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

ABSTRACT

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involving 45,100 patients were finally included in the systematic review, with four published RCTs (n = 1965) and 75 unpublished RCTs (n = 43135). The primary analysis showed no significant difference in ICIs compared to the control group (OR 1.18 [95% CI 1.00–1.38], p = 0.05). In subgroup analyses, anti-PD-L1 combined with anti-CTLA-4 increased the risk of hemorrhage (OR 1.95, p = 0.03), and anti-CTLA-4 increased the risk of hemorrhage in the gastrointestinal system (OR 2.23, p = 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 (IC₀₂₅ = 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.

KEYWORDS:

• Immune checkpoint inhibitors
• hemorrhage profile
• systematic review
• FAERs
• Pharmacovigilance

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions statement

Zhichao He, Mengting Chen, and Junyan Wu contributed to the study idea, design, and literature search. All authors performed material preparation, data collection, and analysis. The first draft of the manuscript was written by Zhichao He, Mengting Chen, and Junyan Wu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics statement

Patient consent was waived because the study is based on anonymous data that can be downloaded from a publicly available source.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2024.2327504.

Additional information

Funding

This paper was not funded.