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

Sep 28, 2026

Atrial fibrillation patients often use multiple drugs, which raises the likelihood of drug-drug interactions and liver injury. This study analyzed drug use in anticoagulated AF patients from the nationwide Italian START registry and applied LiverTox classifications to identify medications potentially linked to hepatic damage. Among 8,215 patients (median age 81), 41.6% received at least one high-risk LiverTox A drug. Logistic regression assessed odds ratios for elevated liver function tests and identified amiodarone, methimazole, and several commonly used agents as associated with increased LFTs.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Methods

START registry

Study rationale and background

Liver function test elevation in atrial fibrillation

Drug-induced liver injury and polypharmacy

LiverTox system

Drug likelihood classification

Objectives

Distribution of high-risk drugs and clinical impact

Results and analysis

LiverTox A drug use and factors associated with elevated LFTs

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Drug-related hepatotoxicity risk in elderly patients with atrial fibrillation: insights from the nationwide Italian START registry Gianluca Gazzaniga1,51, Danilo Menichelli1,51, Daniela Poli2, Gualtiero Palareti3, Emilia Antonucci3, Arianna Pani4, Pasquale Pignatelli5, Daniele Pastori5,6􀀍 & LiverTox inatrial fibrillation 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 toAF 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. Directoral 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. Keywords Atrial fibrillation, LiverTox, Drugs, Toxicity, Polypharmacy Elevation of liver function tests (LFTs) is a common finding in patients with atrial fibrillation (AF)1. This elevation may arise from various causes, including metabolic-associated steatotic liver disease, which is highly prevalent in the AF population due to the burden of cardio-metabolic risk factors, such as obesity and diabetes, that are strongly associated to liver disease2. Furthermore, a significant proportion of AF patients may have undiagnosed liver fibrosis, which can be identified using non-invasive tools like the FIB-4 index3–5. Moreover, AF management often requires polypharmacy, exposing patients to potential drug-drug interactions and drug-induced liver injury (DILI)6. DILI is a relatively rare yet important cause of liver disease, requiring the consideration of all types of medications, even when another cause appears likely. With an estimated incidence of approximately 19 cases per 100,000 individuals7 DILI can be severe, although rarely fatal, and it usually improves upon discontinuation of the offending drug8. The growing number of medications used by patients complicates the detection and diagnosis of DILI, as its presentation can resemble a variety of liver disorders, ranging from acute hepatitis to chronic liver injury, and can occur even months after exposure to certain agents9. 1Department of General Surgery and Surgical Specialty Paride Stefanini, Sapienza University of Rome, Rome, Italy. 2Department of Critical Care Medicine, Thrombosis Centre, Azienda Ospedaliera Universitaria Careggi, Firenze, Italy. 3Arianna Anticoagulazione Foundation, Bologna, Italy. 4Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy. 5Department of Medical and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy. 6IRCCS Neuromed, Località Camere

FAQs

Why is hepatotoxicity a concern in atrial fibrillation patients?

Atrial fibrillation management often involves polypharmacy, increasing drug-drug interactions and the risk of drug-induced liver injury, which may present with elevated liver function tests.

What is the LiverTox approach used in the study?

LiverTox is an open-access resource that classifies medications using a five-point likelihood score for causing DILI based on literature case reports over the previous 50 years.

Which medications were associated with elevated liver function tests?

Among LiverTox A drugs, amiodarone and methimazole were associated with higher LFTs. Among frequently prescribed medications, warfarin, furosemide, ramipril, lansoprazole, and canrenone were also linked to increased LFTs.

Sep 28, 2026

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