Increased VTE Risk with Baricitinib Save
The RA-BRIDGE and RA-BRANCH studies were presented as a late-breaking abstract at EULAR 2026 (LB0009). This was the pooled results from two large FDA post-marketing commitment safety trials — RA-BRIDGE (global) and RA-BRANCH (US-only) — comparing baricitinib (BARI) at 2 mg and 4 mg daily against TNF inhibitors (etanercept or adalimumab) in RA patients specifically enriched for venous thromboembolic event (VTE) risk factors.
The trials randomized 3,640 patients 1:1:1 to BARI 2 mg, BARI 4 mg, or TNFi, with up to ~6 years on-treatment exposure totaling 11,524 patient-years. Patients were required to have at least one VTE risk factor (prior VTE, age ≥60, BMI ≥30, or age 50–59 with BMI 25–29) to be enrolled. The primary endpoint was time to first adjudicated VTE, with a non-inferiority (NI) margin of 1.8 (upper 95% CI of HR). The trials closed early after 82 of 123 pre-specified VTE events were accrued, as further events would not have altered the results.
The analysis showed that non-inferiority was not met, as the pooled BARI (2 mg & 4 mg) patients had 62 VTE events (2.5%) versus 20 (1.7%) in the TNFi group. The incidence rate was 0.79/100 PY for BARI combined versus 0.51/100 PY for TNFi. The hazard ratio was 1.606 (95% CI 0.969–2.660), with the upper CI exceeding the pre-specified NI margin of 1.8 — thus non-inferiority was not demonstrated (meaning there were more VTE events with BARI than with TNFi. No dose-dependent pattern was observed.
Other Safety Endpoints
While these results confirmed the increased VTE risk seen in the ORAL SURVEILLANCE study, MACE (HR 1.06), malignancy (1.32), all-cause mortality (HR 0.97), arterial thromboembolism (HR 1.27), and opportunistic infections (HR 1.25) showed no statistically significant differences between BARI and TNFI, with confidence intervals crossing 1.0. Serious infections were nominally more frequent with baricitinib (IR 3.17 vs. 2.46/100 PY).
Efficacy
Exploratory analysis of the RA-BRIDGE cohort showed BARI 4 mg to be superior to TNFi at week 52 for ACR70, CDAI remission, and DAS28 remission outcomes. BARI 2 mg was nominally inferior to TNFi.
In this VTE-enriched RA population, baricitinib was not non-inferior to TNF inhibitors for VTE risk, with an approximately 60% higher relative hazard that did not reach statistical significance. Importantly, BARI was non-inferior to TNF inhibitors for MACE, malignancy, arterial thrombosis, and opportunistic infection (but not serious infections).
Like the ORAL SURVEILLANCE study that was also enriched in high risk patients, these data confirm the higher risk of VTE with JAK inhibitors, but question whether JAK inhibitors raise the risk on mortality, MACE and malignancy.
Editor's note: Watch an interview about this study with Dr. Jon Giles
Join The Discussion
These findings suggest that JAK inhibitors may not be the optimal choice as first-line therapy in biologic-naïve patients with rheumatoid arthritis. Instead, their use may be better reserved for selected patients who have demonstrated an inadequate response to conventional synthetic DMARDs or biologic DMARDs, a position that aligns with current treatment recommendations and the more cautious approach adopted following the findings of the Oral Surveillance study.
An interesting observation is that, unlike tofacitinib, baricitinib did not demonstrate a significant increase in cardiovascular events or malignancy risk in this analysis. Although indirect comparisons should be interpreted cautiously, this may represent a potentially important differentiating feature within the JAK inhibitor class.
Looking ahead, the forthcoming long-term safety data for upadacitinib will be of particular interest. It remains possible that its greater selectivity for JAK1 could translate into a more favorable safety profile, although this hypothesis will require confirmation through robust comparative and real-world evidence.
GCP - I agree w/ your wise views - but I would restate: these findings CONFIRM JAK inhibs do rais the risk of VTE. The current package insert for all these drugs state these JAKi should be used after TNFi.
But students who have studied both the oral surveillance study and this study have discerned that the risks are not uniform for all RA, PsA, etc pts. The risk is higher w/ VTE risks, Elderly >65, smokers with the cardiac event in the past. With those filters, the prohibition of JAKi is much smaller than originally thought. The current study was a direct comparison of baricitinib and TNFi and failed to show an increased risk of MACE and malignancy comparing therapies. Looking ahead -- you wont get any better data than these two 4+ year studies with over 8000 patients in a blinded randomized trial of two classes. Yet many will try to re-created Oral Surveillance like data from cohorts, registries, claims data, EHR, etc -- those weaker attempts are not DBRPCTs and thus should never be compared. Thats not just my opinion, its what FDA, EMA and epidemiologists would best rely on.
Without a discussion of the power of this study to detect nominally significant differences in the secondary endpoints (“nominally” because they were apparently not alpha protected), a lack of “significant” differences in MACE, malignancies or other events could simply reflect lack of power.
For example, a “true” malignancy HR of 1.32 might not be dismissed.
SZ - true point but how far do you have to go to prove the possibility of a nominal difference and would that be clinically meaningful. I believe that if the scope, scale and time committment of Oral Surveillance study were to be repeated 3-4 more times, we would likely have conflicting results. But thats just my opinion (sorta guided by the gout CONFIRMS and CARES data). Untill then, we only have these two studies to guide us as far as the safety of JAKi. We already know about the efficacy of JAKi - thanks to you and your colleagues!
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