(B-250) Safety Assessment on the Risk of Liver Dysfunction by ACE Inhibitors utilizing the MID-NET® in Japan

Background: Warnings about liver dysfunction in Japanese package inserts vary among angiotensin-converting enzyme (ACE) inhibitors, and studies on the risk assessment of liver dysfunction with ACE inhibitors have been limited.

Objectives: We evaluated the risk of liver dysfunction in patients prescribed ACE inhibitors available in Japan utilizing the MID-NET®.

Methods: We identified patients who were newly prescribed ACE inhibitors between January 1, 2009 and December 31, 2019, and excluded patients with liver dysfunction before the first prescription of ACE inhibitors. The risk of liver dysfunction was compared on hazard ratio (HR) between the control group (patients prescribed enalapril maleate that carries a liver dysfunction-related warning under “Clinically Significant Adverse Reactions (CSARs)” in Japanese package insert) and each exposure group (patients for whom each of the other ACE inhibitors were prescribed). The HR was estimated by using a pairwise Cox proportional hazards model with adjustment by inverse probability weighting based on the high-dimensional propensity score. In addition, we conducted the disproportionality analysis based on Individual Case Safety Reports (ISCRs) and the causal assessment for ISCRs regarding the ACE inhibitors that do not carry a liver dysfunction-related warning under “CSARs” in the package insert.

Results: A total of 29,817 patients were identified for analysis in the cohort. Compared with the control group, the HRs (95% confidence interval) were 1.37(0.79 – 2.38) for captopril, 0.71(0.33 – 1.54) for alacepril, 0.72(0.55 – 0.93) for imidapril hydrochloride, 1.08(0.86 - 1.34) for perindopril erbumine and 0.69(0.52 - 0.91) for lisinopril hydrate. Assessment based on ISCRs indicates no signals of liver dysfunction in the ACE inhibitors that do not carry a liver dysfunction-related warning.

Conclusions: The risk of liver dysfunction by ACE inhibitors is unlikely to be a class-effect. Although continuous safety monitoring is necessary for promoting proper use of ACE inhibitors, the results indicate that no additional safety measures are currently required for ACE inhibitors that do not carry a liver dysfunction-related warning in Japan.