Statin Treatment Options during vaccination against inFLUenza (STOPFlu) : an observational study of the interaction between statins and influenza vaccination

Background Influenza vaccination is routinely advised for many at-risk groups including adults aged≥65-years and, and younger patients with diabetes and cardiovascular disease. Many of these patients are also likely to be prescribed statins for control of cardiovascular risk.

However, the mechanism by which statins protect against heart disease may also inhibit the immune response to vaccination, potentially lowering its efficacy. This is further complicated by statins themselves potentially offering some protection against influenza. Robust evidence is needed to guide clinical practice and ensure vaccine response is maximised.

Objectives To evaluate the potential modifying effect of statins on the effectiveness of the influenza vaccine from health record data. A secondary objective is to estimate any protective benefit of statins as potential prophylaxis against influenza.

Methods Electronic health records of patients in primary care with linkage to hospital episode statistics, are available from the Clinical Practice Research Datalink. Annual cohorts of patients eligible for both statins and the influenza vaccine will be selected from 2010-18.

A composite influenza outcome will be defined based on consultations for influenza-like illness and hospital admissions for influenza.

Our primary analysis will test for an association between statin use and influenza outcomes, amongst patients receiving the influenza vaccine.

Secondary analyses will estimate influenza vaccine effectiveness separately among statin users and nonusers, and the extent of any prophylactic effect of statins.

Cox regression will be used to analyse outcomes as survival data with weighting by the propensity score to adjust for measured confounders. The prior event rate ratio method will be used to adjust for potential unobserved confounders.

We shall also re-apply the analysis protocol to a negative control outcome, such as shingles, for which we expect no association with influenza vaccination, providing further control of confounding.

Timelines for delivery Months 1-4: preparation and processing of the data Months 5–8: main analysis Month 9: Stakeholder meeting with General Practitioners (GP) and GP nurses.

Months 9-11: Sensitivity analyses Months 12-16: Stakeholder meeting with patient-public engagement and involvement (PPEI) group to discuss results, write up and dissemination Anticipated Impact and Dissemination If our results demonstrate that statins weaken vaccine response then the next stage would be an interventional study in which the benefits of a temporary break from statins at the time of vaccination are trialled.

Involvement of the public is key to ensuring acceptability of any identified changes to vaccination protocols as well as for disseminating findings and maintaining influenza-vaccine uptake and adherence to statins. This is reflected through recruitment of a patient representative onto the research team.

We will also seek feedback from GPs and practice nurses through a stakeholder meeting to establish barriers to implementation and a suitable framework for a definitive trial.

An external advisory group consisting of a Senior Epidemiologist from US Centre for Biologics Evaluation and Research, and the Director of the International Longevity Centre UK will provide ongoing scientific scrutiny and advice on dissemination. We aim to present at relevant international conferences and publish in high ranking clinical journals.