlations between change in symptoms (BPRS and CGI-S scores) and change in HRQOL (WHOQOL-BREF scores)., Results: Symptoms and HRQOL both improved significantly over the 12 months of treatment (P<0.001). Significant correlations were observed between changes from baseline to end of study on the BPRS and the CGI-S and each of the WHOQOL-BREF four domain scores and two overall quality-of-life questions. The correlation coefficients ranged from r=-0.45 to r=-0.53 for the BPRS and WHOQOL-BREF. The correlation coefficients were slightly smaller between the CGI-S and WHOQOL-BREF, ranging from r=-0.33 to r=-0.40., Conclusion: For patients with schizophrenia, assessing quality of life has the potential to add valuable information to the clinical assessment that takes into account the patient's own perspective of well-being.

Objectives: This study examined whether participation in a weight control program (WCP) by patients with schizophrenia treated with olanzapine was also associated with improvements in clinical and functional outcomes., Methods: A post-hoc analysis was conducted using data from the Chinese subgroup (n=330) of a multi-country, 6-month, prospective, observational study of outpatients with schizophrenia who initiated or switched to oral olanzapine. At study entry and monthly visits, participants were assessed with the Clinical Global Impression of Severity, and measures of patient insight, social activities, and work impairment. The primary comparison was between the 153 patients who participated in a WCP at study entry (n=93) or during the study (n=60) and the 177 patients who did not participate in a weight control program (non-WCP). Mixed Models for Repeated Measures with baseline covariates were used to compare outcomes over time. Kaplan-Meier survival analysis was used to assess time to response., Results: Participants had a mean age of 29.0 years and 29.3 years, and 51.0% and 57.6% were female for WCP and non-WCP groups, respectively. Average initiated daily dose for olanzapine was 9.5±5.4 mg. WCP participants gained less weight than non-participants (3.9 kg vs 4.9 kg, P=0.03) and showed statistically significant better clinical and functional outcomes: greater improvement in illness severity (-2.8 vs -2.1, P<0.001), higher treatment response rates (94.1% vs 80.9%, P<0.001), shorter time to response (P<0.001), and greater improvement in patients' insight (P<0.001). Patients who enrolled in a WCP during the study had greater initial weight gain than those who enrolled at baseline (P<0.05), but similar total weight gain., Conclusion: Participation in a WCP may not only lower the risk of clinically significant weight gain in olanzapine-treated patients, but may also be associated with additional clinical and functional benefits.

Background: This study examined the prognostic factors associated with survival in advanced non-small cell lung cancer (NSCLC) patients receiving gemcitabine-platinum regimens as first-line therapy in real-world clinical settings in China., Methods: Data was analyzed from a multinational, prospective, non-interventional, observational study of individuals receiving gemcitabine-platinum regimens as first-line therapy for NSCLC, focusing on 300 patients from mainland China. A Cox regression model was used to determine the association of 38 prognostic factors, including patient smoking characteristics, with overall survival., Results: In these 300 patients, the mean age was 58.9 (±10.8) years, with males comprising 71% of the population. Thirty percent of patients had an Eastern Cooperative Oncology Group performance status (PS) of 0 and 70% had a PS of 1. The majority of patients had NSCLC of adenocarcinoma origin (57%). Multivariate Cox regression analyses adjusted for baseline factors revealed that gender, tumor (T) staging, metastasis (M) staging, liver metastases, serum albumin, and superior vena cava obstruction were significant prognostic factors. Smoking during therapy was not significantly associated with survival, although numbers were small for this variable (n = 16). Weight loss of >10% was a significant prognostic factor for adverse events., Conclusions: Gender, T staging, M staging, liver metastases, superior vena cava obstruction, and serum albumin are prognostic factors affecting overall survival in mainland Chinese patients receiving first-line gemcitabine-platinum regimens for advanced NSCLC. These negative prognostic factors may warrant further investigation in clinical trials.

Background: The aims of this analysis were to identify factors associated with early response (at 4 weeks) to olanzapine treatment and to assess whether early response is associated with better longer-term outcomes for patients with schizophrenia in the People's Republic of China., Methods: A post hoc analysis of a multi-country, 6-month, prospective, observational study of outpatients with schizophrenia or bipolar mania who initiated or switched to treatment with oral olanzapine was conducted using data from the Chinese schizophrenia subgroup (n=330). Factors associated with early response were identified using a stepwise logistic regression with baseline clinical characteristics, baseline participation in a weight control program, and adherence with antipsychotics during the first 4 weeks of treatment. Mixed models for repeated measures with baseline covariates were used to compare outcomes over time between early responders and early nonresponders to olanzapine., Results: One hundred and thirty patients (40%) achieved an early response. Early response was independently predicted by higher baseline Clinical Global Impressions-Severity score (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.15-1.97), fewer years since first diagnosis (OR 0.94, CI 0.90-0.98), a greater number of social activities (OR 1.22, CI 1.05-1.40), participation in a weight control program (OR 1.81, CI 1.04-3.15), and high adherence with antipsychotics during the first 4 weeks of treatment (OR 2.98, CI 1.59-5.58). Relative to early nonresponders, early responders were significantly more likely to meet treatment response criteria at endpoint, had significantly greater symptom improvement (Clinical Global Impressions-Severity), and had significantly greater improvement in functional outcomes (all P<0.05)., Conclusion: High levels of adherence to prescribed antipsychotics and participation in a weight control program were associated with early response to olanzapine in Chinese patients with schizophrenia. Early response was associated with greater improvement in symptomatic, functional, and quality of life outcomes at 6 months compared with early nonresponse. Current findings are consistent with previous research outside of the People's Republic of China.

We evaluated via a simulation study several strategies for imputing missing ordinal outcomes in a longitudinal clinical trial, contrasting methods that involve truncation of imputed values outside plausible ranges with those that do not. Our aim was to identify a preferred imputation strategy for estimating treatment difference at study endpoint. Plausible data were simulated via resampling of existing placebo data sets and adding treatment effect; then different imputation strategies were evaluated under missingness at random (MAR) and varying dropout rates. Our conclusion is that imputation methods based on rounding and truncation lead to larger bias than strategies based on simple methods based on (nontruncated) multivariate normal distribution.

Objective: To investigate the impact of somatic symptoms on the severity and course of depression in Asian patients treated for an acute episode of major depressive disorder (MDD)., Methods: Three-month prospective observational study of 917 patients with MDD in psychiatric care settings of which 909 had complete main baseline data. Depression severity was assessed using the physician-rated Clinical Global Impression of Severity (CGI-S) and 17-item Hamilton Depression Rating Scale (HAMD17), and somatic symptoms were assessed using the patient-rated 28-item Somatic Symptom Inventory (SSI). Cluster analysis using baseline SSI scores grouped patients into 3 clusters with no/few, moderate or severe somatic symptoms. Four factors of SSI (pain, autonomic symptoms, energy, and central nervous system) were defined and regression analyses identified which factors were associated with remission and response at 3 months follow-up., Results: Baseline depression severity (HAMD17 and CGI-S scores) was associated with more severe somatic symptoms. Remission rates differed between clusters of patients: 68.4%, 54.7% and 29.3% for no/few, moderate and severe somatic symptoms, respectively (p<0.0001). Corresponding response rates were 81.8%, 72.1% and 55.2% (p<0.0001). Pain symptoms were the somatic symptoms most associated with these clinical outcomes at 3 months., Limitations: Only patients diagnosed with MDD in psychiatric care were assessed., Conclusions: Somatic symptoms are frequent among Asian patients in psychiatric care for MDD and are associated with greater clinical severity and lower response and remission rates. Among somatic symptoms, pain symptoms have the greatest prognostic value and should be taken into account when treating patients with depression., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Patients with major depressive disorder (MDD) may suffer from concomitant pain symptoms. The aim of this study is to determine whether the presence of painful physical symptoms (PPS) influences quality of life when taking into account baseline depression severity., Methods: Patients with a new or first episode of MDD (n = 909) were enrolled in a 3-month prospective observational study in East Asia. The Hamilton Depression Rating Scale, Clinical Global Impression-Severity score, Somatic Symptom Inventory, and EuroQoL questionnaire-5 Dimensions (EQ-5D) and EQ-Visual Analogue Scale (EQ-VAS) were assessed at baseline and 3 months' follow-up. The presence of PPS was defined as a mean score of ≥2 on the Somatic Symptom Inventory pain-related items. Regression analyses determined predictors of quality of life at 3 months, adjusting for age, sex, depressive symptoms, overall severity, and quality of life at baseline., Results: PPS were present (PPS+) at baseline in 52% of patients. During the 3-month follow-up, EQ-VAS scores improved from 47.7 (standard deviation [SD] 20.6) to 72.5 (SD 20.4), and EQ-5D improved from 0.48 (SD 0.34) to 0.80 (SD 0.26). At 3 months, mean EQ-VAS was 66.4 (SD 21.2) for baseline PPS+ patients versus 78.5 (SD 17.6) for baseline PPS- patients, and mean EQ-5D was 0.71 (SD 0.29) versus 0.89 (SD 0.18). PPS+ at baseline was a significant predictor of quality of life at 3 months after adjusting for sociodemographic and baseline clinical variables., Conclusion: The presence of painful physical symptoms is associated with less improvement in quality of life in patients receiving treatment for major depression, even when adjusting for depression severity.

Aims: This study compared all-cause medication discontinuation (any switch, augmentation or medication discontinuation) in matched cohorts of patients with schizophrenia who were initiated on depot or oral antipsychotics. Other objectives included between-group comparisons of resource use, and clinical and functional outcomes., Methods: This post hoc analysis of a one-year, multicentre, prospective, observational study included outpatients with schizophrenia who required a change in their antipsychotic medication because of a physician-perceived risk of medication non-adherence. Patients were matched 1 : 1 using an optimal algorithm with rank-based Mahalanobis distances. All-cause medication discontinuation was compared using the Klein and Moeschberger test for survival and hazard ratios (HR) with 95% confidence intervals (CI) were calculated using a Cox proportional hazards model, stratifying on matched pairs., Results: Forty patients who initiated a depot antipsychotic could be matched to patients who initiated an oral antipsychotic. Fewer depot-treated patients discontinued their antipsychotic medication at least once compared with oral-treated patients [20% (8/40) vs. 40% (16/40)]. Depot-treated patients discontinued their medication later (Klein and Moeschberger test p = 0.025) and were less likely to discontinue their initial antipsychotic medication [HR = 0.33 (95% CI, 0.12-0.92), p = 0.033] than oral-treated patients. There were few differences in resource use and no differences in clinical and functional outcomes between cohorts., Conclusion: In this matched-cohort analysis, patients with schizophrenia who were considered to be non-adherent with their prior oral antipsychotics were less likely to discontinue their medication for any cause if they were initiated on depot compared with oral antipsychotics., (© 2011 Blackwell Publishing Ltd.)

Background: This prospective observational study estimated the effect of prognostic factors, particularly continued smoking during therapy, on survival in advanced non-small cell lung cancer (NSCLC) patients receiving gemcitabine-platinum. Further, prognostic factors were used to build a survival model to improve prognosis prediction in naturalistic clinical settings., Methods: Eligibility criteria included: Stage IIIB/IV NSCLC, no prior chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. A Cox regression model was constructed and validated by randomizing patients into two datasets (Construction [C]:Validation [V]; 3:1 ratio). Country, disease stage, hypercalcemia, "N" factor, weight reduction, performance status, and superior vena cava obstruction were pre-defined variables forced into the model. Continued smoking was tested with adjustment for these variables., Results: One thousand two hundred and fourteen patients (C=891 and V=323) were enrolled. The final predictive model, established in the Construction dataset, identified four significant (p≤0.05) and independent predictors of survival, which were disease stage, performance status, gemcitabine-platinum regimen, and T-stage. Smoking during therapy was not significantly associated with survival (Hazard Ratio [95% CI]: 0.955 [0.572, 1.596], p=0.8618; versus never smokers)., Conclusions: Although continued smoking during therapy was not significantly associated with shorter survival, the model developed in this study forms an evidence-based approach to assessing prognosis in advanced stage NSCLC.

Purpose: In experimental systems, interference with coagulation can affect tumor biology. Furthermore, it has been suggested that low molecular weight heparin therapy may prolong survival in patients with cancer. The primary aim of this study was to assess survival at 1 year of patients with advanced cancer., Patients and Methods: Patients with advanced malignancy (N = 385) were randomly assigned to receive either a once-daily subcutaneous injection of dalteparin (5,000 IU), a low molecular weight heparin, or placebo for 1 year., Results: The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12%, respectively, for patients receiving placebo (P =.19). In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P =.03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively., Conclusion: Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.

Low molecular weight heparins (LMWHs) are frequently used during acute treatment of deep vein thrombosis, but their utility for long-term treatment needs to be defined. In this multi-centre trial, 378 patients with acute deep vein thrombosis were randomised to intravenous unfractionated heparin (group A), once daily subcutaneous LMWH (bemiparin) for one week (group B) or once daily bemiparin in a therapeutic dose for one week followed by a maintenance dose for 12 weeks (group C). Fifty-two per cent of patients in group A, 72% of group B and 72% of group C showed venographic reduction in thrombus size assessed objectively on day 14; 20% greater improvement in group B and C indicates not only non-inferiority of bemiparin (p = 0.00003) but also superiority (p = 0.004) compared to UFH. Day 84 venographic or Doppler sonographic recanalisation of the affected veins was demonstrated in 75.3%, 79.8% and 81.5% in groups A, B and C respectively. Mortality, recurrent thromboembolic events and bleeding were similar in the three groups. Both bemiparin regimens were more effective than UFH in reducing thrombus size during the acute phase of treatment. The efficacy in terms of recurrence of venous thromboembolism and safety of Bemiparin is similar to UFH. Bemiparin is also an effective alternative to warfarin for long-term treatment.

Possible correlation of the effects of pharmacotherapy on the inhibition of the in-vivo generation of thrombin and on the prevention of thrombus extension in patients with deep vein thrombosis (DVT) could help to define patients at higher risk. Patients with symptomatic deep vein thrombosis confirmed by phlebography were randomised to intravenous unfractionated heparin (UFH), or a subcutaneous low-molecular-weight heparin (reviparin) twice daily for one week, or a subcutaneous reviparin once daily for four weeks. The patients were treated with oral anticoagulants for at least 3 months. Main endpoints were regression of thrombus on phlebography on Day 21 and recurrent symptomatic venous thromboembolism up to 3 months. Coagulation parameters, markers of in-vivo thrombin generation, and TFPI-release were determined at randomisation, weeks 1 and 3. Four hundred sixty six responders (reduction of at least 30 per cent in Marder score) and 419 non-responders (Marder score unchanged or changed less than +/-30%) showed no significantly different baseline characteristics. The non-responder group had a higher median Marder score at baseline and after one and three weeks of treatment, and had significantly higher fibrinogen levels, TAT complexes and F1+2 values than responders. There were no significant differences in coagulation parameters between non-responders and patients with asymptomatic + symptomatic VTE with the exception of higher TAT complexes at baseline. Significant differences in Marder score and coagulation parameters at baseline were found between responders and nonresponders. Non-responders have a higher risk tosuffer recurrent VTE and may need intensified treatment.

Patients with coronary heart disease (CHD) are at considerable risk for recurrent ischaemic events. A pre-thrombotic state and/or impaired fibrinolysis might play an important role in causing recurrent ischaemic events. Two hundred and fifty-seven CHD patients underwent the dobutamine stress echocardiography test (DSE) to investigate the possible presence of inducible ischaemia; 89 patients showed evidence of stunned and/or necrotic myocardium (resting wall motion abnormalities). Factor VIII activity and fibrinogen levels were significantly higher in patients with stunned/necrotic myocardium than in CHD patients with normal resting wall motions (factor VIII activity, P = 0.004; fibrinogen, P = 0.04). Of interest, after stimulating the fibrinolytic system with the DSE test, plasminogen activator inhibitor-1 activity was significantly higher in patients with necrotic/stunned myocardium than in patients with resting normal wall motion (P = 0.03), whereas tissue-type plasminogen activator activity after the DSE test was significantly lower in patients with stunned/necrotic myocardium than in patients with normal wall motion (P = 0.001). Overall, 30 CHD patients developed induced ischaemia (new wall motion abnormalities) during the DSE test. CHD patients with stunned and/or necrotic myocardium presented decreased fibrinolytic potential and the presence of a hypercoagulable state due to increased factor VIII activity, and fibrinogen levels. Therefore, these CHD patients must be considered at high risk of re-developing coronary thrombosis and might benefit from a more aggressive anticoagulant therapy., (Copyright 2003 Lippincott Williams & Wilkins)

Background: Stentless bioprostheses are anticipated to cause improved hemodynamics and increased longevity over stented bioprosthesis. We have compared echocardiographic analysis of stented bioprosthesis "Freestyle" with stented "Mosaic" bioprosthesis. Because of similar technology (0 pressure fixation, anticalcification) any differences may relate to stent., Methods: Twenty-eight patients undergoing AVR were randomly assigned to receive either stented or stentless. Echocardiograms, by means of M-mode and Doppler were performed early, 3-6 months and 1 year postoperatively., Results: The peak flow velocity was significantly lower in the stentless group, especially 1 week and 6 months after surgery. Mean transvalvular gradient dropped significantly in stentless group and did not change in stented group. EOA did not change significantly in either of groups. AoV velocity time integral was increasing in stentless group. LV mass had fallen significantly in both groups but degree of mass reduction was comparable., Conclusions: There are marked improvements of stentless valves hemodynamics. However it is not necessary equal to higher degree of LV mass reduction during 1 year follow-up.

Most episodes of myocardial ischemia in patients with known coronary artery disease (CHD) are asymptomatic. Silent myocardial ischemia (SMI) is an important predictor of adverse outcome in patients with proven coronary artery disease. beta-blockers are effective in suppressing ischemia, and improve clinical outcome in patients with coronary artery disease. At present, it is common practice to stop treatment with beta-blockers in clinically asymptomatic patients after coronary artery bypass graft (CABG) and/or myocardial re-vascularization (PTCA/Stent), although the possible presence of SMI/inducible ischemia after myocardial re-vascularization is not known. We examined 56 asymptomatic CHD patients after coronary artery bypass graft (n=36), percutaneous coronary angioplasty PTCA/stent (n=15), or both (n=5); therapy with beta-blockers was stopped in all of them after myocardial revascularization. All these patients underwent a dobutamine stress echocardiography test (DSE test). The DSE test was proposed to these asymptomatic CHD patients to investigate the possible presence of SMI/inducible ischemia after myocardial re-vascularization. All patients had history of myocardial infarction or evidence of mildly impaired left ventricular function at rest as assessed by cardiac catheterization. Abnormal DSE studies occurred in eight of the 56 patients (14%; 95% C.I.: 6-26%). Therapeutic approaches specifically targeted at reducing total ischaemic burden include pharmacologic therapy and myocardial revascularization. On the basis of these data, it can be concluded that asymptomatic CHD patients after myocardial re-vascularization must be re-evaluated to rule out SMI/inducible ischemia that can be treated (e.g. with beta-blockers) reducing cardiovascular morbidity and mortality.

Background: Congestive heart failure (CHF) is associated with a hypercoagulable state., Patients and Methods: A single-center, randomized, double-blind, placebo-controlled trial was performed to test the hypothesis that a prophylactic dose of low molecular weight heparin (bemiparin sodium 3500 IU/daily subcutaneously) will modify a hypercoagulable state in CHF. This study included 100 patients with CHF (New York Heart Association classification II to IV). All patients underwent 3 blood tests, at baseline (before randomization), 24 hours after randomization, and before hospital discharge or within 10 days from randomization., Results: In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 24 hours, there was a significant decrease in plasma levels of D-dimer (-13.8 ng/mL; P =.01) and prothrombin fragments 1 and 2 (-0.11 nmol/L; P =.01), whereas protein C was significantly increased (+3.5%; P =.03). In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 4 to 10 days of therapy, there were significantly decreased plasma levels for factor VII:c (-3.0%; P =.01), D-dimer (-44.0 ng/mL; P =.002), and thrombin-antithrombin complex (-0.7 microg/L; P =.0001), whereas protein C was significantly increased (+16.0%; P =.03). On the other hand, in the group of patients treated with placebo after 24 hours, a significant decrease was observed of protein C (-4.0%; P =.04). After 24 hours, the changes from baseline were significantly different for some of the hemostatic factors in comparison of bemiparin sodium 3500 IU/daily and placebo (factor VII:c: -1.7 versus 0.0%; P =.04; D-dimer: -14 versus +24.3 ng/mL; P =.009; prothrombin fragments 1 and 2: -0.11 versus +0.11 nmol/L; P =.01; protein C: +3.5 versus -4.0%; P =.01). Also at discharge, the changes from baseline were different for some of the markers in comparison of bemiparin sodium with placebo (D-dimer: -44 versus 3.8 ng/mL; P =.002; thrombin-antithrombin complex: -0.70 versus +0.14 microg/L; P =.002; protein C: +16.0 versus +0.5%; P =.02)., Conclusion: Our findings suggest that a hypercoagulable state in heart failure can be modified with bemiparin sodium therapy.

Low-molecular-weight and unfractionated heparins are frequently used to treat venous thromboembolism, but it is not known whether they are equally effective in inhibiting in vivo generation of thrombin. In this multicenter trial, 1048 patients were randomized to intravenous unfractionated heparin (group A), twice daily low-molecular-weight heparin (reviparin) for 1 week (group B), or once daily reviparin for 4 weeks (group C). All patients received vitamin K antagonists. Blood samples withdrawn at the baseline and at weeks 1 and 3 were analyzed using markers of in vivo thrombin generation and other coagulation parameters. During the first 3 weeks symptomatic recurrent deep vein thrombosis-pulmonary embolism (DVT/PE) occurred in 17 (4.5%) of 375 patients in group A compared with 4 (1.0%) of 388 patients in group B, and 9 (2.4%) of 374 patients in group C. Forty percent of patients in group A, 53.4% in group B, and 53.5% in group C showed 30% or greater reduction in thrombus size assessed by venography. Patients in group B had significantly greater reduction in D-dimer, prothrombin fragments 1 and 2 (F1 + 2), endogenous thrombin potential (ETP), and thrombin-antithrombin (TAT) complexes compared to groups A and C. Greater release of tissue factor pathway inhibitor (TFPI) and reduction in levels of thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen were significantly more pronounced in group C patients. Reviparin administered twice daily plus vitamin K antagonist is more effective in inhibiting in vivo thrombin generation compared to intravenous unfractionated heparin plus vitamin K antagonist, and reviparin once daily produced significantly higher TFPI release and greater reduction in TAFI and fibrinogen levels.