Risk of Venous Thromboembolism Associated With Tofacitinib in Patients With Rheumatoid Arthritis

A Population-Based Cohort Study

Rishi J. Desai; Ajinkya Pawar; Farzin Khosrow-Khavar; Michael E. Weinblatt; Seoyoung C. Kim


Rheumatology. 2022;61(1):121-130. 

In This Article

Abstract and Introduction


Objective: To evaluate the risk of venous thromboembolism (VTE) with tofacitinib compared with TNFis in patients with RA.

Methods: RA patients initiating tofacitinib or a TNFi without use of any biologic or tofacitinib any time prior were identified from IBM 'MarketScan' (2012–18), Medicare (parts A, B and D, 2012–17) or 'Optum' Clinformatics (2012–19) and followed until treatment discontinuation, treatment switch, insurance disenrollment or administrative censoring. The primary outcome, VTE, was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. A Cox proportional hazards model provided hazard ratio (HR) and 95% CIs after accounting for confounding through propensity score fine-stratification weighting. HRs were pooled across databases with inverse variance meta-analytic method.

Results: A total of 42 201, 25 078 and 20 374 RA patients were identified from MarketScan, Medicare and Optum, respectively, of whom 7.1, 7.1 and 9.7% were tofacitinib initiators. The crude incidence rates per 100 person-years (95% CI) were 0.42 (0.20–0.77) and 0.35 (0.29–0.42) in MarketScan, 1.18 (0.68–1.92) and 0.83 (0.71–0.97) in Medicare, and 0.19 (0.04–0.57) and 0.34 (0.26–0.44) in Optum for tofacitinib and TNFis, respectively. Propensity score-weighted HRs showed no significant differences in the risk of VTE between tofacitinib and TNFis in any database with a pooled HR (95% CI) of 1.13 (0.77–1.65).

Conclusion: Overall, VTE occurred infrequently (<1 per 100) in a total of 87 653 RA patients initiating tofacitinib or a TNFi. We observed no evidence for an increased risk of VTE for tofacitinib vs TNFis in RA patients.


Tofacitinib, a Janus Kinase (JAK) inhibitor approved in 2012, is an important oral treatment option that is increasingly used to manage RA among patients with high disease activity despite treatment with conventional synthetic DMARDs.[1,2] In recent years, an important safety concern related to incidence of venous thromboembolism (VTE) after treatment with JAK inhibitors has emerged.[3] In an ongoing post-marketing safety trial of patients >50 years of age with active RA and at least one additional cardiovascular risk factor, a greater risk of thrombotic events was observed in patients treated with 10 mg twice daily (BID) dose of tofacitinib compared with those receiving 5 mg dose or a TNF inhibitor (TNFi). Based on these data, the Food and Drug Administration (FDA) recommended a black box label in 2019 to warn prescribers of this risk with tofacitinib and the European Medicines Agency recommended caution in use of tofacitinib in patients who may be at a higher risk of VTE.[4,5]

While we wait for full results of the ongoing trial regarding the risk of VTE with the lower of tofacitinib doses, comparative safety studies using routinely collected healthcare data may be able to provide additional clarity. We previously conducted such an evaluation comparing tofacitinib vs TNFis initiation using data from two large insurance programmes in the USA between 2012 and 2016 and noted a numerical, but not statistically significant, increase in risk of VTE among tofacitinib initiators with a hazard ratio (HR) of 1.33 (95% CI 0.78, 2.24).[6] With accumulation of additional data from more recent years in these two data sources and inclusion of a third data source, we conducted an updated analysis with the primary goal of providing evidence regarding the risk of VTE associated with tofacitinib treatment in RA patients with increased precision.