Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance

Abstract

Objectives: Evaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.

Methods: Patients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis).

Results: Risk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07).

Conclusions: This post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low.

Trial registration number: NCT02092467.

Keywords: Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Therapeutics.

Conflict of interest statement

Competing interests: CCS has acted as a consultant for AbbVie, Gilead Sciences, Pfizer Inc and Regeneron-Sanofi, and has received grant/research support from AbbVie, Bristol-Myers Squibb and Pfizer Inc. MHB has acted as a consultant for AbbVie, Eli Lilly, Gilead Sciences, MSD, Pfizer Inc and Roche, has received grant/research support from Pfizer Inc, Roche and UCB, and is a member of the speakers’ bureau for AbbVie (paid to host institution). MHB is supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre and is in receipt of an NIHR Senior Investigator award. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. MD has acted as a consultant for AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer Inc, Roche and UCB, and has received grant/research support from AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer Inc, Roche and UCB. DLB served as a member of the Steering Committee for ORAL Surveillance, with funding from Pfizer Inc paid to Brigham and Women’s Hospital. He is a member of the advisory board for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; serves on the Board of Directors for AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), the Society of Cardiovascular Patient Care, and TobeSoft; is the Inaugural Chair for the American Heart Association Quality Oversight Committee; is on the Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute), for the PORTICO trial, (funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, the Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), for the ABILITY-DM trial (funded by Concept Medical), Novartis, the Population Health Research Institute, and Rutgers University (for the NIH-funded MINT trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; the RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; the AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), the Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), the Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), the Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), and Wiley (steering committee); holds positions at Clinical Cardiology (Deputy Editor), the NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon (neither DLB nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company and 89bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); is a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Phillips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee for the American College of Cardiology; and conducts unfunded research with FlowCo and Takeda.JTG has acted as a consultant for AbbVie, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead Sciences and UCB, and has received grant/research support from Pfizer Inc. SRY has acted as a consultant for Corbus and Pfizer Inc, and has received remuneration from Pfizer Inc for their services as a member of the Steering Committee for ORAL Surveillance. GGK is a shareholder of IQVIA, has received grant/research support from AbbVie, Acceleron, Amgen, Arena, AstraZeneca, Cytokinetics, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Huya Bioscience International, Johnson & Johnson, Landos Biopharma, Merck, Momentum, Novartis, Otsuka, Pfizer Inc, Sanofi and vTv Therapeutics, is an employee of the University of North Carolina at Chapel Hill. He served as a member of the Steering Committee for ORAL Surveillance, with funding from Pfizer Inc paid to the University of North Carolina at Chapel Hill. IV, JW, CW, KK, SM, JLR, and AY are employees and stockholders of Pfizer Inc. CAC was an employee and stockholder of Pfizer Inc at the time of this analysis. ZS has acted as an advisor for AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, a consultant for AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, has received grant/research support from Pfizer Inc and UCB, and is a member of the speakers’ bureau for AbbVie, Eli Lilly, MSD, Novartis, Pfizer Inc, Roche, Sanofi and UCB.

© 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.

Figures

Figure 1

Adjudicated MACE outcomes with tofacitinib versus TNFi in ORAL Surveillance. HRs are shown on a logarithmic scale. Arrows indicate that the CI extends beyond the graph axis. For patients randomised to the tofacitinib 10 mg two-times-per-day group who had their dose of tofacitinib reduced to 5 mg two times per day, the data collected after patients were switched to tofacitinib 5 mg two times per day were counted in the tofacitinib 10 mg two-times-per-day group. HRs (95% CIs) are based on two simple Cox proportional hazard models (one for comparing combined tofacitinib doses vs TNFi, and the other for comparing tofacitinib 5 mg and 10 mg two times per day vs TNFi), with treatment as the only covariate. HRs and 95% CIs were NI when the total number of patients with events was ≤2 for the corresponding pair of treatments in the comparison or when one of the treatments in the comparison had 0 events. IRs express number of patients with first events per 100 PY. †Results reported in Ytterberg et al and included for reference. *HR 95% CI excludes 1. BID, two times per day; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; IR, incidence rate; MACE, major adverse cardiovascular events; MI, myocardial infarction; n, number of patients with events; N, number of evaluable patients; NI, non-informative; PY, patient-years; TNFi, tumour necrosis factor inhibitor.

Figure 2

Risk of MACE with tofacitinib versus TNFi by history of ASCVD. (A) HRs (95% CIs) are based on two simple Cox proportional hazard models (one for comparing combined tofacitinib doses versus TNFi, and the other for comparing tofacitinib 5 mg and 10 mg two times per day vs TNFi), with treatment as the only covariate. IRs express number of patients with first events per 100 PY. NNH (PY) should be interpreted as the number of PY of exposure to tofacitinib required to have one additional MACE versus TNFi. NNH (5-year) should be interpreted as the number of patients who would need to be treated for that duration with tofacitinib rather than with a TNFi to result in one additional MACE. *IRD 95% CI excluded 0. †Results reported in Ytterberg et al and included for reference. ‡NNH 95% CIs are reported in online supplemental table 2. (B) Treatment-by-HxASCVD interaction p values for HRs (χ2 test with 1 degree of freedom) and IRD (2-sided, normal approximation of difference in IR). See supplementary material for details. (C) Cumulative probability of patients with adjudicated MACE events, calculated based on the Kaplan-Meier estimate, in patients with history of ASCVD (left panel) and without history of ASCVD (right panel). HRs are shown on a logarithmic scale. Arrows indicate that the CI extends beyond the graph axis. For patients randomised to the tofacitinib 10 mg two-times-per-day group who had their dose of tofacitinib reduced to 5 mg two times per day, the data collected after patients were switched to tofacitinib 5 mg two times per day were counted in the tofacitinib 10 mg two-times-per-day group. BID, two times per day; CI, confidence interval; CV RF, cardiovascular risk factor; HR, hazard ratio; HxASCVD, history of atherosclerotic cardiovascular disease; IR, incidence rate; IRD, incidence rate difference; MACE, major adverse cardiovascular events; n, number of patients with events; N, number of evaluable patients; NNH, number needed to harm; PY, patient-years; TNFi, tumour necrosis factor inhibitor.

Figure 3

Risk of MI and stroke with tofacitinib versus TNFi by history of ASCVD. (A) HRs are shown on a logarithmic scale. Arrows indicate that the CI extends beyond the graph axis. For patients randomised to the tofacitinib 10 mg two-times-per-day group who had their dose of tofacitinib reduced to 5 mg two times per day, the data collected after patients were switched to tofacitinib 5 mg two times per day were counted in the tofacitinib 10 mg two-times-per-day group. HRs (95% CIs) are based on two simple Cox proportional hazard models (one for comparing combined tofacitinib doses vs TNFi, and the other for comparing tofacitinib 5 mg and 10 mg two times per day vs TNFi), with treatment as the only covariate. IRs express the number of patients with first events per 100 PY. (B) Treatment-by-HxASCVD interaction p values for HRs (χ2 test with 1 degree of freedom) and IRD (two-sided, normal approximation of difference in IR). See supplementary material for details. BID, two times per day; CI, confidence interval; CV RF, cardiovascular risk factor; HxASCVD, history of atherosclerotic cardiovascular disease; IR, incidence rate; IRD, incidence rate difference; MI, myocardial infarction; n, number of patients with events; N, number of evaluable patients; PY, patient-years; TNFi, tumour necrosis factor inhibitor.

Figure 4

Risk of MACE with tofacitinib versus TNFi in patients without a history of ASCVD, according to CV risk categories. HRs are shown on a logarithmic scale. Arrows indicate that the CI extends beyond the graph axis. Patients without HxASCVD were categorised according to their 10-year risk of MACE, per the ASCVD-PCE risk calculator. In line with EULAR recommendations, a 1.5 multiplier was applied to all ASCVD-PCE scores. Because of missing ASCVD-PCE score, two MACE could not be associated with baseline CV risk (n=1 (MI) in the tofacitinib 5 mg two-times-per-day group and n=1 (stroke) in the tofacitinib 10 mg two-times-per-day group). For patients randomised to the tofacitinib 10 mg two-times-per-day group who had their dose of tofacitinib reduced to 5 mg two times per day, the data collected after patients were switched to tofacitinib 5 mg two times per day were counted in the tofacitinib 10 mg two-times-per-day group. HRs (95% CIs) are based on two simple Cox proportional hazard models (one for comparing combined tofacitinib doses vs TNFi, and the other for comparing tofacitinib 5 mg and 10 mg two times per day vs TNFi), with treatment as the only covariate. IRs express the number of patients with first events per 100 PY. †Results reported in Ytterberg et al and included for reference. ASCVD-PCE, atherosclerotic cardiovascular disease-Pooled Cohort Equations; BID, two times per day; CI, confidence interval; CV, cardiovascular; EULAR, European Alliance of Associations for Rheumatology; HxASCVD, history of atherosclerotic cardiovascular disease; IR, incidence rate; MACE, major adverse cardiovascular events; n, number of patients with events; N, number of evaluable patients; PY, patient-years; TNFi, tumour necrosis factor inhibitor.

Figure 5

Risk of MI with tofacitinib versus TNFi in patients without history of ASCVD, according to CV risk categories. HRs are shown on a logarithmic scale. Arrows indicate that the CI extends beyond the graph axis. Patients without HxASCVD were categorised according to their 10-year risk of MACE, per the ASCVD-PCE risk calculator. In line with EULAR recommendations, a 1.5 multiplier was applied to all ASCVD-PCE scores. Because of missing ASCVD-PCE score, one MI in the tofacitinib 5 mg two-times-per-day group could not be associated with baseline CV risk. For patients randomised to the tofacitinib 10 mg two-times-per-day group who had their dose of tofacitinib reduced to 5 mg two times per day, the data collected after patients were switched to tofacitinib 5 mg two times per day were counted in the tofacitinib 10 mg two-times-per-day group. HRs (95% CIs) are based on two simple Cox proportional hazard models (one for comparing combined tofacitinib doses vs TNFi, and the other for comparing tofacitinib 5 and 10 mg two times per day vs TNFi), with treatment as the only covariate. IRs express the number of patients with first events per 100 PY. ASCVD-PCE, atherosclerotic cardiovascular disease-Pooled Cohort Equations; BID, two times per day; CI, confidence interval; CV, cardiovascular; EULAR, European Alliance of Associations for Rheumatology; HR, hazard ratio; HxASCVD, history of atherosclerotic cardiovascular disease; IR, incidence rate; MACE, major adverse cardiovascular events; MI, myocardial infarction; n, number of patients with events; N, number of evaluable patients; PY, patient-years; TNFi, tumour necrosis factor inhibitor.

Figure 6

Risk of stroke with tofacitinib versus TNFi in patients without a history of ASCVD, according to CV risk categories. HRs are shown on a logarithmic scale. Arrows indicate that the CI extends beyond the graph axis. Patients without history of ASCVD were categorised according to their 10-year risk of MACE, per the ASCVD-PCE risk calculator. In line with EULAR recommendations, a 1.5 multiplier was applied to all ASCVD-PCE scores. Because of missing ASCVD-PCE score, one stroke in the tofacitinib 10 mg two-times-per-day group could not be associated with baseline CV risk. For patients randomised to the tofacitinib 10 mg two-times-per-day group who had their dose of tofacitinib reduced to 5 mg two times per day, the data collected after patients were switched to tofacitinib 5 mg two times per day were counted in the tofacitinib 10 mg two-times-per-day group. HRs (95% CIs) are based on two simple Cox proportional hazard models (one for comparing combined tofacitinib doses versus TNFi, and the other for comparing tofacitinib 5 mg and 10 mg two times per day vs TNFi), with treatment as the only covariate. IRs express the number of patients with first events per 100 PY. ASCVD-PCE, atherosclerotic cardiovascular disease-Pooled Cohort Equations; BID, two times per day; CV, cardiovascular; EULAR, European Alliance of Associations for Rheumatology; HxASCVD, history of atherosclerotic cardiovascular disease; IR, incidence rate; MACE, major adverse cardiovascular events; n, number of patients with events; N, number of evaluable patients; PY, patient-years; TNFi, tumour necrosis factor inhibitor.