Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal.

BACKGROUND: The clinical landscape of pulmonary arterial hypertension (PAH) has evolved in terms of disease definition and classification, trial designs, available therapies and treatment strategies as well as clinical guidelines. This study critically appraises published evidence synthesis studies, i.e. meta-analyses (MA) and network-meta-analyses (NMA), to better understand their quality, validity and discuss the impact of the findings from these studies on current decision-making in PAH. METHODS: A systematic literature review to identify MA/NMA studies considering approved and available therapies for treatment of PAH was conducted. Embase, Medline and the Cochrane's Database of Systematic Reviews were searched from database inception to April 22, 2020, supplemented by searches in health technology assessment websites. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist covering six domains (relevance, credibility, analysis, reporting quality and transparency, interpretation and conflict of interest) was selected for appraisal of the included MA/NMA studies. RESULTS: Fifty-two full publications (36 MAs, 15 NMAs, and 1 MA/NMA) in PAH met the inclusion criteria. The majority of studies were of low quality, with none of the studies being scored as 'strong' across all checklist domains. Key limitations included the lack of a clearly defined, relevant decision problem, shortcomings in assessing and addressing between-study heterogeneity, and an incomplete or misleading interpretation of results. CONCLUSIONS: This is the first critical appraisal of published MA/NMA studies in PAH, suggesting low quality and validity of published evidence synthesis studies in this therapeutic area. Besides the need for direct treatment comparisons assessed in long-term randomized controlled trials, future efforts in evidence synthesis in PAH should improve analysis quality and scrutiny in order to meaningfully address challenges arising from an evolving therapeutic landscape.

Cost-Effectiveness Analyses, Costs and Resource Use, and Health-Related Quality of Life in Patients with Follicular or Marginal Zone Lymphoma: Systematic Reviews.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are types of indolent non-Hodgkin lymphoma (NHL) that develop in the B lymphocytes (also known as B cells). OBJECTIVE: The aim of this study was to conduct a comprehensive review of studies relating to cost effectiveness, costs and resource use, and health-related quality of life (HRQoL) in patients with FL or MZL. METHODS: Three separate systematic reviews were conducted to identify all published evidence on cost effectiveness, costs and resource use, and HRQoL between 2007 and March 2017 using the MEDLINE®, MEDLINE in-process, E-pubs ahead of print (Ovid SP®), Embase (Ovid SP®), NHS EED, and EconLit databases. Select congress proceedings were also searched. Two systematic reviewers independently reviewed titles, abstracts, and full papers against eligibility criteria. Relevant data were extracted into bespoke data extraction templates (DETs) by a single systematic reviewer; these data were then validated for accuracy by a second reviewer against clean copies of the relevant publications. RESULTS: A total of 25 cost-effectiveness studies (24 in FL; 1 in FL and MZL) met the eligibility criteria. Markov models were the most utilised cost-effectiveness model. US FL studies reported an incremental cost-effectiveness ratio (ICER) of $28,565/QALY for first-line rituximab-cyclophosphamide, vincristine, and prednisone (R-CVP) versus CVP, and $43,000/QALY for second-line obinutuzumab plus bendamustine (G + B) followed by G maintenance versus B. In the UK, ICERs were £1529-10,834/quality-adjusted life-year (QALY) for first-line rituximab + chemotherapy versus chemotherapy, £27,988/QALY for second-line G + B + G-maintenance versus B, and £62,653/QALY for second-line idelalisib versus chemotherapy and/or rituximab. Five costs/resource use and four HRQoL studies were identified in FL, and none in MZL. US mean lifetime costs in first-line patients ranged from $108,000 (rituximab) to $130,300 (rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone [CHOP]), and from £2185 (watch-and-wait) to £17,054 (chemotherapy) in the UK. In a multinational study, more rituximab-refractory patients receiving G + B + G-maintenance reported a meaningful improvement in total FACT-Lym scores compared with patients receiving B. In the UK, total FACT-Lym scores were meaningfully higher for newly diagnosed patients compared with patients with progression (136.04 vs. 109.7). CONCLUSIONS AND RELEVANCE: We found a small body of evidence of quality of life, and potentially cost-effective treatment options for FL; however, no evidence was reported on MZL specifically. The significant data gaps in knowledge in these diseases demonstrate a marked need for further studies.

A practical approach to predict expansion of evidence networks: a case study in treatment-naive advanced melanoma.

Network meta-analysis (NMA) is a statistical method used to produce comparable estimates of efficacy across a range of treatments that may not be compared directly within any single trial. NMA feasibility is determined by the comparability of the data and presence of a connected network. In rapidly evolving treatment landscapes, evidence networks can change substantially in a short period of time. We investigate methods to determine the optimum time to conduct or update a NMA based on anticipated available evidence. We report the results of a systematic review conducted in treatment-naive advanced melanoma and compare networks of evidence available at retrospective, current, and prospective time points. For included publications, we compared the primary completion date of trials from clinical trials registries (CTRs) with the date of their first available publication to provide an estimate of publication lag. Using CTRs we were able to produce anticipated networks for future time points based on projected study completion dates and average publication lags which illustrated expansion and strengthening of the initial network. We found that over a snapshot of periods between 2015 and 2018, evidence networks in melanoma changed substantively, adding new comparators and increasing network connectedness. Searching CTRs for ongoing trials demonstrates it is possible to anticipate future networks at a certain time point. Armed with this information, sensible decisions can be made over when best to conduct or update a NMA. Incorporating new and upcoming interventions in a NMA enables presentation of a complete, up-to-date and evolving picture of the evidence.

Identifying and assessing the benefits of interventions for postnatal depression: a systematic review of economic evaluations.

BACKGROUND: Economic evaluations of interventions for postnatal depression (PND) are essential to ensure optimal healthcare decision-making. Due to the wide-ranging effects of PND on the mother, baby and whole family, there is a need to include outcomes for all those affected and to include health and non-health outcomes for accurate estimates of cost-effectiveness. This study aimed to identify interventions to prevent or treat PND for which an economic evaluation had been conducted and to evaluate the health and non-health outcomes included. METHODS: A systematic review was conducted applying a comprehensive search strategy across eight electronic databases and other sources. Full or partial economic evaluations of interventions involving preventive strategies (including screening), and any treatments for women with or at-risk of PND, conducted in OECD countries were included. We excluded epidemiological studies and those focussing on costs only. The included studies underwent a quality appraisal to inform the analysis. RESULTS: Seventeen economic evaluations met the inclusion criteria, the majority focused on psychological /psychosocial interventions. The interventions ranged from additional support from health professionals, peer support, to combined screening and treatment strategies. Maternal health outcomes were measured in all studies; however child health outcomes were included in only four of them. Across studies, the maternal health outcomes included were quality-adjusted-life-years gained, improvement in depressive symptoms, PND cases detected or recovered, whereas the child health outcomes included were cognitive functioning, depression, sleep and temperament. Non-health outcomes such as couples' relationships and parent-infant interaction were rarely included. Other methodological issues such as limitations in the time horizon and perspective(s) adopted were identified, that were likely to result in imprecise estimates of benefits. CONCLUSIONS: The exclusion of relevant health and non-health outcomes may mean that only a partial assessment of cost-effectiveness is undertaken, leading to sub-optimal resource allocation decisions. Future research should seek ways to expand the evaluative space of economic evaluations and explore approaches to integrate health and non-health outcomes for all individuals affected by this condition. There is a need to ensure that the time horizon adopted in studies is appropriate to allow true estimation of the long-term benefits and costs of PND interventions.

Choosing important health outcomes for comparative effectiveness research: a systematic review.

BACKGROUND: A core outcome set (COS) is a standardised set of outcomes which should be measured and reported, as a minimum, in all effectiveness trials for a specific health area. This will allow results of studies to be compared, contrasted and combined as appropriate, as well as ensuring that all trials contribute usable information. The COMET (Core Outcome Measures for Effectiveness Trials) Initiative aims to support the development, reporting and adoption of COS. Central to this is a publically accessible online resource, populated with all available COS. The aim of the review we report here was to identify studies that sought to determine which outcomes or domains to measure in all clinical trials in a specific condition and to describe the methodological techniques used in these studies. METHODS: We developed a multi-faceted search strategy for electronic databases (MEDLINE, SCOPUS, and Cochrane Methodology Register). We included studies that sought to determine which outcomes/domains to measure in all clinical trials in a specific condition. RESULTS: A total of 250 reports relating to 198 studies were judged eligible for inclusion in the review. Studies covered various areas of health, most commonly cancer, rheumatology, neurology, heart and circulation, and dentistry and oral health. A variety of methods have been used to develop COS, including semi-structured discussion, unstructured group discussion, the Delphi Technique, Consensus Development Conference, surveys and Nominal Group Technique. The most common groups involved were clinical experts and non-clinical research experts. Thirty-one (16%) studies reported that the public had been involved in the process. The geographic locations of participants were predominantly North America (n = 164; 83%) and Europe (n = 150; 76%). CONCLUSIONS: This systematic review identified many health areas where a COS has been developed, but also highlights important gaps. It is a further step towards a comprehensive, up-to-date database of COS. In addition, it shows the need for methodological guidance, including how to engage key stakeholder groups, particularly members of the public.

Aspirin in primary prevention of cardiovascular disease and cancer: a systematic review of the balance of evidence from reviews of randomized trials.

BACKGROUND: Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses. METHODS AND FINDINGS: Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbé plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34-36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all-cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk [RR] 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non-significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31-2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82). CONCLUSIONS: Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed.