Abstract
Background/aim: A prospective evaluation of drug-induced liver injury (DILI) in two tertiary hospitals was conducted through a pharmacovigilance program from laboratory signals at hospital (PPLSH) to determine the principal characteristics of DILI in patients older than 65 years, a growing age group worldwide, which is underrepresented in the literature on DILI. Methods: All DILI in patients older than 65 years detected by PPLSH in two hospitals were followed up for 8 years in the La Paz Hospital and 2 years in the Getafe Hospital. A descriptive analysis was conducted that determined the causality of DILI and suspected drugs, the incidence of DILI morbidities, DILI characteristics, laboratory patterns, evolution and outcomes. Results: 458 DILI cases in 441 patients were identified, 31.0% resulting in hospitalisation and 69.0% developing during hospitalisation. The mean age was 76.61 years old (SD, 7.9), and 54.4% were women. The DILI incidence was 76.33/10,000 admissions (95%CI 60.78–95.13). Polypharmacy (taking >4 drugs) was present in 86.84% of patients, 39.68% of whom took >10 drugs. The hepatocellular phenotype was the most frequent type of DILI (53.29%), a higher proportion (65%) had a mild severity index, and, in 55.2% of the evaluated drugs the RUCAM indicated that the causal relationship was highly probable. The most frequently employed drugs were paracetamol (50-cases), amoxicillin-clavulanate (42-cases) and atorvastatin (37-cases). The incidence rate of in-hospital DILI per 10,000 DDDs was highest for piperacillin-tazobactam (66.96/10,000 DDDs). A higher risk of in-hospital DILI was associated with the therapeutic chemical group-J (antiinfectives for systemic use) (OR, 2.65; 95%CI 1.58–4.46) and group-N (central nervous system drugs) (OR, 2.33; 95%CI 1.26–4.31). The patients taking >4 medications presented higher maximum creatinine level (OR, 2.01; 95%CI 1.28–3.15), and the patients taking >10 medications had a higher use of group J drugs (OR, 2.08; 95%IC 1.31–3.32). Conclusion: The incidence rate of DILI in the patients older than 65 years was higher than expected. DILI in elderly patients is mild, has a good outcome, has a hepatocellular pattern, develops during hospitalisation, and prolongs the hospital stay. Knowing the DILI incidence and explanatory factors will help improve the therapy of the elderly population.
Highlights
Over the last 50 years, drug-induced liver injury (DILI) has been the most frequent reason for withdrawing marketing authorisation for certain drugs (Temple and Himmel, 2002; FDA Drug Induced Liver Injury Rank (DILIrank) Dataset (2020))
The laboratory variables were recorded at three time points and included: Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), gamma-glutamyl transferase (GGT), thromboplastin activity, lactate dehydrogenase, creatinine, albumin, blood pH and eosinophils
The result was a positive or negative number depending on whether the patients spent more or fewer days in hospital than expected per department per year, which allowed us to report the length of the hospitalisation according to whether the DILI occurred during hospitalisation or caused the hospitalisation
Summary
Over the last 50 years, drug-induced liver injury (DILI) has been the most frequent reason for withdrawing marketing authorisation for certain drugs (e.g., iproniazid, sitaxentan, and benoxaprofen) (Temple and Himmel, 2002; FDA Drug Induced Liver Injury Rank (DILIrank) Dataset (2020)). DILI has limited the use of numerous medications (e.g., isoniazid and labetalol) and has generated follow-ups with post-marketing regulatory actions. Several drugs have not been approved in the United States because the European marketing experience revealed the drugs’ hepatotoxicity (Center for Drug Evaluation and Research, 2019). Most of the drugs recalled due to hepatotoxicity have caused death or resulted in the need of transplantation at rates of ≤1 per 10,000 (Larrey, 2000). The typical drug development databases with thousands of patients exposed to a new drug will show no cases. The most overt hepatotoxins can be expected to show cases of severe DILI in the 1,000–3,000 patients typically studied and reported in a new drug application, and drugs that cause such predictable and dose-related injury are generally discovered and rejected during preclinical testing. More difficult to detect is the toxicity that is unpredictable or not dose-related that occurs at doses that are well tolerated by most people but seems to depend on individual susceptibilities that have not as yet been characterised (Council for International Organizations of Medical Sciences, 2019)
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