• Steven R Ytterberg, Deepak L Bhatt, Ted R Mikuls, Gary G Koch, Roy Fleischmann, Jose L Rivas, Rebecca Germino, Sujatha Menon, Yanhui Sun, Cunshan Wang, Andrea B Shapiro, Keith S Kanik, Carol A Connell, and ORAL Surveillance Investigators.
• From the Division of Rheumatology, Mayo Clinic, Rochester, MN (S.R.Y.); the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (D.L.B.); the Division of Rheumatology, University of Nebraska Medical Center, Omaha (T.R.M.); the Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill (G.G.K.); Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas (R.F.); Pfizer, Madrid (J.L.R.); Pfizer, New York (R.G.); Pfizer, Groton, CT (S.M., C.W., K.S.K., C.A.C.); Pfizer, Shanghai, China (Y.S.); and Pfizer, Peapack, NJ (A.B.S.).
• N. Engl. J. Med. 2022 Jan 27; 386 (4): 316-326.

BackgroundIncreases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor.MethodsWe conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor.ResultsA total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion.ConclusionsIn this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).Copyright © 2022 Massachusetts Medical Society.

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