Background/Purpose: Patients (pts) with RA have an approximate 2-fold increased risk of cardiovascular (CV) morbidity and mortality and of venous thromboembolic events (VTE)^1,2. Among RA pts, the rates of major adverse CV events (MACE) and VTE were 0.3 – 0.7 incidences per 100 patient-years (PY)³ and 0.3 – 0.8 events per 100 PY⁴, respectively. Treatment of RA with Janus Kinase (JAK) inhibitors is known to increase lipid levels⁵ along with mild, variable impacts on platelet counts^5,6, however these changes have not been linked to a CV⁷ or VTE⁸ risk, respectively.

Assess the rates of MACE and VTE from the integrated safety database of the Phase 3 clinical program of Upadacitinib (UPA), an oral, potent, reversible, JAK1-selective inhibitor, in pts with moderately to severely active RA.

Methods: Treatment-emergent adverse events of MACE and VTE from 5 pivotal, randomized, blinded, Phase 3 trials of UPA 15 mg QD (all 5 trials) or 30 mg QD (4 trials) in RA pts were summarized into the integrated placebo (PBO), MTX, ADA 40 mg, UPA 15 mg and UPA 30 mg treatment groups. Data are presented as exposure adjusted event rates (EAERs, E/100 PY). All suspected MACE and VTEs were adjudicated by an external, independent, CV adjudication committee.

Results: Across trials, 3834 pts received ≥1 dose of UPA 15 mg (n=2630) or 30 mg (n=1204) with no option to switch doses (exposure =4020.1 PY), 1042 pts received PBO (256.8 PY), 530 pts received MTX (368.7 PY) and 579 pts received ADA 40 mg (467.8 PY). History of prior CV events (2-3%) and VTEs (4-7%) were comparable across groups.

The EAERs of MACE and VTE in the UPA groups were comparable to PBO, MTX and ADA (Table). Approximately 40% of MACE events and 1 pulmonary embolism event (UPA 15 mg) were fatal. All pts with a MACE or VTE event had ≥1 CV risk factor (hypertension, diabetes, dyslipidemia) or ≥1 VTE risk factor (prior history of thrombotic event, obesity, or hypertension) at baseline, respectively.

Though treatment with UPA increased the levels of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), their ratio remained constant over time. Analysis of data showed no association of LDL‑C increases and MACE occurrences (Figure). In both UPA groups, neither a dose‑response nor a pattern of time-to-VTE-onset (23 to 1127 days of UPA) was observed. Slight decreases in mean platelet count from baseline were observed.

Conclusion: EAERs of adjudicated MACE and VTE with UPA were comparable with MTX and ADA and consistent with reported background rates in the RA population. Similar to other JAK inhibitors, UPA increased the levels of lipids. However, no association between lipid levels and MACE could be established.

REFERENCES:

1. Solomon et al. Circulation. 2003;11; 107, 1303-7
2. Chung et al. Ann Rheum Dis. 2014;73:1774-80
3. Lauper et al., Arthritis Care Res. 2018;70:1756-63
4. Scott et al. Drug Saf. 2018;41:645-53
5. Nat Rev Rheumatol. 2017;13,234-43
6. Smolen et al. J Rheumatol. 2019;46,7-18
7. Xie W et al. Ann Rheum Dis 2019; doi:10.1136/annrheumdis-2018-214846
8. Desai RJ et al. Arthritis Rheum. 2019; doi:10.1002/art.40798

Table

Figure

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mace-and-vte-across-multiple-upadacitinib-studies-in-rheumatoid-arthritis-integrated-analysis-from-the-select-phase-3-clinical-program/