Atrial fibrillation (AF) is a common form of abnormal heartbeat. Patients with AF are at a high risk of stroke and also stroke related death. To prevent stroke and death, patients with AF are treated with blood thinners such as direct oral anticoagulants (DOACs). The most common side effect of DOACs is bleeding. When DOACs are given together with certain other drugs, their bleeding risk may further increase. Such drugs include (i) non-steroidal anti-inflammatory drugs, which are commonly used painkillers, (ii) antiarrhythmics, which are drugs used to treat abnormal heart beats, and (iii) the antibiotics macrolides and fluoroquinolones. Our study will use the Clinical Practice Research Datalink to compare the risk of bleeding between patients using DOACs together with the drugs of interest and patients using DOACs or other blood thinners but without the drugs of interest. Therefore, this study will determine whether using together DOACs with the drugs of interest is related to an increase in the risk of bleeding. The results of this study will inform physicians and patients about the safety profile of DOACs.
Direct oral anticoagulants (DOACs) cause less bleeds than vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF). The bleeding risk of DOACs can be modified by concomitant use of other medications due to drug-drug interactions (DDIs). Our population-based cohort study will aim to assess whether concomitant use of certain drugs can increase the bleeding risk of DOACs. The study population will consist of patients diagnosed with NVAF between January 2011 and December 2020.
1. Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of gastrointestinal bleeding (GIB) of DOACs via a pharmacodynamic DDI. Cyclooxygenase-2 (COX-2) selective NSAIDs have a lower GIB risk than non-COX-2-selective NSAIDs in the general population. We will assess whether COX-2 selectivity remains beneficial under concurrent DOAC use by comparing the risk of GIB between concomitant use of DOACs and COX-2 selective NSAIDs and concomitant use of DOACs and non-COX-2 selective NSAIDs.
2. Antiarrhythmics may interact with DOACs due to a pharmacokinetic DDI via CYP3A4 inhibition. We will compare the risk of major bleeding between concomitant use of DOACs and antiarrhythmics and concomitant use of VKAs and antiarrhythmics. We will also compare the risk of major bleeding between concomitant use of DOACs and antiarrhythmics moderately inhibiting CYP3A4 and concomitant use of DOACs and antiarrhythmics weakly inhibiting CYP3A4.
3. Macrolides and fluoroquinolones may interact with DOACs via CYP3A4 inhibition. We will compare the risk of major bleeding risk between concomitant use of DOACs and macrolides or fluoroquinolones and concomitant use of VKAs and macrolides or fluoroquinolones.
For confounding control, we will use propensity score-based inverse probability of treatment weighting. Cox models will estimate hazard ratios with 95% confidence intervals of the outcomes in the weighted cohorts. Secondary analyses will stratify by demographics and other potential effect modifiers. Sensitivity analyses will address the impact of different sources of bias.
For Objective 1: Gastrointestinal bleeding (GIB), non-GIB major bleeding
For Objective 2-5: major bleeding, intracranial hemorrhage, GIB, other major bleeding
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Antonios Douros - Corresponding Applicant - McGill University
Christel Renoux - Collaborator - McGill University
Fabian Meinert - Collaborator - Charite´ Universita¨tsmedizin Berlin
Jenny Dimakos - Collaborator - McGill University
Kristian Filion - Collaborator - McGill University
Ying Cui - Collaborator - Sir Mortimer B Davis Jewish General Hospital
HES Admitted Patient Care;ONS Death Registration Data;Practice Level Index of Multiple Deprivation