OBJECTIVES: The ORAL Surveillance randomized safety trial (NCT02092467) showed an association between tofacitinib, a Janus kinase inhibitor (JAKi) and an increased risk of serious cardiovascular events. We wanted to emulate the outcomes using secondary data, focusing on the risk of major cardiovascular events (MACE), cancer and all-cause mortality in patients using JAKis versus tumor necrosis factor inhibitors (TNFis) in immune-mediated conditions.

METHODS: Patients initiating JAKis or TNFis for an immune-mediated condition between 2018–2022 were identified from Oracle Life Sciences’ US Claims database. Propensity-Score Matching was performed to match JAKis and tofacitinib users to TNFis users. All-cause mortality, cardiovascular mortality, MACE, and cancers were investigated during follow-up. Kaplan-Meier (KM) curves were created, incidence of events was compared among treatment groups using log-rank test. Hazard ratios (HRs) were estimated via multivariable Cox regression models.

RESULTS: We identified 23,255 patients initiating JAKis (12,707 received tofacitinib), and 138,826 TNFis. Mean(SD) age was 49.8(15.9), 51.1(15.5) and 46.1(14.4) respectively. 20,576 JAKis and 12,458 tofacitinib users were matched 1:1 to TNFis patients. KM curves showed significantly higher probabilities of all-cause and cardiovascular mortality, and newly diagnosed cancer for JAKis and tofacitinib compared to TNFis (pLogRank<0.05). JAKis were associated with a significantly higher risk of all-cause mortality (HR=1.388[1.199;1.606] , p<0.0001 ), CV mortality (HR=1.623[1.166;2.259] , p=0.0041 ) and cancer (HR=1.213[1.104;1.334], p<0.0001) compared to TNFis. Tofacitinib was associated with significantly higher risk of all-cause mortality (HR=1.301 [1.089;1.555], p=0.0038 ) and CV mortality (1.625 [1.071;2.465] , p=0.0225 ). The same trends were found for the risk of MACE (HR=1.051[0.951;1.161], p=0.3301) and cancer (HR=1.102[0.981;1.238], p=0.1031) these findings were not statistically significant.

CONCLUSIONS: Based on an analysis of a large secondary claims database, the risk of all-cause and CV mortality, and newly diagnosed cancer, were higher in patients initiating JAKis compared to those treated with TNFis confirming the results coming from the randomized safety trial.