Impact of atherosclerotic cardiovascular disease risk in patients treated with upadacitinib versus comparators: post hoc analysis of the select rheumatoid arthritis program

Background In ORAL Surveillance, a post-approval safety study conducted in RA patients aged ≥50 years with ≥1 cardiovascular (CV) risk factor, non-inferiority was not shown for MACE and malignancy (excluding nonmelanoma skin cancer) for tofacitinib versus TNF inhibitor (TNFi) therapy. [1] A post hoc analysis of the ORAL Surveillance data suggested that patients with a history of atherosclerotic cardiovascular disease (ASCVD) were most at risk relative to TNFi. [2] Whether these findings are characteristic of the entire JAK inhibitor class is unclear. Objectives To evaluate the impact of baseline ASCVD risk on the incidence of MACE with upadacitinib (UPA) versus TNFi and MTX in an RA population similar to ORAL Surveillance from the SELECT RA clinical program. Methods Post hoc analysis of adjudicated MACE was performed in two patient populations pooled across six SELECT phase 3 studies: the overall population and the higher CV risk subset (patients aged ≥50 years with ≥1 CV risk factor). Patients received UPA 15 mg once daily (with or without conventional synthetic DMARDs), adalimumab (ADA) 40 mg in combination with MTX, or MTX monotherapy. CV risk factors used to identify the higher-risk patients included prior CV event, hypertension, diabetes mellitus, current or former tobacco/nicotine use, and baseline HDL-C levels <40 mg/dL. Patients were further stratified based on medical history of ASCVD, which included coronary artery disease and other relevant events (e.g., arteriosclerosis, ischemic stroke, and carotid artery disease). In patients without a history of ASCVD, 10-year ASCVD risk categories were calculated with a 1.5 multiplier applied. [3] Exposure-adjusted incidence rates (EAIRs) per 100 patient-years were summarized based on the treatment received; 95% CIs were determined based on the exact method for the Poisson mean. Results Of 4102 enrolled patients (UPA 15 mg, n=3209; ADA, n=579; MTX monotherapy, n=314), approximately half were aged ≥50 years with ≥1 CV risk factor (n=2199 total; UPA 15 mg, n=1717; ADA, n=320; MTX monotherapy, n=162). In the overall SELECT population, EAIRs of adjudicated MACE were 0.3, 0.3, and 0.2 n/100 PY for UPA, ADA, and MTX groups, respectively ( Figure 1 ). Rates of MACE were higher in UPA-treated patients with a history of ASCVD (1.9 n/100 PY) compared to those without a history of ASCVD (0.2 n/100 PY) in the overall population; no occurrences of MACE were reported with ADA or MTX in patients with a medical history of ASCVD, possibly due to the limited patient numbers in these groups. Among patients with no history of ASCVD in the overall population, higher rates of MACE were observed for patients in the high or intermediate 10-year ASCVD risk categories versus the low or borderline risk category, irrespective of treatment. In the higher CV risk subset of the SELECT population, rates of MACE were numerically higher than the overall population but were similar between treatment groups (0.6, 0.5, and 0.5 n/100 PY for UPA, ADA, and MTX groups, respectively). Consistent with the overall population, the incidence of MACE was higher among UPA-treated patients with a history of ASCVD relative to those without a history of ASCVD. The rates of MACE in the higher-risk population were also generally similar across treatment groups for patients within each of the different 10-year ASCVD risk groups. Conclusion In this post hoc analysis, higher rates of MACE were observed in UPA-treated patients with a history of ASCVD versus those with no history of ASCVD. In both the overall SELECT population and the higher CV risk subset, rates of MACE were generally comparable between UPA and ADA in the different ASCVD risk categories. However, given the low sample size and limited patient-years of exposure in ADA and MTX treatment groups, results should be interpreted with caution. References [1]Ytterberg SR, et al. N Engl J Med . 2022;386:316-26. [2]Charles-Schoeman C, et al. Ann Rheum Dis . 2022;0:1-11. [3]Agca R, et al. Ann Rheum Dis. 2017;76:17-28. Acknowledgements AbbVie funded these studies and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Matthew Eckwahl, PhD, of AbbVie. Disclosure of Interests Christina Charles-Schoeman Consultant of: AbbVie, Pfizer, Gilead, Priovant, Octapharma, BMS, Immunovant, and Regeneron-Sanofi, Grant/research support from: AbbVie, BMS, CSL Behring, and Pfizer, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, CESAS Medical, Lilly, Gilead Sciences, MSD, Pfizer, and Roche, Grant/research support from: Pfizer, Roche, and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie, BMS, Lilly, Galapagos, Janssen, MSD, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, BMS, Lilly, Galapagos, Janssen, MSD, Pfizer, Roche, Sanofi, and UCB, Jianzhong Liu Shareholder of: AbbVie, Employee of: AbbVie, Deanne Dilley Shareholder of: AbbVie, Employee of: AbbVie, Hannah Palac Shareholder of: AbbVie, Employee of: AbbVie, sander strengholt Shareholder of: AbbVie, Employee of: AbbVie, Jeffrey Curtis Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Janssen, CorEvitas, Lilly, Novartis, Myriad, Sanofi, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Janssen, CorEvitas, Lilly, Novartis, Myriad, Sanofi, Pfizer, and UCB.