Tofacitinib Does Not Increase Risk of Venous Thromboembolism in Patients With RA


Recently, a link between venous thromboembolism (VTE) and Janus Kinase (JAK) inhibitors has emerged, causing the FDA to recommend a black box label for tofacitinib in 2019. New research, however, suggests that tofacitinib had similarly infrequent cases of VTE (<1 per 100) when compared with tumor necrosis factor inhibitors (TNFIs).

While tofacitinib has been linked to an increased risk in venous thromboembolism (VTE) for patients with rheumatoid arthritis (RA), new research suggests that tofacitinib had similarly infrequent cases of VTE (<1 per 100) when compared with tumor necrosis factor inhibitors (TNFIs), according to a study published in Oxford.1

Tofacitinib is a Janus Kinase (JAK) inhibitor that is commonly used to manage the symptoms of RA, especially in patients who have not found symptom resolution through conventional synthetic disease modifying anti-rheumatic drugs (DMARDs). Recently, a link between VTE and JAK inhibitors has emerged, causing the FDA to recommend a black box label in 2019 cautioning prescribing tofacitinib for patients with a higher risk of VTE.

This cohort study examined that connection using claims data from the IBM “MarketScan” (2012-2018), Medicare parts A, B, and D (2012-2017), and “Optum” Clinformatics (2012-2019) databases, which provided information on demographic characteristics, medical diagnoses and procedures, and prescription records. All eligible patients were aged ≥18 years and had filled a prescription for either a tumor necrosis factor (TNF) inhibitor or tofacitinib. They were studied until discontinuation of the medication, administrative censoring, treatment switch, or disenrollment in insurance. The prescription fill date was used as the index date. All patients needed to have 2 rheumatoid arthritis (RA) diagnoses codes 7 days apart during the baseline period. Patients were excluded if they had cancer or a history of VTE during baseline, if they had used other biologics or targeted synthetic DMARDs, or were currently living in a nursing home.

The study builds on the research of previous ones by estimating incidence rates in population-based cohorts and used a comparator group of patients with RA who are being treated with other medications. Investigators were able to more precisely estimate treatment effect due to additional data accrued from recent years.

“While we wait for full results of the ongoing trial regarding the risk of VTE with the lower [dose] of tofacitinib, comparative safety studies using routinely collected healthcare data may be able to provide additional clarity,” investigators explained.

The primary outcome was to analyze incidences of VTE, which included pulmonary embolism (PE) and deep vein thrombosis (DVT). PE and DVT were studied separately as a secondary endpoint. Age, gender, location, race, RA-related medication usage, and comorbidity were among the 60 variables investigators assessed at baseline. Further, VTE risk factors, including hormonal agents, varicose veins, surgeries, and pregnancies were also identified. Propensity score (PS) was calculated to exclude noncomparable patients. The TNF inhibitor cohort and the tofacitinib cohort were weighted to balance the groups out.

A total of 42,201 patients in the MarketScan group, 25,078 in the Medicare group, and 20,374 in the Optum group participated in the study. Of the 3, 7.1%, 7.1%, and 9.7% were taking tofacitinib, respectively. The mean ages were 50, 71, and 52 years in MarketScan, Medicare, and Optum, respectively.

Incidence rates of VTE were <0.5 per 100 person-years for commercial insurance enrollees and 08.-1.2 per 100 person-years among Medicare patients, however investigators hypothesize higher rates may be due to higher average age and comorbidities in the Medicare cohort. While more patients receiving tofacitinib had used ≥3 non-biologic DMARDs and glucocorticoids, which may be an indication of more severe RA, the risk factors for VTE were similar between both groups. Further, there were no significant differences for VTE risks in the follow-up time between the 2 groups in both PS-weighted Kaplan-Meier (KM) plots and PS-weighted hazard ratios (HRs) with an adjusted HR (95% CI) of 1.13 (0.77-1.65) in the primary analysis. Similar results occurred for the secondary outcomes analyzing DVT and PE.

To minimize a potential limitation of the study, investigators used a comparator group (TNF inhibitors) in addition to adjusting for a variety of variables. Additionally, newer JAK inhibitors were excluded from the analysis.

“Occurrence of VTE in a total of 87,653 RA patients initiating tofacitinib or a TNF inhibitor was infrequent. We observed no evidence for an increased risk of VTE on absolute or relative scale for lower tofacitinib doses versus TNF inhibitors in patients with RA from routine care,” investigators concluded. “While awaiting data from the comparative safety trial of tofacitinib, our results provide reassurance regarding the risk of VTE in patients with RA treated with lower doses of tofacitinib.”


Desai RJ, Pawar A, Khosrow-Khavar F, Weinblatt ME, Kim SC. Risk of venous thromboembolism associated with tofacitinib in patients with rheumatoid arthritis: a population-based cohort study [published online ahead of print, 2021 Mar 22]. Rheumatology (Oxford). 2021;keab294. doi:10.1093/rheumatology/keab294

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