Examining neurologic and thromboembolic risks when using skeletal muscle relaxants with warfarin

Date of ISAC Approval: 
17/01/2020
Lay Summary: 
Anticoagulant medicines are used to thin the blood of a patient allowing the blood to flow more easily through the veins. This means that the blood will be less likely to form a dangerous blood clot. Warfarin is a commonly prescribed anticoagulant medicine. Minimizing the likelihood of patient harm associated with anticoagulant therapy is an international patient safety priority. People who receive anticoagulant therapy often receive many other prescribed medicines to treat other conditions. A drug-drug interaction is said to have occurred when a drug's effect on the body is changed when it is taken together with a second drug. These interactions can decrease or increase the effect of one or both drugs with potentially harmful consequences. Drug-drug interactions involving anticoagulant therapy are a major, preventable cause of harm. To improve knowledge on anticoagulant safety, the United States (US) Office of Disease Prevention and Health Promotion issued a call to generate more evidence on anticoagulant drug interactions. Potential drug-drug interactions between warfarin and skeletal muscle relaxant drugs have not been investigated in detail to date. We plan to conduct a series of studies to generate evidence on these potential drug-drug interactions. Specifically, we will examine the impact of taking warfarin and individual skeletal muscle relaxant drugs together on rates of venous thromboembolism (a blood clot in the veins) and stroke (both consequences of under-anticoagulation). The findings will generate real-world evidence on these potential interactions that can be used to improve patient safety.
Technical Summary: 
Drug interactions with anticoagulant therapy are a major, preventable cause of harm. To improve knowledge on anticoagulant safety, we plan to conduct bidirectional self-controlled case series studies, among concomitant users of warfarin and a skeletal muscle relaxant and, as pre-specified negative control comparators, among concomitant users of an inhaled corticosteroid and a skeletal muscle relaxant. Each study will examine a composite outcome of venous thromboembolism / ischemic stroke. Data will be obtained from both CPRD GOLD and CPRD Aurum with linkage to Hospital Episode Statistics and ONS mortality records. The study populations will consist of any individual initiating warfarin (the object drug of interest, the affected agent in a drug interaction pair) and inhaled corticosteroids (the prespecified negative control object drug). Among object drug users, we will define periods of exposure and non-exposure to skeletal muscle relaxants (precipitant drugs, affected agents in a drug interaction pair). We will limit each cohort to individuals experiencing the outcome of interest during their observation period. We will dichotomise each day of the observation period as a risk or non-risk day, based on the presence or absence of exposure to a skeletal muscle relaxant. We will use conditional Poisson regression models to estimate incidence rate ratios and 95% confidence intervals and conduct sensitivity analyses to examine the robustness of our findings and assess potential violations of the self-controlled case series design's underlying assumptions.
Health Outcomes to be Measured: 
- venous thromboembolism - stroke
Collaborators: 

Professor Darren Ashcroft - Chief Investigator - University of Manchester
Dr Matthew Carr - Corresponding Applicant - University of Manchester

Linkages: 
HES Admitted;ONS;Patient IMD;Practice IMD (Standard)