Potential Treatment Effect Modifiers Research Articles

Potential treatment effect modifiers for manipulative therapy for children complaining of spinal pain.Secondary analyses of a randomised controlled trial

BackgroundIn children, spinal pain is transitory for most, but up to 20% experience recurrent and bothersome complaints. It is generally acknowledged that interventions may be more effective for subgroups of those affected with low back pain. In this secondary analysis of data from a randomized clinical trial, we tested whether five indicators of a potential increased need for treatment might act as effect modifiers for manipulative therapy in the treatment of spinal pain in children. We hypothesized that the most severely affected children would benefit more from manipulative therapy.MethodThis study was a secondary analysis of data from a randomised controlled trial comparing advice, exercises and soft tissue treatment with and without the addition of manipulative therapy in 238 Danish school children aged 9–15 years complaining of spinal pain. A text message system (SMS) and clinical examinations were used for data collection (February 2012 to April 2014).Five pre-specified potential effect modifiers were explored: Number of weeks with spinal pain 6 months prior to inclusion, number of weeks with co-occurring musculoskeletal pain 6 months prior to inclusion, expectations of the clinical course, pain intensity, and quality of life.Outcomes were number of recurrences of spinal pain, number of weeks with pain, length of episodes, global perceived effect, and change in pain intensity. To explore potential effect modification, various types of regression models were used depending on the type of outcome, including interaction tests.ResultsWe found that children with long duration of spinal pain or co-occurring musculoskeletal pain prior to inclusion as well as low quality of life at baseline tended to benefit from manipulative therapy over non-manipulative therapy, whereas the opposite was seen for children reporting high intensity of pain. However, most results were statistically insignificant.ConclusionsThis secondary analysis indicates that children more effected by certain baseline characteristics, but not pain intensity, have a greater chance to benefit from treatment that include manipulative therapy. However, these analyses were both secondary and underpowered, and therefore merely exploratory. The results underline the need for a careful choice of inclusion criteria in future investigations of manipulative therapy in children.Trial registrationNCT01504698; results

Comparative effectiveness of triple therapy versus dual bronchodilation in COPD.

This real-world study compared the effectiveness of triple therapy (TT; long-acting muscarinic antagonists (LAMAs)/long-acting inhaled β-agonists (LABAs)/inhaled corticosteroids (ICSs)) versus dual bronchodilation (DB; LAMAs/LABAs) among patients with frequently exacerbating COPD. A matched historical cohort study was conducted using United Kingdom primary care data. Patients with COPD aged ≥40 years with a history of smoking were included if they initiated TT or DB from no maintenance/LAMA therapy and had two or more exacerbations in the preceding year. The primary outcome was time to first COPD exacerbation. Secondary outcomes included time to treatment failure, first acute respiratory event, and first acute oral corticosteroid (OCS) course. Potential treatment effect modifiers were investigated. In 1647 matched patients, initiation of TT reduced exacerbation risk (adjusted hazard ratio (HR) 0.87, 95% CI 0.76–0.99), risk of acute respiratory event (HR 0.74, 95% CI 0.66–0.84) and treatment failure (HR 0.83, 95% CI 0.73–0.95) compared with DB. Risk reduction for acute respiratory events was greater for patients with higher rates of previous exacerbations. At baseline blood eosinophil counts (BECs) ≥ 0.35×109 cells·L−1, TT was associated with lower risk of OCS prescriptions than DB. This study provides real-life evidence of TT being more effective in reducing exacerbation risk than DB, which became more accentuated with increasing BEC and previous exacerbation rate.

A systematic literature review and network meta-analysis feasibility study to assess the comparative efficacy and comparative effectiveness of pneumococcal conjugate vaccines

ABSTRACTBackground: No head-to-head studies are currently available comparing pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) with 13-valent pneumococcal conjugate vaccine (PCV-13). This study explored the feasibility of using network meta-analysis (NMA) to conduct an indirect comparison of the relative efficacy or effectiveness of the two vaccines.Methods: A systematic literature search was conducted for published randomized controlled trials (RCTs) and non-RCT studies reporting data on vaccine efficacy or effectiveness against invasive pneumococcal disease in children aged <5 years receiving 7-valent pneumococcal conjugate vaccine (PCV-7), PHiD-CV or PCV-13. Study quality was evaluated using published scales. NMA feasibility was assessed by considering whether a connected network could be constructed by examining published studies for differences in study or patient characteristics that could act as potential treatment effect modifiers or confounding variables.Results: A total of 26 publications were included; 2 RCTs (4 publications), 7 indirect cohort studies, and 14 case-control studies (15 publications). Study quality was generally good. The RCTs could not be connected in a network as there was no common comparator. The studies differed considerably in design, dose number, administration schedules, and subgroups analyzed. Reporting of exposure status and subject characteristics was inconsistent.Conclusion: NMA to compare the relative efficacy or effectiveness of PHiD-CV and PCV-13 is not feasible on the current evidence base, due to the absence of a connected network across the two RCTs and major heterogeneity between studies. NMA may be possible in future if sufficient RCTs become available to construct a connected network.

DIFFERENCES IN ELIGIBILITY CRITERIA AND BASELINE PATIENT CHARACTERISTICS AMONGST TRIALS OF BIOLOGIC THERAPIES IN ASTHMA

Introduction The understanding of asthma pathophysiology has evolved over time, impacting investigation of asthma biologics. Differences in eligibility criteria amongst trials for patients with diverse asthma severity and phenotypes have resulted in relevant differences in baseline characteristics. A systematic literature review explored these differences. Methods PubMed, EMBASE, Cochrane, ClinicalTrials.gov, and conferences were searched from 2003 onwards. Randomized controlled trials (RCTs) were included with: ≥24 weeks’ duration; biologic (omalizumab [OMA]/dupilumab [DUPI]/benralizumab [BENRA]/mepolizumab [MEPO]/reslizumab [RESLI]) + daily high-dose ICS + ≥1 controller; adults ≥18 years with moderate/severe uncontrolled asthma and evidence of Type 2 inflammation (eg, blood eosinophils). Results 27 RCTs (9 OMA/3 DUPI/6 BENRA/7 MEPO/2 RESLI) were included. Overall, BENRA/MEPO/RESLI trials enrolled patients with more severe asthma than OMA/DUPI (Table 1). Per inclusion criteria, the number of prior exacerbations was higher in BENRA/MEPO versus OMA/DUPI/RESLI trials. Baseline blood eosinophil levels varied between trials, but were highest in RESLI. There was a trend towards higher baseline FEV1 in OMA/RESLI trials compared with others. Most patients received medium/high dose ICS + LABAs, with more patients in MEPO trials receiving maintenance OCS. Conclusions Transitivity, an important assumption in network meta-analysis (NMA), requires populations and study designs be sufficiently similar or have differences that can be adjusted for by accepted methods. Substantial heterogeneity in baseline characteristics existed between trials of asthma biologics and OMA. These characteristics are potential treatment effect modifiers with limited evidence for adjustment. Therefore, comparison of OMA to other asthma biologics through NMA is not clinically valid and inconsistent with best practices. Table 1. Summary of eligibility criteria and baseline patient characteristics across randomized controlled trials of biologic agents in moderate-to-severe asthma.

Treating depression with physical activity in adolescents and young adults: a systematic review and meta-analysis of randomised controlled trials.

We aimed to establish the treatment effect of physical activity for depression in young people through meta-analysis. Four databases were searched to September 2016 for randomised controlled trials of physical activity interventions for adolescents and young adults, 12-25 years, experiencing a diagnosis or threshold symptoms of depression. Random-effects meta-analysis was used to estimate the standardised mean difference (SMD) between physical activity and control conditions. Subgroup analysis and meta-regression investigated potential treatment effect modifiers. Acceptability was estimated using dropout. Trials were assessed against risk of bias domains and overall quality of evidence was assessed using GRADE criteria. Seventeen trials were eligible and 16 provided data from 771 participants showing a large effect of physical activity on depression symptoms compared to controls (SMD = -0.82, 95% CI = -1.02 to -0.61, p < 0.05, I2 = 38%). The effect remained robust in trials with clinical samples (k = 5, SMD = -0.72, 95% CI = -1.15 to -0.30), and in trials using attention/activity placebo controls (k = 7, SMD = -0.82, 95% CI = -1.05 to -0.59). Dropout was 11% across physical activity arms and equivalent in controls (k = 12, RD = -0.01, 95% CI = -0.04 to 0.03, p = 0.70). However, the quality of RCT-level evidence contributing to the primary analysis was downgraded two levels to LOW (trial-level risk of bias, suspected publication bias), suggesting uncertainty in the size of effect and caution in its interpretation. While physical activity appears to be a promising and acceptable intervention for adolescents and young adults experiencing depression, robust clinical effectiveness trials that minimise risk of bias are required to increase confidence in the current finding. The specific intervention characteristics required to improve depression remain unclear, however best candidates given current evidence may include, but are not limited to, supervised, aerobic-based activity of moderate-to-vigorous intensity, engaged in multiple times per week over eight or more weeks. Further research is needed. (Registration: PROSPERO-CRD 42015024388).

McKenzie Method of Mechanical Diagnosis and Therapy was slightly more effective than placebo for pain, but not for disability, in patients with chronic non-specific low back pain: a randomised placebo controlled trial with short and longer term follow-up

BackgroundThe McKenzie Method of Mechanical Diagnosis and Therapy (MDT) is one of the exercise approaches recommended by low back pain (LBP) guidelines. We investigated the efficacy of MDT compared with...

Patient education in the management of coronary heart disease.

Patient education in the management of coronary heart disease.

Can we predict the outcome for people with patellofemoral pain? A systematic review on prognostic factors and treatment effect modifiers

BackgroundPatellofemoral pain (PFP) is a multifactorial and often persistent knee condition. One strategy to enhance patient outcomes is using clinically assessable patient characteristics to predict the outcome and match a...

Clinical effectiveness of bisphosphonates for the prevention of fragility fractures: A systematic review and network meta-analysis

ObjectivesTo assess the relative efficacy of bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) for the treatment of osteoporosis using network meta-analysis (NMA). MethodsA systematic review of the literature was conducted using PRISMA guidelines. A network meta-analysis was used to determine the relative efficacy of treatments on four fracture outcomes (vertebral, non-vertebral, hip and wrist) and percentage change in femoral neck bone mineral density (BMD). Treatment effects were modelled using an exchangeable treatment effects model. Heterogeneity in treatment effects was explored by considering potential treatment effect modifiers using meta-regression. Where appropriate, inconsistency between direct and indirect evidence was assessed using node-splitting. Results46 randomised controlled trials (RCTs) were identified. Twenty seven RCTs provided fracture data and 35 RCTs provided BMD data for analysis. Zoledronic acid was associated with the greatest treatment effect on vertebral fractures (HR 0.41, 95% CrI: 0.28, 0.56) and percentage change in BMD (3.21, 95%: CrI 2.52, 3.86) compared to placebo. The greatest treatment effect on non-vertebral and wrist fractures was given by risedronate (HR 0.72, 95%: CrI 0.53, 0.89 and HR 0.77, 95%: CrI 0.44, 1.24, respectively). For hip fractures the greatest treatment effect was given by alendronate (HR 0.78, 95% CrI: 0.44, 1.30). ConclusionsAll treatments examined were associated with beneficial effects on fractures and femoral neck BMD relative to placebo. For vertebral fractures and percentage change in femoral neck BMD the treatment effects were statistically significant for all treatments. Pairwise comparisons between treatments indicated that no active treatment was statistically significantly more effective than any other active treatment for fracture outcomes. There was some heterogeneity in treatment effects between studies suggesting differential treatment effects according to study characteristics; however, there was no evidence of differential treatment effects with respect to gender and age.

Stratified Psychiatry via Convexity-Based Clustering with Applications Towards Moderator Analysis.

Understanding heterogeneity in phenotypical characteristics, symptoms manifestations and response to treatment of subjects with psychiatric illnesses is a continuing challenge in mental health research. A long-standing goal of medical studies is to identify groups of subjects characterized with a particular trait or quality and to distinguish them from other subjects in a clinically relevant way. This paper develops and illustrates a novel approach to this problem based on a method of optimal-partitioning (clustering) of functional data. The proposed method allows for the simultaneous clustering of different populations (e.g., symptoms of drug and placebo treated patients) in order to identify prototypical outcome profiles that are distinct from one or the other treatment and outcome profiles common to the different treatments. The clustering results are used to discover potential treatment effect modifiers (i.e., moderators), in particular, moderators of specific drug effects and placebo response. A depression clinical trial is used to illustrate the method.

Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease: Cochrane Systematic Review and Meta-Analysis

BackgroundAlthough recommended in guidelines for the management of coronary heart disease (CHD), concerns have been raised about the applicability of evidence from existing meta-analyses of exercise-based cardiac rehabilitation (CR). ObjectivesThe goal of this study is to update the Cochrane systematic review and meta-analysis of exercise-based CR for CHD. MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Science Citation Index Expanded were searched to July 2014. Retrieved papers, systematic reviews, and trial registries were hand-searched. We included randomized controlled trials with at least 6 months of follow-up, comparing CR to no-exercise controls following myocardial infarction or revascularization, or with a diagnosis of angina pectoris or CHD defined by angiography. Two authors screened titles for inclusion, extracted data, and assessed risk of bias. Studies were pooled using random effects meta-analysis, and stratified analyses were undertaken to examine potential treatment effect modifiers. ResultsA total of 63 studies with 14,486 participants with median follow-up of 12 months were included. Overall, CR led to a reduction in cardiovascular mortality (relative risk: 0.74; 95% confidence interval: 0.64 to 0.86) and the risk of hospital admissions (relative risk: 0.82; 95% confidence interval: 0.70 to 0.96). There was no significant effect on total mortality, myocardial infarction, or revascularization. The majority of studies (14 of 20) showed higher levels of health-related quality of life in 1 or more domains following exercise-based CR compared with control subjects. ConclusionsThis study confirms that exercise-based CR reduces cardiovascular mortality and provides important data showing reductions in hospital admissions and improvements in quality of life. These benefits appear to be consistent across patients and intervention types and were independent of study quality, setting, and publication date.

Critical Appraisal of Network Meta-Analyses Evaluating the Efficacy and Safety of New Oral Anticoagulants in Atrial Fibrillation Stroke Prevention Trials

ObjectivesTo critically appraise published network meta-analyses (NMAs) evaluating the efficacy or safety of the new oral anticogulants (NOACs) dabigatran, rivaroxaban, and apixaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). MethodsA systematic literature review was performed to identify the relevant NMAs using MEDLINE, EMBASE, Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. The synthesis studies were evaluated using the “Questionnaire to assess the relevance and credibility of the NMA.” ResultsEleven NMAs evaluating NOACs among adults with nonvalvular AF were identified. Most NMAs included three large phase III randomized controlled trials, comparing NOACs to adjusted-dose warfarin (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], and Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]). The main differences identified related to potential treatment effect modifiers regarding the mean time spent in therapeutic range (TTR) in the warfarin arm, the risk of stroke or systemic embolism across the trials (mean CHADS2 score: C = congestive heart failure, H = hypertension, A = older than age 75 years, D = diabetes mellitus, S2 = prior stroke or history of transient ischemic attack) or primary versus secondary prevention, and type of populations used in the analysis. Kansal et al. [Kansal AR, Sharma M, Bradley-Kennedy C, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada: comparative efficacy and cost-effectiveness. Thromb Haemost 2012;108:672–82] appropriately adjusted the ROCKET-AF TTR to match the RE-LY population on the basis of individual patient data. Meta-regressions are not expected to minimize confounding bias given limited data, whereas subgroup analyses had some impact on the point estimates for the treatment comparisons. ConclusionsResults of the synthesis studies were generally comparable and suggested that the NOACs had similar efficacy, although some differences were identified depending on the outcome. The extent to which differences in the distribution of TTR, CHADS2 score, or primary versus secondary prevention biased the results remains unclear.

Efficacy of Treatments in Relapsed or Relapsed and Refractory Multiple Myeloma: An Indirect Treatment Comparison

Background: In the phase 3, randomized, international, double-blind PANORAMA 1 trial, panobinostat in combination with bortezomib and dexamethasone (PAN/BTZ/DEX, n=387) demonstrated superior progression-free survival (PFS), time to progression (TTP) and near complete response plus complete response rate (nCR+CR) over placebo/BTZ/DEX (n=381) in patients with relapsed or relapsed and refractory multiple myeloma (RR MM). These results support the addition of panobinostat to BTZ/DEX and demonstrate that this regimen is a valuable addition to the current treatment options for RR MM. However, evidence on the efficacy of PAN/BTZ/DEX relative to other relevant treatments is lacking. The aim of this study was to perform an indirect treatment comparison (ITC) to estimate the relative efficacy of PAN/BTZ/DEX compared to commonly used treatment regimens.Methods: A systematic literature review was conducted. MEDLINE, MEDLINE In-Process, EMBASE, the Cochrane Library, and conference proceedings were searched covering clinical studies dating from January 2003 to April 2014. Studies included phase 2-4 clinical trials specifically focusing on RR MM, reporting results in English for the most commonly used agents: intravenous BTZ, lenalidomide (LEN), thalidomide (THAL), and doxorubicin (DOX). Data were extracted on study details, study duration, and efficacy outcomes including the hazard ratio (HR) of PFS, the HR of TTP, and the number of patients who achieved nCR+CR.Multi-arm randomized controlled trials were selected for inclusion in the evidence base of the ITC. Included studies were similar in terms of trial design (e.g. patient selection criteria), patient characteristics (e.g. age, time since diagnosis, number of prior lines of therapy), and included treatments that could be linked via common comparators. Data were analysed by applying fixed effects models to estimate HRs of PFS, HRs of TTP, and odds ratios (OR) of nCR+CR. PAN/BTZ/DEX was chosen as the reference treatment for ease of comparability and interpretability of the results.The models were conducted using Markov Chain Monte Carlo simulation methods implemented in WinBUGS 1.4. The mean of the posterior distribution was taken as the point estimate and 95% credible intervals (CI), i.e. range of values containing the true mean with a probability of 95%, were calculated.Results: The analysis screened 637 studies of which 83 were assessed by full text. Five relevant trials were identified (PANORAMA 1, MM-009, MM-010, APEX, and DOXIL-MMY-3001) that included PAN/BTZ/DEX, BTZ/DEX, BTZ, DEX, LEN/DEX, and BTZ/DOX. Since no trial was conducted to assess the efficacy of BTZ/DEX versus DEX, results of a matched-pairs comparison analysis (using propensity score matching) were utilized in the evidence network. The patient populations across the studies were similar in terms of median age (61-64 years), disease duration (24-48 months at baseline), and proportions of patients with one prior line of therapy (32-46%), except the matched pairs analysis, where only patients with one prior line of therapy were considered. The number of patients included in the studies totaled 4,109.Results of the comparison between PAN/BTZ/DEX and other treatments in terms of PFS indicated that PAN/BTZ/DEX was associated with the lowest risk of progression or death. Similarly, the HR of time to progression was estimated to be higher for other drugs than for PAN/BTZ/DEX. The odds ratio of nCR+CR indicated higher response rates for PAN/BTZ/DEX than for other treatments. Coefficients and CIs are reported in Table 1.Discussion: The analyses implicitly assume that covariates acting as potential relative treatment effect modifiers (e.g. patients with relapsed and refractory MM, ß2-microglobulin level) are similar across trials. The numerical trends of the analyses suggest that PAN/BTZ/DEX is at least as efficacious as other treatments in RR MM with significant advantage against most comparators.Table 1Results of the indirect treatment comparisonsPAN/BTZ/DEXBTZ/DEXBTZDEXLEN/DEXDOX/BTZPFS (HR,+/-1 CI)1.001.60 (1.32-1.92)2.77 (1.53-4.62)5.11 (2.51-9.20)1.87 (0.87-3.49)1.66 (0.87-2.90)TTP (HR,+/-1 CI) 1.001.67 (1.37-2.02)2.90 (1.60-4.83)5.35 (2.59-9.65)1.90 (0.89-3.50)1.61 (0.83-2.82)CR+nCR (OR,+/-1 CI)1.000.50 (0.34-0.69)0.44 (0.14-1.04)0.05 (0.01-0.15)0.49 (0.08-1.63)0.60 (0.17-1.51) DisclosuresRichardson:Takeda: Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees. Majer:Novartis: Consultancy. Krishna:Novartis: Employment. Woodman:Novartis: Employment, Equity Ownership.

Critical Appraisal Of Network Meta-Analyses Evaluating The Efficacy And Safety Of New Oral Anticoagulants In Atrial Fibrillation Stroke Prevention Trials.

Abstract Objectives To critically appraise published network meta-analyses (NMAs) evaluating the efficacy or safety of the new oral anticogulants (NOACs) dabigatran, rivaroxaban, and apixaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). Methods A systematic literature review was performed to identify the relevant NMAs using MEDLINE, EMBASE, Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. The synthesis studies were evaluated using the "Questionnaire to assess the relevance and credibility of the NMA." Results Eleven NMAs evaluating NOACs among adults with nonvalvular AF were identified. Most NMAs included three large phase III randomized controlled trials, comparing NOACs to adjusted-dose warfarin (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], and Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]). The main differences identified related to potential treatment effect modifiers regarding the mean time spent in therapeutic range (TTR) in the warfarin arm, the risk of stroke or systemic embolism across the trials (mean CHADS 2 score: C=congestive heart failure, H=hypertension, A=older than age 75 years, D=diabetes mellitus, S2=prior stroke or history of transient ischemic attack) or primary versus secondary prevention, and type of populations used in the analysis. Kansal et al. [Kansal AR, Sharma M, Bradley-Kennedy C, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada: comparative efficacy and cost-effectiveness. Thromb Haemost 2012;108:672–82] appropriately adjusted the ROCKET-AF TTR to match the RE-LY population on the basis of individual patient data. Meta-regressions are not expected to minimize confounding bias given limited data, whereas subgroup analyses had some impact on the point estimates for the treatment comparisons. Conclusions Results of the synthesis studies were generally comparable and suggested that the NOACs had similar efficacy, although some differences were identified depending on the outcome. The extent to which differences in the distribution of TTR, CHADS 2 score, or primary versus secondary prevention biased the results remains unclear.

PRS6 - Systematic Review of Observational Studies and Rcts of Omalizumab in Severe Persistent Allergic Asthma and Meta-Analysis Feasibility Assessment

To compare the effectiveness of omalizumab versus standard of care (SOC) based on randomized controlled trials (RCTs) compared with ‘real-world’, single cohort, observational studies that assess patients ‘before and after’ the use of omalizumab. A systematic literature review was conducted to identify RCTs and observational studies that assessed omalizumab in patients with severe persistent allergic asthma. Study and patient characteristics, outcome definitions, and differences in baseline risk and observed study effects were compared in terms of exacerbations and hospitalizations across the RCTs and observational studies. 11 RCTs and 24 observational studies were identified. A wide range of clinically significant exacerbation rates was observed across RCTs in terms of baseline risk (SOC: 0.40–2.86) and the treatment effect (rate ratio [RR]: 0.39–0.75). This differed from observational studies in terms of baseline risk (before omalizumab: 3.48–6.00) and the treatment effect (RRs: 0.12–0.46). A limited range of severe exacerbation rates was observed in RCTs regarding baseline risk (SOC: 0.42–0.48) and the treatment effect (RR: 0.50–0.56). However, considerable differences were identified in observational studies in terms of baseline risk (before omalizumab: 2.20–4.50) and the treatment effect (RR: 0.05–0.39). In terms of hospitalization rates, a limited range was observed for RCTs with respect to baseline risk (SOC: 0.12–0.17) and the treatment effect (RR: 0.12–0.54). Again, a wider range was observed across the observational studies in terms of baseline risk (before omalizumab: 0.32–4.45) and the treatment effect (RR: 0.09–0.71). ‘Real-world’ evidence reinforces the efficacy of omalizumab in patients with severe allergic asthma derived from RCTs, although differences in potential treatment effect modifiers were identified. Patients in observational studies may represent a more severe population compared with those in RCTs.

Prehospital noninvasive ventilation for acute respiratory failure: systematic review, network meta-analysis, and individual patient data meta-analysis.

This meta-analysis aimed to determine the effectiveness of prehospital continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP) in acute respiratory failure. Fourteen electronic databases and research registers were searched from inception to August 2013. Randomized or quasi-randomized controlled trials that reported mortality or intubation rate for prehospital CPAP or BiPAP were selected and compared to a relevant comparator in patients with acute respiratory failure. An aggregate data network meta-analysis was used to jointly estimate intervention effects relative to standard care. A network meta-analysis using a mixture of individual patient-level data and aggregate data was carried out to assess potential treatment effect modifiers. Eight randomized and two quasi-randomized controlled trials (six CPAP, four BiPAP, sample sizes 23 to 207) were identified. The aggregate data network meta-analysis suggested that CPAP was the most effective treatment in terms of mortality (probability=0.989) and intubation rate (probability=0.639) and reduced both mortality (odds ratio [OR]= 0.41; 95% credible interval [CrI]=0.20 to 0.77) and intubation rate (OR= 0.32; 95% CrI=0.17 to 0.62), compared to standard care. The effect of BiPAP on mortality (OR= 1.94; 95% CrI=0.65 to 6.14) and intubation rate (OR= 0.40; 95% CrI=0.14 to 1.16) was uncertain. The network meta-analysis using individual patient-level data and aggregate data suggested that sex was a modifier of the effect of treatment on mortality. Prehospital CPAP can reduce mortality and intubation rates compared to standard care, while the effectiveness of prehospital BiPAP is uncertain.

The use of individual patient-level data (IPD) to quantify the impact of pretreatment predictors of response to treatment in chronic hepatitis B patients

ObjectivesEvidence synthesis is an integral part decision-making by reimbursement agencies. When direct evidence is not available, network-meta-analysis (NMA) techniques are commonly used. This approach assumes that the trials are sufficiently...

Prevalence of diabetes treatment effect modifiers: the external validity of trials to older adults

Potential treatment effect modifiers (TEMs) are specific diseases or conditions with a well-described mechanism for treatment effect modification. The prevalence of TEMs in older adults with type 2 diabetes mellitus (DM) is unknown. Objectives were to 1) determine the prevalence of pre-specified potential TEMs; 2) demonstrate the potential impact of TEMs in the older adult population using a simulated trial; 3) identify TEM combinations associated with number of hospitalizations to test construct validity. Data are from the nationally-representative United States National Health and Examination Survey, 1999-2004: 8646 Civilian, non-institutionalized adults aged 45-64 or 65+ years, including 1443 with DM. TEMs were anemia, congestive heart failure, liver inflammation, polypharmacy, renal insufficiency, cognitive impairment, dizziness, frequent mental distress, mobility difficulty, and visual impairment. A trial was simulated to examine prevalence of potential TEM impact. The cross-sectional association between TEM patterns and number of hospitalizations was estimated to assess construct validity. The prevalence of TEMs was substantial such that 19.0% (95% CI 14.8-23.2) of middle-aged adults and 38.0% (95% CI 33.4-42.5) of older adults had any two. A simulated trial with modest levels of interaction suggested the prevalence of TEMs could nullify treatment benefit in 3.9-27.2% of older adults with DM. Compared to having DM alone, hospitalization rate was increased by several combinations of TEMs with substantial prevalence. We provide national benchmarks that can be used to evaluate TEM prevalence reported by clinical trials of DM, and correspondingly their external validity to older adults.

Motor control or graded activity exercises for chronic low back pain? A randomised controlled trial

BackgroundChronic low back pain remains a major health problem in Australia and around the world. Unfortunately the majority of treatments for this condition produce small effects because not all patients respond to each treatment. It appears that only 25–50% of patients respond to exercise. The two most popular types of exercise for low back pain are graded activity and motor control exercises. At present however, there are no guidelines to help clinicians select the best treatment for a patient. As a result, time and money are wasted on treatments which ultimately fail to help the patient.MethodsThis paper describes the protocol of a randomised clinical trial comparing the effects of motor control exercises with a graded activity program in the treatment of chronic non specific low back pain. Further analysis will identify clinical features that may predict a patient's response to each treatment. One hundred and seventy two participants will be randomly allocated to receive either a program of motor control exercises or graded activity. Measures of outcome will be obtained at 2, 6 and 12 months after randomisation. The primary outcomes are: pain (average pain intensity over the last week) and function (patient-specific functional scale) at 2 and 6 months. Potential treatment effect modifiers will be measured at baseline.DiscussionThis trial will not only evaluate which exercise approach is more effective in general for patients will chronic low back pain, but will also determine which exercise approach is best for an individual patient.Trial registration numberACTRN12607000432415