Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.
Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.
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DOI：
10.1016/s0140-6736(11)61383-4
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发表时间：
2011-10-29
期刊：
影响因子：
168.9
通讯作者：
Tawakol, Ahmed
中科院分区：
文献类型：
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作者：
Fayad, Zahi A.;Mani, Venkatesh;Woodward, Mark;Kallend, David;Abt, Markus;Burgess, Tracy;Fuster, Valentin;Ballantyne, Christie M.;Stein, Evan A.;Tardif, Jean-Claude;Rudd, James H. F.;Farkouh, Michael E.;Tawakol, Ahmed
Dalcetrapib调节胆固醇酯转移蛋白（CETP）活性，提高高密度脂蛋白胆固醇（HDL-C）。torcetrapib失效后，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症特性。dal-PLAQUE是首个使用新型无创多模态成像来评估动脉粥样硬化的结构和炎症指标作为主要终点的多中心研究。在这项2b期、双盲、多中心试验中，患有或高风险冠心病的患者（18-75岁）被随机（1:1）分配到dalcetrapib 600mg /天或安慰剂组，为期24个月。随机化使用计算机生成的随机化代码进行，并按中心分层。患者和调查人员被蒙面接受治疗。主要终点是24个月后mri评估指标（总血管面积、壁面积、壁厚和归一化壁指数[平均颈动脉]）和6个月后18f -氟脱氧葡萄糖（18F-FDG） PET/CT评估指标血管（右颈动脉、左颈动脉或胸升主动脉）内动脉炎症，在试验解盲前建立无伤害界限。分析的目的是治疗。该试验注册在ClinicalTrials.gov, NCT00655473。189名患者被筛选，130名随机分配到安慰剂组（66名患者）或dalcetrapib组（64名患者）。对于主要的MRI和PET/CT终点，dalcetrapib组的CIs低于无伤害边界，或者不良变化的数值低于安慰剂组。24个月后，与服用安慰剂的患者相比，服用dalcetrapib的患者的mri衍生的总血管面积变化减少；相对于安慰剂，基线的绝对变化为- 4.01 mm2 （90% CI为- 7.23至- 0.80；标称p= 0.04）。PET/CT测量的指数血管最病变段靶背景比（TBR）在两组之间没有差异，但颈动脉分析显示，与安慰剂组相比，dalcetrapib组最病变段TBR降低了7% （- 7.3 [90% CI - 13.5至- 0.8]；标称p= 0.07）。Dalcetrapib没有增加办公室血压，两组之间不良事件的频率相似。在24个月的时间里，Dalcetrapib没有显示出与动脉壁相关的病理效应。此外，该试验提示dalcetrapib可能对血管有益，包括在24个月内减少血管总扩张，但dalcetrapib的长期安全性和临床疗效有待分析。罗氏有限公司
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 18F-fluorodeoxyglucose (18F-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 mm2 (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.