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      Systematic literature review and meta-analysis on use of Thrombopoietic agents for chemotherapy-induced thrombocytopenia

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          Abstract

          Background

          Currently, there are no approved options to prevent or treat chemotherapy-induced thrombocytopenia (CIT). We performed a systematic literature review and meta-analysis on use of thrombopoietic agents for CIT.

          Patients and methods

          We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, EMBASE, ClinicalTrials.gov, and health technology assessments from January 1995 to March 2021 for studies evaluating thrombopoietic agents for CIT, including recombinant human thrombopoietin (rhTPO), megakaryocyte growth and development factor (MGDF), romiplostim, and eltrombopag. Random effects meta-analyses were conducted for efficacy and safety endpoints.

          Results

          We screened 1503 titles/abstracts, assessed 138 articles, and abstracted data from 39 publications (14 recombinant human thrombopoietin, 7 megakaryocyte growth and development factor, 9 romiplostim, 8 eltrombopag, and 1 romiplostim/eltrombopag). Random effects meta-analyses of data from multiple studies comparing thrombopoietic agents versus control (comparator, placebo, or no treatment) showed that thrombopoietic agents did not significantly improve chemotherapy dose delays and/or reductions (21.1% vs 40.4%, P = 0.364), grade 3/4 thrombocytopenia (39.3% vs 34.8%; P = 0.789), platelet transfusions (16.7% vs 31.7%, P = 0.111), grade ≥ 2 bleeding (6.7% vs 16.5%; P = 0.250), or thrombosis (7.6% vs 12.5%; P = 0.131). However, among individual studies comparing thrombopoietic agents with placebo or no treatment, thrombopoietic agents positively improved outcomes in some studies, including significantly increasing mean peak platelet counts (186 x 10 9/L with rhTPO vs 122 x 10 9/L with no treatment; P < 0.05) in one study and significantly increasing platelet count at nadir (56 x 10 9/L with rhTPO vs 28 x 10 9/L with not treatment; P < 0.05) in another study. Safety findings included thrombosis ( n = 23 studies) and bleeding ( n = 11), with no evidence of increased thrombosis risk with thrombopoietic agents.

          Conclusion

          Our analyses generate the hypothesis that thrombopoietic agents may benefit patients with CIT. Further studies with well-characterized bleeding and platelet thresholds are warranted to explore the possible benefits of thrombopoietic agents for CIT.

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          Most cited references67

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          The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

          Systematic reviews and meta-analyses are essential to summarise evidence relating to efficacy and safety of healthcare interventions accurately and reliably. The clarity and transparency of these reports, however, are not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (quality of reporting of meta-analysis) statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realising these issues, an international group that included experienced authors and methodologists developed PRISMA (preferred reporting items for systematic reviews and meta-analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this explanation and elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA statement, this document, and the associated website (www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.
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            Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.

            We study recently developed nonparametric methods for estimating the number of missing studies that might exist in a meta-analysis and the effect that these studies might have had on its outcome. These are simple rank-based data augmentation techniques, which formalize the use of funnel plots. We show that they provide effective and relatively powerful tests for evaluating the existence of such publication bias. After adjusting for missing studies, we find that the point estimate of the overall effect size is approximately correct and coverage of the effect size confidence intervals is substantially improved, in many cases recovering the nominal confidence levels entirely. We illustrate the trim and fill method on existing meta-analyses of studies in clinical trials and psychometrics.
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              Meta-analysis in clinical trials revisited.

              In this paper, we revisit a 1986 article we published in this Journal, Meta-Analysis in Clinical Trials, where we introduced a random-effects model to summarize the evidence about treatment efficacy from a number of related clinical trials. Because of its simplicity and ease of implementation, our approach has been widely used (with more than 12,000 citations to date) and the "DerSimonian and Laird method" is now often referred to as the 'standard approach' or a 'popular' method for meta-analysis in medical and clinical research. The method is especially useful for providing an overall effect estimate and for characterizing the heterogeneity of effects across a series of studies. Here, we review the background that led to the original 1986 article, briefly describe the random-effects approach for meta-analysis, explore its use in various settings and trends over time and recommend a refinement to the method using a robust variance estimator for testing overall effect. We conclude with a discussion of repurposing the method for Big Data meta-analysis and Genome Wide Association Studies for studying the importance of genetic variants in complex diseases.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 June 2022
                2022
                : 17
                : 6
                : e0257673
                Affiliations
                [1 ] Hematology Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
                [2 ] Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France
                [3 ] Servicio de Hematología, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico
                [4 ] EpidStrategies, Johns Hopkins University, Rockville, Maryland, United States of America
                [5 ] School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
                [6 ] EpidStrategies, Ann Arbor, Michigan, United States of America
                [7 ] Global Development, Amgen Inc., Thousand Oaks, California, United States of America
                Institute of Experimental Hematology and Transfusion Medicine, University Clinic of Bonn, GERMANY
                Author notes

                Competing Interests: GAS has received research support from Amgen, Dova/Sobi Pharmaceuticals, and Janssen Scientific Affairs and has participated in advisory boards (in past 5 years) for Amgen, Janssen Scientific Affairs, Bayer Pharmaceuticals, Dova Pharmaceuticals, Bristol-Myers Squibb, Pfizer, Novartis, Anthos Therapeutics, and Hengrui (USA) Ltd. IRC and LJMR have nothing to disclose. JF and LCB are employees of EpidStrategies that received research funding for the study from Amgen Inc. MM is a contractor to EpidStrategies that received research funding for the study from Amgen Inc. JKP is an employee of and holds stock in Amgen Inc.

                [¤]

                Current address: Hemostasis, Thrombosis and Transfusion Services, University of Miami Health System/Sylvester Comprehensive Cancer Center, Miami, Florida, United States of America

                Author information
                https://orcid.org/0000-0002-8781-903X
                Article
                PONE-D-21-02115
                10.1371/journal.pone.0257673
                9183450
                35679540
                7d0037c4-10d5-48c8-bd3d-1dc2a7878c02
                © 2022 Soff et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 April 2021
                : 7 September 2021
                Page count
                Figures: 2, Tables: 2, Pages: 18
                Funding
                Funded by: Amgen Inc.
                This study was supported by Amgen Inc: https://www.amgen.com/. Amgen Inc. participated in the development of the concept and interpretation of data and provided medical writing support of the manuscript. GAS received research support from Amgen Inc. IRC and LJMR have nothing to disclose. JF and LCB are employees of EpidStrategies that received research funding for the study from Amgen Inc. MM is a contractor to EpidStrategies that received research funding for the study from Amgen Inc. JKP is an employee of Amgen Inc.
                Categories
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                Anatomy
                Body Fluids
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                Body Fluids
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                Platelets
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                Body Fluids
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