Objectives: Patients with untreated immune-mediated inflammatory diseases have increased risk for major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE). We describe events and risk factors for MACE and VTE in the RA, PsA, and AS of upadacitinib (UPA) clinical trial programs.

Methods: Treatment-emergent adverse events (TEAEs) of MACE (cardiovascular [CV] death; non-fatal myocardial infarction; non-fatal stroke) and VTE (pulmonary embolism [PE]; deep vein thrombosis) from 9 (6 RA; 2 PsA; 1 AS) randomized, controlled trials were summarized for UPA 15 mg (approved rheumatology dose), UPA 30 mg (UPA30), adalimumab (ADA) 40 mg, and MTX. TEAEs were blindly adjudicated by an independent CV adjudication committee. Patients were not censored at the time of event; data are presented as exposure adjusted event rates (EAERs) in events per 100 patient-years (E/100 PY), with cutoff date of 30 June 2021. Kaplan-Meier analyzed time-to-event, and EAERs were evaluated over 6-month increments. Cox-regression univariable analyses assessed the relationship between potential risk factors and MACE/VTE occurrence on UPA.

Results: Across trials, 4298, 2125, 1008, and 314 patients received ≥1 dose of UPA15, UPA30, ADA 40 mg, and MTX, respectively. At baseline, 40%–50% had ≥2 CV risk factors (% ≥65 years, 6–23%). EAERs of MACE and VTE in RA and PsA are presented in Figure 1, with 0 MACE and 1 VTE (PE) reported in AS. Of the 41 MACE reported with UPA15 across RA and PsA, only 2 RA patients did not have ≥1 CV risk factors at baseline. There were 2 fatal VTEs across trials, both on UPA15 in RA. Overlapping confidence intervals were observed across UPA doses and comparators for MACE and VTE in RA and PsA. There was no pattern of time-to-event of EAERs by 6-month intervals over 42 months observed on UPA. Factors potentially associated with MACE (Figure 2) or VTE (data not shown in abstract) occurrence in RA pts receiving UPA15 included age ≥ 65y, baseline hypertension, diabetes mellitus, smoking, history of CV event or VTE, and use of aspirin, statins, or antithrombotics. In PsA, aspirin use was associated with increased risk of MACE.

Conclusion: Rates of adjudicated MACE and VTE with UPA were infrequent and consistent with background rates in RA, PsA, and AS populations. The pt characteristics found to be associated with MACE and VTE are known risk factors for these events. Continued follow-up is ongoing to further contextualize the risk of MACE and VTE in UPA clinical trials.