Effect of Rimonabant on Progression of Atherosclerosis in Patients with Abdominal Obesity and Coronary Artery Disease (CAD) – STRADIVARIUS

Further information: Management of Cholesterol Disorders from Cardiovascular Medicine, 3rd Edn*

“The Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant-The Intravascular Ultrasound Study (STRADIVARIUS)” trial was a randomized, double-blind, placebo-controlled trial that enrolled 839 patients from December 2004 to December 2005 in 112 centers in North America, Australia, and Europe [1]. While obesity has reached epidemic proportions in the United States and other countries, and studies have shown a correlation between abdominal obesity and heart disease, there have been no clinical trials demonstrating a benefit for weight management drugs in patients with coronary heart disease (CHD). Therefore, trial investigators conducted STRADIVARIUS to determine whether weight loss and metabolic effects of the cannabinoid type 1 receptor antagonist rimonabant can reduce the progression of CHD in patients with obesity and the metabolic syndrome.

Rimonabant is an experimental drug not yet approved in the United States, but is available in some European countries. It is the first drug of a new class that inhibit cannabinoid type 1 (CB1) receptors, and blocking the receptors can result in reduced food intake, cause an increase in high-density lipoprotein (HDL) cholesterol, and cause reductions in triglycerides and C-reactive protein (CRP). Patients enrolled in the trial were given dietary counseling, randomized to receive either 20 mg of rimonabant or placebo, and underwent coronary intravascular ultrasonography at baseline. The study began with 839 patients, and it was completed by 676 patients. The primary endpoint was a calculation of disease progression, percent atheroma volume (PAV), and the secondary endpoint was total atheroma volume (TAV).

Although patients on rimonabant lost 9.5 lbs and 2 inches in waist circumference, had a rise in HDL cholesterol of 22%, decrease in triglycerides of 20%, and CRP decrease of 50%, the PAV did not show a significant effect. The TAV did show a statistically significant effect, but the success of a trial is based on whether or not it reaches the primary endpoint, and therefore the trial failed. Although the drug shows promise in the treatment of obesity for patients with heart disease, additional safety data showed that there was a significant increase in psychiatric and gastrointestinal adverse effects, such as depression and nausea. Additional imaging and outcomes trials are needed to determine whether rimonabant can be useful in the management of CHD.

[1] Nissen SE, Nicholls SJ, Wolski K et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease (CAD). JAMA 2008;299(13):1547-1560

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Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia

Further information: Management of Cholesterol Disorders from Cardiovascular Medicine, 3rd Edn*

“The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE)” trial was designed to determine whether the daily use of 10 mg of ezetimibe in combination with 80 mg of simvastatin would reduce the progression of atherosclerosis in patients with familial hypercholesterolemia, according to the measurement of arterial intima-media thickness. The investigators [1] studied these patients because they have a greatly increased risk of premature coronary artery disease and an increased rate of progression of intima-media thickness which began in their childhood.

The trial was a prospective, randomized, double-blind, multicenter study that lasted 24 months, from April 2002 to April 2004. The total number of patients with familial hypercholesterolemia who underwent screening was 1180. Of those, 720 were randomized with 363 assigned to the simvastatin-only group, and 357 assigned to the simvastatin-plus ezetimibe (combined-therapy) group. All patients underwent initial ultrasonography of the carotid and femoral arteries to assess the intima-media thickness, and repeat scans were done within a week of each other at baseline and at 24 months to assure the quality control of the image acquisition. The primary outcome was predefined as the change from baseline in the ultrasonic measurement of the mean (±SE) intima-media thickness of the carotid artery, and that was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries in the two study groups. Fasting blood samples were drawn for lipid measurements.

The primary outcome measure was 0.0058 ± 0.0037 mm in the simvastatin-only group and 0.0111 ± 0.0038 mm in the combined therapy group. The difference of 0.0053 mm did not reach statistical significance (P=0.29), and the investigators found no significant changes between the groups regarding mean measures of intima-media thickness of the common carotid artery (P=0.93), the carotid bulb (P=0.37), the internal carotid artery (P=0.21), or the femoral artery (P=0.16). Although the results of the study showed no reduction in the thickness of the carotid-artery wall, there were significant reductions in levels of both LDL cholesterol and C-reactive protein (CRP). After 24 months, the mean levels of LDL cholesterol decreased from 317.8 ± 66.1 mg/dl to 192.7 ± 60.3 mg/dl in the simvastatin-only group and from 319.0 ± 64.0 mg/dl to 141.3 ± 52.6 mg/dl in the combined-therapy group, a difference of 16.5 % (P<0.01). Triglycerides and CRP measurements were significantly lower in the combined-therapy group than in the simvastatin-only group. Numerous studies have shown that reductions of lipid levels and CRP were associated with vascular benefit and significant reductions in cardiovascular mortality.

[1] Kastelein JJP, Akdim F, Strones ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia
ENHANCE. N Engl J Med 2008;358:1431-43

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Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events

Further information: Management of Cholesterol Disorders from Cardiovascular Medicine, 3rd Edn*

It is well-established that plasma levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) are indicators of individuals who are at risk of cardiovascular disease, and it has been determined that variation in LDL and HDL levels is inherited.

A cohort of 28,449 subjects were recruited for The Malmö Diet and Cancer Study (MDCS), the prospective, epidemiological study in cancer, and 5414 subjects from the original cohort were randomly selected for the cardiovascular arm (MDCS-CC) to investigate risk factors in cardiovascular disease [1]. The investigators conducting this study sought to validate the association between several single-nucleotide polymorphisms (SNPs) that have been identified with the level of LDL or HDL cholesterol at nine loci, and then to evaluate the ability of the panel of the lipid-modulating SNPs to predict a first cardiovascular event.

After validating the association between SNPs and either LDL or HDL, a genotype score was created on the basis of the number of unfavorable alleles. Cox proportional-hazards models were used to determine the time to the first cardiovascular event in relation to the genotype score, and nine SNPs were independently associated with incident cardiovascular disease.

All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol, and as genotype scores increased, LDL cholesterol level increased from 152 mg/dl to 171 mg/dl (4-5 mmol/l), whereas HDL cholesterol decreased from 60 mg/dl to 51 mg/dl (2 to 1 mmol/l). In mean follow-up of 11 years, 238 participants in the study had a first cardiovascular event, and the genotype score was associated with incident cardiovascular disease in models adjusted for covariates that included baseline lipid levels (P<0.001). Although use of genotype scores did not improve the clinical risk prediction, as assessed by the C statistic, there was significant improvement in risk classification with the use of models that included the genotype score when compared with those that did not include it.

[1] Kathiresan S, Melander O, Anevski D. Polymorphisms Associated with cholesterol and risk of cardiovascular events. N Engl J Med 2008;358:1240-9

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Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease

Further information: Molecular Biology for the Clinician from Cardiovascular Medicine, 3rd Edn*

The investigators of this study [1] who represent the Cardiogenics Consortium, a research group of five countries in the European Union, evaluated nearly 10,000 individuals to identify the chromosomal locus 9p21.3 as being associated with the risk of coronary artery disease (CAD) and myocardial infarction (MI).

Seven case-controlled studies were used for the meta-analysis, and there were 4645 patients with CAD or MI and 5177 controls. A meta-analysis of the data as well as of previously published data was conducted.

The risk allele (C) of the lead single-nucleotide polymorphism (SNP), rs1333049, was uniformly associated with CAD in each study (P<0.05). In pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% confidence interval [CI], 1.22–1.37; P=0.0001). Further analysis suggested that haplotype analysis was not homogeneous across the haplotypic background (test for interaction, P=0.0079). An autosomal-additive mode of inheritance best explained the underlying association. In addition to the case-control samples, the investigators performed a meta-analysis of the rs1333049 SNP in 12,004 cases and 28,949 controls that increased the overall level of evidence for association with CAD to P=6.04 × 10^-10 (odds ratio, 1.24; 95% CI, 1.20–1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP.

The study shows unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD. However, further studies are needed to precisely define the incremental information obtained when risk variants at chromosome 9p21.3 are identified in algorithms predicting CAD events in risk scores.  

[1] Schunkert H, Gotz A, Braund P, et al. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation 2008;117:1675-1684

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.