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|Objective:||To investigate the effects of CER-001, an HDL mimetic comprising a combination of recombinant human apolipoprotein A-I (apoA-I) and two phospholipids, on atherosclerosis using IVUS and QCA.|
|Study design:||Prospective, double-blinded, randomized ascending dose trial in 51 centres (USA, the Netherlands, Canada, and France). IVUS and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2–5) weeks after the last study infusion.|
In total, 507 patients with ACS in the last 14 days (unstable angina [44-59%], non-ST segment elevation myocardial infarction [32-49%] or ST-segment elevation myocardial infarction [5-10%]) were randomized; 417 and 461 had paired IVUS and QCA measurements. All patients had a clinical indication for coronary angiography and a research-mandated IVUS recording approved by the IVUS core laboratory.
• Nominal change (follow-up minus baseline) in total atheroma volume on IVUS. Other pre-specified endpoints were the nominal change in per cent atheroma volume on IVUS, and the nominal changes in the coronary artery score (per cent diameter stenosis of all lesions measured) on QCA.
At baseline, patients underwent a baseline IVUS examination of the designated target coronary artery. Eligible patients were randomized (3:1) to receive 6 weekly infusions of placebo or CER-001 (3 mg/kg, 6 mg/kg, or 12 mg/kg). Three weeks after the last study infusion (2–5 week window), a follow-up IVUS examination was performed in the same segment of the target artery studied at baseline. Patients were also followed-up at 6 months after the last dose of study treatment for major adverse cardiovascular events and anti-apoA-I antibodies.
The primary analysis was based on the modified intent-to-treat population, which included all randomized subjects with a post-randomization efficacy recording, irrespective of their protocol adherence. The primary endpoint was analysed using an analysis of a covariance model that included the treatment group and baseline value as a covariate. The adjusted mean in the CER-001 12 mg/kg group was compared with the adjusted mean in the placebo group at the 0.05 significance level as the primary analysis. Data for the other CER-001 groups (6 and 3 mg/kg) were also compared with placebo using the same analysis model.
CER-001 had no positive effects on coronary atherosclerosis, as evaluated by IVUS and QCA. CER-001was generally well tolerated during the study. The proportion of patients with major cardiovascular (CV) events was similar across the groups. Key findings are summarised in Table 1.
*Statistical significance for primary analysis p=0.81
|Authors’ conclusion:||CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study.|
There is indisputable epidemiologic evidence that a low plasma level of HDL cholesterol is associated with increased risk of cardiovascular disease complications.1 There is also evidence that low plasma HDL cholesterol is a predictor for the risk of recurrent cardiovascular events in the short-term in patients with ACS.2 Such findings underlie thinking that specifically targeting HDL may offer potential for reducing the high level of residual cardiovascular risk that persists in high-risk individuals receiving best evidence-based treatment.
ACS patients are at highest residual cardiovascular risk, with ~10% of recurrent events occurring within the first 6–12 months, and ~20–30% within 2 years.3-5 There is some evidence to suggest that HDL infusions may have favourable effects on atherosclerotic burden in such high-risk patients.6-8 Based on these findings, the current study investigated the potential of CER-001, an HDL mimetic, for reducing atherosclerosis or atheroma progression in ACS patients receiving best evidence-based treatment, including statins.
Yet despite a large prospective placebo-controlled design, the study failed to show any benefit with any dose of CER-001 on coronary atherosclerosis. These findings are consistent with other imaging studies in ACS patients which have so far failed to show significant benefit versus placebo on coronary atherosclerosis burden.6,7 The authors have questioned whether the dosing regimen, composition of the investigational treatment, or patient population may have been limiting factors. Indeed, in the dal-OUTCOMES study,9 there was no significant benefit on major cardiovascular events with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib, which specifically targeted HDL. Given that there was also no evidence of any association between baseline plasma HDL-C concentration and risk for major cardiovascular events in this patient population, has led some to postulate that the potentially atheroprotective activities of HDL are functionally defective in the inflammatory ACS setting, and therefore HDL may be less able to prevent coronary atherosclerosis progression and the ensuing clinical events. However, such speculation is based on in vitro experimental findings.
So what do the results of this study mean for the potential role of HDL in residual risk?
First, it must be noted that there were no specific inclusion criteria regarding plasma HDL-C levels in CHI-SQUARE. Therefore, such a question cannot be answered by this study. Furthermore, the lack of benefit on coronary atherosclerosis observed in CHI-SQUARE implicates other factors in residual cardiovascular risk. A low plasma HDL cholesterol concentration is also commonly associated with elevated triglycerides; this dyslipidaemic profile is a key driver of atherogenic risk in individuals with metabolic syndrome and/or type 2 diabetes.10 Indeed, as discussed in this month’s Focus article, there is renewed enthusiasm for a role for triglyceride-rich lipoproteins and their remnants in the high level of persistent residual cardiovascular risk in high-risk patients.
1. Boden WE. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High--Density Lipoprotein Intervention Trial. Am J Cardiol 2000;86:19L–22L.
|Key words||high-density lipoprotein (HDL); CER-001; apoA-I mimetic; coronary atherosclerosis; acute coronary syndrome; clinical trial|