Antithrombotic drugs for cardiovascular risk reduction in patients with lower limb peripheral arterial disease: protocol for a systematic review and network meta-analysis of randomised controlled trials

INTRODUCTION: The optimal antithrombotic regimen to reduce the risk of vascular events in patients with peripheral arterial disease (PAD) is contentious. This systematic review and network meta-analysis (NMA) aims to define the relative efficacy and risks of previously investigated antithrombotic medication regimens in preventing major cardiovascular events, vascular limb events and mortality in patients with PAD. METHODS AND ANALYSIS: A peer-reviewed, systematic search will be executed in English on Medline, Embase, Cochrane (CENTRAL), Web of Science and Google Scholar databases in late 2022. The WHO International Clinical Trials Registry platform will also be searched for ongoing trials. Abstracts will be screened independently by two researchers for randomised controlled trials meeting the review criteria. All associated publications including the study protocol will be sought and evaluated together against prespecified inclusion/exclusion criteria. Two researchers will extract the data into a prepiloted extraction form. Risk-of-bias assessments will be performed using the Cochrane ‘Risk-of-Bias V.2’ criteria by individuals with domain expertise. All differences will be resolved by consensus or a third individual for ties. Included trials will be summarised. An NMA will be performed, subject to checks of assumptions. Both primary and secondary outcomes will be analysed on a whole network basis. Pairwise comparisons and league tables will be produced. Prespecified subgroup analyses will include sex, ethnicity, disease status, conservative versus interventional management and key comorbidities. The findings will be evaluated using the Grading of Recommendation Assessment, Development and Evaluation, informed by patient and public involvement work. ETHICS AND DISSEMINATION: This is a systematic review of data in the public domain and does not require ethical approval. Dissemination will include presentations to key vascular and patient organisations, publication in a peer-reviewed journal and an open-access repository of the study data. PROSPERO REGISTRATION NUMBER: CRD42023389262.