Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.

BACKGROUND: Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS: We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS: The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001). INTERPRETATION: Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Designs of RADIANCE 1 and 2: carotid ultrasound studies comparing the effects of torcetrapib/atorvastatin with atorvastatin alone on atherosclerosis.

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.

Carotid intima-media thickness in low-risk individuals with asymptomatic atherosclerosis: baseline data from the METEOR study.

OBJECTIVE: Carotid intima-media thickness (CIMT) is an index for changes in atherosclerosis burden and changes in CIMT may relate to clinical events. We present baseline data from the METEOR study, a randomized, placebo-controlled trial evaluating the efficacy of rosuvastatin 40 mg on changes in CIMT. We set out to compare differences in CIMT between several subgroups of individuals. DESIGN AND METHODS: A total of 984 individuals aged 45-70 years (men) or 55-70 (women) were randomized. Participants were required to have: maximum CIMT > or = 1.2-< 3.5 mm; 2+ risk factors and 10-year coronary heart disease (CHD) risk < 10%, or < 2 CHD risk factors. Demographic characteristics were compared in two groups: USA versus Europe, and individuals with maximum CIMT < 2 mm versus those with CIMT > or = 2 mm. BASELINE DATA: Overall, mean age was 57 years and mean low-density lipoprotein cholesterol was 152 mg/dL (3.9 mmol/L). Body mass index (BMI), triglyceride and high-sensitivity C-reactive protein levels were all higher in US individuals, whereas smoking, hypertension and high-density lipoprotein cholesterol levels were higher in Europeans. Mean CIMT levels were the same in both populations, and the percentage of individuals with > or = 2 CHD risk factors was similar. Increased baseline CIMT (> 2 mm) was related to increasing age, male gender, smoking, hypertension and lipid levels. CONCLUSIONS: In this global trial, differences in baseline characteristics between participants from the USA and Europe are apparent. However, a strong association between CIMT and several cardiovascular risk factors was observed across the two continents.

Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia.

BACKGROUND: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, may reduce atherosclerotic vascular disease by increasing levels of high-density lipoprotein (HDL) cholesterol. METHODS: A total of 850 patients with heterozygous familial hypercholesterolemia underwent B-mode ultrasonography at baseline and at follow-up to measure changes in carotid intima-media thickness. The patients completed an atorvastatin run-in period and were subsequently randomly assigned to receive either atorvastatin monotherapy or atorvastatin combined with 60 mg of torcetrapib for 2 years. RESULTS: After 24 months, in the atorvastatin-only group, the mean (+/-SD) HDL cholesterol level was 52.4+/-13.5 mg per deciliter and the mean low-density lipoprotein (LDL) cholesterol level was 143.2+/-42.2 mg per deciliter, as compared with 81.5+/-22.6 mg per deciliter and 115.1+/-48.5 mg per deciliter, respectively, in the torcetrapib-atorvastatin group. During the study, average systolic blood pressure increased by 2.8 mm Hg in the torcetrapib-atorvastatin group, as compared with the atorvastatin-only group. The increase in maximum carotid intima-media thickness, the primary measure of efficacy, was 0.0053+/-0.0028 mm per year in the atorvastatin-only group and 0.0047+/-0.0028 mm per year in the torcetrapib-atorvastatin group (P=0.87). The secondary efficacy measure, annualized change in mean carotid intima-media thickness for the common carotid artery, indicated a decrease of 0.0014 mm per year in the atorvastatin-only group, as compared with an increase of 0.0038 mm per year in the torcetrapib-atorvastatin group (P=0.005). CONCLUSIONS: In patients with familial hypercholesterolemia, the use of torcetrapib with atorvastatin, as compared with atorvastatin alone, did not result in further reduction of progression of atherosclerosis, as assessed by a combined measure of carotid arterial-wall thickness, and was associated with progression of disease in the common carotid segment. These effects occurred despite a large increase in HDL cholesterol levels and a substantial decrease in levels of LDL cholesterol and triglycerides. (ClinicalTrials.gov number, NCT00136981 [ClinicalTrials.gov].).

Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial.

CONTEXT: Atherosclerosis is often advanced before symptoms appear and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (FRS) and mild to moderate subclinical atherosclerosis. OBJECTIVE: To assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness (CIMT) over 2 years. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled study (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin [METEOR]) of 984 individuals, with either age (mean, 57 years) as the only coronary heart disease risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.2-<3.5 mm), and elevated LDL cholesterol (mean, 154 mg/dL); conducted at 61 primary care centers in the United States and Europe between August 2002 and May 2006. INTERVENTION: Participants received either a 40-mg dose of rosuvastatin or placebo. MAIN OUTCOME MEASURES: Rate of change in maximum CIMT (assessed with B-mode ultrasound) for 12 carotid sites; changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites and in mean CIMT of the common carotid artery sites. CIMT regression was assessed in the rosuvastatin group only. RESULTS: Among participants in the rosuvastatin group, the mean (SD) baseline LDL cholesterol level of 155 (24.1) mg/dL declined to 78 (27.5) mg/dL, a mean reduction of 49% (P<.001 vs placebo group). The change in maximum CIMT for the 12 carotid sites was -0.0014 (95% CI, -0.0041 to 0.0014) mm/y for the rosuvastatin group vs 0.0131 (95% CI, 0.0087-0.0174) mm/y for the placebo group (P<.001). The change in maximum CIMT for the rosuvastatin group was -0.0038 (95% CI, -0.0064 to -0.0013) mm/y for the common carotid artery sites (P<.001), -0.0040 (95% CI, -0.0090 to 0.0010) mm/y for the carotid bulb sites (P<.001), and 0.0039 (95% CI, -0.0009 to 0.0088) mm/y for the internal carotid artery sites (P = .02). The change in mean CIMT for the rosuvastatin group for the common carotid artery sites was 0.0004 (95% CI, -0.0011 to 0.0019) mm/y (P<.001). All P values are vs placebo group. Overall, rosuvastatin was well tolerated with infrequent serious adverse cardiovascular events (6 participants [0.86%] had 8 events [1.1%] over 2 years). CONCLUSIONS: In middle-aged adults with an FRS of less than 10% and evidence of subclinical atherosclerosis, rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo. Rosuvastatin did not induce disease regression. Larger, longer-term trials are needed to determine the clinical implications of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225589

From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report.

Screening for early-stage asymptomatic cancers (eg, cancers of breast and colon) to prevent late-stage malignancies has been widely accepted. However, although atherosclerotic cardiovascular disease (eg, heart attack and stroke) accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic (subclinical) atherosclerosis, and there is no government- or healthcare-sponsored reimbursement for atherosclerosis screening. Part I and Part II of this consensus statement elaborated on new discoveries in the field of atherosclerosis that led to the concept of the "vulnerable patient." These landmark discoveries, along with new diagnostic and therapeutic options, have set the stage for the next step: translation of this knowledge into a new practice of preventive cardiology. The identification and treatment of the vulnerable patient are the focuses of this consensus statement. In this report, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force presents a new practice guideline for cardiovascular screening in the asymptomatic at-risk population. In summary, the SHAPE Guideline calls for noninvasive screening of all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as very low risk) to detect and treat those with subclinical atherosclerosis. A variety of screening tests are available, and the cost-effectiveness of their use in a comprehensive strategy must be validated. Some of these screening tests, such as measurement of coronary artery calcification by computed tomography scanning and carotid artery intima-media thickness and plaque by ultrasonography, have been available longer than others and are capable of providing direct evidence for the presence and extent of atherosclerosis. Both of these imaging methods provide prognostic information of proven value regarding the future risk of heart attack and stroke. Careful and responsible implementation of these tests as part of a comprehensive risk assessment and reduction approach is warranted and outlined by this report. Other tests for the detection of atherosclerosis and abnormal arterial structure and function, such as magnetic resonance imaging of the great arteries, studies of small and large artery stiffness, and assessment of systemic endothelial dysfunction, are emerging and must be further validated. The screening results (severity of subclinical arterial disease) combined with risk factor assessment are used for risk stratification to identify the vulnerable patient and initiate appropriate therapy. The higher the risk, the more vulnerable an individual is to a near-term adverse event. Because <10% of the population who test positive for atherosclerosis will experience a near-term event, additional risk stratification based on reliable markers of disease activity is needed and is expected to further focus the search for the vulnerable patient in the future. All individuals with asymptomatic atherosclerosis should be counseled and treated to prevent progression to overt clinical disease. The aggressiveness of the treatment should be proportional to the level of risk. Individuals with no evidence of subclinical disease may be reassured of the low risk of a future near-term event, yet encouraged to adhere to a healthy lifestyle and maintain appropriate risk factor levels. Early heart attack care education is urged for all individuals with a positive test for atherosclerosis. The SHAPE Task Force reinforces existing guidelines for the screening and treatment of risk factors in younger populations. Cardiovascular healthcare professionals and policymakers are urged to adopt the SHAPE proposal and its attendant cost-effectiveness as a new strategy to contain the epidemic of atherosclerotic cardiovascular disease and the rising cost of therapies associated with this epidemic.

Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin in subclinical atherosclerosis--the rationale and methodology of the METEOR study.

BACKGROUND: Increased carotid intima media thickness (IMT) is associated with established coronary heart disease (CHD) and is a marker of atherosclerosis. Statins are an effective treatment for dyslipidaemia, and have been shown to retard progression or promote carotid IMT regression in patients at high risk of CHD. Rosuvastatin is a highly efficacious statin, and the Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) study is designed to assess the impact of rosuvastatin on carotid IMT progression in low risk subjects with signs of subclinical atherosclerosis. METHODS: In this randomised, parallel-group study, asymptomatic subjects at low risk of cardiovascular disease, but with evidence of atherosclerosis (defined as carotid IMT >or=1.2 mm and <3.5 mm), will receive rosuvastatin (40 mg/day) or placebo for 104 weeks. The study will enrol 840 European and US subjects randomised 5:2 between rosuvastatin and placebo. The primary end point will be the change in carotid IMT from baseline to study end, measured using B-mode ultrasonography. Other efficacy end points include changes in the serum lipid profile and C-reactive protein. Safety parameters will also be assessed. CONCLUSION: The METEOR study will evaluate whether long-term rosuvastatin treatment promotes regression, or slows progression, of subclinical atherosclerosis in asymptomatic subjects at low risk of cardiovascular disease.

Cardiovascular risk assessment in individual patients from carotid intimal-medial thickness measurements.

Carotid intimal-medial thickness measurements are a low-cost, noninvasive method to assess atherosclerotic burden in the general population. A large evidence base exists to validate estimates of absolute cardiovascular risk obtained from measurements of carotid intimal-medial thickness. Precise and reliable carotid intimal-medial thickness measurements from several ultrasonic interrogation angles and anatomic sites are required to obtain the most valid estimates of cardiovascular risk in an individual patient. This paper reviews basic measurement concepts and outlines important considerations in the clinical assessment of absolute cardiovascular risk in individual patients from measurements of carotid intimal-medial thickness.

Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view.

BACKGROUND: Carotid intima-media thickness (CIMT) measurements are currently widely used in randomized controlled trials (RCTs) to study the efficacy of interventions. In designing a RCT with CIMT as a primary outcome, several ultrasound options may be considered. We discuss the various options and provide a pooled estimate of CIMT progression. In addition, we quantify the effect of these choices on the sample size for a RCT. SUMMARY OF COMMENT: To estimate the average CIMT progression rate, we performed a pooled analysis using CIMT progression rates of control groups from published RCTs. The pros and cons of the following ultrasound options are discussed: which arterial segments may be studied; whether near and far wall CIMT measurements should be performed; whether a single image (1 angle of interrogation) or multiple images (more angles of interrogation) should be used; whether a manual or an automated edge detection reading system should be used; and whether images should be read in a random fashion or in batches. The pooled analysis showed an annual rate of change in mean common CIMT of 0.0147 mm (95% CI, 0.0122 to 0.0173) and in mean maximum CIMT of 0.0176 mm (95% CI, 0.0149 to 0.0203). CONCLUSIONS: Given the current evidence together with our experience with recently developed ultrasound protocols, we favor the use of mean maximum CIMT rather than mean common CIMT as the primary outcome measure in RCTs designed to evaluate the efficacy of pharmacological and nonpharmacological interventions in carotid artery atherosclerosis.

Heritability of carotid artery intima-medial thickness in type 2 diabetes.

BACKGROUND AND PURPOSE: Carotid artery intima-medial thickness (IMT), a marker of subclinical atherosclerosis, is a strong predictor of subsequent cardiovascular morbidity. The role of genetic factors in thickening of the carotid wall remains largely unknown. We hypothesize that in families with multiple members having diabetes, carotid IMT is likely to be associated with both inherited and environmental factors. METHODS: To determine the extent of the familial aggregation of carotid IMT in the presence of type 2 diabetes, we studied 252 individuals with type 2 diabetes (mean age 60.6 years) from 122 families. Common carotid artery IMT was measured by high-resolution B-mode ultrasonography. Other measured factors included lipid levels, body mass index, fasting glucose, hemoglobin A1c, albumin/creatinine ratio, and self-reported medical history. Heritability estimates were obtained by using variance component methodology, as implemented in the SOLAR software package. Tests for association between carotid IMT and variables were performed by using mixed model analysis while accounting for the correlation due to family structure. RESULTS: The age-, sex-, and race-adjusted heritability estimate for carotid IMT was 0.32 (SE 0.17, P=0.02). Further adjustment for total cholesterol, hypertension status, and current smoking status resulted in a heritability estimate of 0.41 (SE 0.16, P=0.004). The strongest predictors of carotid IMT, after adjusting for age and sex, were ethnicity (African American versus white), total cholesterol, and smoking status. CONCLUSIONS: These data provide empirical evidence that subclinical cardiovascular disease has a significant genetic component and merits a search for the genes involved in susceptibility to the atherosclerotic complications of diabetes.