Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.

By S. Nissen, T. Tsunoda, E. Tuzcu, Paul-Henry Schoenhagen, C. Cooper, M. Yasin, G. Eaton, M. Lauer, W. Sheldon, C. Grines and 4 more. Journal of the American Medical Association (JAMA), 2003

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CONTEXT Although low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for coronary disease, no data exist regarding potential benefits of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of apolipoprotein A-I identified in individuals in rural Italy who exhibit very low levels of HDL. Infusion of recombinant ApoA-I Milano-phospholipid complexes produces rapid regression of atherosclerosis in animal models. OBJECTIVE We assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes (ACS). DESIGN The study was a double-blind, randomized, placebo-controlled multicenter pilot trial comparing the effect of ETC-216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS). SETTING Ten community and tertiary care hospitals in the United States. PATIENTS Between November 2001 and March 2003, 123 patients aged 38 to 82 years consented, 57 were randomly assigned, and 47 completed the protocol. INTERVENTIONS In a ratio of 1:2:2, patients received 5 weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed within 2 weeks following ACS and repeated after 5 weekly treatments. MAIN OUTCOME MEASURES The primary efficacy parameter was the change in percent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy measures included the change in total atheroma volume and average maximal atheroma thickness. RESULTS The mean (SD) percent atheroma volume decreased by -1.06% (3.17%) in the combined ETC-216 group (median, -0.81%; 95% confidence interval [CI], -1.53% to -0.34%; P =.02 compared with baseline). In the placebo group, mean (SD) percent atheroma volume increased by 0.14% (3.09%; median, 0.03%; 95% CI, -1.11% to 1.43%; P =.97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was -14.1 mm3 or a 4.2% decrease from baseline (P<.001). CONCLUSIONS A recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. Although promising, these results require confirmation in larger clinical trials with morbidity and mortality end points.

Subfields: Endocrinology, Diabetes and Metabolism, Epidemiology, Pulmonary and Respiratory Medicine

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Citations in the corpus

Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport (2012, background): “The initial clinical data to suggest that infusions of HDL-VS (preβ-HDL) would be effective in decreasing coronary atherosclerosis was provided by the apoA-I Milano infusion study (40).”
Progress and challenges in translating the biology of atherosclerosis (2011, background): “Apolipoprotein A-I (Apo-AI), the major protein component of HDL, has received much attention as a possible therapeutic target for atherosclerosi”
Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis (2006, background): “…atherogenesis and the cholesterol efflux capacity of HDL particles, although infusion of apoA-I Milano/phospholipid complex has been shown to lead to a reduction in atheroma volume in patients with acute coronary syndromes, suggestive of plaque cholesterol efflux (Nissen et al., 2003) (see below).”
Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. (2006, methodology): “Using this more conservative end point, only a small study of patients administered an intravenous HDL-C mimetic (apolipoprotein A-1 Milano phospholipid) has previously shown regression.(11) Designing a contemporary IVUS regression-progression trial creates major challenges that warrant further comm”
Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. (2016, background): “c Clinically significant heart disease (154), hyperthyroidism or hypothyroidism (38), type 1 diabetes (27), history of malignancy (16), fasting triglyceride level greater than 400 mg/dL (4.”