Designs of RADIANCE 1 and 2: carotid ultrasound studies comparing the effects of torcetrapib/atorvastatin with atorvastatin alone on atherosclerosis.
ABSTRACT OBJECTIVE: The RADIANCE studies were designed to assess the effects of torcetrapib/atorvastatin (T/A) compared with atorvastatin alone on slowing atherosclerotic progression in patients with heterozygous familial hypercholesterolemia (RADIANCE 1) or mixed hyperlipidemia (RADIANCE 2), as measured by change in carotid intima-media thickness (CIMT). RESEARCH DESIGN AND METHODS: RADIANCE 1 and 2 were randomized, double-blind, controlled trials with a duration of 2 years. In both studies, eligible subjects began treatment with atorvastatin during a run-in period and were titrated to target LDL-C levels defined by NCEP ATP III guidelines. Subjects then proceeded to a double-blind randomized treatment period where they received one of two regimens: (i) fixed combination T/A (torcetrapib dose, 60 mg), or (ii) atorvastatin alone. In both regimens, the dose of atorvastatin was established during the run-in period (20-80 mg, RADIANCE 1; 10-80 mg RADIANCE 2). B-mode ultrasonography was performed in duplicate at baseline and at end of study, and every 6 months in between. MAIN OUTCOME MEASURES: The primary efficacy measure in both studies was the annualized rate of change in maximum CIMT of 12 pre-defined carotid segments. Further outcome measures included lipid and safety assessments. Current status: The number of subjects randomized was 904 in RADIANCE 1 and 752 in RADIANCE 2. Results are anticipated in 2007.
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ABSTRACT: Carotid intima-media thickness (CIMT) measurements have been widely used as primary endpoint in studies into the effects of new interventions as alternative for cardiovascular morbidity and mortality. There are no accepted standards on the use of CIMT measurements in intervention studies and choices in the design and analysis of a CIMT study are generally based on experience and expert opinion. In the present review, we provide an overview of the current evidence on several aspects in the design and analysis of a CIMT study on the early effects of new interventions. A balanced evaluation of the carotid segments, carotid walls, and image view to be used as CIMT study endpoint; the reading method (manual or semi-automated and continuously or in batch) to be employed, the required sample size, and the frequency of ultrasound examinations is provided. We also discuss the preferred methods to analyse longitudinal CIMT data and address the possible impact of, and methods to deal with missing and biologically implausible CIMT values. Linear mixed effects models are the preferred way to analyse CIMT data and do appropriately handle missing and biologically implausible CIMT values. Furthermore, we recommend to use extensive CIMT designs that measure CIMT at regular points during the multiple carotid sites as such approach is likely to increase the success rates of CIMT intervention studies designed to evaluate the effects of new interventions on atherosclerotic burden.Journal of stroke. 01/2013; 15(1):38-48.
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ABSTRACT: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.Arthritis & Rheumatology 01/2012; 64(1):285-96. · 7.48 Impact Factor
Article: Lessons from the torcetrapib trials