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Clinical Trial
. 2023 Sep;82(9):1130-1141.
doi: 10.1136/ard-2023-223916. Epub 2023 Jun 12.

Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme

Roy Fleischmann  1 , Jeffrey R Curtis  2 , Christina Charles-Schoeman  3 , Eduardo Mysler  4 , Kunihiro Yamaoka  5 , Christophe Richez  6 , Hannah Palac  7 , Deanne Dilley  7 , Jianzhong Liu  7 , Sander Strengholt  7 , Gerd Burmester  8
Affiliations
Clinical Trial

Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme

Roy Fleischmann et al. Ann Rheum Dis. 2023 Sep.

Abstract

Objective: Increased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular (CV) risk (ORAL Surveillance). We assessed post hoc the potential risk of upadacitinib in a similar RA population.

Methods: Pooled safety data from six phase III trials were evaluated post hoc for AEs in patients receiving upadacitinib 15 mg once a day (with or without conventional synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant methotrexate (MTX), or MTX monotherapy in the overall trial population and in a subset of patients with higher CV risk (aged ≥50 years, ≥1 CV risk factor). Higher-risk patients from a head-to-head study of upadacitinib 15 mg versus adalimumab (SELECT-COMPARE) were assessed in parallel. Exposure-adjusted incidence rates for treatment-emergent AEs were summarised based on exposure to upadacitinib or comparators.

Results: A total of 3209 patients received upadacitinib 15 mg, 579 received adalimumab and 314 received MTX monotherapy; ~54% of the patients were included in the overall and SELECT-COMPARE higher-risk populations. Major adverse cardiovascular events (MACE), malignancy (excluding non-melanoma skin cancer (NMSC)) and venous thromboembolism (VTE) were more frequent in the higher-risk cohorts versus the overall population but were generally similar across treatment groups. Rates of serious infections in higher-risk populations and herpes zoster (HZ) and NMSC in all populations were higher with upadacitinib 15 mg than comparators.

Conclusions: An increased risk of MACE, malignancy (excluding NMSC) and VTE was observed in higher-risk populations with RA, yet risk was comparable between upadacitinib-treated and adalimumab-treated patients. Higher rates of NMSC and HZ were observed with upadacitinib versus comparators across all populations, and increased rates of serious infections were detected in upadacitinib-treated patients at higher CV risk.

Trial registration numbers: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847 and NCT03086343.

Keywords: antirheumatic agents; arthritis; cardiovascular diseases; methotrexate; tumor necrosis factor inhibitors.

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Conflict of interest statement

Competing interests: RF: research grants and consulting fees from AbbVie, Amgen, AstraZeneca, Biogen, BMS, Boehringer-Ingleheim, Flexion, Galapagos, Galvani, Genentech, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi-Aventis and UCB. JRC: consulting fees and research support from AbbVie, Amgen, Bristol Myers Squibb, Janssen, CorEvitas, Lilly, Novartis, Myriad, Sanofi, Pfizer and UCB. CC-S: research grants from AbbVie, BMS, CSL Behring and Pfizer; consultancy for AbbVie, Priovant Therapeutics, Octapharma, BMS, Pfizer, Gilead and Regeneron-Sanofi. EFM: research grants and consulting fees from AbbVie, Amgen, Astra Zeneca, Novartis, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen and Sanofi. KY: consultancy fees from AbbVie, Pfizer, Gilead G.K., Asahi Kasei Pharma, Astellas Pharma, Eli Lilly Japan and Japan Tobacco; member of the speaker’s bureau at Astellas, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly Japan, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe Pharma, Pfizer and Takeda; and research funding from Bristol Myers Squibb, Chugai, GlaxoSmithKline and Mitsubishi-Tanabe Pharma. CR: consultancy and speaking fees from Amgen, AstraZeneca, Roche, BMS, Galapagos, GSK, Lilly, Hospira, Biogen, Sandoz, Mylan, Novartis and Pfizer. GRB: speaking or consulting fees from AbbVie, BMS, Lilly, Galapagos, Janssen, MSD, Pfizer, Roche, Sanofi and UCB. JL, HP, DD and SS: AbbVie employees and may own stocks or options.

Figures

Figure 1
Figure 1
Exposure-adjusted incidence of adjudicated MACE. MACE defined as CV death (includes acute myocardial infarction, sudden cardiac death, heart failure, CV procedure-related death, death due to CV haemorrhage, fatal stroke, pulmonary embolism and other CV causes), non-fatal myocardial infarction and non-fatal stroke. ADA, adalimumab; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CV, cardiovascular; EAIR, exposure-adjusted incidence rate; EOW, every other week; MACE, major adverse cardiovascular event; MTX, methotrexate; PY, patient-years; QD, once daily; UPA, upadacitinib.
Figure 2
Figure 2
Exposure-adjusted incidence of adjudicated MACE in higher CV risk populations by age. MACE defined as CV death (includes acute myocardial infarction, sudden cardiac death, heart failure, CV procedure-related death, death due to CV haemorrhage, fatal stroke, pulmonary embolism and other CV causes), non-fatal myocardial infarction and non-fatal stroke. ADA, adalimumab; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CV, cardiovascular; EAIR, exposure-adjusted incidence rate; EOW, every other week; MACE, major adverse cardiovascular event; MTX, methotrexate; PY, patient-years; QD, once daily; UPA, upadacitinib.
Figure 3
Figure 3
Exposure-adjusted incidence of MACE in higher CV risk populations by medical history of a CV event. aDue to the small number of events in these subgroups, HRs for upadacitinib versus adalimumab were not calculated. bNo events occurred in patients treated with adalimumab who had a history of a CV event. MACE defined as CV death (includes acute myocardial infarction, sudden cardiac death, heart failure, CV procedure-related death, death due to CV haemorrhage, fatal stroke, pulmonary embolism and other CV causes), non-fatal myocardial infarction and non-fatal stroke. ADA, adalimumab; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CV, cardiovascular; EAIR, exposure-adjusted incidence rate; EOW, every other week; MACE, major adverse cardiovascular event; MTX, methotrexate; PY, patient-years; QD, once daily; UPA, upadacitinib.
Figure 4
Figure 4
Exposure-adjusted incidence of malignancies (excluding NMSC). Data are presented as treatment-emergent malignancy rates, with a data cut-off of no more than 30 days after the last dose of study drug for upadacitinib or MTX and up to 70 days for adalimumab if patients discontinued prematurely from the study. ADA, adalimumab; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CV, cardiovascular; EAIR, exposure-adjusted incidence rate; EOW, every other week; MTX, methotrexate; NMSC, non-melanoma skin cancer; PY, patient-years; QD, once daily; UPA, upadacitinib.
Figure 5
Figure 5
Exposure-adjusted incidence of adjudicated VTE. VTE events include deep vein thrombosis and pulmonary embolism. ADA, adalimumab; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CV, cardiovascular; EAIR, exposure-adjusted incidence rate; EOW, every other week; MTX, methotrexate; PY, patient-years; QD, once daily; UPA, upadacitinib; VTE, venous thromboembolism.
Figure 6
Figure 6
Exposure-adjusted incidence of serious infection. ADA, adalimumab; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CV, cardiovascular; EAIR, exposure-adjusted incidence rate; EOW, every other week; MTX, methotrexate; PY, patient-years; QD, once daily; UPA, upadacitinib.
Figure 7
Figure 7
Exposure-adjusted incidence of herpes zoster. ADA, adalimumab; csDMARD, conventional synthetic disease-modifying antirheumatic drug; EAIR, exposure-adjusted incidence rate; EOW, every other week; MTX, methotrexate; PY, patient-years; QD, once daily; UPA, upadacitinib.
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