Drug-related hepatotoxicity risk in elderly patients with atrial fibrillation: insights from the nationwide Italian START registry

Atrial fibrillation (AF) patients frequently require polypharmacy, increasing the risk of drug-drug interactions and hepatotoxicity. We analyzed the use of drugs potentially associated with liver injury in anticoagulated AF patients. We applied the LiverTox classification to AF patients from the START registry, categorizing them based on the use of LiverTox A drugs (high risk of liver toxicity). Logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (95%CIs) for factors associated with the use of these drugs and their impact on liver function tests (LFTs). Median age was 81 years with 46% of women. 8,215 AF patients were taking 40,355 distinct molecules at enrolment, with a median of 5 drugs per patient (IQR 3-7). Overall, 3,416 (41.6%) received at least one LiverTox A drug. These patients were more often male, overweight, smokers, hypertensive, diabetic, with cardiovascular or cerebrovascular history, and on polypharmacy. The most commonly prescribed LiverTox A drugs were statins, amiodarone, and allopurinol, both in the overall population and within subgroups stratified by major cardiovascular conditions. In multivariable logistic regression, among LiverTox A drugs, amiodarone (OR 1.61, 95%CI 1.29-2.00) and methimazole (OR 1.83, 95%CI 1.04-3.03) were associated with elevated LFTs. Among frequently prescribed drugs, warfarin, furosemide, ramipril, lansoprazole, and canrenone were also associated with increased LFTs. Direct oral anticoagulants, compared to warfarin, showed a lower risk of increased LFTs after adjustment for confounders. In conclusion, many AF patients are treated with drugs at high risk of hepatotoxicity.