Levothyroxine dose and risk of atrial fibrillation: a nested case-control study

Background — Contemporary data on the effect of levothyroxine dose on the occurrence of atrial fibrillation (AF) are lacking, particularly in the older population. Our objective was to determine the effect of cumulative levothyroxine exposure on risk of AF and ischemic stroke in older adults.

Methods — We conducted a population-based observational study using healthcare databases from Ontario, Canada. We identified adults aged ≥66 years without a history of AF who filled at least one levothyroxine prescription between April 1st 2007 and March 31st 2016. Cases were defined as cohort members who had incident AF (emergency room visit or hospitalization) between the date of first levothyroxine prescription and December 31st, 2017. Index date was date of AF. Cases were matched with up to five controls without AF on the same index date. Secondary outcome was ischemic stroke. Cumulative levothyroxine exposure was estimated based on total milligrams (mg) of levothyroxine dispensed in the year prior to index date. Using nested case-control approach, we compared outcomes between older adults who received high (≥0.125 mg/day), medium (0.075-0.125 mg/day), or low (0-0.075 mg/day) cumulative levothyroxine dose. We compared outcomes between current, recent past, and remote past levothyroxine use.

Results — Of 189,672 older adults treated with levothyroxine (mean age 82 years; 72% women), 30,560 (16.1%) had an episode of AF. Compared to low levothyroxine exposure, high and medium exposure was associated with significantly increased risk of AF after adjustment for covariates (adjusted odds ratio, aOR 1.29, 95% confidence interval, CI 1.23-1.35; aOR 1.08, 95% CI 1.04-1.11; respectively). No association was observed between levothyroxine exposure and ischemic stroke. Compared with current levothyroxine use, older adults with remote levothyroxine use had lower risks of AF (aOR 0.56, 95% CI 0.52-0.59) and ischemic stroke (aOR 0.61, 95% CI 0.56-0.67).

Conclusions — Among older persons treated with levothyroxine, levothyroxine at doses above 0.075 mg/day is associated with an increased risk of AF compared to lower exposure.