Uncovering the Risks: Bleeding and Thrombotic Complications of JAK Inhibitors in Hematological Conditions: A Comprehensive Systematic Review and Meta-Analysis

Introduction:

Janus kinase (JAK) inhibitors have emerged as a significant advancement in treating various autoimmune and inflammatory conditions, including several hematological disorders such as myelofibrosis and polycythemia vera. However, their safety profile, particularly concerning bleeding and thrombotic risks, remains a critical concern. To address this, we are conducting a systematic review and meta-analysis to comprehensively evaluate these potential risks of JAK inhibitors. This investigation aims to provide a clearer understanding and guide the safer therapeutic use of these medications.

Methods

As per the preferred reporting items for systemic reviews and meta-analysis (PRISMA) guidelines, a comprehensive literature search was performed on 3 databases (PubMed, Cochrane Register of Controlled Trials, and Clinicaltrials.gov) using MeSH terms and keywords for ‘Janus Kinase Inhibitors’ AND ‘Intervention Studies’ AND ‘Hemorrhage OR Thrombosis OR Clot ‘from the date of inception to March 31, 2024. Our literature research produced 1716 articles. After excluding irrelevant and review articles during primary and secondary screening, fifteen studies reporting bleeding or thrombotic complications in JAK inhibitor trials were included. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with a 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2).

Results

A total of 1906 patients with a median age of 66 (26-90.5) years from 15 studies (2014-2022) reporting bleeding or thrombotic complications in JAK inhibitor trials were included. 56.9% (539/948) were male and 43.1% (409/948) were female. The median follow-up time was 24 (1-60) months. The majority of trials were phase 2 (27%, n=4) or phase 3 (27%, n=4). Most studies used Ruxolitinib (40%, n=6) followed by Pacritinib (13%, n=2). Myelofibrosis was the most common underlying condition in patients (70.8%, n=1350), followed by polycythemia vera (16.2%, n=309) and essential thrombocytopenia (3.7%, n=70). The pooled rate of bleeding events was 12.9% (95% CI 0.06-0.22, I2=96%, p<0.01, n=1657). The pooled rates of grade 1-2 and grade 3-4 bleeding events were 10.5% (95% CI 0.02-0.24, I2=89%, p<0.01, n=298) and 3.9% (95% CI 0.2-0.06, I2=49%, p=0.12, n=653). Epistaxis and upper GI bleeding were the most common bleeding events. The pooled rate of mortality due to bleeding events was 1.3% (95% CI 0.00-0.04, I2=60%, p=0.11, n=474). The median platelet count in this cohort was 400 (250-530) microliters. The pooled rate of thrombotic events was 5.7% (95% CI 0.03-0.09, I2=78%, p<0.01, n=1128). Venous thromboembolism was the most common thrombotic event. The pooled mortality rate due to thrombotic events was 0.9% (95% CI 0.00-0.02, I2=0%, p=0.77, n=412).

Conclusion:

Our systematic review and meta-analysis revealed notable findings regarding the safety profile of JAK inhibitors. The pooled rate of bleeding events was 12.9%, with epistaxis and upper GI bleeding being the most common types. Thrombotic events were observed at a rate of 5.7%, predominantly venous thromboembolism. While the mortality rates due to bleeding and thrombotic events were relatively low (1.3% and 0.9%, respectively), these risks highlight the need for careful monitoring and risk assessment in patients undergoing JAK inhibitor therapy. Further studies and clinical trials are essential to gain more comprehensive information and refine the safety guidelines for using JAK inhibitors.