Reporting of Thromboembolic Events with JAK Inhibitors: Analysis of the FAERS Database 2010–2019

Abstract

Introduction A potentially elevated risk for pulmonary thrombosis with Janus kinase inhibitors (JAKinibs) was identified, as well as an increased risk for portal vein thrombosis, in ruxolitinib patients. Consequently, the objective of this investigation was to repeat a comprehensive analysis of the US FDA's Adverse Event Reporting System (FAERS) database to assess postmarketing reporting rates of thromboembolic events (TEs) in patients treated with JAKinibs. Methods FAERS data (1 January 2010 to 30 September 2019) were searched for reports of all FDA-approved JAKinibs across all indications. For each drug-adverse drug reaction (ADR) pair, the reporting odds ratio (ROR) [two-sided 95% confidence interval (CI)] and empirical Bayesian geometric mean (EBGM) [one-sided 95% lower bound] were calculated to detect drug-ADR pairs with higher-than-expected reporting rates within the FAERS. Significance was declared when both lower 95% CI bounds were > 1. Results Significantly elevated reporting rates of pulmonary thrombosis were evident with tofacitinib ]; EBGM 2.01 [1.53]), as was pulmonary embolism with baricitinib EBGM 7.72 [3.82]) and portal vein thrombosis with ruxolitinib ]; EBGM 4.52 [3.11]). Deep vein thrombosis reports were increased with baricitinib EBGM 9.49 [5.91]), as was thrombosis with ruxolitinib ]; EBGM 1.72 [1.52]). The relationship between the time of treatment initiation and event occurrence indicated that time to events occurred randomly. Conclusions This study found significant reporting rates for TEs in patients treated with JAKinibs across brands and indications, providing additional evidence that JAKinibs may be contraindicated in patients at risk of TEs.

Potential Adverse Events Reported With the Janus Kinase Inhibitors Approved for the Treatment of Rheumatoid Arthritis Using Spontaneous Reports and Online Patient Reviews

“…The potential AEs such as respiratory disorder or pulmonary infarction co-reported from both spontaneous reporting databases might be related to pulmonary embolism ( Di Nisio et al, 2016 ). Our results are in close agreement with a previous study in which TEs were found in patients treated with JAK inhibitors with significant reporting rates ( Setyawan et al, 2021 ). However, it is notable that there was an increased rate of thrombosis, pulmonary embolism, and deep vein thrombosis with upadacitinib used for about a year after approval, since in the previous study, FAERS data reported for approximately 45 days after upadacitinib approval were analyzed, and only pulmonary embolism was found to be a significant signal ( Setyawan et al, 2021 ).…”

“…Our results are in close agreement with a previous study in which TEs were found in patients treated with JAK inhibitors with significant reporting rates ( Setyawan et al, 2021 ). However, it is notable that there was an increased rate of thrombosis, pulmonary embolism, and deep vein thrombosis with upadacitinib used for about a year after approval, since in the previous study, FAERS data reported for approximately 45 days after upadacitinib approval were analyzed, and only pulmonary embolism was found to be a significant signal ( Setyawan et al, 2021 ). However, this study, which analyzed the data over a period of 1.5 years, found more thromboembolism-related potential adverse events with upadacitinib, suggesting that further caution and analysis are needed in the future.…”

Thromboembolic events in Janus kinase inhibitors: A pharmacovigilance study from 2012 to 2021 based on the Food and Drug Administration's Adverse Event Reporting System

“…This study not only confirms but further expands the findings in JAKinib‐associated TEs signal detection field previously reported 7,8,22,23 . First, consistent with the results of Setyawan et al ., 8 ruxolitinib showed elevated reporting of disproportionality with PVT and thrombosis.…”

Association between Carotid Intima-Media Thickness and the Use of Biological or Small Molecule Therapies in Patients with Rheumatoid Arthritis

“…Indeed, it was not confirmed in the multivariate analysis. Further, there may be bias in clinical practice when we initiate this type of therapy due to concerns regarding some jakinibs and cardiovascular events [ 41 , 42 ], and that given this, we may be selecting patients who have fewer CVRFs and are younger for this treatment. A study of 46 patients prospectively assessed the effect of treatment with tofacitinib and methotrexate on CIMT and observed a significant reduction in 12 patients [ 43 ].…”