ContextAlthough 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.ObjectiveWe assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid
complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes
(ACS).DesignThe 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).SettingTen community and tertiary care hospitals in the United States.PatientsBetween November 2001 and March 2003, 123 patients aged 38 to 82 years
consented, 57 were randomly assigned, and 47 completed the protocol.InterventionsIn 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 MeasuresThe 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.ResultsThe 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).ConclusionsA 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.

https://jamanetwork.com/journals/jama/articlepdf/197579/jpc30068_2292_2300.pdf

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

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors)
are associated with skeletal muscle complaints, including clinically important
myositis and rhabdomyolysis, mild serum creatine kinase (CK) elevations, myalgia
with and without elevated CK levels, muscle weakness, muscle cramps, and persistent
myalgia and CK elevations after statin withdrawal. We performed a literature
review to provide a clinical summary of statin-associated myopathy and discuss
possible mediating mechanisms. We also update the US Food and Drug Administration
(FDA) reports on statin-associated rhabdomyolysis. Articles on statin myopathy
were identified via a PubMed search through November 2002 and articles on
statin clinical trials, case series, and review articles were identified via
a PubMed search through January 2003. Adverse event reports of statin-associated
rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature
review found that reports of muscle problems during statin clinical trials
are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of
statin-associated rhabdomyolysis reported between January 1, 1990, and March
31, 2002. Cerivastatin was the most commonly implicated statin. Few data are
available regarding the frequency of less-serious events such as muscle pain
and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis
and other adverse effects with statin use can be exacerbated by several factors,
including compromised hepatic and renal function, hypothyroidism, diabetes,
and concomitant medications. Medications such as the fibrate gemfibrozil alter
statin metabolism and increase statin plasma concentration. How statins injure
skeletal muscle is not clear, although recent evidence suggests that statins
reduce the production of small regulatory proteins that are important for
myocyte maintenance.

https://jamanetwork.com/journals/jama/articlepdf/196305/JSC20298.pdf

Statin-Associated Myopathy

ContextHigh-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression.ObjectiveTo investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS).Design and SettingA randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2 to 3 weeks after the last study infusion.PatientsBetween July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks.InterventionSixty patients were randomly assigned to receive 4 weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111.Main Outcome MeasuresThe primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points.ResultsThe higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was −3.4% with CSL-111 and −1.6% for placebo (P = .48 between groups, P<.001 vs baseline for CSL-111). The nominal change in plaque volume was −5.3 mm3 with CSL-111 and −2.3 mm3 with placebo (P = .39 between groups, P<.001 vs baseline for CSL-111). The mean changes in plaque characterization index on IVUS (−0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (−0.039 mm for CSL-111 and −0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = .01 and P =.03, respectively). Administration of CSL-111 40 mg/kg was associated with mild, self-limiting transaminase elevation but was clinically well tolerated.ConclusionsShort-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography. Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted.Trial Registrationclinicaltrials.gov Identifier: NCT00225719Published online: March 26, 2007 (doi:10.1001/jama.297.15.jpc70004).

/pdf/effects-of-reconstituted-high-density-lipoprotein-infusions-41qn5uwx7a.pdf

Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial.

According to traditional thinking, atherosclerosis results from passive lipid deposition in the vascular wall. Thus, therapies predominantly targeted lipid metabolism. The contemporary view of atherosclerosis, however, has broadened to include an active and complex role for inflammation, orchestrated in part by mediators of the immune system. This recognition prompted the question of whether antiinflammatory interventions might provide a novel avenue for the treatment of atherosclerosis. Uncertainties about the type of antiinflammatory regimen and appropriate patient selection currently hamper clinical investigation. Yet cardiovascular scientists have begun to address these questions at the bench, in experimental models, and indirectly in humans. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase (statins) have emerged as promising tools with dual functions. Originally designed to target elevated lipids, the "traditional" cause of atherosclerosis, statins might also confer cardiovascular benefit by directly or indirectly modulating the inflammatory component of this prevalent disease. Yet controversy persists regarding the (clinical) relevance of these potential non-LDL-lowering "pleiotropic" functions of statins. This overview addresses the controversy by reviewing in vitro and in vivo evidence regarding statins as antiinflammatory agents.

Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents?

Background— Recent clinical trials have demonstrated that aggressive lipid lowering by statins could prevent recurrent events after acute coronary syndrome (ACS). We hypothesized that this efficacy was caused by a significant reduction in plaque volume by aggressive LDL cholesterol (LCL-C) lowering. The present study investigated the effect of early statin treatment on plaque volume of a nonculprit lesion by serial volumetric intravascular ultrasound in patients with ACS. Methods and Results— Seventy patients with ACS were enrolled. All patients underwent emergency coronary angiography and percutaneous coronary intervention (PCI). They were randomized to intensive lipid-lowering therapy (n=35; atorvastatin 20 mg/d) or control (n=35) groups after PCI. Volumetric intravascular ultrasound analyses were performed at baseline and 6-month follow-up for a non-PCI site in 48 patients (atorvastatin, n=24; control, n=24). LDL-C level was significantly decreased by 41.7% in the atorvastatin group compared with the c...

Early Statin Treatment in Patients With Acute Coronary Syndrome Demonstration of the Beneficial Effect on Atherosclerotic Lesions by Serial Volumetric Intravascular Ultrasound Analysis During Half a Year After Coronary Event: The ESTABLISH Study

Background We studied whether lipid-lowering therapy with atorvastatin (target LDL cholesterol [LDL-C] <100 mg/dL) compared with a moderate treatment regimen that used other lipid-lowering drugs le...

Use of Intravascular Ultrasound to Compare Effects of Different Strategies of Lipid-Lowering Therapy on Plaque Volume and Composition in Patients With Coronary Artery Disease

Jörg Kreuzer

Papers

Use of Intravascular Ultrasound to Compare Effects of Different Strategies of Lipid-Lowering Therapy on Plaque Volume and Composition in Patients With Coronary Artery Disease