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A Randomized Controlled Trial

Steven E. Nissen, MD; Taro Tsunoda, MD; E. Murat Tuzcu, MD; Paul Schoenhagen, MD; Christopher J. Cooper, MD; Muhammad Yasin, MD; Gregory M. Eaton, MD; Michael A. Lauer, MD; W. Scott Sheldon, DO; Cindy L. Grines, MD; Stephen Halpern, MD; Tim Crowe, BS; James C. Blankenship, MD; Richard Kerensky, MD

JAMA. 2003;290:2292-2300.

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.

Author Affiliations: Department of Cardiovascular Medicine (Drs Nissen, Schoenhagen, and Tuzcu and Mr Crowe) and Diagnostic Radiology (Dr Schoenhagen), Cleveland Clinic Foundation, Cleveland, Ohio; Toho University School of Medicine, Tokyo, Japan (Dr Tsunoda); Division of Cardiology, Department of Medicine, Medical College of Ohio, Toledo (Dr Cooper); Department of Internal Medicine and Cardiac Diseases, Integris Southwest Medical Center, Oklahoma City, Okla (Dr Yasin); Cardiac Catheterization Program Medcentral Health Systems and Department of Cardiology, Mid Ohio Heart Clinic, Mansfield (Dr Eaton); Angiographic Core Laboratory and Department of Cardiology, Borgess Heart Institute, Kalamazoo, Mich (Dr Lauer); Department of Cardiology, North Ohio Heart Center, Elyria (Dr Sheldon); Cardiac Catheterization Laboratory Division of Cardiac Diseases, William Beaumont Hospital, Royal Oak, Mich (Dr Grines); Coronary Unit, Department of Cardiology, Warrack Hospital and Radiant Research, Santa Rosa, Calif (Dr Halpern); Cardiac Catheterization Laboratories and Cardiovascular Outpatient Monitoring Unit, Department of Cardiology, Geisinger Medical Center, Danville, Pa (Dr Blankenship); and Division of Cardiology, Department of Medicine, University of Florida, Gainesville (Dr Kerensky).

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