Title: Antibiotic treatment and major bleeding in anticoagulant medication users: analysis of health record data to support safer monitoring and prescribing.
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Background Depending on the specific drug, 2-4% of anticoagulant medication users have a major bleed needing hospitalisation, of whom 20% die within 30 days. Several studies have implicated antibiotic-anticoagulant drug- drug interactions as the likely cause of a significant number of bleeds in anticoagulant medication users, but previous estimates of the risk of bleeding associated with specific antibiotics are inconsistent and do not fully account for the risk related to the underlying infection Aim This project aims to determine the risk of major bleeding associated with antibiotic treatment in anticoagulant medication users and effectively disseminate the findings to improve care and help reduce the incidence of these adverse outcomes. Methods I will address the research aim through a series of epidemiological studies using prescribing, hospital admission, and mortality data from the Clinical Practice Research Datalink (CPRD). The CPRD is an electronic database of anonymised health records, covering 11.3 million patients from 674 general practices across the UK. I will identify a cohort of new anticoagulant medication users in the CPRD. Associations between treatment with different antibiotics and major bleeding will be determined in two ways. First, a retrospective cohort study using logistic regression models to estimate odds of bleeding associated with the 10 most commonly prescribed antibiotics in the UK, using amoxicillin as an active comparator. Second, a propensity score matched cohort study estimating the odds of bleeding for antibiotics recommended for the same indication. A third study will use a self-controlled case series design to determine the impact of infection without antibiotic treatment on bleeding risk. Estimates for warfarin and Direct Oral Anticoagulants will be reported separately. Outcomes will include death or hospitalisation from gastrointestinal or intracranial bleeding and clinically relevant non-major bleeding. Several sensitivity analyses will test the robustness of the findings using methods such as negative control exposures and negative control outcomes. Project timelines 3 month unfunded run-in period to prepare and submit protocols and analysis plans and obtain governance approvals. Months 1-4: Extract required primary care data and work with CPRD to access linked hospital and mortality data. Months 5-12: Data cleaning and preparation of cohort of anticoagulant medication users. Months 13-20: Analysis to estimate associations between different antibiotic treatments and bleeding. Months 21-28: Analysis to estimate impact of infection without antibiotic treatment on bleeding. Months 29-34: Prepare and write academic reports, papers and lay summaries. Months 35-40: Dissemination. A programme of training, development, and patient and public involvement activities will run alongside the project timetable. Impact and dissemination I will liaise with national and regional guideline development groups to publicise the project and disseminate findings through peer-reviewed publication, presentation and other targeted approaches. I will liaise with NHS staff to disseminate the findings to service providers through concise clinically relevant summaries. I will work with patient and public involvement representatives to develop lay summaries of the findings and ensure that these reach relevant charities and the wider public. Thrombosis UK and Anticoagulation UK will support the dissemination activities through their network of patients and healthcare professionals.

Lay abstract: The main oral anticoagulants used in the UK are warfarin and a group of drugs known as Direct Oral Anticoagulants, or DOACs. Their main use is to prevent blood clots and stroke in people with an irregular heart rhythm. Bleeding is the most serious complication of using anticoagulant medication. Several antibiotics are thought to interact with anticoagulants and increase the chance of a major bleed. However, the available research does not clearly identify which antibiotics are safe and prescribing advice is mostly based on anecdote. It is important to know which antibiotics increase the risk of bleeding to enable healthcare professionals to avoid potentially harmful antibiotics but appropriately prescribe those that are safe. This project aims to determine the risk of major bleeding associated with antibiotic treatment in anticoagulant medication users and effectively disseminate the findings to improve care and help reduce the incidence of these adverse outcomes. Urinary, or skin infection. Analysis 3 will determine the risk of bleeding in people with an infection that did not need antibiotic treatment and will answer the question of whether infection alone is associated with the risk of bleeding. Each analysis will also investigate which patients are most at risk and when risk is greatest. This will provide important information about which patients and time-periods may benefit from closer monitoring and improve the overall care provided to patients. Patient and public involvement Members of the Wales Centre for Primary and Emergency Care Research Service Users group (SUPER) reviewed this summary, as did two patient and public representatives who worked with the applicant on previous CPRD research. Going forward, this project will collaborate with a lay advisory group recruited from the SUPER group and Anticoagulation UK. The applicants training and development plan includes training to improve his skills in maximising the potential benefits from patient and public involvement in data science research. The requested time and finances will enable meaningful patient and public involvement throughout the lifespan of the project. Dissemination The findings of this project will be disseminated to organisations that write clinical guidelines (for example, NICE, Public Health England), and to NHS staff. The applicant will work with patient and public involvement representatives to develop lay summaries of the findings and ensure that these reach the wider public. Thrombosis UK and Anticoagulation UK will support the dissemination activities through their network of healthcare professionals and anticoagulant medication users.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD;CARDIOVASCULAR;INFECTION