The association between influenza vaccination, all-cause mortality and cardiovascular mortality: a protocol for a living systematic review and prospective meta-analysis

Introduction Influenza virus infection is known to increase the risk of cardiovascular events, especially in populations with pre-existing cardiovascular disease. Considering that influenza is vaccine preventable, international guidelines recommend high-risk populations with CVD receive an influenza vaccine every year, but there are various classifications of recommendations and levels of evidence. Previous systematic reviews concluded uncertain evidence on influenza vaccine efficacy for preventing cardiovascular events in the general population or in populations with pre-existing CVD. Limited safety data of influenza vaccines were reported for populations with pre-existing CVD. Randomized control trials with larger sample sizes relative to previous studies are emerging, the findings of these trials are likely to be highly influential on summary efficacy estimates. Methods and analysis We aim to perform a living systematic review and a prospective meta-analysis to evaluate the efficacy and safety of influenza vaccines compared to no vaccines or placebo for preventing mortality or cardiovascular disease events in the general population and in populations with pre-existing CVD. Ethics and dissemination Formal ethical review is not required as this study does not need primary data collection. We will publish results of the living systematic review and prospective meta-analysis in a peer-reviewed journal. Findings will also be presented at relevant meetings. PROSPERO registration number CRD42021222519. Strengths and limitations of this study The living systematic review will continually incorporate the latest research findings and keep the synthesized information updated. A prospective meta-analysis will better address this evolving evidence. Safety of influenza vaccines in populations with pre-existing cardiovascular diseases will be studied in particular to complete the current evidence base. Observational studies may affect the overall quality of the study results. We will stratify the analysis by study design and present both randomized and non-randomized results.