Rachael Fleurence

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.

Launching PCORnet, a national patient-centered clinical research network

The Patient-Centered Outcomes Research Institute (PCORI) has launched PCORnet, a major initiative to support an effective, sustainable national research infrastructure that will advance the use of electronic health data in comparative effectiveness research (CER) and other types of research. In December 2013, PCORIs board of governors funded 11 clinical data research networks (CDRNs) and 18 patient-powered research networks (PPRNs) for a period of 18 months. CDRNs are based on the electronic health records and other electronic sources of very large populations receiving healthcare within integrated or networked delivery systems. PPRNs are built primarily by communities of motivated patients, forming partnerships with researchers. These patients intend to participate in clinical research, by generating questions, sharing data, volunteering for interventional trials, and interpreting and disseminating results. Rapidly building a new national resource to facilitate a large-scale, patient-centered CER is associated with a number of technical, regulatory, and organizational challenges, which are described here.

Economic Burden of Multiple Sclerosis: A Systematic Review of the Literature

Multiple sclerosis (MS) is a disease of the CNS, typically striking adults during the primary productive time of their life. The symptoms of MS can restrict the individual’s physical activity and income-earning ability, resulting in a major financial burden on the patient, family, health system and society. This systematic literature review was conducted to document the economic burden of MS.Employing pre-defined search terms and inclusion/exclusion criteria, systematic searches were conducted in MEDLINE, EMBASE, PsycINFO, the Health Economic Evaluations Database (HEED), the NHS Economic Evaluation Database (EED) and the UK National Institute for Health and Clinical Excellence (NICE) website as well as conference abstracts.We identified 29 cost-of-illness studies that met the a priori inclusion criteria. The cost categories responsible for the majority of costs associated with MS varied across countries. There was a significant increase in costs associated with an increase in disease severity as measured by the Kurtzke Expanded Disability Status Scale (EDSS) score. The increase in magnitude was coupled with changes in the distribution of costs; although direct medical costs were important contributors in earlier stages of disease, they were outweighed by indirect costs in later stages, mainly due to relapses and productivity losses.Considering the increased costs associated with relapse occurrence and increasing disease severity, pharmaceutical or non-pharmaceutical interventions aimed at delaying the progression of disease may help to reduce the economic burden of MS.

Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials.

Background The extent to which individual statins vary in terms of clinical outcomes across all populations, in addition to secondary and primary prevention has not been studied extensively in meta-analyses. Methods We systematically studied 199,721 participants in 92 placebo-controlled and active-comparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into account the dose differences across trials. Systematic review registration: PROSPERO 2011:CRD42011001470. Results There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. No trial directly compared all six statins to each other. Across all populations, statins were significantly more effective than control in reducing all-cause mortality (OR 0.87, 95% credible interval 0.82–0.92) and major coronary events (OR 0.69, 95% CI 0.64–0.75). In terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.48–0.94) and fluvastatin (OR 0.59, 95% CI 0.36–0.95) were significantly more effective than rosuvastatin at comparable doses. In participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.75–0.90) and major coronary events (OR 0.69, 95% CI 0.62–0.77). Atorvastatin was significantly more effective than pravastatin (OR 0.65, 95% CI 0.43–0.99) and simvastatin (OR 0.68, 95% CI 0.38–0.98) for secondary prevention of major coronary events. In primary prevention, statins significantly reduced deaths (OR 0.91, 95% CI 0.83–0.99) and major coronary events (OR 0.69, 95% CI 0.61–0.79) with no differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and simvastatin (62%) had the highest overall probability of being the best treatment in terms of both outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant differences in preventing major coronary events compared with other statins. No significant heterogeneity or inconsistency was detected. Conclusions Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention. This analysis provides evidence for potential differences between individual statins, which are not fully explained by their low-density lipoprotein cholesterol-reducing effects. The observed differences between statins should be investigated in future prospective studies.

Rates and probabilities in economic modelling: transformation, translation and appropriate application.

Economic modelling is increasingly being used to evaluate the cost effectiveness of health technologies. One of the requirements for good practice in modelling is appropriate application of rates and probabilities. In spite of previous descriptions of appropriate use of rates and probabilities, confusions persist beyond a simple understanding of their definitions. The objective of this article is to provide a concise guide to understanding the issues surrounding the use of rates and probabilities reported in the literature in economic models, and an understanding of when and how to transform them appropriately. The article begins by defining rates and probabilities and shows the essential difference between the two measures. Appropriate conversions between rates and probabilities are discussed, and simple examples are provided to illustrate the techniques and pitfalls. How the transformed rates and probabilities may be used in economic models is then described and some recommendations are suggested.

The Cost Effectiveness of Bisphosphonates for the Prevention and Treatment of Osteoporosis: A Structured Review of the Literature

Osteoporotic fragility fractures constitute a significant public health concern. The lifetime risk of any osteoporotic fracture is very high (40–50% in women and 13–22% in men). Fractures are associated with significant mortality and morbidity and represent a substantial economic burden to society. Bisphosphonates (alendronate, etidronate, risedronate and ibandronate) are indicated for the treatment and prevention of osteoporosis but are costly compared with other treatments, such as vitamin D and calcium.Our search identified 23 studies evaluating the cost effectiveness of bisphosphonate therapy for the treatment and prevention of fragility fractures; these studies were from five geographical areas and employed a variety of comparators and assumptions. We identified 11 studies investigating bisphosphonates in women with low bone mineral density (BMD) [T-score >2.5 standard deviations {SDs} below normal {mean} peak values for young adults] and previous fractures, five studies investigating bisphosphonates in women with low BMD and no previous fracture, one study of bisphosphonates in women with osteopenia, five studies involving screening and two studies of bisphosphonates in special populations (women initiating corticosteroid treatment and men).In women with low BMD and previous fractures, bisphosphonate therapy was most cost effective in populations aged ≥70 years and was unlikely to be cost effective in populations aged ≤50 years. There was uncertainty concerning the cost effectiveness of bisphosphonates in such populations aged 60–69 years. In women with low BMD without previous fractures, treatment with alendronate or risedronate appeared to be cost effective across countries (UK, US, Denmark), but there was some uncertainty about the cost effectiveness of etidronate in patients in the highest age groups.Identifying risk factors for fractures through means such as spine radiographs to detect vertebral deformities improves the cost effectiveness of treatment. In women with osteopenia, alendronate therapy may be cost effective in women with a T-score of -2.4SD in the US. Screening for low BMD and treatment with alendronate or etidronate appears to be cost effective in postmenopausal women in general and in women with rheumatoid arthritis initiating corticosteroid therapy. Alendronate therapy without screening was also shown to be potentially cost effective in certain at-risk male populations, as well as in women initiating corticosteroid therapy after the age of 40 years.Decision makers in the US, UK and Sweden should consider funding the use of bisphosphonates for the prevention and treatment of osteoporosis in women aged >70 years, particularly if they have other risk factors for fracture. Further studies are required to make more definitive conclusions in other countries and patient populations. Screening strategies for low BMD followed by bisphosphonate treatment should also be considered in the general female population aged >65 years in the UK and US and in patients with rheumatoid arthritis initiating corticosteroid therapy.

Economic evaluations of interventions for the prevention and treatment of osteoporosis: a structured review of the literature

Economic evaluations are increasingly being used by decision-makers to estimate the cost-effectiveness of interventions. The objective of this study was to conduct a structured review of economic evaluations of interventions to prevent and treat osteoporosis. Articles were identified independently by two reviewers through searches on MEDLINE, the bibliographies of reviews and identified economic models, and expert opinion, using predefined inclusion and exclusion criteria. Data on country, type and level of interventions, type of fractures, interventions, study population and the authors’ stated conclusions were extracted. Forty-two relevant studies were identified. The majority of studies (71%) were conducted in Sweden, the UK and the US. The main interventions investigated were hormone replacement therapy (27%), bisphosphonates (17%) and combinations of vitamin D and calcium (16%). In 38% of studies, hip fracture was the sole fracture outcome. Eighty-eight percent (88%) of studies investigated female populations only. A relatively large number of economic evaluations were identified in the field of osteoporosis. Major changes have recently occurred in the treatment of this disease, following the publication of the results of the Women’s Health Initiative trial. Methodological developments in economic evaluations, such as the use of probabilistic sensitivity analysis and cost-effectiveness acceptability curves, have also taken place. Such changes are reflected in the studies that were reviewed. The development of economic models should be an iterative process that incorporates new information, whether clinical or methodological, as it becomes available.

Patient-Powered Research Networks Aim To Improve Patient Care And Health Research

The era of big data, loosely defined as the development and analysis of large or complex data sets, brings new opportunities to empower patients and their families to generate, collect, and use their health information for both clinical and research purposes. In 2013 the Patient-Centered Outcomes Research Institute launched a large national research network, PCORnet, that includes both clinical and patient-powered research networks. This article describes these networks, their potential uses, and the challenges they face. The networks are engaging patients, family members, and caregivers in four key ways: contributing data securely, with privacy protected; including diverse and representative groups of patients in research; prioritizing research questions, participating in research, and disseminating results; and participating in the leadership and governance of patient-powered research networks. If technical, regulatory, and organizational challenges can be overcome, PCORnet will allow research to be conducted more efficiently and cost-effectively and results to be disseminated quickly back to patients, clinicians, and delivery systems to improve patient health.

A systematic review of approaches for engaging patients for research on rare diseases

ABSTRACTBACKGROUNDPatients with rare diseases have limited access to useful information to guide treatment decisions. Engagement of patients and other stakeholders in clinical research may help to ensure that research efforts in rare diseases address relevant clinical questions and patient-centered health outcomes. Rare disease organizations may provide an effective means to facilitate patient engagement in research. However, the effectiveness of patient-engagement approaches, particularly for the study of rare diseases, has not been well studied.OBJECTIVESTo synthesize evidence about engagement of patients and other stakeholders in research on rare diseases, including the role of rare disease organizations in facilitating patient-centered research.METHODS/RESEARCH DESIGNA systematic review and gray literature search were guided by a technical expert panel composed of patient representatives, clinicians, and researchers. English-language studies that engaged patients or other stakeholders in research on rare diseases or evaluated engagement were included. Studies were assessed on how well key research questions were answered, based on the level of detail describing engagement activities and whether outcomes from engagement were assessed.RESULTSThirty-five studies were included, although many reported minimal information on engagement. Patients and other stakeholders were most commonly engaged to identify patient-centered research agendas, to select which study outcomes were important to patients, to provide input on study design, and to identify strategies for increasing enrollment in trials. Rare disease organizations mainly helped provide access to patients and communicated research opportunities and findings. They also helped promote collaborative networks and provided financial support for research infrastructures. Although authors reported benefits of engagement and identified changes to their research processes, no empirical assessments of engagement practices and their effectiveness were found.CONCLUSIONSResearchers studying rare diseases can obtain patient input regarding which research questions and health outcomes to study; however, the most effective approaches to engagement have not been well defined.

Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials

Aims The extent to which individual statins vary in terms of their impact on serum lipid levels has been studied mainly on the basis of placebo-controlled trials. Our objective was to review and quantify the dose-comparative effects of different statins on serum lipid levels using both placebo- and active-comparator trials. Methods We systematically reviewed randomized trials evaluating different statins in participants with, or at risk of developing, cardiovascular disease. We performed random-effects Bayesian network meta-analyses to quantify the the relative potency of individual statins across all possible dose combinations using both direct and indirect evidence. Dose-comparative effects were determined by estimating the mean change from baseline in serum lipids as compared to control treatment. (systematic review registration: PROSPERO 2011:CRD42011001470). Results We included 181 placebo-controlled and active-comparator trials including 256,827 individuals. There were 83 two-armed placebo-controlled trials and the remaining 98 were two- or multi-armed active-comparator trials. All statins reduced serum LDL and total cholesterol levels: higher doses resulted in higher reductions in pretreatment LDL and total cholesterol concentrations. In absolute terms, all statins significantly reduced LDL cholesterol levels as compared to control treatment from average baseline levels of approximately 150 mg/dl, except for fluvastatin at ≤20 mg/day and lovastatin at ≤10 mg/day. Atorvastatin, rosuvastatin, and simvastatin were broadly equivalent in terms of their LDL cholesterol-lowering effects. Dose-comparative effects of indivudual statins were not different between those with and without coronary heart disease at baseline. According to meta-regression analyses, LDL cholesterol-lowering effects of individual statins were not impacted by differences across trials in terms of baseline mean age and proportion of women as trial participants. Pretreatment LDL cholesterol concentrations had a marginally statistically significant effect on LDL cholesterol change from baseline. Mean differences from baseline in HDL cholesterol as compared to control treatment was not significant for any statin-dose combination. Conclusions The findings of this comprehensive review provide supporting evidence for the dose–response relationship of statins in reducing LDL and total cholesterol. The LDL cholesterol-reducing effects of some statins appear less pronounced than the findings of previous meta-analyses, which is particularly the case for the high-dose formulations of atorvastatin and rosuvastatin. The most consistent evidence for a combined reduction in both LDL and total cholesterol was achieved with atorvastatin at >40 mg/day, rosuvastatin at >10 mg/day, and simvastatin at >40 mg/day, which appear equivalent in terms of their LDL and total cholesterol-reducing effects.