Atrial fibrillation (AF) is a heart condition that promotes the formation of blood clumps which can block blood supply to the brain causing stroke. Direct oral anticoagulants (DOACs), also known as blood thinners, are often offered to patients with AF to prevent stroke. Despite the benefits of DOACs, they can lead to bleeding in the stomach. Studies have found that gastroprotective agents (GPAs), drugs which lower the amount of acid in the stomach , can reduce the risk of stomach bleeding among people taking anti-inflammatory drugs or other blood thinners such as aspirin. However, it is unclear whether the potential benefits of GPAs also apply to DOAC users, or which specific patients could benefit from GPAs. Additionally, it is unknown whether GPAs could affect the anticoagulative effectiveness of DOACs, thereby altering the risk of stroke and intracranial haemorrhage, also known as brain bleed.
Given these uncertainties, this study aims to investigate the potential benefits and harms of GPAs among patients with AF initiating DOACs. Using de-identified electronic databases, we will investigate whether GPAs can reduce the risk of bleeding in the stomach requiring hospitalisation among DOAC users with AF. Secondly, we will examine whether GPAs can affect the risk of stroke and intracranial haemorrhage. Thirdly, we will explore which patient groups could benefit most from GPAs. These findings would help clinicians to make better informed decisions on patient suitability for DOAC and GPA cotherapy and prevent adverse bleeding events in DOAC users.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia which increases the risk of ischaemic stroke and other embolic events. Direct oral anticoagulants (DOACs) are effective at reducing AF-related embolism but increase the risk of gastrointestinal bleeding (GIB). Studies have suggested that proton pump inhibitors (PPI) can potentially reduce GIB. However, whether these potential benefits apply to DOAC users with AF, remains unclear. Furthermore, it is unknown whether PPIs could affect the anticoagulative effectiveness of DOACs, thereby altering the risk of stroke and intracranial haemorrhage. We will use the Clinical Practice Research Datalink, linked with Hospital Episode Statistics and Office of National Statistics, to investigate the role of gastroprotective agents (GPAs) in DOAC users with AF. Patients with AF who initiated DOACs from 1st January 2016 through 30th April 2023 will be included in the study. We will compare the risk of GIB requiring hospitalisation, ischaemic stroke/systemic embolism, and intracranial haemorrhage between DOAC users who initiate PPI, H2-receptor antagonists, and non-GPA users. These findings can help guidelines and clinicians with decision making on patient suitability for DOAC and GPA cotherapy, helping prevent GIB events among DOAC users.
The study design will follow the target trial emulation framework. We will emulate separate target trials for different DOACs: edoxaban, apixaban, rivaroxaban and dabigatran. We will implement the clone-censor-weight method to allocate treatment groups. Per-protocol analyses will be conducted using marginal structural cox proportional hazards models (approximated with pooled logistic regression). Weights will control for time-varying confounding and adherence to treatment allocation. These models will obtain adherence-adjusted hazard ratios for each outcome. Standardised risk curves will be derived by incorporating a product term between exposure status and follow-up time in the models. Subgroup analyses will be performed to observe if GPAs may benefit certain patient groups.
gastrointestinal bleeding requiring hospitalisation; composite measure of ischaemic stroke or systemic embolism; intracranial haemorrhage.
Wallis Lau - Chief Investigator - University College London ( UCL )
Jan Chobanov - Corresponding Applicant - University College London ( UCL )
Ian Wong - Collaborator - University College London ( UCL )
Kenneth Man - Collaborator - University College London ( UCL )
Olivia Bryant - Collaborator - University College London ( UCL )
HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation