Background/Purpose: A potentially increased risk of venous thromboembolism (VTE) was noted in pre-marketing trials of baricitinib, which is a Janus kinase inhibitor (JAK-I). This led the FDA to restrict approval of baricitinib to only the low dose (2mg) for treatment of rheumatoid arthritis (RA). It remains unknown whether the risk of VTE is attributable to JAK-inhibition and extends to tofacitinib, which is increasingly used in RA since its approval in 2012.

Methods: We conducted a new-user cohort study using administrative claims data from the Truven Marketscan (2012-2016) and Medicare (parts A, B, and D, 2012-2015) databases to evaluate the risk of VTE with tofacitinib versus tumor necrosis factor (TNF)-inhibitors in RA patients.  RA patients ≥18 years were identified during a 180-day baseline period of continuous insurance enrollment prior to a cohort entry date marked by treatment initiation with tofacitinib or a TNF inhibitor (adalimumab, certolizumab, etanercept, golimumab, or infliximab) without use of any biologics or tofacitinib any time prior. Patients were followed for the outcome of VTE, defined as a composite of pulmonary embolism or deep vein thrombosis diagnosis in inpatient claims, on as treated basis. A propensity score (PS) based fine-stratification weighting approach was used to account for 60 confounding variables. A weighted Cox proportional hazards model provided hazard ratio (HR) and 95% confidence intervals (CI). HRs were pooled across databases with inverse variance meta-analytic methods.

Results: A total of 34,074 and 17,086 RA patients were identified with a mean age of 50 and 71 years from Truven and Medicare, respectively; of whom 5.6% and 5.8% were tofacitinib initiators. A greater proportion of tofacitinib initiators had used ≥3 non-biologic disease modifying agents and glucocorticoids at baseline, indicating more active or longer duration RA in this group. PS-adjustment provided excellent balance on all 60 covariates. The incidence rates (IRs)/100 person-years were 0.60 and 0.34 in Truven and 1.12 and 0.92 in Medicare for tofacitinib and TNF-Is, respectively (Table 1). PS-adjusted HRs showed no significant differences in the risk of VTE between tofacitinib and TNF-Is in either database. The pooled HR was 1.33 with 95% CI ranging from 0.78 to 2.24.

Conclusion: We observed a numerically higher, but statistically non-significant, risk of VTE for tofacitinib versus TNF-Is in RA patients. The absolute rates of VTE in routine care RA patients were low and comparable to those observed in pre-marketing trials of baricitinib and tofacitinib. Although residual confounding is possible and the precision of estimates was limited due to a small event count, these results are helpful in ruling out the possibility of a large increase in the risk of VTE with tofacitinib and provide preliminary evidence regarding the safety of this JAK inhibitor agent with respect to VTE risk.