PMID- 37308218 OWN - NLM STAT- MEDLINE DCOM- 20230825 LR - 20231011 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 82 IP - 9 DP - 2023 Sep TI - Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme. PG - 1130-1141 LID - 10.1136/ard-2023-223916 [doi] AB - 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. CI - (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Fleischmann, Roy AU - Fleischmann R AD - Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA RFleischmann@dfwra.com. FAU - Curtis, Jeffrey R AU - Curtis JR AD - Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA. FAU - Charles-Schoeman, Christina AU - Charles-Schoeman C AUID- ORCID: 0000-0002-1768-7019 AD - Department of Medicine, Division of Rheumatology, University of California Los Angeles, Los Angeles, California, USA. FAU - Mysler, Eduardo AU - Mysler E AD - Organizacion Medica de Investigacion, Buenos Aires, Argentina. FAU - Yamaoka, Kunihiro AU - Yamaoka K AD - Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Japan. FAU - Richez, Christophe AU - Richez C AUID- ORCID: 0000-0002-3029-8739 AD - University Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, and CHU of Bordeaux, Department of Rheumatology, Bordeaux, France. FAU - Palac, Hannah AU - Palac H AD - AbbVie Inc, North Chicago, Illinois, USA. FAU - Dilley, Deanne AU - Dilley D AD - AbbVie Inc, North Chicago, Illinois, USA. FAU - Liu, Jianzhong AU - Liu J AD - AbbVie Inc, North Chicago, Illinois, USA. FAU - Strengholt, Sander AU - Strengholt S AD - AbbVie Inc, North Chicago, Illinois, USA. FAU - Burmester, Gerd AU - Burmester G AUID- ORCID: 0000-0001-7518-1131 AD - Department of Rheumatology and Clinical Immunology, Charite Universitatsmedizin Berlin, Berlin, Germany. LA - eng SI - ClinicalTrials.gov/NCT02629159 SI - ClinicalTrials.gov/NCT02706847 SI - ClinicalTrials.gov/NCT02675426 SI - ClinicalTrials.gov/NCT03086343 SI - ClinicalTrials.gov/NCT02706951 SI - ClinicalTrials.gov/NCT02706873 PT - Clinical Trial, Phase III PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230612 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - FYS6T7F842 (Adalimumab) RN - 0 (Antirheumatic Agents) RN - 0 (Heterocyclic Compounds, 3-Ring) RN - YL5FZ2Y5U1 (Methotrexate) RN - 4RA0KN46E0 (upadacitinib) SB - IM MH - Humans MH - Adalimumab/adverse effects MH - *Antirheumatic Agents/adverse effects MH - *Arthritis, Rheumatoid/drug therapy/chemically induced MH - *Cardiovascular Diseases/chemically induced/epidemiology/drug therapy MH - *Herpes Zoster/chemically induced/epidemiology MH - Heterocyclic Compounds, 3-Ring/adverse effects MH - Methotrexate/adverse effects MH - Treatment Outcome MH - *Venous Thromboembolism/chemically induced PMC - PMC10423494 OTO - NOTNLM OT - antirheumatic agents OT - arthritis OT - cardiovascular diseases OT - methotrexate OT - tumor necrosis factor inhibitors COIS- 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. EDAT- 2023/06/13 01:13 MHDA- 2023/08/16 06:43 PMCR- 2023/08/13 CRDT- 2023/06/12 20:43 PHST- 2023/01/23 00:00 [received] PHST- 2023/05/17 00:00 [accepted] PHST- 2023/08/16 06:43 [medline] PHST- 2023/06/13 01:13 [pubmed] PHST- 2023/06/12 20:43 [entrez] PHST- 2023/08/13 00:00 [pmc-release] AID - ard-2023-223916 [pii] AID - 10.1136/ard-2023-223916 [doi] PST - ppublish SO - Ann Rheum Dis. 2023 Sep;82(9):1130-1141. doi: 10.1136/ard-2023-223916. Epub 2023 Jun 12.