Subclinical hypothyroidism is a condition characterized by abnormal thyroid hormone levels. It is known to increase the chances of having heart attacks and dying. It is also possible that it increases the chances of having heart-related rhythm disorders, called arrhythmias. Levothyroxine replacement therapy is used to treat subclinical hypothyroidism, but its use is not widely recommended for all patients with this condition. Studies suggest a potential relationship between levothyroxine use and the risk of arrhythmia, but this potential side effect has not been thoroughly investigated. The proposed study aims to evaluate this relationship using the electronic health records of patients with subclinical hypothyroidism. We will compare the occurrence of clinically-relevant arrhythmias among patients who received levothyroxine and those who did not. We will investigate the risk of clinically-relevant arrhythmias overall and different types of arrhythmias. The findings of this study will contribute to our understanding of the relationship between levothyroxine and arrhythmias among patients with subclinical hypothyroidism.
Mild subclinical hypothyroidism (SCH) is defined by a serum thyroid-stimulating hormone (TSH) above reference ranges with normal free thyroxine (FT4) levels. SCH has been associated with an increased risk of cardiovascular events and mortality. In this context, the association between SCH and cardiac arrhythmias has been investigated, but the risk remains unclear. Levothyroxine is a drug considered for the treatment of SCH; however, unlike for patients with overt hypothyroidism, its use is not widely recommended for all patients with mild SCH. Epidemiological studies have suggested that there may be a causal relationship between levothyroxine use and the risk of arrhythmias that is mediated by TSH and FT4 levels, but this relationship remains poorly understood. We will conduct a retrospective cohort study to evaluate the association between levothyroxine use among people with mild SCH and the risk of clinically-relevant arrhythmias (atrial fibrillation, atrial flutter, ventricular tachycardia, and sudden cardiac death). This study will include all patients with mild SCH using the Clinical Practice Research Datalink Aurum, which will be linked to Hospital Episode Statistics Admitted Patient Care data and Office for National Statistics vital statistics. Using a prevalent new user design, we will match each patient who receives levothyroxine to someone who did not, on age, sex, duration of SCH history, history of cardiovascular disease, calendar time, and time-conditional propensity scores. The primary outcome will be the first occurrence of any clinically-relevant arrhythmia. Secondary outcomes will be atrial fibrillation, atrial flutter, ventricular tachycardias, and sudden cardiac death. We will use Cox proportional analysis to estimate hazard ratios for arrhythmia between patients who received levothyroxine versus those who did not. In secondary analyses, we will examine the mediating role of TSH and FT4 levels and determine if the relationship between levothyroxine and arrhythmias varies with dose, age, sex, and cardiovascular disease history.
The primary outcome will be the first occurrence of any clinically-relevant arrhythmia, a composite endpoint that includes atrial fibrillation, atrial flutter, ventricular tachycardia, and sudden cardiac death. Secondary outcomes will be the individual components of this composite endpoint.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Kristian Filion - Corresponding Applicant - McGill University
Antonios Douros - Collaborator - McGill University
Bianca Bianchini - Collaborator - Federal University of Rio Grande do Sul - UFRGS
Christopher Filliter - Collaborator - Sir Mortimer B Davis Jewish General Hospital
James Brophy - Collaborator - McGill University
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
pauline reynier - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Tatiane da Silva Dal Pizzol - Collaborator - Not from an Organisation
Bianca Bianchini - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data