Background/Purpose: To identify independent risk factors for major adverse cardiovascular (CV) events (MACE) in ORAL Surveillance (NCT02092467), a long-term, randomized, open-label, non-inferiority, Phase 3b/4 safety study of tofacitinib vs TNFi in high-risk (aged ≥ 50 yrs with ≥ 1 additional CV risk factor) patients (pts) with RA and an inadequate MTX response.

Methods: Pts on stable doses of MTX were randomized 1:1:1 to receive tofacitinib 5 or 10 mg BID or a TNFi (adalimumab 40 mg every 2 weeks or etanercept 50 mg every week). Incidence rates (IRs; unique pts with events/100 pt-yrs) and hazard ratios (HRs; tofacitinib vs TNFi) were evaluated for the co-primary endpoint of adjudicated MACE, as well as myocardial infarction (MI) and stroke; MACE was defined as CV death (excluding CV death due to pulmonary embolism), non-fatal MI, and non-fatal stroke. Across outcomes, IRs and HRs are also presented for fatal and non-fatal events. A post hoc analysis identified independent overall risk factors for MACE across treatment groups by Cox regression models. Baseline (BL) categorical covariates were initially screened in 2 univariate Cox analyses (main risk factor p < 0.1 and risk factor–treatment interaction p ≥ 0.2) and were then selected in the final multivariate Cox model using backward selection, with p < 0.1 stay criteria. IRs and HRs for MACE were then stratified by the 4 most important risk factors identified (per largest HRs and smallest p values in the multivariate Cox model).

Results: 4,362 pts were included (tofacitinib 5 mg BID, n=1,455; tofacitinib 10 mg BID, n=1,456; TNFi, n=1,451). Median (range) age was 60.0 (50.0–88.0) yrs. MACE was reported by 47 pts, 51 pts, and 37 pts receiving tofacitinib 5 mg BID, tofacitinib 10 mg BID, and TNFi, respectively (Figure). IRs for MACE, MI, fatal and non-fatal MACE, and non‑fatal MI were numerically higher with both tofacitinib doses vs TNFi (95% CIs overlapped; Figure a, b). Generally, IRs for fatal MI, and stroke (including fatal/non-fatal events), were similar across treatment groups (Figure a–c). HRs for MACE, MI, and stroke were generally > 1 for tofacitinib vs TNFi (Figure a–c); HR 95% CIs for non-fatal MI excluded 1 for tofacitinib 5 mg BID and all tofacitinib vs TNFi. BL covariates identified as the most important independent overall risk factors for MACE were current smoking, aspirin use, age ≥ 65 yrs, and male sex (Table 1). In pts with 1 of these risk factors present, IRs for MACE were numerically higher with both tofacitinib doses vs TNFi (95% CIs overlapped; Table 2). Across treatment groups, in pts without these risk factors present, IRs for MACE were similar (Table 2). Generally, HRs for MACE were > 1 for tofacitinib vs TNFi, in pts with or without risk factors present (Table 2).

Conclusion: The incidence of MACE was numerically higher with tofacitinib vs TNFi treatment. Across treatment groups, the BL covariates, current smoking, aspirin use, age ≥ 65 yrs, and male sex were identified as independent overall risk factors in pts experiencing MACE; tofacitinib vs TNFi treatment in pts with any of these risk factors present was associated with numerically higher incidence of MACE.

Acknowledgments: Study sponsored by Pfizer Inc. Medical writing support was provided by K Woollcott, CMC Connect, funded by Pfizer Inc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/risk-factors-for-major-adverse-cardiovascular-events-in-patients-aged-%e2%89%a5-50-years-with-ra-and-%e2%89%a5-1-additional-cardiovascular-risk-factor-results-from-a-phase-3b-4-randomized-safety-stud/