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Effects of rHDL on Atherosclerosis–Safety and Efficacy - ERASE – Presented at ACC 2007
Description:
The goal of the trial was to evaluate the effect on plaque burden of reconstituted high-density lipoprotein (rHDL) compared with placebo among patients with recent acute coronary syndromes.
Study Design
Study Design:
Patients Screened: 381
Patients Enrolled: 183
Mean Follow Up: 6 weeks
Mean Patient Age: Mean age, 58 years
Female: 17
Patient Populations:
Age 30-75 years; clinical need for coronary angiography, defined as ≥1 narrowing ≥20% in coronary angiography at baseline; and within 2 weeks of having an acute coronary syndrome defined as unstable angina or non–ST-segment or ST-segment elevation MI
Exclusions:
Stenosis ≥50% in the left main coronary artery; renal insufficiency, liver disease, active cholecystitis, or gall bladder symptoms; uncontrolled diabetes mellitus; New York Heart Association class III or IV heart failure; known soybean allergy; history of alcohol or drug abuse; planned treatment with warfarin or heparin during the study infusion period; or previous or planned coronary artery bypass graft surgery.
Primary Endpoints:
Percentage change in atheroma volume from baseline to 6 weeks
Secondary Endpoints:
Absolute change in plaque volume; change in plaque characterization indexes on IVUS; and change in coronary score (defined as the per-patient mean of the minimal lumen diameter for all lesions measured) on quantitative coronary angiography
Drug/Procedures Used:
Patients were randomized in a double-blind manner to treatment with CSL-111 40 mg/kg (n = 111), CSL-111 80 mg/kg (n = 12), or matching placebo (n = 60). Study drug was administered via infusions once a week for 4 weeks. The 80 mg group was discontinued due to an increase in liver function test abnormalities after only 12 patients were enrolled in the arm. Patients underwent intravascular ultrasound (IVUS) at baseline and 6 weeks.
Principal Findings:
At study entry, mean HDL was 42.1 mg/dl and mean low-density lipoprotein (LDL) was 81.9 mg/dl. The large majority of patients were on a lipid-lowering agent (91.3%) and were dyslipidemic (98.9%). Diabetes was present in 20% of patients, and 20% had a prior myocardial infarction (MI).
The primary endpoint of percent change in atheroma volume from baseline to 6 weeks did not differ between treatment groups (-3.4% in the CSL-111 group vs. -1.6% in the placebo group; p = 0.48 between groups), nor did the absolute change in atheroma volume (−5.3 mm3 vs. −2.3 mm3, p = 0.39). The change in atheroma volume at 6 weeks within the CSL-111 group was different from baseline (p < 0.001) and trended toward a significant reduction within the placebo group (p = 0.07). Mean change in plaque characterization index on IVUS was −0.0097 for CSL-111 and +0.0128 for placebo (p = 0.01). Reduction in coronary score on angiography was less with CSL-111 compared with placebo (−0.039 mm for CSL-111 vs. −0.071 mm for placebo; p = 0.03).
Adverse events occurred with a similar frequency in the CSL-111 40 mg and placebo treatment groups. Hypotension was more likely to occur in the CSL-111 40 mg group than the placebo group (13.8% vs 7.1%). The 80 mg CSL-111 group was discontinued due to high rates of abnormal liver function tests, including alanine aminotransferase >5 times the upper limit of normal (ULN) in 50% of the group and aspartate aminotransferase >5x ULN in 33% of the group.
Interpretation:
Among patients with recent acute coronary syndromes, treatment with the novel reconstituted HDL agent CSL-111 was associated with a change in atheroma volume within the treatment arm from baseline to 6-week follow-up, but was not associated with a reduction in atheroma volume compared with placebo.
CSL-111 is an apolipoprotein A-I isolated from human plasma and phosphatidylcholine derived from soybean. Therapies targeting raising HDL cholesterol levels have shown mixed results. Commercial development of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib was recently stopped after a large trial showed an increase in mortality with torcetrapib. The present compound is a different class of agents targeting increasing HDL, and is not a CETP inhibitor, but is derived from human plasma. The lipid effects of the agent in the study were not reported. A larger trial would be required to evaluate the clinical safety and efficacy of this agent.
References:
Tardif JC, Gregoire J, L'allier PL, et al. Effects of Reconstituted High-Density Lipoprotein Infusions on Coronary Atherosclerosis: A Randomized Controlled Trial. JAMA 2007;297; 1675-1682.
Presented by Dr. Jean-Claude Tardif at the American College of Cardiology Annual Scientific Session, New Orleans, LA, March 2007.
Keywords: Phosphatidylcholines, Coronary Artery Disease, Myocardial Infarction, Atherosclerosis, Plaque, Atherosclerotic, Hypotension, Apolipoprotein A-I, Liver Function Tests, Cholesterol Ester Transfer Proteins, Coronary Angiography, Cholesterol, HDL, Ultrasonography, Interventional, Diabetes Mellitus, Soybeans
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