Overview of Systematic Reviews of Non–Vitamin K Oral Anticoagulants in Atrial Fibrillation
2018; Lippincott Williams & Wilkins; Volume: 11; Issue: 12 Linguagem: Inglês
10.1161/circoutcomes.118.004769
ISSN1941-7705
AutoresIoannis Doundoulakis, Christina Antza, Fani Apostolidou‐Kiouti, Evangelos Akrivos, Haralambos Karvounis, Vasilios Kotsis, Anna‐Bettina Haidich, George Giannakoulas,
Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoHomeCirculation: Cardiovascular Quality and OutcomesVol. 11, No. 12Overview of Systematic Reviews of Non–Vitamin K Oral Anticoagulants in Atrial Fibrillation Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBOverview of Systematic Reviews of Non–Vitamin K Oral Anticoagulants in Atrial FibrillationEvidence of Publication Overlap Ioannis Doundoulakis, MD, MSc (Res), Christina Antza, MD, MSc (Res), Fani Apostolidou-Kiouti, MD, Evangelos Akrivos, MSc, Haralambos Karvounis, MD, PhD, Vasilios Kotsis, MD, PhD, Anna-Bettina Haidich, PhD and George Giannakoulas, MD, PhD Ioannis DoundoulakisIoannis Doundoulakis First Department of Cardiology, AHEPA Hospital (I.D., H.K., G.G.), Aristotle University of Thessaloniki, Greece. , Christina AntzaChristina Antza Third Department of Internal Medicine, Hypertension-24h ABPM ESH Center of Excellence, Papageorgiou Hospital (C.A., V.K.), Aristotle University of Thessaloniki, Greece. , Fani Apostolidou-KioutiFani Apostolidou-Kiouti Department of Hygiene, Social and Preventive Medicine and Medical Statistics, Medical School (F.A.-K., A.B.-H.), Aristotle University of Thessaloniki, Greece. , Evangelos AkrivosEvangelos Akrivos Laboratory of Computing, Medical Informatics and Biomedical Imaging Technologies, Medical School (E.A.), Aristotle University of Thessaloniki, Greece. , Haralambos KarvounisHaralambos Karvounis First Department of Cardiology, AHEPA Hospital (I.D., H.K., G.G.), Aristotle University of Thessaloniki, Greece. , Vasilios KotsisVasilios Kotsis Third Department of Internal Medicine, Hypertension-24h ABPM ESH Center of Excellence, Papageorgiou Hospital (C.A., V.K.), Aristotle University of Thessaloniki, Greece. , Anna-Bettina HaidichAnna-Bettina Haidich Department of Hygiene, Social and Preventive Medicine and Medical Statistics, Medical School (F.A.-K., A.B.-H.), Aristotle University of Thessaloniki, Greece. and George GiannakoulasGeorge Giannakoulas George Giannakoulas, MD, PhD, Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kyriakidi str 1, 54636, Thessaloniki, Greece. Email E-mail Address: [email protected] First Department of Cardiology, AHEPA Hospital (I.D., H.K., G.G.), Aristotle University of Thessaloniki, Greece. Originally published14 Dec 2018https://doi.org/10.1161/CIRCOUTCOMES.118.004769Circulation: Cardiovascular Quality and Outcomes. 2018;11:e004769This article is commented on by the following:Replication, Duplication, and Waste in a Quarter Million Systematic Reviews and Meta-AnalysesSee Editorial by Siontis and IoannidisOver the past decade, several non–vitamin K antagonist oral anticoagulants (NOACs), which selectively inhibit thrombin or activated factor X, have been developed for the anticoagulation treatment of patients with atrial fibrillation (AF). At the same time, an increasing number of systematic reviews (SRs) have been published in the field of antithrombotic treatment of AF with NOACs. This is the first effort to summarize evidence in an overview of SRs (OoSRs) focusing exclusively on AF patients. The number of SRs was compared with the number of primary randomized clinical trials (RCTs) to evaluate possible important overlap in SRs.Methods and ResultsData Searches and Study SelectionThe authors declare that all supporting data are available within the article. This OoSRs was registered in PROSPERO (International Prospective Register of Systematic Reviews) with registration number: CRD42017078915 and was reported according to pertinent reporting guidelines for this type of study design.1 This work constitutes an umbrella approach to identify both SRs and RCTs.A purposive literature search for SRs and RCTs took place from inception to September 3, 2017. We searched MEDLINE (via PubMed), the Cochrane Library, and PROSPERO for SRs and clinicaltrials.gov to find further RCTs with restriction to the English language. A more comprehensive search strategy was applied in MEDLINE, using medical subject heading (Appendix I in the Data Supplement). For all included studies, reference lists were also searched. Two independent overview authors (Drs Doundoulakis and Apostolidou-Kiouti) screened the titles and abstracts against the eligibility criteria for inclusion.We searched for SRs which compared the efficacy and safety of NOACs with warfarin in patients with AF and analyzed the full texts to extract the eligible RCTs. SRs which included observational studies were also eligible. Studies that did not use warfarin in the control group or those that included other drugs as a comparator (eg, aspirin) were excluded. Narrative reviews that did not report any search strategy and did not critically appraise the quality of included studies were also excluded. Finally, a third reviewer (Dr Antza) intervened when there was a disagreement between the other 2 authors.Data Extraction and Quality AssessmentTwo reviewers (Drs Doundoulakis and Apostolidou-Kiouti) independently extracted data/items including citation details; objectives of the included review; type of review; participant details; setting and context; number of databases sourced and searched; date range of database searching; number of studies, types of studies and country of origin of studies included in each review; instrument used to appraise the primary studies and the rating of their quality; outcomes reported that are relevant to the OoSRs question; method of synthesis/analysis used to synthesize the evidence; major conclusions; comments or notes by the OoSRs authors; metric used and effect size (for meta-analyses); CIs (for meta-analyses). Authors were contacted in case of missing data. If the requested data could not be retrieved, the study was not included in the analysis.Two overview authors (Drs Doundoulakis and Apostolidou-Kiouti) independently assessed the risk of bias in the included SRs using the Risk of Bias in Systematic Reviews tool.2 The list of RCTs was reviewed to identify overlapping studies which were included in ≥2 eligible SRs of RCTs. A citation matrix was created to depict graphically if 1 RCT was included in >1 review. The RCT of Calkins et al (Appendix III in the Data Supplement) was not included in the citation matrix, as it was published in 2017 and was not included in any SR. Three protocols from the clinicaltrials.gov were also not included (Appendix III in the Data Supplement). To quantify the overlap of primary studies included in different SRs, we calculated the measure of the corrected covered area (CCA=, where N is the number of included publications [included double counting] in evidence synthesis [this is the sum of the ticked boxes in the citation matrix]; c is the number of RCTs and r is the number of SRs of RCTs) of overlap indicating slight (0%–5%), moderate (6%–10%), high (11%–15%), and very high (>15%) overlap.3 Cases of dual (co)authorship were also identified in case authors of SRs had also (co)authored 1 or several of the included RCTs.4 Moreover, an extensive check was performed to identify whether each author participated >1 SR and to analyze possible reasons.Search ResultsWe found 66 SRs (Appendices II and III in the Data Supplement). All the included studies were published between 2012 and 2017 in English. Overall, 45 SRs collected their data only from RCTs, 12 from both randomized and nonrandomized studies, and 9 only from observational studies. Risk of bias of the SRs was rated as low, high, or unclear according to the Risk of Bias in Systematic Reviews tool (Appendix IV in the Data Supplement). Only one of the SRs,5 which were included in our OoSRs, has evaluated the overall quality of evidence outcome using the Grading of Recommendations Assessments, Development, and Evaluation approach.6Eighteen RCTs included a total of 78 796 patients with AF, with sample sizes varying from 90 to 21 105 (Appendix V in the Data Supplement). There were no head-to-head trials. Appendix VI in the Data Supplement shows the forest plots of all SRs of RCTs with relative risk as type of metric for efficacy and safety of NOACs.Overlap in SRsThe number of SRs which collected their data from RCTs or both from randomized and nonrandomized studies (n=57) was far greater than the number of RCTs (n=14). Therefore, CCA= = =24%. This CCA value indicates a very high overlap (Table). With regard to dual coauthorship, 7 out of 66 of the included reviews were affected by dual (co)authorship. Of note, dual (co)authorship was not mentioned in any protocol. From the 359 authors who were included in the author lists of the publications, 1 participated in 13 SRs, 7 in 4 SRs, 1 in 3 SRs, 30 in 2 SRs, and all the others in 1 SR. We also calculated the CCA using only SRs of observational studies. In contrast to the CCA of SRs of RCTs, this was lower (CCA=10%), suggesting that the overlap of observational studies is limited.Table. Map of Primary Studies Contained Within Each Included Systematic Review Which Collected Data From RCTsStudy ID Granger 2011Patel 2011Connolly 2009Giugliano 2013Hori 2012Nin 2012Ezekowitz 2007Ogawa 2011Kuwahara 2016Weitz 2010Chung 2011Cappato 2014Yamashita 2012Cappato 2015Systematic Reviews Adam 2012√√√ Ando 2015√√√√ Ando 2017√√√√√ Bai 2017√√√ Baker 2012√√√√ Bin 2013√ Biondi-Zoccai 2013√√√√√√√ Blandino 2016√ Bloom 2014√√ Briceno 2015√√√√√ Caldeira 2015√√√√√ Caldeira 2015√√√√ Caldeira 2015√√√√√ Caldeira 2015√√√√√ Capodanno 2012√√√ Chen 2015√√√√ De Haro 2016√√√ Dentali 2012√√√√√√√√√ Fernandez 2015√√√√ Fu 2014√√√√ Gandara 2016√√√ Gomez 2013√√√ Gomez 2016√√√√√ Harenberg 2012√√√ Hohnloser 2013√ Jia 2014√√√√√ Katsanos 2016√√√√ Lega 2014√√√ Lip 2012√√√ Lip 2016√√√√ Lu 2015√ Mantha 2012√√√ Miller 2012√√√ Nielsen 2015√√√√√√√ Ntaios 2017√√√√ Nunes 2014√√√ Owens 2017√√√√ Pan 2017√√√√ Providência 2014√ Rasmussen 2012√√√ Renda 2016√√√√√ Ruff 2014√√√√ Sardar 2013√√√ Sardar 2014√ Savarese 2016√√√√ Schneeweiss 2012√√√ Shurrab 2013√ Skjøth 2014√√√√ Testa 2012√√√ Ukaigwe 2016√ Vamos 2016√ Verdecchia 2014√√√√ Wang 2016√√√√√ Wells 2012√√√√√ Wu 2016√ Xiong 2015√√√√ Zhao 2017√Total No. of Reviews4443422411765333322RCT indicates randomized clinical trials.CommentOur OoSRs shows that the number of SRs for the efficacy and safety of NOACs has increased dramatically compared with the number of RCTs: a result that clearly requires a future research turn, aiming to an increase in publication of real-world studies, head-to-head RCTs or RCTs in subpopulations of AF patients, such as those undergoing ablation and cardioversion.This is the first effort to summarize evidence in an OoSRs focusing exclusively on patients with AF. Although overlap is often inevitable when results get updated based on new primary evidence, current extensive review overlap suggests that there is a waste of efforts with few RCTs covered by multiple overlapping SRs, as indicated by a high CCA of 24%. The publication of multiple reviews on the same topic has been recently discussed by Naudet et al7 and Siontis et al.8 According to the authors, the presentation of the same data by different independent researchers constitutes an advantage because there are publications with conflicting results on the same topic. Furthermore, new primary RCTs that emerge can be added and update previous SRs. However, the huge number of SRs composed from a small number of RCTs reflects lost effort and time because researchers usually begin the composition of data without taking into account previous SRs. In addition, authors may incorrectly select the included studies in their effort to make their SR unique, as far as the topic is concerned, and to publish their work. In the present OoSRs, there are many SRs that conclude to similar results, but there are also SRs that omit RCTs maybe in their effort to create a different publication. Table demonstrates that several SRs has omitted previously published RCTs which nonetheless were included in other SRs.As we can see from the forest plots in Appendix VI in the Data Supplement, the question about efficacy and safety of NOACs in AF has been answered early even from the first SRs, with an exception the SRs of ablation and cardioversion in which the CIs for the relative risk of NOACc versus warfarin for stroke and major bleeding are very wide. However, a number of subsequent SRs have been published after the first ones with the aim to fill the same knowledge gap. They reported different outcomes or studied subgroups which originated from the same RCTs after adding or removing some of the RCTs. Moreover, the risk of bias of the SRs seems not to be important for the final effect size because adding or removing some RCTs seems to change a little the final outcome. This is the expected result because all RCTs are significantly in favor of the NOACs. As long as new SRs will continue to be published, the issue of overlapping will become more significant. One possible solution for this problem could be the deposit of SR protocols (eg, in PROSPERO). In this way, journals and reviewers may be able to reject quickly and easily SRs that have already been published and, thus, the publication of the same results will be avoided.On dual coauthorship, the number 7 out of 66 may seem low, but dual (co)authorship is required to be noted in each SR because it may be a potential source of bias. Authors with dual (co)authorship may have competing interests, for instance when deciding which RCTs to include. Generally, authors may have already developed personal views about specific interventions or trials.An important finding of the present OoSRs was that in many cases, the same author published >1 SR. Usually, 1 group of authors updated their previous publication adding a new RCT. Another strategy is the publication of an additional SR with the use of observational studies, in addition to RCTs. Additionally, there are cases of segmented publication, where the same RCTs are used, but the outcomes are modified (eg, presenting only the risk of major bleeding) or the subgroup is different (eg, including only patients with heart failure or chronic kidney disease). Finally, in some cases, the statistical analysis of the same RCTs may be different (network meta-analysis).LimitationsWe did not try to determine whether all these SRs were necessary to be published or not. This would be a subjective decision. However, publication overlap of SRs was high, and most of the recent SRs did not review the already published ones, which were similar. Some of the overlapping SRs were slices of the evidence focusing on narrow outcomes. Understanding the real merits of interventions, however, requires the full analysis of their outcomes. Thus, SRs with limited coverage of outcomes are suboptimal.ConclusionsSRs (first level of synthesis) and OoSRs (second level of synthesis) can be considered as lenses, through which evidence from primary studies is viewed. OoSRs, a new type of publication, provides a broad evidence synthesis, highlights factors for discordant reviews, identifies knowledge gaps, biases, priorities for future research, overlap of primary research studies in each of the included research syntheses, and assesses the quality and the contemporaneity of the included reviews. From our OoSRs, it was evident that there are few RCTs covered by multiple overlapping SRs in the field of efficacy and safety of NOACs in AF.AcknowledgmentsDr Doundoulakis proposed the idea, proposed the structure of the article, acted as first independent reviewer, proposed the statistical analysis and formulated the article. Dr Antza appraised the article, made final suggestions. Dr Apostolidou-Kiouti performed the statistical analysis, acted as second independent reviewer. Dr Akrivos performed the statistical analysis. Dr Karvounis critically appraised the article. Dr Kotsis critically appraised the article, made the final suggestions. Dr Haidich supervised the statistical analysis, critically appraised the article, and made final suggestions. Dr Giannakoulas proposed the idea, critically appraised the article, and made final suggestions. We thank Angelos M. Katramados for English language editing.Sources of FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.DisclosuresDr Giannakoulas has received honoraria for lectures and advisory boards from Pfizer, Bayer, and Boehringer Ingelheim. Additionally, authors were not involved in primary studies (systematic reviews or randomized clinical trials) included in our overview. In this way, potential source of bias by dual (co) authorship does not exist in our article. The other authors report no conflicts.FootnotesThe Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCOUTCOMES.118.004769.George Giannakoulas, MD, PhD, Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kyriakidi str 1, 54636, Thessaloniki, Greece. Email [email protected]auth.grReferences1. Bougioukas KI, Liakos A, Tsapas A, Ntzani E, Haidich AB. 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Circulation: Cardiovascular Quality and Outcomes. 2018;11 December 2018Vol 11, Issue 12 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCOUTCOMES.118.004769PMID: 30562066 Manuscript receivedMarch 27, 2018Manuscript acceptedNovember 14, 2018Originally publishedDecember 14, 2018 Keywordsatrial fibrillationmeta-analysisanticoagulantsarrhythmiawarfarinPDF download Advertisement SubjectsArrhythmiasAtrial FibrillationMeta AnalysisQuality and Outcomes
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