ArticlesSafety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial
Introduction
The improvement of cardiovascular outcomes in patients with, or at high risk of, atherosclerotic disease is needed, despite significant reductions in events achieved with low-density lipoprotein cholesterol (LDL-C)–lowering therapies, particularly statins.1, 2, 3 One potential approach to reduce atherosclerotic plaque burden is to raise high-density lipoprotein cholesterol (HDL-C),4, 5 for which epidemiological studies have consistently shown an inverse relation with risk of coronary artery disease.6, 7 Even in statin-treated patients, low HDL-C plasma concentrations are an independent risk factor for cardiovascular events,8, 9 whereas higher levels of HDL-C are associated with reduced plaque progression10 and reduced frequency of cardiovascular events.11
Drugs that act on cholesteryl ester transfer protein (CETP) can result in substantial increases in serum HDL-C. A previously investigated CETP inhibitor, torcetrapib, effectively increased HDL-C, but was associated with an increase in mortality,12 subsequently thought to be due to compound-specific off-target effects, such as increases in blood pressure and vascular inflammation.13 Dalcetrapib is a novel modulator of CETP activity that increases HDL-C.14, 15, 16 To date, its tolerability has been reassuring with no evidence of clinically relevant increases in blood pressure.15, 16, 17 Preclinical experiments in rabbits showed a decrease in atherosclerosis with dalcetrapib;18 however, the direct clinical effects of dalcetrapib on atherosclerosis are unknown.
MRI and PET/CT are promising techniques for assessment of vascular morphology and vascular inflammation, respectively, and for quantification of the effects of drug interventions on plaque stability and burden.19, 20, 21, 22 By directly measuring the effect on the vessel wall of cumulative cardiovascular risk factors combined,23, 24 these non-invasive imaging techniques can serve as valuable biomarkers.25 A multimodality approach with these two techniques to assess dalcetrapib's effects was therefore used in dal-PLAQUE—MRI to measure established classic variables of plaque morphology, and assess the progression or regression of atherosclerosis, and PET/CT measurement of 18F-fluorodeoxyglucose (18F-FDG) uptake to identify plaque inflammation. This 24-month dal-PLAQUE trial is the longest placebo-controlled active-drug MRI study until now, as well as the first to use non-invasive multimodality imaging for primary endpoints. The primary aim of the study was to show, with a dual-imaging approach, whether dalcetrapib causes an increase in atherosclerotic plaque progression or vascular inflammation compared with placebo.
Section snippets
Study design
This phase 2b double-blind, randomised, placebo-controlled study was investigator initiated with the final study protocol designed in collaboration with the sponsor (F Hoffmann-La Roche Ltd). This study was done at 11 centres in Canada and the USA, in compliance with the principles of the Declaration of Helsinki and according to Good Clinical Practice guidelines. The protocol was reviewed and approved by the institutional review board of every centre. All participants provided written informed
Results
Of 189 patients screened, 130 were randomly assigned to either placebo or dalcetrapib 600 mg/day (figure 1). Baseline demographics including risk factors of atherosclerotic disease and coronary heart disease were generally balanced between the two groups (table 1). More patients had coronary heart disease in the dalcetrapib group whereas more had peripheral arterial disease in the placebo group. Despite a slight imbalance in statin use, LDL-C concentrations were well matched in both groups at
Discussion
The primary endpoints for dal-PLAQUE showed dalcetrapib did not increase plaque progression over 24 months or inflammation in the vessel wall over 6 months compared with placebo. For the coprimary PET/CT and MRI endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. These data suggest dalcetrapib might be associated with favourable vascular changes. After 24 months, total vessel area increased less with
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