Translational and Molecular Imaging Institute and Department of Radiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Lancet. 2011 Oct 29;378(9802):1547-59. doi: 10.1016/S0140-6736(11)61383-4. Epub 2011 Sep 9.
Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.
In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473.
189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.
Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed.
F Hoffmann-La Roche Ltd.
达塞曲匹可调节胆固醇酯转移蛋白（CETP）的活性，从而提高高密度脂蛋白胆固醇（HDL-C）。在 torcetrapib 失败后，尚不清楚与 CETP 相互作用产生的 HDL 是否具有促动脉粥样硬化或促炎特性。dal-PLAQUE 是第一项使用新型多模态非侵入性成像技术评估动脉粥样硬化结构和炎症指标的多中心研究，这些指标为主要终点。
在这项 2b 期、双盲、多中心试验中，患有或有冠心病风险的患者（年龄 18-75 岁）被随机分配（1:1）接受达塞曲匹 600mg/天或安慰剂治疗 24 个月。随机分配采用计算机生成的随机分配码，并按中心分层。患者和研究人员对治疗情况不知情。主要终点是 24 个月时 MRI 评估的指数（总血管面积、壁面积、壁厚度和正常化壁指数[平均颈动脉]）和 6 个月时（18）F-氟脱氧葡萄糖（（18）F-FDG）正电子发射断层扫描/计算机断层扫描（PET/CT）评估指数血管（右颈动脉、左颈动脉或升主动脉）内的动脉炎症，在试验揭盲前确定了无伤害边界。分析是基于意向治疗。这项试验在 ClinicalTrials.gov 注册，NCT00655473。
189 名患者接受了筛选，130 名患者被随机分配至安慰剂（66 名患者）或达塞曲匹组（64 名患者）。对于主要的 MRI 和 PET/CT 终点，置信区间低于无伤害边界，或达塞曲匹组的不良变化在数值上低于安慰剂组。与安慰剂组相比，接受达塞曲匹治疗的患者在 24 个月时的总血管面积变化降低；与安慰剂相比，从基线相对变化的绝对值为-4.01mm2（90%CI-7.23 至-0.80；名义 p=0.04）。两组之间指数血管中最严重病变节段目标与背景的比值（TBR）无差异，但颈动脉分析显示达塞曲匹组的最严重病变节段 TBR 较安慰剂组降低了 7%（-7.3[90%CI-13.5 至-0.8]；名义 p=0.07）。达塞曲匹没有增加诊室血压，两组不良反应的发生频率相似。
达塞曲匹在 24 个月内没有显示出与动脉壁相关的病理性作用的证据。此外，这项试验表明达塞曲匹可能具有有益的血管作用，包括 24 个月内总血管扩张的减少，但达塞曲匹的长期安全性和临床疗效仍需要分析。
罗氏制药有限公司。
