试验将已在服用一种他汀药物的受试者随机分配接受烟酸缓释剂或依折麦布，当中期分析显示烟酸在主要终点即 颈动脉内膜中层厚度（CIMT）的改变上具有优势时，该试验被提前终止。该研究终止后，另有107例受试者完成了 结束评估。

    烟酸致使平均和最大CIMT显著降低（逆转），而依折麦布治疗未引起显著改变。进一步分析将增加的 累计药物暴露与烟酸治疗较依折麦布较大幅度地逆转CIMT联系起来。在服用他汀的患者中，烟酸诱导了CIMT逆转 且在这一终点上优于依折麦布。

J Am Coll Cardiol 2010；55: 2721-2726

点 评

Oliver Weing??1rtner??¨ Michael B??hm. Saarland University Hospital， Homburg/Saar， Germany

     The ARBITER 6-HALTS Trial: too early for a change in paradigm in the treatment of hypercholesterolemia? Reducing the residual cardiovascular （CV） risk in statin-treated patients is a challenge in preventive cardiology. The ARBITER-6 HALTS Trial aimed to investigate this important issue. The final evaluation demonstrated the superiority of niacin， which reduces not only LDL-C but also triglycerides and Lp(a) and is currently the most potent drug for increasing HDL-C， over ezetimibe in statin-treated patients. However， the premature termination of the study was unfortunate and might have exaggerated potential benefits of niacin therapy. Moreover， if the results of ARBITER-6 are due to the effect of niacin on HDL-C， LDL-C， LP(a)， or any combination of these cannot be elucidated by currently available data.

    In addition， the results have to be interpreted with caution for several reasons: First， the ARBITER 6-Trial is small and patients included were highly selected; most of the enrolled patients were treated with statins for several years prior to enrolment， resulting in an average baseline LDL-cholesterol of 82 mg/dl (2.13 mmol/l). They thus do not represent the general population including patients with higher LDL-C. Second， HDL-C levels at baseline (42 mg/dl; 1.1 mmol/l) were low. Niacin can increase HDL-C while ezetimibe has virtually no impact on HDL-C. It is thus questionable whether the results would have been the same in a population with higher HDL-C levels. Third， the use of CIMT as a surrogate marker for coronary atherosclerosis is controversial since therapies other than niacin have been shown to retard the progression of CIMT， but do not reduce the incidence of CV events. Most importantly， the clinical effect of ezetimibe cannot be extrapolated from measurements of CIMT. The results of the JUPITER Trial demonstrated that rosuvastatin therapy is associated with a reduction of CV events， despite a lack of impact on CIMT. Moreover， recent studies suggested that patients with high cholesterol absorption might specifically benefit from ezetimibe that inhibit cholesterol absorption. Since markers of cholesterol metabolism were not assessed in the ARBITER 6-Trial， no comments can be made in this regard. Finally， drug tolerance and patient compliance play a pivotal role in reducing serum cholesterol levels and CV risk. ARBITER 6-Trial demonstrated the significant side effects and concomitant higher drop-out rates with niacin treatment compared to ezetimibe.

    Taken together， Firm conclusions of reducing residual CV risk in statin-treated patients must await the findings of large scale studies involving clinical endpoints. Some upcoming trials include the Improved Reduction of Outcomes Efficacy International Trial (IMPROVE-IT) assessing the effect of ezetimibe/simvasatin on high-risk acute coronary syndrome(ACS)， the AIM-HIGH trial， studying the effect of extended-release niacin combined with simvastatin on myocardial infarction， stroke， and ACS， and the HPS2-THRIVE trial evaluating the combination of niacin and laropiprant. These trials will provide hard clinical endpoints， which are necessary for a better understanding of the relationship between lipid metabolism and CV risk.

内容摘要

ARBITER 6-HALTS试验：改变高胆固醇血症的治疗模式为时尚早

    他汀治疗患者的剩留心血管（CV）风险 仍是预防心脏病学面临的重要挑战。ABRITER-6 HALTS试验提示他汀基础上联合烟酸优于联合依折麦布，但该试验 提前终止可能导致夸大了烟酸的益处。应谨慎解读这一试验的阳性结果：① 样本量小，入选患者已接受长期他 汀治疗，基线LDL-C仅82 mg/dl，不能代表整体人群；② 基线HDL-C水平低，该策略用于高HDL-C患者能否获益存 在疑问；③ 以CIMT作为冠状动脉硬化标志物存在争议，延缓或逆转CIMT并不等同于临床CV事件的减少，依折麦布 的临床效应亦不能以CIMT测量来评价；④近期研究表明，胆固醇高吸收者可从抑制胆固醇吸收的依折麦布治疗获 益，而ARBITER-6试验并未评价脂代谢标志物；⑤ 良好的药物耐受性和患者依从性对降低血脂和CV风险至关重要 ，而ARBITER-6试验中烟酸组不良反应和退出治疗的患者比例均显著高于依折麦布组。

    IMPROVE-IT（在高危ACS患 者中评估依折麦布/辛伐他汀的效应）、AIM-HIGH（评价缓释烟酸联合辛伐他汀对MI、卒中和ACS的影响）、HPS2 -THRIVE（评估烟酸联合laropiprant复方制剂）等多项纳入临床硬终点的大型试验将对他汀治疗患者剩留CV风险 控制的许多悬而未决的问题做出解答。 Interventional Cardiology