Physicians' Academy for Cardiovascular Education

dal-PLAQUE: Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging

Literature -

Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE):


Zahi A Fayad, Venkatesh Mani, Mark Woodward, David Kallend, Markus Abt, Tracy Burgess, Valentin Fuster, Christie M Ballantyne, Evan A Stein, Jean-Claude Tardif, James H F Rudd, Michael E Farkouh, Ahmed Tawakol, for the dal-PLAQUE Investigators

Lancet 2011 DOI:10.1016/S0140-6736(11)61383-4


Background

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.


Methods

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.


Findings

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.



Interpretation

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.


Background

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.1-3 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.14-16 To date, its tolerability has been reassuring with no evidence of clinically relevant increases in blood pressure.15-17 Preclinical experiments in rabbits showed a decrease in atherosclerosis with dalcetrapib;18 however, the direct clinical effects of dalcetrapib on atherosclerosis are unknown.

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. 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.


Main results

Dalcetrapib given for 2 years increased HDL-C concentrations by 26•9% (90% CI 20•0–33•9%) without affecting those of low-density lipoprotein cholesterol (LDL-C) and triglycerides.

No adverse effects on the arterial wall or blood pressure were recorded. Dalcetrapib was associated with a reduction in carotid vessel wall inflammation at 6 months (absolute change in average carotid target background ratio was –0•19 [90% CI –0•29 to –0•09; p=0•001] for dalcetrapib versus –0•04 [–0•14 to 0•06; p=0•48] for placebo), as well as a reduced vessel wall area at 24 months (absolute change relative to placebo –4•01 mm² [90% CI –7•23 to –0•80, p=0•04]).
 

Conclusion

The results from this non-invasive multimodality imaging clinical trial of dalcetrapib compared with placebo showed no evidence of a pathological effect of this novel CETP modulator. Moreover, MRI provided evidence of a lower increase in total vessel area after 24 months in patients given dalcetrapib than in those given placebo. Additionally, PET/CT imaging provided an observation of a link between increases in HDL-C concentrations, reductions in vascular inflammation, and subsequent reductions in structural vascular changes. Two large ongoing clinical trials of dalcetrapib, dal-PLAQUE 2, assessing atherosclerotic disease progression by coronary IVUS and carotide B-mode ultrasound (cIMT),19 and dal-OUTCOMES,20 assessing cardiovascular morbidity and mortality, will provide further insights into the therapeutic effects of dalcetrapib. The imaging methods used in dal-PLAQUE were used to detect the effects of dalcetrapib on vascular endpoints; confirmation of the long-term safety and clinical efficacy of dalcetrapib awaits the completion of dal-OUTCOMES.
 

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