Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis
Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis
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DOI：
10.1056/nejmoa2109927
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发表时间：
2022-01-27
影响因子：
158.5
通讯作者：
Connell, Carol A.
中科院分区：
文献类型：
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作者：
Ytterberg, Steven R.;Bhatt, Deepak L.;Connell, Carol A.
研究背景托法替尼引起的血脂水平升高和癌症促使了一项试验，在接受托法替尼治疗的类风湿性关节炎患者中，与接受肿瘤坏死因子（TNF）抑制剂相比，主要不良心血管事件（MACE）和癌症。安全端-点试验涉及50岁或以上且至少有一次心血管疾病的活动性类风湿性关节炎患者，尽管接受甲氨蝶呤治疗风险因素患者以1：1：1的比例随机分配接受托法替布5 mg或10 mg每日2次或TNF抑制剂治疗。共同主要终点是判定的MACE和癌症，不包括非黑色素瘤皮肤癌。如果与TNF抑制剂相比，托法替尼联合剂量的风险比的双侧95%置信区间的上限小于1.8，则表明托法替尼的非劣效性。在CRTSA中，共有1455例患者接受托法替尼5 mg每日两次，1456例患者接受托法替尼10 mg每日两次，1451接受了TNF抑制剂。在中位随访4.0年期间，托法替布联合剂量组的MACE和癌症发生率（分别为3.4% [98例患者]和4.2% [122例患者]）高于TNF抑制剂组（2.5% [37例患者]和2.9% [42例患者]）。MACE的风险比为1.33（95%置信区间[CI]，0.91 - 1.94），癌症的风险比为1.48（95% CI，1.04 - 2.09）;未显示托法替尼的非劣效性。托法替尼组判定的机会性感染（包括带状疱疹和结核）、所有带状疱疹（非严重和严重）和判定的非黑色素瘤皮肤癌的发生率高于TNF抑制剂组。在所有三个组的疗效是相似的，从第2个月的改善，持续通过trial completion.CONCLUSIONSIn this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk enriched population，MACE和癌症的风险较高，与tofacitinib和不符合非劣效性标准。托法替布组的几种不良事件更常见。
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.