Mapping the characteristics, methodological quality and standards of reporting of network meta-analyses on antithrombotic therapies: An overview
Introduction
Mortality rates associated with thromboembolic events are extremely high worldwide, especially in low- and middle-income countries, overall accounting for 1 in every 4–5 deaths [1,2]. Between 2010 and 2013, estimates per 100,000 global deaths per condition were 105.5 for ischaemic heart disease, 42.3 for ischaemic stroke, 32.3 for venous thromboembolism and 1.7 for atrial fibrillation [2].
Patients with these conditions benefit significantly from antithrombotic interventions used as treatment or prophylaxis (e.g., anticoagulants and antiplatelet agents used alone or combined with other therapies), as they can reduce thromboembolic events [3,4]. The introduction of direct-acting oral anticoagulants (DOACs), including direct inhibitors of thrombin (dabigatran) or of factor Xa (rivaroxaban, apixaban, edoxaban) has provided additional therapeutic alternatives aimed at overcoming some challenges in the management of vitamin K antagonists (VKAs). This last is associated with several drug–drug and drug–food interactions, increased risk of bleeding, longer half-life and the need for further laboratory monitoring when compared to oral anticoagulants [5]. Therefore, DOACs are now recommended by the US and European guidelines as first-choice agents for most thromboembolic cases, except for some specific scenarios such as atrial fibrillation with moderate-to-severe mitral stenosis or mechanical prosthetic valves [[6], [7], [8], [9]]. In cardiac surgical procedures, including percutaneous coronary interventions, other antithrombotic strategies are routinely used to enhance therapeutic efficacy while maintaining safety [10]. All these interventions have been associated with significant clinical benefits as proven by several clinical trials, systematic reviews and meta-analyses.
Network meta-analysis (NMA), an extension of pairwise meta-analysis, simultaneously combines direct and indirect evidence to obtain comparative pooled effects of pairs of treatments in a network (i.e., comparison of multiple interventions across studies) [11]. This technique, thus, provides a broader overview of the effects (e.g., efficacy, safety) of all therapeutic alternatives available in one single model [12]. In the past years, the number of published NMAs has increased exponentially in several fields, especially in cardiology [13]. Until 2010, fewer than 10 NMAs on the effect of interventions to treat cardiovascular conditions were available; this number jumped to around 56 publications between 2011 and 2014 and 80 articles between 2015 and 2018 [14,15]. This cumulative evidence led to development of further techniques (e.g., overviews, evidence gap mapping, living systematic reviews) to summarize studies' findings, rate their quality and promptly present them to end-users [[16], [17], [18], [19]]. The main goal of these approaches is to increase the standards of evidence generation and synthesis, as around one third of meta-analyses in healthcare are redundant, 20% have methodological flaws beyond repair and 13% lead to misleading conclusions [15,20].
Yet, only a few overviews (i.e., systematic reviews of published systematic reviews, also called umbrella reviews) synthetizing the overloading evidence of antithrombotics in different clinical conditions such as atrial fibrillation and deep venous thrombosis have been published [18,21]. Most of them focus on a single cardiovascular disease and include only pairwise meta-analyses of randomized clinical trials (RCTs), or restrict the review by articles' publication year or language. None of them assessed both the methodological quality and standards of conduct and reporting of NMAs in this field, which may hinder the true value of information and lead to equivocal decisions in practice.
Thus, we aimed to map the characteristics and methodological quality and standards of reporting of all published NMAs on the effects of antithrombotic therapies – including antiplatelet and anticoagulant agents for the treatment or prophylaxis of heart diseases or during cardiac surgical procedures – and highlight potential evidence gaps.
Section snippets
Material and methods
A systematic review of systematic reviews with meta-analysis (i.e., overviews or umbrella reviews) was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, Joanna Briggs Institute and the Cochrane recommendations [[22], [23], [24]]. This study was registered in PROSPERO (CRD2020166468).
Results
A total of 639 records were retrieved from the electronic databases after removing duplicates. During the screening process, 234 articles were included for full-text analysis, of which 86 studies were considered eligible for data extraction and analysis (Fig. 1). The list of included and excluded studies is available in Supplementary Material S2 and S3, respectively.
The descriptive characteristics of the 86 systematic reviews with NMAs available in this study are presented in Table 1. The NMAs
Discussion
This overview mapped the characteristics and critically appraised the standards of conduct and evidence reporting of 86 peer-reviewed NMAs published between 2007 and 2022 on the effect of antithrombotic therapies in heart diseases and cardiac surgical procedures. We found that 88.4% of the evaluated studies have critically low methodological quality according to AMSTAR-2 and that adherence to the PRISMA-NMA recommendations is still underwhelming – less than two thirds of studies completely
Conclusion
The global increase of mortality and morbidity associated with cardiovascular diseases warrants the prioritization of strategies to manage these conditions, including the conduct of evidence-based syntheses such as NMAs. The number of these publications summarizing the comparative findings of the efficacy and safety profile of antithrombotics in heart diseases has increased exponentially in the past decade. However, although they represent a systematic and low-cost approach to ground
Funding
None.
Declaration of Competing Interest
The authors have declared that no competing interests exist.
Acknowledgements
The authors acknowledge the Pharmaceutical Assistance Postgraduate Programme, Federal University of Paraná and the State University of Western Paraná for the support to perform this study.
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