心血管生物标记物对临床治疗的助益不大

Both conventional and novel cardiovascular biomarkers are of little value in the clinical management of patients who have or may develop cardiovascular disease, according to two unrelated studies published in the July 1 issue of JAMA.

The first study was designed to determine whether C-reactive protein plays a causal role in coronary heart disease—a topic that remains hotly debated because of the conflicting results of many studies of the issue. The researchers in this study found that CRP does not likely cause CHD, said Dr. Paul Elliott of Imperial College London and his associates.

The investigators first performed a genome-wide association analysis involving nearly 18,000 subjects participating in five large cohort studies and a replication study involving more than 13,000 subjects, to identify the genetic loci associated with CRP levels in different populations. They confirmed that CRP levels correspond with known common genetic variants at several loci.

Then Dr. Elliott and his colleagues compiled data on CRP levels from 35 observational studies involving 28,112 patients with CHD (cases) and 100,823 subjects without CHD (controls), and performed a mendelian randomization study. They found no association between variants in the CRP locus and CHD, “arguing against a causal role for CRP in atherosclerosis” (JAMA 2009;302:37-48).

Previous observational studies that have linked CRP levels with CHD “may be confounded by association with other CHD risk factors, or reflect a secondary inflammatory response associated with atherosclerosis (reverse causation), rather than indicate a causal relationship,” Dr. Elliott and his associates said.

They added that therapies aimed at reducing CRP levels probably will not be effective against CHD.

The second biomarkers study examined the clinical usefulness of measuring two conventional cardiovascular biomarkers—CRP and B-natriuretic peptide (BNP)—and four novel biomarkers—cystatin C, lipoprotein-associated phospholipase 2 (Lp-PLA2), midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP).

The researchers assessed these biomarkers in a population-based cohort of 5,067 middle-aged men and women (mean age 58 years) who did not have cardiovascular disease. There were 418 cardiovascular and 230 cardiac events during a median follow-up of 13 years.

Both individually and in combination, measuring these biomarkers only “minimally improved the accuracy of risk prediction models over and above conventional CV risk factors,” said Dr. Olle Melander of Lund University, Malmö, Sweden, and associates.

“With use of biomarkers, it is possible to define groups with twofold differences in cardiovascular risk. Nonetheless, the translation of this benefit to individual risk prediction appears minimal,” they noted (JAMA 2009;302:49-57).

In particular, adding these biomarkers to standard risk assessment usually would not “result in reclassification of individuals to new, clinically meaningful risk categories,” and would lead to changes in therapy for only an estimated 1% of patients.

Neither Dr. Elliott nor Dr. Melander reported any financial conflicts of interest.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

根据7月1日出版的《美国医学会杂志》(JAMA)上刊登的两个不相关的研究，不论是常规的还是新的心血管生物标记物，对于患有或可能发生心血管疾病的患者的临床治疗，价值都微乎其微。

第一个研究的目的在于确定C反应蛋白是否在冠心病中发挥了因果作用——由于许多研究结果存在分歧，这一话题仍众说纷纭。在此研究中，伦敦皇家学院的Paul Elliot博士及其同事宣称：研究人员发现C反应蛋白不太可能导致冠心病。

研究者首先进行了一个包括近18,000受试者参与的5个大型队列研究的全基因组关联性分析和一个超过13,000受试者的重复性研究，用以鉴别在不同人群中与C反应蛋白水平相关的基因位点。他们证实C反应蛋白水平与已知多处位点的常见遗传变异有关。

然后Elliot博士和同事汇集了28,112名冠心病患者（病例组）和100,823名无冠心病的受试者（对照组）参与的35个观察性研究的C反应蛋白水平的数据 ，并进行了一个孟德尔随机化研究。他们发现C反应蛋白位点的变异与冠心病无关联，“反驳了C反应蛋白在动脉粥样硬化中起到因果作用”（JAMA 2009;302:37-48）。

以前认为C反应蛋白水平与冠心病有关的观察性研究“可能被其他冠心病的风险因素混淆了，或是反映了一个与动脉粥样硬化相关的继发炎症反应（反向因果关系），而并非表明其中存在因果关系，”Elliott博士和同事解释道。

他们补充说，那些以降低C反应蛋白水平为目的的治疗方法对于对抗冠心病可能无效。

第二个生物标记物的研究测量了两种常规的心血管生物标记物——CRP和B型钠尿肽（BNP）和4种新型生物标记物——胱抑素C、脂蛋白相关磷脂酶2 (Lp-PLA2)、肾上腺髓质前体中间肽段 (MR-proADM) 和前体心房钠尿肽中间肽段 (MR-proANP)。

研究者在一个基于5,067名未患心血管疾病中年男性和女性（平均年龄58岁）的人群队列中评估了这些生物标记物。在平均随访的13年中出现了418例心血管事件和230例心脏病事件。

无论是单独还是联合，测量这些生物标记物仅能“最低限度地提高常规心血管风险因素基础上的风险预测模型的准确度”，瑞典马尔默隆德大学的Olle Melander博士和同事说。

他们指出，“通过使用生物标记物，其可能区分在心血管疾病风险方面具有两倍差异的组别。 然而，将这一优点转化为来预测个体风险的作用似乎很小。” (JAMA 2009;302:49-57)。

特别是添加这些生物标记物到标准的风险评估中通常不会“导致个体被重新分类于新的、具有临床风险意义的类别中”，并且估计仅会导致1%的患者的治疗方案发生改变。

Elliot和Melander博士均未作任何经济利益冲突声明。 

爱思唯尔  版权所有