Cumulative Network Meta-analyses Research Articles

Antidepressant prescriptions have not fully reflected evolving evidence from cumulative network meta-analyses and guideline recommendations

ObjectivesThis study compares three major elements of evidence-based medicine (EBM) practices, namely evidence synthesis, clinical practice guidelines (CPGs), and real-world prescriptions in the United States, regarding antidepressant treatments of major depression over the past 3 decades. Study Design and SettingWe conducted network meta-analyses (NMAs) of antidepressants every 5 years up to 2016 based on a comprehensive data set of double-blind randomized controlled trials. We identified CPGs and extracted their recommendations. We surveyed the prescriptions in the United States at 5-year intervals up to 2015. ResultsMost drugs recommended by CPGs presented favorable performance in efficacy and acceptability in NMAs. However, CPG recommendations were often in terms of drug classes rather than individual drugs, whereas NMAs suggested distinctive difference between drugs within the same class. The update intervals of all CPGs were longer than 5 years. All the antidepressants prescribed frequently in the United States were recommended by CPGs. However, changes in prescriptions did not correspond to alterations in CPGs or to apparent changes in the effects indicated by NMAs. Many factors including marketing efforts, regulations, or patient values may have played a role. ConclusionEnhancements including accelerating CPG updates and monitoring the impact of marketing on prescriptions should be considered in future EBM implementation.

Visualizing the evolution of evidence: Cumulative network meta-analyses of new generation antidepressants in the last 40 years.

It is often challenging to present the available evidence in a timely and comprehensible manner. We aimed to visualize the evolution of evidence about antidepressants for depression by conducting cumulative network meta‐analyses (NMAs) and to examine whether it could have helped the selection of optimal drugs. We built a Shiny web application that performs and presents cumulative NMAs based on R netmeta. We used a comprehensive dataset of double‐blind randomized controlled trials of 21 antidepressants in the acute treatment of major depression. The primary outcomes were efficacy (treatment response) and acceptability (all‐cause discontinuation), and treatment effects were summarized via odds ratios. We evaluated the confidence in evidence using the CINeMA (Confidence in Network Meta‐Analysis) framework for a series of consecutive NMAs. Users can change several conditions for the analysis, such as the period of synthesis, among the others. We present the league tables and two‐dimensional plots that combine efficacy, acceptability and level of confidence in the evidence together, for NMAs conducted in 1990, 1995, 2000, 2005, 2010, and 2016. They reveal that through the past four decades, newly approved drugs often showed initially exaggerated results, which tended to diminish and stabilize after approximately a decade. Over the years, the drugs with relative superiority changed dramatically; but as the evidence network grew larger and better connected, the overall confidence improved. The Shiny app visualizes how evidence evolved over years, emphasizing the need for a careful interpretation of relative effects between drugs, especially for the potentially amplified performance of newly approved drugs.Highlights Network meta‐analysis is considered to be a proper way of demonstrating the available evidence, since it allows comparisons between multiple interventions, and has been proved to be statistically powerful.It is challenging to present the voluminous results of NMA in an efficient and comprehendible manner.Evidence evolution based on the relatively new method NMA has not been investigated yet.The results of NMA should not only include the effects but also the confidence in the evidence, which can help interpret the findings appropriately.Effective use of rapidly developing statistical analysis and presentation tools such as Shiny package in R, may facilitate and simplify the visualization of NMA output.We should stay conservative towards new drugs, as their performance was often shown to be exaggerated initially, and it took time to become stable.

Cumulative network meta-analyses, practice guidelines, and actual prescriptions for postmenopausal osteoporosis: a meta-epidemiological study.

To compare the results of cumulative network meta-analyses (NMAs) with the recommendations in postmenopausal osteoporosis practice guidelines and actual prescribing practices in the USA. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched to retrieve randomized controlled trials (RCTs) in July 2017. The Agency for Healthcare Research and Quality's National Guideline Clearinghouse and associated society websites were searched to retrieve guidelines in June 2018. We used the Medical Expenditure Panel Survey (MEPS) to analyze prescription data from 1996 to 2015. Two independent investigators selected eligible RCTs. One investigator selected potential eligible guidelines, which were confirmed by another investigator. Two independent investigators extracted data from included RCTs. One investigator extracted recommendations from guidelines, which were confirmed by another investigator. (Registration: UMIN000031894) RESULTS: We analyzed data from 1995, 2000, 2005, 2010, and 2015. We chose hip fracture as the primary outcome of cumulative NMAs. We included 51 trials, 17 guidelines, and 5099 postmenopausal osteoporosis patients from the MEPS. Bisphosphonate, including alendronate, and combination of vitamin D and calcium (vDCa) were consistently recommendable from an efficacy viewpoint in NMAs and recommended in guidelines. Alendronate was the most prescribed drug (more than 30% over the observation period); however, vDCa was seldom prescribed. The maximum proportion was 5.3% from 2011 to 2015. In postmenopausal osteoporosis, there was no apparent discrepancy between guideline recommendations and drug prescribing rankings, with the exception of vDCa, when we used cumulative NMAs as references.

Leveraging Cumulative Network Meta-analysis and Value of Information Analysis to Understand the Evolving Value of Medical Research

Leveraging cumulative network meta-analysis (NMA) and value of information (VOI) analysis, this article aims to understand the evolving value of medical research and to identify gaps in the evidence for future research. As an illustration, we identified 31 randomized controlled trials (RCT) from 1980 to 2013 that examined a network of 3 interventions for coronary artery disease: medical therapy (MED), percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) surgery. We conducted Bayesian NMA to combine evidence from a new RCT with existing knowledge. Then, using the Duke Databank for Cardiovascular Diseases database, we developed an accelerated failure time model to estimate the joint effects of patient characteristics and treatment choices on survival outcomes. With the estimated coefficients and covariance matrices, we projected survival benefits and its surrounding uncertainty among 50,000 simulated patients treated with MED, PCI, or CABG. The value of resolving residual uncertainty from future trials was quantified through the VOI analysis. We repeated these steps for each published RCT to estimate dynamic changes in VOI estimates. Our cumulative NMA found that CABG conferred a lower, but not statistically significant, mortality than PCI (hazard ratio [HR], 0.90; 95% uncertainty interval, 0.80-1.05). MED had a nonsignificantly higher long-term mortality than PCI (HR, 1.11; 0.98-1.31) but significantly higher than CABG (HR, 1.07; 1.23-1.41). The greatest potential gains from future research would come from additional head-to-head trials between CABG v. PCI with the value of future research equaling 0.27 life years per patient. The combination of cumulative NMA and VOI approaches can improve the efficiency of comparative effectiveness research by using all of the available evidence to determine future research priorities.

Cumulative network-meta-analyses, practice guidelines and actual prescriptions of drug treatments for postmenopausal osteoporosis: a study protocol for cumulative network meta-analyses and meta-epidemiological study

IntroductionCumulative network meta-analysis (NMA) is a method to provide a global comparison of multiple treatments with real-time update to evidence users. Several studies investigated the ranking of cumulative NMA and...

Evidence synthesis, practice guidelines and real-world prescriptions of new generation antidepressants in the treatment of depression: a protocol for cumulative network meta-analyses and meta-epidemiological study

IntroductionDepressive disorders are the most common, burdensome and costly mental disorders. Their treatments have developed through the past decades and we now have more than a dozen new generation antidepressants,...

Herceptin\xae (trastuzumab) in HER2-positive early breast cancer: a systematic review and cumulative network meta-analysis

BackgroundOriginator trastuzumab (Herceptin®; H) is an antibody-targeted therapy to treat patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). We investigated the overall survival (OS) advantage conferred by the addition of H to chemotherapy for HER2+ EBC patients and how the OS advantage changed over time.MethodsA systematic literature review (SLR) identified randomized controlled trials (RCTs) and non-randomized studies (NRSs) published from January 1, 1990 to January 19, 2017, comparing systemic therapies used in the neoadjuvant/adjuvant settings to treat HER2+ EBC patients. Bayesian cumulative network meta-analyses (cNMAs) of OS were conducted to assess the published literature over time. Heterogeneity was assessed through sensitivity and subgroup analyses.ResultsThe SLR identified 31 unique studies (28 RCTs, 3 NRSs) included in the OS analyses from 2008 to 2016. In the reference case cNMA (RCTs alone), initial evidence demonstrated an OS advantage for H/chemotherapy compared with chemotherapy alone in HER2+ EBC patients. As additional OS data were published, the precision around this survival benefit strengthened over time. Both H/anthracycline-containing chemotherapy and H/non-anthracycline-containing chemotherapy regimens provided similar OS advantages for HER2+ EBC patients.ConclusionThis analysis represents the most comprehensive SLR/cNMA to date of published OS data in HER2+ EBC studies. These findings demonstrate why H/chemotherapy is now the established standard of care in HER2+ EBC. In the case of H, the benefits of early patient access far outweighed the risk of waiting for more precise information.Systematic review registrationPROSPERO CRD42017055763

Herceptin\xae (trastuzumab) in HER2-positive early breast cancer: protocol for a systematic review and cumulative network meta-analysis

BackgroundHuman epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive disease that makes up about 20% of all invasive breast cancers. HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival. Numerous clinical trials and reviews have investigated the efficacy of HER2-targeted therapies over the past few decades; however, no study has specifically investigated the vast body of evidence on trastuzumab in comparison to chemotherapy regimens, endocrine therapies, and other targeted therapies. This systematic review and cumulative network meta-analysis (NMA) will synthesize available evidence to evaluate the survival benefit conferred by the addition of originator trastuzumab to standard chemotherapy and to compare the most widely used trastuzumab regimens in patients with HER2+ early breast cancer, based on results from randomized controlled trials (RCTs) and comparative observational studies.Methods/designA systematic search of Embase, MEDLINE®, and the Cochrane Library has been designed by an experienced medical information specialist and peer reviewed by another senior information specialist. RCTs and comparative observational studies of patients with HER2+ early breast cancer indexed from 1990 onwards will be eligible for inclusion. Two investigators will independently assess studies for inclusion and use standardized data extraction templates to collect data on study and patient characteristics. The primary outcome of interest is overall survival. Bayesian cumulative NMA methods will be used to quantify the evolution of publicly available evidence using both fixed and random effects models.DiscussionThis study will evaluate survival trends associated with originator trastuzumab in patients with HER2+ early breast cancer. As originator trastuzumab has been researched in both clinical and real-world settings for close to 20 years, a cumulative NMA is likely to show improved precision around the parameter estimates for trastuzumab now compared with when the drug was initially launched in the USA in 1998. A better understanding of the evolution of publicly available comparative evidence for originator trastuzumab will further inform treatment for patients with HER2+ early breast cancer, providing benefit to patients, health professionals, and researchers.Systematic review registrationPROSPERO CRD42017055763 https://www.crd.york.ac.uk/PROSPERO

Live cumulative network meta-analysis: protocol for second-line treatments in advanced non-small-cell lung cancer with wild-type or unknown status for epidermal growth factor receptor

IntroductionMany second-line treatments for advanced non-small-cell lung cancer (NSCLC) have been assessed in randomised controlled trials, but which treatments work the best remains unclear. Novel treatments are being rapidly developed....

Wasted research when systematic reviews fail to provide a complete and up-to-date evidence synthesis: the example of lung cancer.

BackgroundMultiple treatments are frequently available for a given condition, and clinicians and patients need a comprehensive, up-to-date synthesis of evidence for all competing treatments. We aimed to quantify the waste of research related to the failure of systematic reviews to provide a complete and up-to-date evidence synthesis over time.MethodsWe performed a series of systematic overviews and networks of randomized trials assessing the gap between evidence covered by systematic reviews and available trials of second-line treatments for advanced non-small cell lung cancer. We searched the Cochrane Database of Systematic Reviews, Database of s of Reviews of Effects, MEDLINE, EMBASE, and other resources sequentially by year from 2009 to March 2, 2015. We sequentially compared the amount of evidence missing from systematic reviews to the randomized evidence available for inclusion each year. We constructed cumulative networks of randomized evidence over time and evaluated the proportion of trials, patients, treatments, and treatment comparisons not covered by systematic reviews on December 31 each year from 2009 to 2015.ResultsWe identified 77 trials (28,636 patients) assessing 47 treatments with 54 comparisons and 29 systematic reviews (13 published after 2013). From 2009 to 2015, the evidence covered by existing systematic reviews was consistently incomplete: 45 % to 70 % of trials; 30 % to 58 % of patients; 40 % to 66 % of treatments; and 38 % to 71 % of comparisons were missing. In the cumulative networks of randomized evidence, 10 % to 17 % of treatment comparisons were partially covered by systematic reviews and 55 % to 85 % were partially or not covered.ConclusionsWe illustrate how systematic reviews of a given condition provide a fragmented, out-of-date panorama of the evidence for all treatments. This waste of research might be reduced by the development of live cumulative network meta-analyses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0555-0) contains supplementary material, which is available to authorized users.

Medical safety: from stories to policy.

Narrative Matters Health AffairsVol. 20, No. 2: Health Care Trends Medical Safety: From Stories To PolicyRandall R. BovbjergPUBLISHED:March/April 2001No Accesshttps://doi.org/10.1377/hlthaff.20.2.241AboutSectionsView articleView Full TextView PDFPermissions ShareShare onFacebookTwitterLinked InRedditEmail ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions View article"Medical Safety: From Stories To Policy." Health Affairs, 20(2), pp. 241–242TOPICSPatient safetyCaregiversLegal and regulatory issuesMedical malpractice Loading Comments... Please enable JavaScript to view the comments powered by Disqus. DetailsExhibitsReferencesRelated Article MetricsCitations: Crossref 5 History Published online 1 March 2001 InformationCopyright 2001 by Project HOPE - The People-to-People Health Foundation, Inc.PDF downloadCited byEvidence synthesis, practice guidelines and real-world prescriptions of new generation antidepressants in the treatment of depression: a protocol for cumulative network meta-analyses and meta-epidemiological study9 December 2018 | BMJ Open, Vol. 8, No. 12Balancing Innovation and Access: Patent Challenges Tip the ScalesScience, Vol. 326, No. 5951Doctors’ responses to medical errorsCritical Reviews in Oncology/Hematology, Vol. 52, No. 3Description and Outcomes of the Doctorquality Incident Reporting System Used at Baylor Medical Center at Grapevine11 December 2017 | Baylor University Medical Center Proceedings, Vol. 15, No. 2Paths to Reducing Medical Injury: Professional Liability and Discipline vs. Patient Safety — And the Need for a Third Way1 January 2021 | Journal of Law, Medicine & Ethics, Vol. 29, No. 3-4

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