Real-world analysis identifies drugs linked to higher risk of liver damage

Real-world data can be used to identify the most potentially hepatotoxic drugs based on incidence rates of severe acute liver injury in patients without pre-existing liver or biliary disease, according to a series of cohort studies.

Of 194 suspected hepatotoxic drugs, 17 dispensed in VA outpatient settings had serious acute liver injury rates of 5.0 or more events per 10,000 person-years, of which 11 were not included in the highest hepatotoxicity category by case reports, reported Vincent Lo Re. III, MD, MSCE, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues at JAMA Internal Medicine.

“We identified several drugs that pose significantly higher or lower risk than previously suggested by case-based analyses,” Lo Re said. Page Med today.

“We were not surprised by our findings,” he added. “Case reports place responsibility on the practitioner to publish the clinical findings of the case, which undoubtedly leads to under-reporting. Case reports can also vary in terms of data quality and do not rely on standard definitions of acute liver injury.”

Seven of 17 drugs—stavudine, erlotinib (Tarceva), lenalidomide (Revlimid) or thalidomide, chlorpromazine, metronidazole, prochlorperazine (Compazine), and isoniazid—were found to be the most hepatotoxic, with hospitalization rates of 10.0 or higher for severe acute liver injury per 10,000 person-years. The highest rate was observed with stavudine, a nucleoside HIV reverse transcriptase inhibitor, at 86.4 events per 10,000 person-years.

The other 10 drugs—moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin—had rates between 5.0 and 9.9 events per 10,000 person-years.

Antimicrobial medications, particularly antifungal medications and older antiretroviral medications, accounted for 64% of people with the highest rates of severe acute liver injury.

After adjustment for diabetes, obesity, hyperlipidemia, and polypharmacy, rates of severe acute liver injury remained similar.

In addition to the 11 of 17 drugs with the highest incidence of hepatotoxicity that were not included in LiverTox, a database of case reports of drug-induced liver injury, seven study drugs had a higher incidence lowest severe acute liver injury – less than 1.0 events. per 10,000 person-years — were included in the highest risk category in LiverTox, noted Grace Zhang, MD, and Jessica Rubin, MD, MPH, of the University of California, San Francisco, in an editorial d ‘accompaniement.

“What explains this difference in results between the present study and LiverTox? ” they asked. “Despite its compelling value, LiverTox’s ability to capture the true incidence of drug-related hepatotoxic effects is limited due to its reliance on published case reports.”

Lo Re and colleagues also pointed out that “categorization of hepatotoxic drugs using case reports does not take into account the number of individuals exposed and may not accurately reflect the incidence of serious ALI (acute liver injury).”

Another notable finding of the study is that statins, often considered linked to adverse liver effects, were in the lowest risk category for serious acute liver injury.

“Their hepatic adverse effects have long been feared by practitioners and patients,” write Zhang and Rubin. “LiverTox has classified almost all statins as a Category A (high-risk) drug,” but the database “does not account for the denominator – the nearly 100 million patients in the United States… who are prescribed statins every year.

The study has important implications for clinical care, Lo Re and colleagues emphasized, noting that there is currently no systematic approach to classifying drug-induced hepatotoxicity.

“Patients who begin treatment with a high rate of serious acute liver injury may require closer monitoring of liver-related laboratory tests to detect the development of liver dysfunction earlier, which could improve prognosis.” , explained Lo Re. “Additionally, in electronic health record systems, automated messages could alert clinicians ordering a drug with a high rate of serious acute liver injury of the potential risk of this outcome and prompt them to consider a laboratory monitoring.”

For this study, researchers evaluated 194 drugs used in the VA health system that had at least four published case reports of hepatotoxicity. They retrospectively analyzed VA electronic health record data from nearly 8 million people without pre-existing liver or biliary disease who began outpatient treatment with a drug suspected of causing hepatotoxicity between October 2000 and September 2021; 55% were taking multiple medications. Most (92.5%) were male and the mean age of the medication cohorts was 64.4 years.

Lo Re and his team identified 1,739 hospitalizations for severe acute liver injury, defined as either an alanine aminotransferase (ALA) level greater than 120 U/L plus a total bilirubin level greater than 2.0 mg/dL, or by an international normalized ratio of 1.5 or greater plus a total bilirubin level greater than 2.0 mg/dL, recorded within the first 2 days after admission. Of these patients, 27.2% died within 180 days of hospitalization and five patients underwent liver transplantation.