TNF-α抑制剂可使RA患者心血管受益

针对美国数个医保计划数据库的大型观察性研究结果显示，类风湿性关节炎(RA)患者接受肿瘤坏死因子-α(TNF-α)抑制剂治疗后6个月内，心血管事件风险低于接受非生物性疾病缓解抗风湿药物(DMARD)治疗的患者(Am. J. Med. 2013;126:730.e9-17)。

波士顿布里格姆妇女医院的Daniel H. Solomon博士及其同事报告称，在治疗方案中添加TNF-α抑制剂的11,587例RA患者中，最初随访6个月内复合心血管事件发生率为2.52/100人·年，而添加非生物性DMARD的8,656例患者为3.05/100人·年。对于≥65岁患者而言，心血管受益更为明显[危险比(HR)，0.52]，但该受益在6个月后逐渐消失。

研究者解释称：“无论是在首次暴露结转分析还是接受治疗分析中，无心血管事件生存率曲线在6个月之后开始偏离。与非生物性DMARD相比， TNF-α抑制剂首次暴露结转分析HR为0.80，6个月接受治疗分析为0.71，但12个月时，曲线趋于重合，HR接近于零。”

作为大型协作研究SABER(生物治疗安全性评价)的一部分，研究者通过数个医保计划数据库，分析了接受甲氨蝶呤治疗的RA患者添加或转换为TNF-α抑制剂或非生物性DMARD治疗后的心血管结局。患者均＞16岁(平均年龄56岁)。

主要终点指标为心梗、卒中或冠脉血运重建等复合心血管结局，上述各项指标又单独作为次要终点指标。除两组患者卒中发生率相似之外，其他各项心血管结局均与复合结局类似。

研究者指出，虽然观察性研究有其自身的局限性，但上述结果仍具有重要的临床意义。“随着越来越多的证据表明炎症在动脉粥样硬化中扮演重要角色，免疫抑制治疗方案已应用于心血管疾病患者治疗。他汀类和阿司匹林或在某种程度上可通过其抗炎作用降低心血管风险，与此同时，针对与心血管疾病相关的细胞因子的靶向治疗也成为颇具吸引力的治疗选择。由于RA等全身免疫性疾病患者较普遍应用有效的免疫抑制剂治疗，因此，研究这些药物对心血管疾病的作用，或许有助于深入了解这一策略应用于普通人群的可能性。”

该研究结果与既往研究结果基本一致，即TNF-α抑制剂治疗与降低心血管风险相关。

研究者认为，TNF-α抑制剂似乎对心血管疾病的多个方面产生影响，例如斑块稳定、内皮功能以及梗死后重塑等。因此，可以预期TNF-α抑制剂或可减少缺血性心血管风险。上述结果支持了心血管疾病炎性基础，突显了免疫抑制剂降低心血管风险的潜在作用。因此，有必要开展随机对照临床试验，以评估靶向免疫抑制剂降低心血管风险的作用。

该研究由美国医疗保健研究与质量局(AHRQ)和食品药品管理局(FDA)资助。研究者报告与雅培等多家公司或机构存在利益关系。

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By: SHARON WORCESTER, Cardiology News Digital Network

Patients with rheumatoid arthritis who began taking a tumor necrosis factor–alpha blocking agent had a lower cardiovascular event risk during the subsequent 6 months than did those who took a nonbiologic disease-modifying antirheumatic drug in a large, observational study of several administrative and health plan datasets.

The incidence rate for a composite cardiovascular endpoint through the first 6 months of follow-up was 2.52/100 person-years in 11,587 subjects with rheumatoid arthritis (RA) who added a TNF-alpha blocker to their treatment regimen, compared with a rate of 3.05/100 person-years in 8,656 subjects with RA who added a nonbiologic DMARD, Dr. Daniel H. Solomon of Brigham and Women’s Hospital, Boston, and his colleagues reported.

The findings were most pronounced among those aged 65 years and older (hazard ratio, 0.52), and the benefits waned after 6 months.

"In both the first exposure carried forward and the as-treated analyses, the cardiovascular event–free survival curves diverged over the first 6 months. The hazard ratio for the TNF-alpha blocking agent, compared with the nonbiologic DMARD in the first exposure, carried forward was 0.80, and the as-treated analysis at 6 months was 0.71. However, by 12 months the curves appeared to converge with the hazard ratios approaching the null," the investigators explained (Am. J. Med. 2013;126:730.e9-17).

The study involved participants older than 16 years (mean age of 56 years) in several U.S. insurance programs. Those included in the current study – which was part of a larger study collaborative known as SABER (Safety Assessment of Biologic Therapy) – were RA patients using methotrexate who were either adding or switching to a TNF-alpha blocker or a nonbiologic DMARD.

The study’s primary endpoint consisted of a composite cardiovascular outcome of myocardial infarction, stroke, or coronary revascularization; each of these components alone represented a secondary study endpoint.

"The component cardiovascular outcomes followed a similar pattern (to the composite outcome), except stroke, where the incidence rates were similar across exposures," the investigators noted.

Despite the limitations inherent in an observational study, the findings may have important clinical implications, they said.

"As greater evidence accumulates for the role of inflammation in atherosclerosis, consideration has been given to the use of immunosuppressive treatment regimens in cardiovascular disease. While statins and aspirin may reduce cardiovascular risk in part through their anti-inflammatory properties, targeting cytokines known to be part of cardiovascular disease is an attractive therapeutic option. Because the use of potent immunosuppressive agents is common in a systemic inflammatory condition such as rheumatoid arthritis, studying the effect of these agents on cardiovascular disease may provide important insights into the potential role of this strategy in the general population."

The results of the current study generally agree with prior findings demonstrating a link between TNF-alpha blocker use and reduced risk of cardiovascular outcomes.

"TNF-alpha appears to affect several aspects of cardiovascular disease, such as plaque stabilization, endothelial function, and postinfarct remodeling. Thus, one would anticipate that blockade of TNF-alpha would reduce ischemic cardiovascular outcomes. This finding supports the inflammatory underpinnings of cardiovascular disease and highlights a potential role for immunosuppression in cardiovascular risk reduction," they wrote, concluding that randomized controlled clinical trials testing targeted immunosuppression to reduce cardiovascular risk are warranted.

This study was supported by the Agency for Healthcare Research and Quality and the Food and Drug Administration. Dr. Solomon reported receiving research grants from Abbott, Amgen, and Lilly, and serving in unpaid roles on two Pfizer trials. He also directed an educational course supported by Bristol-Myers Squibb, and serves as a consultant to the Consortium of Rheumatology Researchers of North America Inc. (CORRONA). Other study authors reported receiving research grants from, and/or serving as a consultant for Amgen, Abbott, BMS, Centocor, Genentech/Roche, Janssen, Pfizer, UCB, and CORRONA.