Mixed Treatment Comparison Research Articles

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis.

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis.

Long-acting injectable antipsychotics in patients with schizophrenia: systematic review and mixed treatment meta-analysis

Long-acting injectable antipsychotics (LAIs) are recommended for schizophrenic patients who cannot adhere to oral medication. We systematically reviewed randomized controlled trials of 6 LAIs available in Thailand including fluphenazine, flupentixol, haloperidol, zuclopenthixol, paliperidone, and risperidone in PubMed/ MEDLINE and the Cochrane library (1955–Nov 2013). Inclusion was limited to studies of schizophrenia ?24 weeks duration published in English. We selected 17 of 1,245 articles including 1,904 patients. The number of patients ranged from 19 to 747 per study (median 54). Mean study duration was 52.3 weeks (24?96 weeks) and median quality score using a Jadad scoring method was 4 (2–5). We applied a Bayesian model with a mixed treatment comparison approach for 3 competing risk outcomes including relapse, and discontinuation because of adverse events or other reasons. Based on the random effect model preferred by a goodness of fit analysis, risperidone had the lowest 52 week probability of relapse (mean ± SD, 0.26 ± 0.321) followed by paliperidone (0.30 ± 0.314). Zuclopenthixol had the lowest probability of discontinuation because of an adverse event (0.07 ± 0.159) or other reasons (0.26 ± 0.295). Risperidone had the highest probability of preventing relapse (0.35 ± 0.476) or discontinuation for other reasons (0.31 ± 0.461). Zuclopenthixol had the highest probability of preventing discontinuation because of adverse effects (0.31 ± 0.464). All 6 LAIs tended to have a lower risk of relapse compared with placebo. Differences between LAIs preventing any treatment discontinuation or relapse were seen, but limited in our analysis. Keywords: Competing risk outcomes, long acting injectable antipsychotics, meta-analysis, mixed treatment comparison

RETRACTED: Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis. For this network meta-analysis, we considered randomised trials comparing any of the following interventions: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose. We identified 8973 manuscripts from our search, of which 74 randomised trials with a total of 58,556 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0·37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0·57, 95% credibility interval [CrI] -0·69 to -0·46) and etoricoxib 60 mg/day (ES -0·58, -0·73 to -0·43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for celecoxib (p=0·030), diclofenac (p=0·031), and naproxen (p=0·026). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis. On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients. Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland.

The cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis in Canada

Background: Multiple sclerosis (MS) causes significant disability and diminished quality-of-life. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is a new oral treatment for relapsing-remitting MS (RRMS) approved in the US, Australia, Canada, and Europe. Objectives: A cost-effectiveness model was developed to compare the health economic impact of DMF against other disease-modifying therapies (DMTs) as first-line RRMS treatment from a Canadian Ministry of Health perspective. Methods: A Markov cohort model was developed to simulate patients’ progression through health states based on the Kurtzke Expanded Disability Status Scale (EDSS) over a life-time horizon. Patients entered the model based on a distribution of baseline EDSS scores, from which they could progress to higher or regress to lower EDSS state, or remain in the same state. Relapses could occur at any EDSS score. Results from a mixed-treatment comparison were used to inform model inputs for disease progression and relapse rates per treatment. Costs included direct medical costs stratified by EDSS score. Utilities were accrued based on time spent in each EDSS state. Results: Compared with glatiramer acetate, DMF yielded 0.528 incremental quality-adjusted life-years (QALYs) at an incremental cost of $23 338 Canadian dollars (CAD), resulting in an incremental cost-effectiveness ratio (ICER) of CAD $44 118/QALY. The ICER for DMF compared with Rebif 44 mcg was CAD $10 672. Results were consistent across a wide range of one-way and probabilistic sensitivity analyses. Conclusions: Based on traditional cost-effectiveness thresholds in Canada (CAD $50 000–60 000), DMF can be considered a cost-effective option compared to other first-line DMTs.

Cost-Utility Analysis of Lurasidone Versus Aripiprazole in Adults with Schizophrenia

BackgroundIn 2014, lurasidone, an atypical antipsychotic, was approved for the treatment of schizophrenia in adults. It is an alternative treatment option to aripiprazole, and when compared with aripiprazole, lurasidone was associated with improved symptom reduction and reduced risk of weight gain and relapse. We conducted a cost-utility analysis of lurasidone versus aripiprazole from the perspective of healthcare services, using Scotland and Wales as specific case studies.MethodsA 10-year Markov model, incorporating a 6-week acute phase and a maintenance phase across three health states (discontinuation, relapse, death) was constructed. Six-week probabilities of discontinuation and adverse events were based on a published independent mixed-treatment comparison; long-term risks of relapse and discontinuation were from an indirect comparison. Costs included drug therapy, relapse, and outpatient, primary and residential care. Costs and benefits were discounted at 3.5 %. Utility estimates were taken from published literature, and cost effectiveness was expressed as total 10-year incremental costs and quality-adjusted life-years (QALYs).ResultsLurasidone yielded a cost saving of £3383 and an improvement of 0.005 QALYs versus aripiprazole, in Scotland. Deterministic sensitivity analysis demonstrated that results were sensitive to relapse rates, while probabilistic sensitivity analysis suggested that lurasidone had the highest expected net benefit at willingness-to-pay thresholds of £20,000–30,000 per QALY. The probability that lurasidone was a cost-effective treatment strategy was approximately 75 % at all willingness-to-pay thresholds, with similar results being obtained for the Welsh analysis.ConclusionsOur analysis suggests that lurasidone would provide an effective, cost-saving alternative for the healthcare service in the treatment of adult patients with schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1007/s40273-016-0405-0) contains supplementary material, which is available to authorized users.

Budget impact analysis of delayed-release dimethyl-fumarate in the treatment of relapsing-remitting multiple sclerosis in Italy

INTRODUCTION: Multiple Sclerosis (MS) is a condition with a significant economic and social burden that affects young adults, in their active working phase. The most recent evaluations show an annual average social cost of € 38-39 thousand per patient. Today the approval of the new oral therapies allows physicians to select further options that can meet patients’ clinical unmet needs.OBJECTIVES: To evaluate the economic impact of a recently approved therapy, delayed-release dimethyl-fumarate (DMF; also known as gastro-resistant DMF), on the overall management costs of relapsing-remitting multiple sclerosis (RRMS) in Italy.METHODS: A budget impact model, adopting the perspective of the Italian National Healthcare Service (NHS), was used to compare healthcare costs of two different treatment scenarios: a) base-case, where DMF is not available for RRMS patients (Scenario A), vs. b) alternative-case, where DMF is available for RRMS patients (Scenario B). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, administration, therapy and disease monitoring, relapse management, treatment-related adverse events) have been calculated over 3 years and compared for the two scenarios. Impact of relapses for the disease modifying therapies (DMTs) included in the analysis was estimated using an elaboration of the results from published mixed treatment comparison. RRMS population treated with DMTs was estimated using Italian prevalence and incidence data. According to these estimates, the number of treated patients amounted to 36,078 at Year 1, 38,832 at Year 2, and 40,673 at Year 3.RESULTS: According to the current price and to the assumptions reported in the methodology section, it was estimated that the introduction of DMF (Scenario B) determines a decrease of the budget impact, if compared with the base case (Scenario A) in the perspective of Italian NHS. Over three years, the budget impact would be € 1,376 mln in the Scenario A and € 1,354 mln in the Scenario B (-22.18 mln €; -1.61% relative budget variation). The main drivers for cost-saving were pharmacological treatment costs and reduced burden of relapses (corresponding to more than 1,800 avoided relapses).CONCLUSIONS: At the current cost conditions applied in Italy and according to the described assumptions, the use of DMF is economically sustainable for the Italian NHS. Plausibly, the introduction and usage of this new therapy in RRMS patients will ensure clinical benefits for patients without resulting in additional costs for the Italian NHS.[In Italian]

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

ObjectivesThe paper aimed to estimate the incremental cost-effectiveness ratio (ICER) at the public published price for delayed-release dimethyl fumarate versus relevant Multiple Sclerosis disease-modifying therapies available in France in June 2015.MethodsThe economic model was adapted to the French setting in accordance with the Haute Autorité de Santé guidelines using a model previously developed for NICE. A cohort of Relapsing Remitting Multiple Sclerosis patients was simulated over a 30-year time horizon. Twenty one health states were taken into account: Kurtzke Expanded Disability Status Scale (EDSS) 0–9 for Relapsing Remitting Multiple Sclerosis patients, EDSS 0–9 for Secondary Progressive Multiple Sclerosis patients, and death. Estimates of relative treatment efficacy were determined using a mixed-treatment comparison. Probabilities of events were derived from the dimethyl fumarate pivotal clinical trials and the London Ontario Dataset. Costs and utilities were extracted from the published literature from both the payer and societal perspectives. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model results.ResultsFrom both perspectives, dimethyl fumarate and interferon beta-1a (IFN beta-1a) 44mcg were the two optimal treatments, as the other treatments (IFN beta-1a 30mcg, IFN beta-1b 250mcg, teriflunomide, glatiramer acetate, fingolimod) were dominated on the efficiency frontier. From the societal perspective, dimethyl fumarate versus IFN beta-1a 44mcg incurred an incremental cost of €3,684 and an incremental quality-adjusted life year (QALY) of 0.281, corresponding to an ICER of €13,110/QALY.ConclusionsDespite no reference threshold for France, dimethyl fumarate can be considered as a cost-effective option as it is on the efficiency frontier.

Clinical effectiveness and cost-effectiveness of interventions for the treatment of anogenital warts: systematic review and economic evaluation.

Typically occurring on the external genitalia, anogenital warts (AGWs) are benign epithelial skin lesions caused by human papillomavirus infection. AGWs are usually painless but can be unsightly and physically uncomfortable, and affected people might experience psychological distress. The evidence base on the clinical effectiveness and cost-effectiveness of treatments for AGWs is limited. To systematically review the evidence on the clinical effectiveness of medical and surgical treatments for AGWs and to develop an economic model to estimate the cost-effectiveness of the treatments. Electronic databases (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Web of Science) were searched from inception (or January 2000 for Web of Science) to September 2014. Bibliographies of relevant systematic reviews were hand-searched to identify potentially relevant studies. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for ongoing and planned studies. A systematic review of the clinical effectiveness literature was carried out according to standard methods and a mixed-treatment comparison (MTC) undertaken. The model implemented for each outcome was that with the lowest deviance information criterion. A de novo economic model was developed to assess cost-effectiveness from the perspective of the UK NHS. The model structure was informed through a systematic review of the economic literature and in consultation with clinical experts. Effectiveness data were obtained from the MTC. Costs were obtained from the literature and standard UK sources. Of 4232 titles and abstracts screened for inclusion in the review of clinical effectiveness, 60 randomised controlled trials (RCTs) evaluating 19 interventions were included. Analysis by MTC indicated that ablative techniques were typically more effective than topical interventions at completely clearing AGWs at the end of treatment. Podophyllotoxin 0.5% solution (Condyline(®), Takeda Pharmaceutical Company Ltd; Warticon(®) solution, Stiefel Laboratories Ltd) was found to be the most effective topical treatment evaluated. Networks for other outcomes included fewer treatments, which restrict conclusions on the comparative effectiveness of interventions. In total, 84 treatment strategies were assessed using the economic model. Podophyllotoxin 0.5% solution first line followed by carbon dioxide (CO2) laser therapy second line if AGWs did not clear was most likely to be considered a cost-effective use of resources at a willingness to pay of £20,000-30,000 per additional quality-adjusted life-year gained. The result was robust to most sensitivity analyses conducted. Limited reporting in identified studies of baseline characteristics for the enrolled population generates uncertainty around the comparability of the study populations and therefore the generalisability of the results to clinical practice. Subgroup analyses were planned based on type, number and size of AGWs, all of which are factors thought to influence treatment effect. Lack of data on clinical effectiveness based on these characteristics precluded analysis of the differential effects of treatments in the subgroups of interest. Despite identification of 60 studies, most comparisons in the MTC are informed by only one RCT. Additionally, lack of head-to-head RCTs comparing key treatments, together with minimal reporting of results in some studies, precluded comprehensive analysis of all treatments for AGWs. The results generated by the MTC are in agreement with consensus opinion that ablative techniques are clinically more effective at completely clearing AGWs after treatment. However, the evidence base informing the MTC is limited. A head-to-head RCT that evaluates the comparative effectiveness of interventions used in clinical practice would help to discern the potential advantages and disadvantages of the individual treatments. The results of the economic analysis suggest that podophyllotoxin 0.5% solution is likely to represent a cost-effective first-line treatment option. More expensive effective treatments, such as CO2 laser therapy or surgery, may represent cost-effective second-line treatment options. No treatment and podophyllin are unlikely to be considered cost-effective treatment options. There is uncertainty around the cost-effectiveness of treatment with imiquimod, trichloroacetic acid and cryotherapy. This study is registered as PROSPERO CRD42013005457. The National Institute for Health Research Health Technology Assessment programme.

A mixed treatment comparison to compare the efficacy and safety of botulinum toxin treatments for cervical dystonia.

A systematic pair-wise comparison of all available botulinum toxin serotype A and B treatments for cervical dystonia (CD) was conducted, as direct head-to-head clinical trial comparisons are lacking. Five botulinum toxin products: Dysport® (abobotulinumtoxinA), Botox® (onabotulinumtoxinA), Xeomin® (incobotulinumtoxinA), Prosigne® (Chinese botulinum toxin serotype A) and Myobloc® (rimabotulinumtoxinB) have demonstrated efficacy for managing CD. A pair-wise efficacy and safety comparison was performed for all toxins based on literature-reported clinical outcomes. Multi-armed randomized controlled trials (RCTs) were identified for inclusion using a systematic literature review, and assessed for comparability based on patient population and efficacy outcome measures. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was selected as the efficacy outcome measurement for assessment. A mixed treatment comparison (MTC) was conducted using a Bayesian hierarchical model allowing indirect comparison of the interventions. Due to the limitation of available clinical data, this study only investigated the main effect of toxin treatments without explicitly considering potential confounding factors such as gender and formulation differences. There was reasonable agreement between the number of unconstrained data points, residual deviance and pair-wise results. This research suggests that all botulinum toxin serotype A and serotype B treatments were effective compared to placebo in treating CD, with the exception of Prosigne. Based on this MTC analysis, there is no significant efficacy difference between Dysport, Botox, Xeomin and Myobloc at week four post injection. Of the adverse events measured, neither dysphagia nor injection site pain was significantly greater in the treatment or placebo groups.

Once-daily fluticasone furoate/vilanterol versus twice daily combination therapies in asthma-mixed treatment comparisons of clinical efficacy.

BackgroundFluticasone furoate (FF)/vilanterol (VI) is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combination. FF/VI, 92/22mcg and 184/22mcg, are approved in Europe as maintenance therapy in persistent asthma. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes.MethodsData from 31 parallel-group randomised controlled trials (RCTs) of ICS/LABA, of ≥8 weeks’ duration in patients aged ≥12 years with asthma, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for four efficacy outcomes (primary analysis). Lung function, assessed by change from baseline morning peak expiratory flow (PEF) (n = 18 studies) and forced expiratory volume in 1 s (FEV1) (n = 28), was the outcome of primary interest. Secondary objectives were assessment of relative efficacy in terms of exacerbation rates (n = 6) and health status (n = 7). Overall, 24 different treatment arms were included in the MTC; we report findings comparing FF/VI (92/22mcg and 184/22mcg) with fluticasone propionate/salmeterol (FP/SAL) (250/50mcg and 500/50mcg) and budesonide/formoterol (BUD/FORM) (320/9mcg and 640/18mcg).ResultsFor PEF (margin = 12 l/min), FF/VI 92/22mcg demonstrated ≥94 % probability and FF/VI 184/22mcg >99 % probability of non-inferiority to corresponding doses of both FP/SAL and BUD/FORM. For FEV1 (margin = 100 ml), FF/VI demonstrated ≥98 % (92/22mcg) and >99 % (184/22mcg) probability of non-inferiority to both FP/SAL and BUD/FORM. Findings for exacerbations were inconclusive due to lack of data: FF/VI 92/22mcg demonstrated 74 % and 82 % probability of non-inferiority (margin = 10 %) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg, respectively. For Asthma Quality of Life Questionnaire (AQLQ) score, FF/VI 92/22mcg demonstrated >99 % and 90 % probability of non-inferiority (margin = 0.25) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg. Data were unavailable to assess non-inferiority of FF/VI 184/22mcg on exacerbations or AQLQ.ConclusionsBoth strengths of once-daily FF/VI in asthma were comparable with corresponding doses of twice-daily FP/SAL and BUD/FORM in terms of lung function in this MTC analysis. FF/VI 92/22mcg was comparable with FP/SAL and BUD/FORM on AQLQ, but exacerbation results were inconclusive. Model limitations include disconnected treatment networks and variability across studies. Our data support previous RCT findings suggesting that the efficacy of once-daily FF/VI in improving lung function and health status in asthma is comparable with twice-daily ICS/LABAs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40733-015-0016-0) contains supplementary material, which is available to authorized users.

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States

Objective:To assess the cost-effectiveness of delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), an effective therapy for relapsing forms of multiple sclerosis (MS), compared with glatiramer acetate and fingolimod, commonly used treatments in the US.Methods:A Markov model was developed comparing delayed-release DMF to glatiramer acetate and fingolimod using a US payer perspective and 20-year time horizon. A cohort of patients, mean age 38 years, with relapsing-remitting MS and Kurtzke Expanded Disability Status Scale (EDSS) scores between 0–6 entered the model. Efficacy and safety were estimated by mixed-treatment comparison of data from the DEFINE and CONFIRM trials and clinical trials of other disease-modifying therapies. Data from published studies were used to derive resource use, cost, and utility inputs. Key outcomes included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Alternative scenarios tested in a sensitivity analysis included drug efficacy, EDSS-related or relapse-related costs, alternative perspectives, drug acquisition costs, and utility.Results:Base-case results with a 20-year time horizon indicated that delayed-release DMF increased QALYs +0.450 or +0.359 compared with glatiramer acetate or fingolimod, respectively. Reductions in 20-year costs with delayed-release DMF were −$70,644 compared with once-daily glatiramer acetate and −$32,958 compared with fingolimod. In an analysis comparing delayed-release DMF to three-times-weekly glatiramer acetate and assuming similar efficacy and safety to the once-daily formulation, 20-year costs with delayed-release DMF were increased by $15,806 and cost per QALY gained was $35,142. The differences in costs were most sensitive to acquisition cost and inclusion of informal care costs and productivity losses. The differences in QALYs were most sensitive to the impact of delayed-release DMF on disease progression and the EDSS utility weights.Conclusion:Delayed-release DMF is likely to increase QALYs for patients with relapsing forms of MS and be cost-effective compared with fingolimod and glatiramer acetate.

Comparative Efficacy and Acceptability of Anti-TNF-Alpha Therapy in Ankylosing Spondylitis: A Mixed-Treatments Comparison

Background: Tumor necrosis factor α (TNFα) antagonists, namely, golimumab, adalimumab, infliximab, etanercept and certolizumab have been prescribed to alleviate and treat ankylosing spondylitis (AS). However, the lack of comparative evidence does not enable us to make constructive recommendations particularly for AS patient populations. Methods: Eligible controlled trials regarding the above 5 anti-TNFα therapies were searched electronically through PubMed, Embase and Cochrane until April 1, 2015. Odds ratios (ORs) were estimated and compared for efficacy (ASAS20, ASAS40, ASAS5/6 responses and ASAS partial remission) and acceptability (serious adverse effects (SAE)) among the anti-TNFα reagents. Results: Totally, 25 trials with 2989 participants were incorporated in this mixed treatment comparison. All the 5 TNFα blockers achieved better ASAS20, ASAS40, ASAS5/6 and ASAS-PR responses than the placebo. Furthermore, there was no significant distinction existed among inter-drug comparisons, except that unfavorable effects induced by certolizumab seemed to be less severe than those by etanercept (OR = 0.22, 95% CI: 0.05-0.93). Apart from that, etanercept was estimated to arrive at the most favorable ASAS20 response (90.6%) and SAE (83.6%), while infliximab seemed to accomplish the best ASAS40 (83.6%) and ASAS-PR responses (77.3%). In addition, adalimumab was estimated to rank the highest ASAS5/6 response (75.0%). Conclusions: Etanercept, infliximab and adalimumab might be prioritized among the commonly recognized 5 anti-TNFα therapies specific for AS patients, though existing evidence did not suffice to confirm significant superiority among the above 5 anti-TNFα reagent.

Network Meta-analysis to Synthesize Evidence for Decision Making in Cardiovascular Research.

Clinical decision-making requires synthesis of evidence from literature reviews focused on a specific theme. Evidence synthesis is performed with qualitative assessments and systematic reviews of randomized clinical trials, typically covering statistical pooling with pairwise meta-analyses. These methods include adjusted indirect comparison meta-analysis, network meta-analysis, and mixed-treatment comparison. These tools allow synthesis of evidence and comparison of effectiveness in cardiovascular research.

Estimating the Relative Effectiveness of Treatments in Relapsed/Refractory Multiple Myeloma through a Systematic Review and Network Meta-Analysis

Introduction: Recently introduced treatments have improved survival outcomes in relapsed or refractory multiple myeloma (rrMM), with positive outlooks from ongoing trials. However, evidence on relative effectiveness to inform best practice is lacking due to the paucity of head-to-head clinical trials. This systematic review aimed to compare all treatments in rrMM via a mixed treatment comparison (MTC), taking into account prior lines of therapy. Novel statistical techniques using a network meta-analysis (NMA) were developed to estimate relative effectiveness.Methods: A literature search was conducted August 2014 and repeated December 2014. Randomised control trials (RCTs) were included if they reported median duration of progression-free survival (PFS), overall survival (OS) or time to progression (TTP) as a primary or secondary rrMM treatment outcomes. A Bayesian NMA using non-informative prior distributions was fitted in the software application R using JAGS. Such models allow for the estimation of all pairwise comparisons within a connected network of evidence. Fixed effects were assumed, as each direct comparison in the network is informed by a maximum of two trials, which does not allow for the estimation of a heterogeneity parameter. Considerable heterogeneity was observed across studies. In particular the number of prior treatment lines among patients recruited into trials in rrMM varied markedly and was often not reported in enough detail to include this potentially important variable in the analysis. As a result, trials conducted in heavily pre-treated patient populations (3 or more prior lines of therapy) were excluded from the primary analysis.Results: A total of 24 RCTs reporting relevant outcomes for 20 different treatment regimens were identified for data extraction. It was not possible to link all 20 regimens within a single evidence network, but the majority (16) were incorporated within two networks (see figure 1). As a result, the analysis estimated all pairwise comparisons within each of the networks; it is not possible to draw conclusions for comparisons across networks. Results are presented in figure 2 for the yellow (larger) and blue networks (smaller).Three studies were excluded from the presented analysis as median PFS had not yet been reached at follow up. Median follow up across all identified studies ranged from 5.59 to 36 months. Within the yellow network, carfilzomib in combination with lenalidomide and dexamethasone was the most effective treatment, followed by lenalidomide and dexamethasone and then bortezomib. In the smaller blue evidence network, bortezomib in combination with dexamethasone and panobinostat was the most effective treatment.Discussion: Decision-making to optimise patient care, supported by clinical guidelines, requires evidence-based assessment of available treatments. In practise this is often restricted to a series of pair-wise comparisons of treatments such that drawing appropriate inferences across all available options is not possible. To our knowledge, the application of NMA and subsequent results presented here are the first of their kind in rrMM. Previous meta-analyses have been reported for individual treatments, but not for all available options. Our analysis appears broadly consistent with evidence from clinical trials for licensed treatments which are now the established standard of care in rrMM. One limitation of our analysis relates to the published evidence on prior treatment lines in rrMM patients. Fitting a meta-regression to explain heterogeneity may lead to confounding of the treatment effect given the available evidence. Patient level data would allow for a more reliable analysis of the effect of prior treatment lines on PFS. A further consideration is the level of evidence included within our analysis. NMA typically focuses on data drawn from RCTs though methods are available to allow for the inclusion of non-RCT evidence. A great deal of published evidence of this sort is available in the rrMM setting and future analytical approaches should explore how the inclusion of this evidence affects our findings. [Display omitted] [Display omitted] [Display omitted] DisclosuresRuggeri:Cogentia UK: Research Funding. Maguire:Cogentia Healthcare Consulting: Research Funding. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. O'Dwyer:Celgene: Honoraria, Research Funding.

Comparison of Watchman device with new oral anti-coagulants in patients with atrial fibrillation: A network meta-analysis

BackgroundNew oral anticoagulants (NOAC) and the Watchman device represent an alternative to warfarin for stroke prophylaxis in atrial fibrillation (AF) patients. However, no studies compare these new treatments. We performed a network meta-analysis to indirectly compare Watchman and NOACs among AF patients. MethodsWe performed a MEDLINE search for studies comparing warfarin with NOACs (dabigatran, rivaroxaban, apixaban and edoxaban) or Watchman in AF patients with reported clinical outcomes. Mixed treatment comparison model generation was performed to directly and indirectly compare NOACs, warfarin and Watchman. Results14 studies with 246,005 patients were included in the analysis, among which 124,823 were treated with warfarin, 120,450 were treated with NOACs and 732 had Watchman implanted. Mean age was 72±9years, 53% were male, and mean CHADS2 score was 2.1±1.6. Both NOACs and Watchman were superior to warfarin in hemorrhagic stroke prevention (OR=0.46 [0.30–0.82] and OR=0.21 [0.05–0.99], respectively). NOACs significantly reduced total stroke (OR=0.78 [0.58–0.96]) and major bleeding (OR=0.78 [0.65–0.91]) compared with warfarin. Indirect comparison between NOAC and Watchman revealed no significant differences in outcomes, though there was a trend toward higher rates of ischemic stroke with Watchman compared with NOAC (OR 2.60 [0.60–13.96]) with the opposite findings with hemorrhagic stroke (OR=0.44 [0.09–2.14]). ConclusionsNOAC therapy was superior to warfarin for multiple outcomes while Watchman reduced hemorrhagic stroke. Further studies are needed to assess Watchman versus NOAC to optimize therapy for stroke prevention in AF patients.

Abstract 19342: The Impact of PCSK9 Inhibitors on Lipid Levels and Outcomes in Patients With Primary Hypercholesterolemia: A Network Meta-analysis

Introduction: We performed a network meta-analysis of randomized controlled trials (RCTs) in patients with primary hypercholesterolemia to compare the impact of PCSK9 inhibitors with placebo and ezetimibe on lipid levels and outcomes. Hypothesis: PCSK9 inhibitors will significantly lower LDL-C greater than ezetimibe and improve outcomes. Methods: MEDLINE/PubMed, Cochrane CENTRAL, and ClinicalTrials.gov were searched for RCTs assessing PCSK9 inhibitors versus other therapies in patients with primary hypercholesterolemia. Mixed treatment comparison model generation was performed to directly and indirectly compare PCSK9 inhibition on lipid levels with ezetimibe and placebo. Odds ratios with 95% confidence intervals (OR [95% CIs]) were generated with random-effect models to compare outcomes. Results: Our meta-analysis included 17 RCTs with 13,083 patients that were randomized to PCSK9 inhibitors (n=8,250), placebo (n=3,957), ezetimibe (n=846), or PCSK9 inhibitors and ezetimibe (n=30). The mean age was 59±10, 52% were male, 34% had coronary artery disease, 51% had hypertension, 19% had diabetes mellitus, baseline LDL of 122±36 mg/dL, total cholesterol of 199±39 mg/dL, and HDL of 51±14 mg/dL. PCSK9 inhibitors significantly reduced LDL cholesterol by 57% relative to placebo (p<0.001) and 36.1% relative to ezetimibe (p<0.001). PCSK9 inhibitors reduced the incidence of all-cause mortality (OR 0.43 [95% CI 0.22-0.82], p=0.01) with a trend for cardiovascular death (OR 0.50 [95% CI 0.22-1.13], p=0.10) and cardiovascular events (OR 0.67 [95% CI 0.43-1.04], p=0.07) when compared with placebo. Conclusions: PCSK9 inhibition significantly improved lipid profiles and reduced the incidence of all-cause mortality compared with placebo. Thus, PCSK9 inhibitor therapy, once approved, may serve as an excellent alternative for patients with statin intolerance and for those who do not respond to conventional lipid reduction therapy.

Cost Effectiveness of Daclatasvir/Asunaprevir Versus Peginterferon/Ribavirin and Protease Inhibitors for the Treatment of Hepatitis c Genotype 1b Naïve Patients in Chile.

IntroductionDaclatasvir and Asunaprevir (DCV/ASV) have recently been approved for the treatment of chronic hepatitis C virus infection. In association, they are more effective and safer than previous available treatments, but more expensive. It is unclear if paying for the additional costs is an efficient strategy considering limited resources.MethodsA Markov model was built to estimate the expected costs in Chilean pesos (CL$) and converted to US dollars (US$) and benefits in quality adjusted life years (QALYs) in a hypothetic cohort of naive patients receiving DCV/ASV compared to protease inhibitors (PIs) and Peginterferon plus Ribavirin (PR). Efficacy was obtained from a mixed-treatment comparison study and costs were estimated from local sources. Utilities were obtained applying the EQ-5D survey to local patients and then valued with the Chilean tariff. A time horizon of 46 years and a discount rate of 3% for costs and outcomes was considered. The ICERs were estimated for a range of DCV/ASV prices. Deterministic and probabilistic sensitivity analyses were performed.ResultsPIs were extendedly dominated by DCV/ASV. The ICER of DCV/ASV compared to PR was US$ 16,635/QALY at a total treatment price of US$ 77,419; US$11,581 /QALY at a price of US$ 58,065; US$ 6,375/QALY at a price of US$ 38,710; and US$ 1,364 /QALY at a price of US$ 19,355. The probability of cost-effectiveness at a price of US$ 38,710 was 91.6% while there is a 21.43% probability that DCV/ASV dominates PR if the total treatment price was US$ 19,355. Although the results are sensitive to certain parameters, the ICER did not increase above the suggested threshold of 1 GDP per capita.ConclusionsDCV/ASV can be considered cost-effective at any price of the range studied. These results provide decision makers useful information about the value of incorporating these drugs into the public Chilean healthcare system.

A Bayesian missing data framework for generalized multiple outcome mixed treatment comparisons.

Bayesian statistical approaches to mixed treatment comparisons (MTCs) are becoming more popular because of their flexibility and interpretability. Many randomized clinical trials report multiple outcomes with possible inherent correlations. Moreover, MTC data are typically sparse (although richer than standard meta-analysis, comparing only two treatments), and researchers often choose study arms based upon which treatments emerge as superior in previous trials. In this paper, we summarize existing hierarchical Bayesian methods for MTCs with a single outcome and introduce novel Bayesian approaches for multiple outcomes simultaneously, rather than in separate MTC analyses. We do this by incorporating partially observed data and its correlation structure between outcomes through contrast-based and arm-based parameterizations that consider any unobserved treatment arms as missing data to be imputed. We also extend the model to apply to all types of generalized linear model outcomes, such as count or continuous responses. We offer a simulation study under various missingness mechanisms (e.g., missing completely at random, missing at random, and missing not at random) providing evidence that our models outperform existing models in terms of bias, mean squared error, and coverage probability then illustrate our methods with a real MTC dataset. We close with a discussion of our results, several contentious issues in MTC analysis, and a few avenues for future methodological development.

A Mixed Treatment Comparison (Mtc) to Compare the Efficacy of Anti-Thrombotic Agents in the Acute Treatment of Venous Thromboembolism (Vte) in Patients with Active Cancer

New oral anticoagulants (NOACs) are available for the treatment and prevention of VTE but evidence on their clinical effectiveness compared with existing treatments is limited. This research compared the clinical effectiveness of dabigatran, rivaroxaban, adjusted standard dose warfarin (warfarin), and low molecular weight heparin (LMWH) in people with active cancer following VTE. This research was conducted during a review of the company’s submission (CS) to the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal programme for the oral direct thrombin inhibitor, dabigatran. Randomised controlled trials (RCTs) for inclusion were identified using the CS for dabigatran (as part of Technology Appraisal [TA]327), and two similar submissions for rivaroxaban (TA261 and TA287). RCTs were assessed for comparability based on patient population, disease severity, and treatments received. A Bayesian MTC was conducted, and fixed and random effects models were explored. Odds ratio (OR) was chosen as the summary statistic for VTE recurrence and major bleed. The network of 9 RCTs formed a “radiating star”. The fixed effects model had the lowest deviance information criterion (DIC) for VTE recurrence and major bleed and so was chosen as the best-fitting model. There was reasonable agreement between the number of unconstrained data points and the residual deviance for both outcomes. Results compared to dabigatran were (OR>1 favours dabigatran): VTE recurrence LMWH OR 0.96 (95% Credible Interval [95%CrI]: 0.15–3.37), rivaroxaban OR 1.29 (95%CrI: 0.12–5.42), warfarin OR 1.87 (95%CrI: 0.31–6.45); major bleed LMWH OR 0.85 (95%CrI: 0.15–2.67), warfarin OR 0.74 (95%CrI: 0.15–2.15). No data were available on major bleed for rivaroxaban in people with active cancer. There were no significant differences in the outcomes evaluated. However, the available evidence suggests that LMWH may have the lowest risk of VTE recurrence in the treatments assessed.

A Mixed Treatment Comparison (Mtc) to Compare the Efficacy of Anti-Thrombotic Agents in Treatment and Secondary Prevention of Venous Thromboembolism (Vte) in Patients with Deep Vein Thrombosis (Dvt)

A Mixed Treatment Comparison (Mtc) to Compare the Efficacy of Anti-Thrombotic Agents in Treatment and Secondary Prevention of Venous Thromboembolism (Vte) in Patients with Deep Vein Thrombosis (Dvt)