Neil Hawkins

Interpreting Indirect Treatment Comparisons and Network Meta-Analysis for Health-Care Decision Making: Report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: Part 1

Evidence-based health-care decision making requires comparisons of all relevant competing interventions. In the absence of randomized, controlled trials involving a direct comparison of all treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best choice(s) of treatment. Mixed treatment comparisons, a special case of network meta-analysis, combine direct and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than a traditional meta-analysis. This report from the ISPOR Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on the interpretation of indirect treatment comparisons and network meta-analysis to assist policymakers and health-care professionals in using its findings for decision making. We start with an overview of how networks of randomized, controlled trials allow multiple treatment comparisons of competing interventions. Next, an introduction to the synthesis of the available evidence with a focus on terminology, assumptions, validity, and statistical methods is provided, followed by advice on critically reviewing and interpreting an indirect treatment comparison or network meta-analysis to inform decision making. We finish with a discussion of what to do if there are no direct or indirect treatment comparisons of randomized, controlled trials possible and a health-care decision still needs to be made.

Conducting indirect-treatment-comparison and network-meta-analysis studies: Report of the ISPOR task force on indirect treatment comparisons good research practices: Part 2

Evidence-based health care decision making requires comparison of all relevant competing interventions. In the absence of randomized controlled trials involving a direct comparison of all treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best treatment(s). Mixed treatment comparisons, a special case of network meta-analysis, combine direct evidence and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than traditional meta-analysis. This report from the International Society for Pharmacoeconomics and Outcomes Research Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on technical aspects of conducting network meta-analyses (our use of this term includes most methods that involve meta-analysis in the context of a network of evidence). We start with a discussion of strategies for developing networks of evidence. Next we briefly review assumptions of network meta-analysis. Then we focus on the statistical analysis of the data: objectives, models (fixed-effects and random-effects), frequentist versus Bayesian approaches, and model validation. A checklist highlights key components of network meta-analysis, and substantial examples illustrate indirect treatment comparisons (both frequentist and Bayesian approaches) and network meta-analysis. A further section discusses eight key areas for future research.

Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta‐analysis of randomized controlled trials

Background  Ustekinumab, a novel monoclonal antibody for the treatment of moderate to severe plaque‐type psoriasis, has recently received regulatory approval in Europe, bringing the total number of biologic agents licensed in this indication to five. To assist treatment selection in daily practice it is essential to understand the benefit/risk profile of these agents and in the absence of a clinical trial comparing all available biologics a number of reviews have used statistical techniques to generate estimates of the comparative effectiveness of these therapies through the available network of randomized clinical trials. These estimates have previously been published for a limited range of psoriasis biologic treatments, although, to date no review has compared all the currently available agents in Europe.

Effect of Antihyperglycemic Agents Added to Metformin and a Sulfonylurea on Glycemic Control and Weight Gain in Type 2 Diabetes: A Network Meta-analysis

BACKGROUND Few studies have examined the effect of adding a third antihyperglycemic drug when blood glucose control is not achieved by using metformin and a sulfonylurea. PURPOSE To compare the efficacy of add-on antihyperglycemic drugs in patients with type 2 diabetes that is not controlled with metformin and a sulfonylurea. DATA SOURCES MEDLINE, EMBASE, Cochrane Library, LILACS, and ClinicalTrials.gov electronic databases. STUDY SELECTION Randomized trials at least 24 weeks in duration. Studies evaluated the effects of adding a third antihyperglycemic drug to treatment of adults aged 18 years or older with type 2 diabetes and a hemoglobin A(1c) (HbA(1c)) level greater than 7.0% who were already receiving a combination of metformin and a sulfonylurea. DATA EXTRACTION Primary end points were change in HbA(1c) level, change in weight, and frequency of severe hypoglycemia. DATA SYNTHESIS Eighteen trials involving 4535 participants that lasted a mean of 31.3 weeks (24 to 52 weeks) were included. Compared with placebo, drug classes did not differ in effect on HbA(1c) level (reduction ranging from -0.70% [95% credible interval {CrI}, -1.33% to -0.08%] for acarbose to -1.08% [CrI, -1.41% to -0.77%] for insulin). Weight increase was seen with insulins (2.84 kg [CrI, 1.76 to 3.90 kg]) and thiazolidinediones (4.25 kg [CrI, 2.76 to 5.66 kg]), and weight loss was seen with glucagon-like peptide-1 agonists (-1.63 kg [CrI, -2.71 to -0.60 kg]). Insulins caused twice the absolute number of severe hypoglycemic episodes than noninsulin antihyperglycemic agents. LIMITATIONS Most of the trials were short term, and trial quality varied. With so few trials relative to antihyperglycemic agents, investigators relied on indirect comparisons, which increased the uncertainty of the findings and conclusions. CONCLUSION There is no clear difference in benefit between drug classes when adding a third agent to treatment of patients with type 2 diabetes who are already receiving metformin and a sulfonylurea. The most appropriate option should depend on each patients clinical characteristics. PRIMARY FUNDING SOURCE Conselho Nacional de Desenvolvimento Científico e Tecnológico and Coordenacăo de Aperfeicoamento de Pessoal de Nível Superior.

Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: A tutorial

BackgroundData on survival endpoints are usually summarised using either hazard ratio, cumulative number of events, or median survival statistics. Network meta-analysis, an extension of traditional pairwise meta-analysis, is typically based on a single statistic. In this case, studies which do not report the chosen statistic are excluded from the analysis which may introduce bias.MethodsIn this paper we present a tutorial illustrating how network meta-analyses of survival endpoints can combine count and hazard ratio statistics in a single analysis on the hazard ratio scale. We also describe methods for accounting for the correlations in relative treatment effects (such as hazard ratios) that arise in trials with more than two arms. Combination of count and hazard ratio data in a single analysis is achieved by estimating the cumulative hazard for each trial arm reporting count data. Correlation in relative treatment effects in multi-arm trials is preserved by converting the relative treatment effect estimates (the hazard ratios) to arm-specific outcomes (hazards).ResultsA worked example of an analysis of mortality data in chronic obstructive pulmonary disease (COPD) is used to illustrate the methods. The data set and WinBUGS code for fixed and random effects models are provided.ConclusionsBy incorporating all data presentations in a single analysis, we avoid the potential selection bias associated with conducting an analysis for a single statistic and the potential difficulties of interpretation, misleading results and loss of available treatment comparisons associated with conducting separate analyses for different summary statistics.

Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom

Objective: To assess the cost-effectiveness of radiofrequency catheter ablation (RFCA) compared with anti-arrhythmic drug (AAD) therapy for the treatment of atrial fibrillation (AF) from the perspective of the UK NHS. Design: Bayesian evidence synthesis and decision analytical model. Methods: A systematic review and meta-analysis was conducted and Bayesian statistical methods used to synthesise the effectiveness evidence from randomised control trials. A decision analytical model was developed to assess the costs and consequences associated with the primary outcome of the trials over a lifetime time horizon. Main outcome measure: Costs from a health service perspective and outcomes measured as quality-adjusted life years (QALYs). Results: The incremental cost-effectiveness ratio of RFCA varied between £7763 and £7910 for each additional QALY according to baseline risk of stroke, with a probability of being cost-effective from 0.98 to 0.99 for a cost-effectiveness threshold of £20 000. Results were sensitive to the duration of quality of life benefits from treatment. Conclusions: RFCA is potentially cost-effective for the treatment of paroxysmal AF in patients’ predominantly refractory to AAD therapy provided the quality-of-life benefits from treatment are maintained for more than 5 years. These findings remain subject to limitations in the existing evidence regarding the nature of life benefits and the prognostic importance of restoring normal sinus rhythm conferred using RFCA.

Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: A systematic review and network meta-analysis

Indirect evidence from randomized controlled trials (RCTs) was used to estimate the effect of dapagliflozin, a new agent with a novel mechanism of action (SGLT‐2 inhibition), relative to other anti‐diabetes therapies after 1 year of treatment.

Individual patient data network meta-analysis of mortality effects of implantable cardiac devices

Objective Implantable cardioverter defibrillators (ICD), cardiac resynchronisation therapy pacemakers (CRT-P) and the combination therapy (CRT-D) have been shown to reduce all-cause mortality compared with medical therapy alone in patients with heart failure and reduced EF. Our aim was to synthesise data from major randomised controlled trials to estimate the comparative mortality effects of these devices and how these vary according to patients’ characteristics. Methods Data from 13 randomised trials (12 638 patients) were provided by medical technology companies. Individual patient data were synthesised using network meta-analysis. Results Unadjusted analyses found CRT-D to be the most effective treatment (reduction in rate of death vs medical therapy: 42% (95% credible interval: 32–50%), followed by ICD (29% (20–37%)) and CRT-P (28% (15–40%)). CRT-D reduced mortality compared with CRT-P (19% (1–33%)) and ICD (18% (7–28%)). QRS duration, left bundle branch block (LBBB) morphology, age and gender were included as predictors of benefit in the final adjusted model. In this model, CRT-D reduced mortality in all subgroups (range: 53% (34–66%) to 28% (−1% to 49%)). Patients with QRS duration ≥150 ms, LBBB morphology and female gender benefited more from CRT-P and CRT-D. Men and those <60 years benefited more from ICD. Conclusions These data provide estimates for the mortality benefits of device therapy conditional upon multiple patient characteristics. They can be used to estimate an individual patients expected relative benefit and thus inform shared decision making. Clinical guidelines should discuss age and gender as predictors of device benefits.

Cost-effectiveness of cardiac resynchronization therapy in patients with asymptomatic to mild heart failure: insights from the European cohort of the REVERSE (Resynchronization Reverses remodeling in Systolic Left Ventricular Dysfunction)

AIMS To assess the cost-effectiveness of cardiac resynchronization therapy (CRT) compared with optimal medical therapy in patients with New York Heart Association (NYHA) II heart failure (HF) or NYHA I with previous HF symptoms. METHODS AND RESULTS A proportion in state model with Monte Carlo simulation was developed to assess the costs, life years and quality-adjusted life year (QALYs) associated with CRT-ON and -OFF over a 10 year time period. Data from 262 patients in the European cohort of the REVERSE clinical trial (QRS ≥ 120 ms, left ventricular ejection fraction ≤ 40%, CRT-ON, n = 180, CRT-OFF, n = 82) were used to model all-cause mortality, change in NYHA class and resource use. EQ-5D preference weights were taken from a previous cost-effectiveness model of CRT and unit costs from national UK databases. Costs and benefits were discounted at 3.5% p.a. Extensive deterministic and probabilistic sensitivity analyses were performed. Compared with CRT-OFF, 0.94 life years or 0.80 QALYs were gained in the CRT ON group at an additional cost of €11 455, yielding an incremental cost-effectiveness ratio of €14.278 per quality-adjusted life year (QALY) gained. At a threshold of €33 000 (£30 000) per QALY gained, the probability that CRT is cost-effective is 79.6%. Cardiac resynchronization therapy becomes cost effective after ∼4.5 years. Cardiac resynchronization therapy needs only to demonstrate a modest impact on all cause mortality (hazard ratio = 0.82) in order to demonstrate cost-effectiveness. The results are robust to changes in all other parameters. CONCLUSION Cardiac resynchronization therapy is a cost-effective intervention for patients with mildly symptomatic HF and for asymptomatic patients with left ventricular dysfunction and previous HF symptoms.

The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia.

Objective:To assess the cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia, as implementation at the local health centre level has yet to be undertaken in many resource-limited countries despite recommendations in recent updated World Health Organization (WHO) guidelines. Design:A probabilistic decision analytical model of HIV/AIDS progression in children based on the CD4 cell percentage (CD4%) was populated with data from the placebo-controlled Children with HIV Antibiotic Prophylaxis trial that had reported a 43% reduction in mortality with cotrimoxazole prophylaxis in HIV-infected children aged 1–14 years. Methods:Unit costs (US