Introduction: Non Vitamin-K Oral Anticoagulants (NOACs) revolutionized the approach to anticoagulation in patients with Non-Valvular Atrial Fibrillation (NVAF). Compared to the older vitamin-K oral anticoagulants, NOACs demonstrated a better risk-benefit profile in phase-III trials, with higher patient preference in real-world settings. For these reasons, international guidelines endorse the use of NOACs as first-line treatment for the thromboembolic risk reduction in NVAF. However, no conclusive data exist on which is the best option among NOACs, and choosing one over others may be challenging: to date, no head-to-head trial has been conducted, and comparisons from observational studies resulted in contradictory findings. This study aims to provide a comprehensive and efficient synthesis, through a Systematic Review and Network-Meta Analysis (NMA), of all real-world studies on the efficacy and safety of NOACs in patients with NVAF.
Methods: According to the PRISMA Statement, Pubmed and Embase will be searched, using an appropriate set of keywords related to NOACs and relevant outcomes, including thromboembolic and bleeding events. Two investigators will independently screen all records for eligibility, according to pre-specified inclusion and exclusion criteria. For each study included, the risk of bias will be assessed, and relevant data will be extracted. NMA for pre-specified outcomes of interest will be performed, with further subgroup and sensitivity to detect potential interactions according to baseline characteristics of patients.
Discussion: Findings from this NMA are expected to shed light on actual differences among NOACs, towards identifying which represent the most convenient option in patients with NVAF. Data from this project will deepen our knowledge of NOACs and may guide prescription patterns and clinical practice, also allowing the identification of subgroups of patients who may be predisposed to poorer outcomes when treated with a specific NOAC.
The proposed research project is both highly significant and innovative in three ways:
1) Clinical Relevance: To date, it is unclear whether NOACs present different risk-benefit profiles, and if one may be better than others in terms of efficacy, safety, or both. No head-to-head RCT has been performed, so the data on the comparison between NOACs mainly come from observational and real-world studies. The pooling of such evidence can provide useful insights into the potential superiority of one treatment over others, both in terms of efficacy and safety. These data will serve as guidance for clinical practice and may change prescription patterns among treating physicians.
2) Identification of subgroups of patients with different risk-benefit profiles: Subgroup and sensitivity analysis will help to focus on specific clusters of individuals that may benefit from a particular treatment strategy. Elderly patients, as well as patients with chronic kidney disease, frequently present a greater risk of adverse events, and this may affect the performance of different NOACs in terms of efficacy and safety. Our analysis will allow us to account for these differences, potentially providing differential recommendations according to several covariates.
3) Innovative methodology: Differently from the classical meta-analysis, Network Meta-Analysis (NMA) is an advanced technique that will allow indirect comparisons among NOACs. This will increase the power of the analysis, as well as the significance and comprehensiveness of the overall studies. By the end of this project, we will be able to describe comparisons between NOACs that may not have been investigated in original studies, due to technical difficulty, or low number of patients (e.g., between reduced dose regimens), thanks to indirect confronts. In the era of evidence-based medicine, this approach can be the right answer to the need for an effective synthesis of real-world evidence about NOACs.