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.

In a small village in northern Italy called Limone sul Garda live approximately 40 carriers with a naturally occurring variant of apolipoprotein A-I known as ApoA-I Milano. Individuals with ApoA-I Milano are characterized by very low levels of high-density lipoprotein cholesterol (HDL-C) (10-30 mg/dL [0.25-0.78 mmol/L]), apparent longevity,¹ and much less atherosclerosis than expected for their HDL-C levels.² The ApoA-I Milano protein differs from native ApoA-I in that cysteine is substituted at position 173 for arginine allowing disulfide-linked dimer formation. Recombinant ApoA-I Milano has been formulated in a complex with a naturally occurring phospholipid to mimic the properties of nascent HDL (ETC-216, Esperion Therapeutics, Ann Arbor, Mich). Studies in mice and rabbits with experimental atherosclerosis have demonstrated that rApoA-I Milano/phospholipid complexes rapidly mobilize cholesterol and thereby reduce atherosclerotic plaque burden. The antiatherosclerotic effects (reductions in plaque lipid and macrophage content) occur in animals as rapidly as 48 hours after a single infusion.³

We hypothesized that short-term weekly infusions of ETC-216 might rapidly regress coronary atherosclerosis in patients following an acute coronary syndrome (ACS). To test this hypothesis, we conducted a prospective, randomized, double blind, placebo-controlled clinical trial of ETC-216 using intravascular ultrasound (IVUS) to measure atheroma burden. Intravascular ultrasound is an imaging modality that provides detailed images of the vessel wall using a using a high-frequency (40 MHz) miniaturized transducer.⁴ A motorized pullback device is used to generate cross-sectional images throughout the length of the vessel, enabling precise quantification of atherosclerotic disease burden. This approach has been used recently in studies designed to assess the effect of pharmacological agents on atherosclerosis.^5-7 We used IVUS to measure change in atheroma volume after a regimen consisting of 5 infusions of ETC-216 or placebo at weekly intervals.

URL : https://jamanetwork.com/journals/jama/fullarticle/197579