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Abstract & Commentary
This widely publicized small trial has catapulted the mutant form of ApoA-1 Milano into the limelight. Many investigators have been working with this interesting lipoprotein since it was discovered in the 1980s that 38 carriers from a small village in Northern Italy have very low HDL levels but very little vascular disease. The substitution of a cysteine moiety for an arginine in the lipoprotein ApoA-1 complex results in ApoA-1 Milano, which appears to have marked protective qualities with respect to the development of atherosclerosis. Esperion, a small biotech company, has produced a recombinant form of ApoA-1 Milano complexed with phospholipids.
In this study, 47 patients who presented with an acute coronary syndrome within 14 days completed the protocol, consisting of 5 weekly intravenous injections of the recombinant ApoA-1 Milano/phospholipid complex. The experimental agent was given in 2 doses, with randomization to placebo and active treatment in a 1:2:2 treatment group ratio. Five doses of placebo or the lipoprotein were given in blinded fashion over 5 weeks. All subjects had IVUS investigation of their coronary tree before treatment and within 2 weeks following the final dose. Inclusion criteria included the presence of at least a 20% narrowing in a major epicardial coronary vessel with no more than a 50% narrowing, and a minimum target atherosclerotic segment length of 30 mm; this was the segment used for analysis. Assessment of the global atheroma volume of the artery, as well as the maximal average change in the atheroma thickness and change in atheroma volume within the most and least severely diseased 10 mm long segments in the vessel, was chosen for evaluation.
Images were obtained at 30 frames per second every millimeter with a mechanical motorized pullback. Slices of 0.5 mm each were obtained over a pullback length of 30-80 mm. Analyses of the crosssectional area inside and outside the external elastic membrane were made within the atheroma area, as well as with maximum measurable atheroma thickness. Coronary angiography was also performed and the angiographic end point was a change in mean coronary diameter at baseline and follow-up. A total of 4000 IVUS cross sections were analyzed at the core laboratory at the Cleveland Clinic; the mean pullback length was 49 mm, resulting in an average of 86 analyzable cross sections per patient. The primary end point was a change in percent atheroma volume at the end of the study in the combined 2 active treatment groups. Thus, a positive result would be a negative change in percent atheroma volume (decreased in athero ma).
In the placebo patients, the mean change was 0.14%, with a median change of 0.03% , neither different from baseline. However, the combined treatment groups that received ApoA-1 Milano had a reduction in percent mean atheroma volume of 1.06%, with a 0.8% reduction in the median volume (P = .02). Secondary end points included mean total atheroma volume, which decreased in the active treatment cohort by 14.1 mm3 (P = .001) vs a change of -2.9 mm3, compared to baseline (P = NS). The maximal atheroma thickness in the active treatment group was -0.04 mm, median change -0.03 mm (P < .001). In the placebo patients, the thickness change was -0.008, median 0.009, which was not significant. There was predominant regression of atheroma disease in the most severely diseased 10 mm segment (P < .001) but no treatment effect noted in the less severely diseased sub segments. Neither placebo nor the combined treatment subgroups had a demonstrable alteration in luminal diameter on coronary angiography.
Nissen and associates conclude that "the current study provides compelling evidence of atherosclerosis regression following short-term treatment with the exogenous HDL mimetic . . . these results should be confirmed in a larger, long-term study with clinical end points." Nissen et al point out that the degree of regression was substantially greater over 5 weeks than the changes noted in prior positive angiographic trials, with a 1% decrease in atheroma volume and -4.2% in global atheroma volume in the ApoA-1 Milano cohorts. Much of the reduction in atherosclerosis burden occurred within the vessel wall internal to the external elastic membrane; furthermore, regression of disease was greatest in the most severely diseased 10 mm subsegment (P < .001).
Nissen et al stress "the rapidity and magnitude of the changes in atherosclerotic disease burden" and suggest that this is the most rapid regression of atherosclerosis yet documented. They stress that the degree of regression over 5 weeks was greater than that found in 3 years in the HATS trial with simvastatin and niacin. They believe that the mechanism of ApoA-1 Milano/phospholipid in diminishing atherosclerosis is probably due to enhanced reversed cholesterol transport, and they postulate that this compound forms a large HDL particle that "may be particularly active" in this regard, concordant with in vitro experiments. The speed of regression suggests a "more dynamic process," and Nissen et al postulate that if these results can be replicated, drugs that work to enhance reverse cholesterol transfer might be used immediately following an acute coronary syndrome for weeks to months, with conversion to oral statin later. Nissen et al emphasize that the IVUS technique, providing a 360° view of the blood vessel wall, permits "shorter duration studies in smaller numbers of patients than previously possible from interventional methods." Finally, Nissen et al make the point that their study represents a "proof of concept" approach that "must be explored in larger trials" (Nissen SE, et al. JAMA. 2003;290:2292-2300).
Comment by Jonathan Abrams, MD
This publication suggests a truly exciting approach to reversing atherosclerosis. This was the first of 2 recently reported trials that have induced an era of IVUS-mania. At the American Heart Association meeting in Orlando, Nissen also presented the results of the REVERSAL trial, which also used intravascular ultrasound, demonstrating that a high dose of atorvastatin was able to prevent progression of coronary atherosclerosis over an 18-month period, when compared to 40 mg of pravastatin, which was associated with continued progression of the disease. It is unlikely that large IVUS trials with thousands of patients would be practical; we should anticipate expansion of smaller trials because of the compressed time interval in which to make observations of treating atherosclerosis with a variety of pharmacology approaches, including new lipid approaches such as cholesterol ester transport protein inhibitors or enhanced ABCA-1 transporter activity. An important point to remember is that in the ApoA-1 Milano trial, angiographic evidence supporting regression was not demonstrated, thus emphasizing the remarkable sensitivity of the IVUS method, allowing for regression to be seen in just over 1 month. Whether ApoA-1 Milano will become an effective therapy is unknown at this time. There does not appear to be an oral formulation. The questions and problems stimulated by this study are elegantly discussed in an accompanying editorial by Dan Rader.1 His comments are highly recommended to the interested reader.
It would appear that at least 2 major developments from this fascinating study are noteworthy: 1) The recombinant mutant ApoA-1 Milano induced regression of atherosclerosis with results that are concordant with many previous observations made with HDL arising from this noted Italian town where the naturally occurring variant A-1 lipoprotein was first discovered more than 20 years ago; and 2) The IVUS technique, available for many years and particularly popularized by Nissen et al at the Cleveland Clinic, appears to be a very promising technique for the rapid evaluation of lipid-modifying approaches. I believe that these results firmly underscore the reality that our view of dyslipidemia being LDL-centric needs to be modified. It is often stated that low HDL is a better independent predictor of coronary disease than high LDL. This study should encourage those investigating various aspects of reverse cholesterol transport or other approaches for attacking atherosclerosis, as mentioned above. The future looks bright. This study is but one battle, yet it signifies that perhaps the war against atherosclerosis can ultimately be won.
Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.
1. Rader DJ. JAMA. 2003;290:2322-2324.