Title: Statin Treatment Options during vaccination against inFLUenza (STOPFlu) : an observational study of the interaction between statins and influenza vaccination
Funder: Department of Health and Social Care

Abstract: Background Influenza vaccination is routinely advised for many at-risk groups including adults aged&ge;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&ndash;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.

Lay abstract: Influenza (flu) is a common viral infection that can have serious complications. It is estimated that an average of about 600 people a year in the UK die after contracting flu. Flu vaccination is a key component of national health policy, protecting susceptible individuals immune system to recognise and fight the flu virus. Vaccination is targeted at those most at risk: people aged over 64 and younger adults with chronic medical conditions such as diabetes and respiratory disease. Currently, more than 70% of adults aged over 64 are vaccinated each year against flu. Flu vaccination is estimated to help avert between 5,500 and 9,000 premature deaths per year. Although the flu vaccine is generally effective, recent research indicates that the immune response to the vaccine is reduced in patients, who take statins, compared to those who do not. Statin medications are commonly prescribed to older adults for lowering cholesterol and reducing the risk of heart disease. The National Institute for Clinical Excellence recommends offering statins to people with at least a 10% risk of developing heart disease in the next 10 years. Amongst the over 75 s alone, about 1.8 million people are estimated to be taking statins in the UK. In our initial PPEI work, patients identified the risk of hospitalisation from influenza amongst statins users as a particular concern. Currently, there is no firm evidence that temporarily withholding statin therapy at the time of flu vaccination might improve vaccine effectiveness. The aim of this study is to strengthen the evidence by making efficient use of existing GP health record data on patient vaccination history, inpatient and outpatient visits and prescription drugs. A limitation of previous studies is that the statin users and nonusers being compared may have differed by factors that were not measured, but which could affect patient outcomes. We will address this using a modern statistical method that makes use of patient outcomes in the period before vaccination to account for unmeasured differences between statin users and non-users. GP health records can also support a long term study of patient health. Therefore, this project will additionally study the risk of dementia following influenza infection and whether the risk can be modulated by the flu vaccine or statins. Our study does not question the established role of statins in disease prevention. Using existing big data , we will tackle the important question of whether statins interfere with the effect of vaccination and this could lead to new strategies for prescribing statins to patients that need a flu vaccine. Given the large number of older people taking statins, this is an important public health issue that could have a substantial impact on the success of future vaccination campaigns

Research activity codes: 3.4 VACCINES
Health categories: INFECTION