An analysis of results from a randomized phase 3b/4 study demonstrated an increased risk of venous thromboembolic events with treatment of tofacitinib versus a tumor necrosis factor inhibitor (TNFi) among patients with rheumatoid arthritis (RA) aged 50 years or older with at least one cardiovascular (CV) risk factor. These data were presented at the American College of Rheumatology (ACR) Convergence 2021.
The ORAL Surveillance trial was an open label noninferiority study of major adverse CV events (MACE) and malignancies associated with tofacitinib versus TNFi treatment in patients with active, moderate to severe RA. Participants were enrolled if they had demonstrated a previously inadequate response to methotrexate and were at high risk of MACEs due to age and having at least 1 additional CV risk factor. In this study, the risk of venous thromboembolism (VTE) was assessed, including incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE).
Patients were initially randomized 1:1:1 to twice daily tofacitinib at 5 mg (n = 1,455) or 10 mg (n = 1,455) or a TNFi (n = 1,451; etanercept 50 mg every week or adalimumab 40 mg every 2 weeks), with methotrexate maintenance. However, a 2019 review observed a statistically and clinically important difference in PE incidence within the tofacitinib 10 mg treatment arm, resulting in a dose switch 5 mg BID for the rest of the trial.
Sixty-six patients experienced VTE events. The incidence rates (events per 100 patient-years) for VTE, DVT, and PE were < 1.0 across all treatment arms. The probabilities of VTE events were higher in both tofacitinib treatment arms versus the TNFi arm and higher in the tofacitinib 10 versus five mg groups. VTE events were also more common in patients with a history of VTE compared with patients without a previous history, across all treatment arms. The Number Needed to Harm for tofacitinib (overall) versus TNFi were 763 and 198 patient-years for VTE; 1,347 and 589 patient-years for DVT; and 870 and 229 patient-years for PE. Independent risk factors for PE across treatment arms included a history of VTE, baseline use of oral contraceptives or hormone replacement therapy, body mass index ≥ 30 kg/m2; age ≥ 65 years, and a history of hypertension.
“Incidence rates were generally consistent with ranges reported for tofacitinib and biologic DMARDs among patients at a high risk of a CV event; PE incidence rates with tofacitinib 10 mg [twice daily] in ORAL Surveillance was higher than those reported in tofacitinib or biologic DMARD clinical trial or registry data,” the researchers concluded.
Source: Charles-Schoeman C, et al. The Risk of Venous Thromboembolic Events in Patients with RA Aged ≥ 50 Years with ≥ 1 Cardiovascular Risk Factor: Results from a Phase 3b/4 Randomized Safety Study of Tofacitinib vs TNF Inhibitors. Arthritis Rheumatol. 2021;73(suppl 10). Presented at ACR Convergence 2021 (Virtual), Nov. 5-9, 2021.