TNF抑制剂可降低RA患者的心血管风险

尽管尚缺乏来自前瞻性研究的明确结果，但越来越多的证据表明，肿瘤坏死因子(TNF)抑制剂的强力抗炎作用可显著降低类风湿性关节炎(RA)患者的心血管(CV)风险。

近期两项分析均显示，TNF抑制剂可使CV事件发生率显著降低50%。

在第一项分析中，德国Charité医院的Gerd Burmester博士及其同事对4项安慰剂对照研究进行了Meta分析。在这4项研究中，1,411例RA患者接受阿达木单抗/甲氨蝶呤联合治疗，1,036例仅使用甲氨蝶呤而未使用TNF抑制剂。基线时，两组的人口学特征和心血管疾病风险相似。

 
Burmester博士

在16周~104周的研究期间，使用阿达木单抗的患者的主要不良CV事件发生率为1.3%，而未使用阿达木单抗的患者为2%。比例风险模型分析显示，前者的主要CV事件风险相对后者显著降低2/3。此外，与未使用阿达木单抗的患者相比，使用阿达木单抗的患者的致死性心肌梗死发生率也显著降低，但两组的非致死性心肌梗死和非致死性卒中发生率无显著差异。

Burmester博士表示，该Meta分析的局限性在于所有纳入的4项研究均缺乏评估CV预后的效能。

在第二项分析中，阿姆斯特丹VU医学中心Reade康复与风湿病中心的Alper M. van Sijl博士及其同事对一个包括309例未使用TNF抑制剂的随机选择的RA患者队列和一个包括519例自初次使用TNF抑制剂(阿达木单抗或依那西普)起即被随访的RA患者队列进行了分析。

随访期间，使用TNF抑制剂的患者队列的CV事件发生率为8/1,000人-年，而未使用TNF抑制剂的患者队列为23/1,000人-年，差异显著。校正基线年龄和性别差异的比例风险模型分析显示，TNF抑制剂使CV事件发生率显著降低50%。

van Sijl博士表示，该分析结果证实TNF抑制剂的强力抗炎作用与RA患者CV风险的降低有关，但由于研究设计方面的原因，尚不清楚这是TNF抑制剂的真正作用还是使用TNF抑制剂治疗CV低危患者的一种偏倚。

此外，6月份在伦敦举行的欧洲风湿病学年会上公布的另一项研究也获得相似结果。该研究对超过109,000例美国RA患者的病历进行分析发现，与未使用TNF抑制剂的RA患者相比，TNF抑制剂每治疗6个月，CV事件发生率就降低13%。

Burmester博士声明是阿达木单抗生产商雅培公司的顾问、讲师并从该公司获得研究支持。van Silj博士声明无经济利益冲突。

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By: MITCHEL L. ZOLER, Cardiology News Digital Network

Evidence continues to accumulate that the potent anti-inflammatory effect of drugs that block tumor necrosis factor can significantly dampen cardiovascular-disease risk in patients with rheumatoid arthritis, even though definitive proof from a prospective trial is still lacking.

Two recent pieces of suggestive evidence came from a meta-analysis of four placebo-controlled trials of adalimumab (Humira) that together included nearly 2,500 patients with rheumatoid arthritis, and from two prospective cohort studies of 828 RA patients that compared the outcomes of those treated with either adalimumab or etanercept (Enbrel) to the outcomes of similar patients who did not receive an anti–tumor necrosis factor drug.

In both studies, treatment with an anti-TNF agent was linked to a statistically significant cut in cardiovascular (CV) events of about 50%.

These results support another recent, similar finding reported in June at the Annual European Congress of Rheumatology in London. In that study, analysis of medical records from more than 109,000 U.S. patients with RA showed that every 6 months of treatment with an anti-TNF drug reduced the rate of CV events by 13%, compared with RA patients who did not receive a TNF blocker.

The meta-analysis of four trials included data collected in theARMADA (Arthritis Rheum. 2003;48:35-45), DEO19 (Arthritis Rheum. 2004;50:1400-11), PREMIER (Arthritis Rheum. 2006;54:26-37), andOPTIMA (Ann. Rheum. Dis. 2012 May [doi: 10.1136/annrheumdis-2011-201247]) trials. Collectively, these four studies included 1,411 RA patients treated with both adalimumab and methotrexate, and 1,036 patients who received methotrexate but no anti-TNF drug. At baseline, patients in these two treatment groups had similar demographic and CV disease risk profiles.

During study periods that ranged from 16 to 104 weeks, the incidence of major adverse CV events was 1.3% in patients who received adalimumab, and 2% in those who didn’t. This difference represents a statistically significant, 2/3 drop in the risk for a major CV event in a proportional-hazard model, said Dr. Gerd Burmester, lead investigator for the analysis and a rheumatologist and professor of medicine at Charité Hospital in Berlin. His analysis also showed a statistically significant risk reduction with adalimumab in the rate of nonfatal myocardial infarction, but no significant effect of adalimumab on the rates of nonfatal myocardial infarction or nonfatal stroke compared with patients not receiving adalimumab.

A limitation of the analysis was that none of the four trials was powered to assess CV outcomes, Dr. Burmester said.

The second study used data collected from two cohorts: the CARRÉ(Cardiovascular Research and Rheumatoid Arthritis) study, a prospective Dutch cohort study of 309 randomly selected RA patients who were not treated with a TNF blocker; and the Biologics cohort, which involves 519 Dutch RA patients who have been followed since they began treatment with an anti-TNF drug for the first time, either adalimumab or etanercept.

During follow-up, there were 8 CV events per 1,000 patient-years in the cohort receiving an anti-TNF drug, compared with 23 events per 1,000 patient-years in patients not on an anti-TNF agent, a statistically significant reduction. In a proportional hazards model that adjusted for baseline differences in age and gender, treatment with an anti-TNF agent reduced the rate of CV events by about half, a statistically significant effect, said Dr. Alper M. van Sijl, a researcher at the Reade Centre for Rehabilitation and Rheumatology at the VU Medical Center in Amsterdam.

"Our observations confirm the association between strong suppression of inflammation [with an anti-TNF drug] and curbing the cardiovascular risk in RA," said Dr. van Sijl and his colleagues. But they cautioned that because of the design of the study it remains unclear whether this was a real effect of the anti-TNF drugs, or a bias to treat patients with lower CV disease risk with a TNF blocker.

Dr. Burmester said that he has been a consultant to, served as a speaker for, and received research support from Abbott, the company that markets adalimumab. Dr. van Silj said that he had no disclosures.