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. 2023 Nov;9(4):e003392.
doi: 10.1136/rmdopen-2023-003392.

MACE and VTE across upadacitinib clinical trial programmes in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

Christina Charles-Schoeman  1 , Ernest Choy  2 , Iain B McInnes  3 , Eduardo Mysler  4 , Peter Nash  5 , Kunihiro Yamaoka  6 , Ralph Lippe  7 , Nasser Khan  8 , Anna K Shmagel  8 , Hannah Palac  8 , Jessica Suboticki  8 , Jeffrey R Curtis  9
Affiliations

MACE and VTE across upadacitinib clinical trial programmes in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

Christina Charles-Schoeman et al. RMD Open. 2023 Nov.

Abstract

Objectives: To provide an integrated analysis of major adverse cardiovascular events (MACEs) and events of venous thromboembolism (VTE) and associated risk factors across rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) phase 2b/3 upadacitinib clinical programmes.

Methods: Data were analysed and summarised from clinical trials of RA, PsA and AS treated with upadacitinib 15 mg once daily (QD) and 30 mg QD (as of 30 June 2021). Data from adalimumab (RA and PsA) and methotrexate (RA) arms were included as comparators. Adjudicated MACEs and VTE events were presented as exposure-adjusted rates per 100 patient-years (E/100 PY). Univariable Cox proportional hazard regression analyses assessed potential associations of risk factors for MACE and VTE.

Results: In total, 4298 patients received upadacitinib 15 mg (RA n=3209, PsA n=907 and AS n=182) and 2125 patients received upadacitinib 30 mg (RA n=1204 and PsA n=921). In patients with RA and PsA, rates of MACE (0.3-0.6 E/100 PY) and VTE (0.2-0.4 E/100 PY) were similar across upadacitinib doses; in patients with AS, no MACEs and one VTE event occurred. Most patients experiencing MACEs or VTE events had two or more baseline cardiovascular risk factors. Across RA and PsA groups, rates of MACEs and VTE events were similar.

Conclusions: Rates of MACEs and VTE events with upadacitinib were consistent with previously reported data for patients receiving conventional synthetic and biologic disease-modifying anti-rheumatic drugs and comparable with active comparators adalimumab and methotrexate. Associated patient characteristics are known risk factors for MACEs and VTE events.

Trial registration numbers: RA (SELECT-NEXT: NCT02675426; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847; SELECT-COMPARE: NCT02629159; SELECT-EARLY: NCT02706873, SELECT-CHOICE: NCT03086343), PsA (SELECT-PsA 2: NCT03104374; SELECT-PsA 1: NCT03104400), and AS (SELECT-AXIS 1: NCT03178487).

Keywords: Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Spondylitis, Ankylosing.

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Conflict of interest statement

Competing interests: CC-S has received grant/research support from AbbVie, Bristol-Myers Squibb, CSL Behring, Alexion Pharmaceuticals, Priovant Therapeutics and Pfizer. She is a consultant for AbbVie, Priovant Therapeutics, Octapharma, Bristol-Myers Squibb, Gilead Sciences, Pfizer, Galapagos and Sanofi-Regeneron. EC has received research grants and/or has served as member of advisory boards and/or speaker bureaus for AbbVie, Amgen, Bio-Cancer, Biocon, Biogen, Bristol-Myers Squibb, Celgene, Chugai Pharma, Eli Lilly, Fresenius Kabi, Galapagos, Gilead, Inmedix, Janssen, Merck Serono, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma and UCB. IBM has received research grants and/or consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, EveloBio, Janssen, LEO, Lilly, Novartis, Moonlake, Pfizer and UCB. EM has received research grants and/or has served as a member of advisory boards and/or speaker bureaus for AbbVie, Amgen, AstraZeneca, Eli Lilly, BMS, Janssen, Novartis, Pfizer, Sanofi, Sandoz and Roche. PN has received research grants and/or consulting fees from and/or is a member of speakers’ bureaus for AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead and Janssen. KY is a member of speakers’ bureaus for AbbVie, GK, Astellas, BMS, Chugai, Mitsubishi-Tanabe, Pfizer and Takeda. RL, NK, HP, AKS and JS are full-time employees of AbbVie and may hold AbbVie stock or stock options. JRC has received research grants and/or consulting fees from AbbVie, Amgen, ArthritisPower, Aqtual, Bendcare, BMS, CorEvitas, FASTER, GSK, IlluminationHealth, Janssen, Labcorp, Lilly, Myriad, Novartis, Pfizer, Sanofi, Scipher, Setpoint and UCB.

Figures

Figure 1
Figure 1
MACE breakdown by event type in RA and PsA. AS is not represented here as there were no MACE. ADA, adalimumab; CV, cardiovascular; E, events; E/100, events per 100; EAIR; exposure-adjusted incidence rate (n/100 PY); EOW, every other week; MACE, major adverse cardiovascular events; MI, myocardial infarction; MTX, methotrexate; PsA, psoriatic arthritis; PY, patient-years; QD, once daily; RA, rheumatoid arthritis; UPA, upadacitinib.
Figure 2
Figure 2
MACE risk factors in patients receiving UPA 15 mg (univariable analysis). Red boxes indicate statistical significance (p<0.05). *Hazard ratios not estimated due to zero events in ≥1 parameter. †Equivalent to LDL-C ≥130 mg/dL vs <130 mg/dL. ‡Equivalent to HDL-C <40 mg/dL vs ≥40 mg/dL.BMI, body mass index; COX-2, cyclooxygenase-2; CRP, C-reactive protein; CV, cardiovascular; dx, diagnosis; HDL-C, high-density lipoprotein cholesterol; HRT, hormone-replacement therapy; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular event; MTX, methotrexate; NE, not estimable; PsA, psoriatic arthritis; RA, rheumatoid arthritis; UPA, upadacitinib; VTE, venous thromboembolism; y, years.
Figure 3
Figure 3
Events of MACE in RA and PsA by length of upadacitinib exposure in 12-month increments. ADA, adalimumab; E, event; EOW, every other week; MACE, major adverse cardiovascular event; MTX, methotrexate; PsA, psoriatic arthritis; PY, patient-years; QD, once daily; RA, rheumatoid arthritis; UPA, upadacitinib.
Figure 4
Figure 4
VTE breakdown by event type* in RA and PsA. ADA, adalimumab; DVT, deep vein thrombosis; E, event; E/100, event per 100; EAIR, exposure-adjusted incidence rate; EOW, every other week; MTX, methotrexate; PE, pulmonary embolism; PsA, psoriatic arthritis; PY, patient-years; QD, once daily; RA, rheumatoid arthritis; UPA, upadacitinib; VTE, venous thromboembolism.
Figure 5
Figure 5
VTE risk factors in patients receiving UPA 15 mg (univariable analysis). Red boxes indicate statistically significant differences (p<0.05). *Hazard ratios not estimated due to zero events in ≥1 parameter. †Equivalent to LDL-C ≥130 mg/dL vs <130 mg/dL. ‡Equivalent to HDL-C <40 mg/dL vs ≥40 mg/dL. BMI, body mass index; COX-2, cyclooxygenase-2; CRP, C-reactive protein; CV, cardiovascular; dx, diagnosis; HDL-C, high-density lipoprotein cholesterol; HRT, hormone-replacement therapy; LDL-C, low-density lipoprotein cholesterol; MTX, methotrexate; NE, not estimable; PsA, psoriatic arthritis; RA, rheumatoid arthritis; UPA, upadacitinib; VTE, venous thromboembolic event; y, years.
Figure 6
Figure 6
Events of VTE in RA and PsA by length of upadacitinib exposure in 12-month increments. ADA, adalimumab; E, event; EOW, every other week; MTX, methotrexate; PsA, psoriatic arthritis; PY, patient-years; QD, once daily; RA, rheumatoid arthritis; VTE, venous thromboembolism; UPA, upadacitinib.
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