Drug safety · 2026
Signal Detection of Adverse Events Associated with PCSK9 Inhibitors: A Nationwide Sequence Symmetry and Combined Worldwide Disproportionality Analysis.
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Viguier Thibault, Bezin Julien, Hlavaty Alex, Khouri Charles, Pariente Antoine
Аннотация
BACKGROUND AND AIM: Despite the increasing use of proprotein convertase subtilisin/kexin type 9-inhibitors (PCSK9i), their safety assessment from large real-world databases remains limited. We aimed to perform a large-scale safety signals detection study regarding PCSK9i.
METHODS: A sequence symmetry analysis (SSA) was conducted using the French nationwide health system databases (SNDS); PCSK9i initiators (2018-2023 time-period) were matched to ezetimibe ones, to control for temporal trends and potential indication bias. Outcomes of interest included all designated medical events (DMEs) and all drug classes considered by Anatomical Therapeutic Chemical (ATC) classification levels III and IV. In SSAs, potential safety signals for PCSK9i were defined as the combination of both a crude sequence ratio (SRc) and an ezetimibe-adjusted one (SRa) with a 95% confidence interval (CI) lower limit exceeding 1. For the outcomes corresponding to DMEs, disproportionality analyses were performed in the World Health Organization (WHO) pharmacovigilance database VigiBase® to complete the assessment.
RESULTS: In total, sequence symmetries could be studied for 36,163 PCSK9i initiators and 34,269 ezetimibe ones. Over the 700 outcomes analyzed, two potential signals were identified via SSA, that related to ATC-III drug initiations for inhaled glucocorticoids (SRc: 1.25 [1.16-1.38]; SRa: 1.19 [1.06-1.35]) and colony stimulating factors (SRc: 4.22 [2.81-6.71]; SRa: 2.25 [1.37-4.17]); they were duplicated when considering the corresponding ATC-IV classes. No related signal was detected in VigiBase®.
CONCLUSIONS: This study, combining analyses from large medico-administrative and spontaneous reports databases, identified only two potential signals relating to PCSK9i. Both appeared to be linked to residual indication bias or confounding factors.
METHODS: A sequence symmetry analysis (SSA) was conducted using the French nationwide health system databases (SNDS); PCSK9i initiators (2018-2023 time-period) were matched to ezetimibe ones, to control for temporal trends and potential indication bias. Outcomes of interest included all designated medical events (DMEs) and all drug classes considered by Anatomical Therapeutic Chemical (ATC) classification levels III and IV. In SSAs, potential safety signals for PCSK9i were defined as the combination of both a crude sequence ratio (SRc) and an ezetimibe-adjusted one (SRa) with a 95% confidence interval (CI) lower limit exceeding 1. For the outcomes corresponding to DMEs, disproportionality analyses were performed in the World Health Organization (WHO) pharmacovigilance database VigiBase® to complete the assessment.
RESULTS: In total, sequence symmetries could be studied for 36,163 PCSK9i initiators and 34,269 ezetimibe ones. Over the 700 outcomes analyzed, two potential signals were identified via SSA, that related to ATC-III drug initiations for inhaled glucocorticoids (SRc: 1.25 [1.16-1.38]; SRa: 1.19 [1.06-1.35]) and colony stimulating factors (SRc: 4.22 [2.81-6.71]; SRa: 2.25 [1.37-4.17]); they were duplicated when considering the corresponding ATC-IV classes. No related signal was detected in VigiBase®.
CONCLUSIONS: This study, combining analyses from large medico-administrative and spontaneous reports databases, identified only two potential signals relating to PCSK9i. Both appeared to be linked to residual indication bias or confounding factors.