Hemorrhage profile associated with immune checkpoint inhibitors: a systematic review and a real-world study based on the FAERS database.

Objectives: To investigate the risk of hemorrhage associated with Immune Checkpoint Inhibitors (ICIs) and characterize its clinical features.

Methods: We systematically reviewed randomized clinical trials (RCTs) of hemorrhage related to ICIs and calculated odds ratios (ORs) with 95% confidence intervals (CIs). Pharmacovigilance studies were conducted by collecting ICIs-related hemorrhage cases from the FAERS database and assessing disproportionalities by reporting odds ratios (RORs) and information components (ICs).

Results: A total of 79 RCTs involving 45,100 patients were finally included in the systematic review, with four published RCTs ( = 1965) and 75 unpublished RCTs ( = 43135). The primary analysis showed no significant difference in ICIs compared to the control group (OR 1.18 [95% CI 1.00-1.38],  = 0.05). In subgroup analyses, anti-PD-L1 combined with anti-CTLA-4 increased the risk of hemorrhage (OR 1.95,  = 0.03), and anti-CTLA-4 increased the risk of hemorrhage in the gastrointestinal system (OR 2.23,  = 0.04). 3555 cases of hemorrhage from the FAERS database were included in the disproportionate analysis, and the result suggested that ICIs increased the risk of hemorrhage (IC = 0.23).

Conclusion: Our study suggests that ICIs increase the risk of hemorrhage, and in particular, anti-CTLA-4 significantly increases the risk of hemorrhage in the gastrointestinal system.