Percent Atheroma Volume Research Articles

Cardiovascular computed tomographic assessment of the effect of combination lipoprotein therapy on coronary arterial plaque: Rationale and design of the AFRICA (Atorvastatin plus Fenofibric acid in the Reduction of Intermediate Coronary Atherosclerosis) study

Whether combination lipoprotein therapy targeting apolipoprotein B (apoB)- and apoA-containing lipoprotein particles and triglycerides (TGs) in low-risk, asymptomatic subjects with coronary atherosclerosis alters the natural progression of plaques is unknown. This study was designed to compare the progression of coronary atherosclerosis in asymptomatic, low-risk subjects without previously known coronary artery disease but with the presence of plaque on a combination of atorvastatin 40 mg plus fenofibric acid 135 mg daily for 18 months, using cardiovascular computed tomography (CCT). This is an investigator-initiated, single-center, prospective, double-blind, randomized, placebo-controlled, parallel-arm study. Asymptomatic subjects at low risk of cardiovascular events defined as <10% 10-year risk based on the Framingham Risk Score will be recruited, if they do not qualify for lipoprotein-lowering therapy based on the National Cholesterol Education Panel Adult Treatment Panel III guidelines. Subjects will qualify based on lipid parameters if their low-density lipoprotein cholesterol is >/=100 mg/dL and <190 mg/dL, TGs are >150 mg/dL, and the TGs/high-density lipoprotein cholesterol ratio is >3.5. Patients must have nonobstructive plaque based on CCT. Randomization will be 1:1 to either a combination of atorvastatin 40 mg plus fenofibric acid 135 mg daily or placebo for 18 months. Patients will undergo CCT at baseline and at the end of the treatment period. The primary end point will be the between-group difference in percent atheroma volume. Ultimately, this study can guide physicians about the use of a statin-fibric acid derivative combination in asymptomatic, low-risk persons with atherosclerosis.

The Metabolic Syndrome, Its Component Risk Factors, and Progression of Coronary Atherosclerosis

The mechanism that confers adverse cardiovascular prognosis in patients with the metabolic syndrome (MetS) remains unclear. We sought to investigate the association of MetS and its component risk factors with progression of coronary atherosclerosis. We performed a systematic review of 3459 patients who participated in 7 clinical trials that monitored coronary atheroma progression with intravascular ultrasonography. Patients with or without MetS were compared with regard to clinical characteristics, coronary atheroma burden at baseline, and change on serial evaluation. Relationships between plaque progression (> or =5% increase in percent atheroma volume [PAV]), MetS, and its component risk factors were investigated. The metabolic syndrome was highly prevalent and was associated with greater progression of PAV (+0.51% +/- 0.23% vs +0.23% +/- 0.24%; P = .003). Multivariable analysis showed that MetS was associated with a greater likelihood of undergoing progression of PAV (adjusted odds ratio [OR], 1.25; 95% confidence interval [CI], 1.05-1.48; P = .01). When the individual components were used in the model instead of MetS, hypertriglyceridemia (OR, 1.26; 95% CI, 1.06-1.49; P = .008) and a body mass index of 30 or higher (1.18, 1.00-1.40; P = .05) predicted progression of PAV. However, after adjusting for its individual components, MetS was no longer an independent predictor (OR, 1.04; 95% CI, 0.79-1.37; P = .79). Although accelerated disease progression is observed in the setting of MetS, this is owing to the presence of individual component risk factors rather than to the presence of the syndrome itself.

Impact of Olmesartan on Progression of Coronary Atherosclerosis: A Serial Volumetric Intravascular Ultrasound Analysis From the OLIVUS (Impact of OLmesarten on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound) Trial

The aim of this study was to evaluate the impact of olmesartan on progression of coronary atherosclerosis.Prior intravascular ultrasound (IVUS) trial results suggest slowing of coronary atheroma progression with some medicines but have not shown convincing evidence of regression with angiotension-II receptor blocking agents.A prospective, randomized, multicenter trial-OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound)-was performed in 247 stable angina pectoris patients with native coronary artery disease. When these patients underwent percutaneous coronary intervention for culprit lesions, IVUS was performed in their nonculprit vessels (without angiographically documented coronary stenosis [<50%]). Patients were randomly assigned to receive 10 to 40 mg of olmesartan or control and treated with a combination of beta-blockers, calcium channel blockers, diuretics, nitrates, glycemic control agents, and/or statins per physician's guidance. Serial IVUS examinations (baseline and 14-month follow-up) were performed to assess coronary atheroma volume. Volumetric IVUS analyses included lumen, plaque, vessel volume, percent atheroma volume (PAV), percent change in total atheroma volume (TAV) and PAV.Patient characteristics and blood pressure control were identical between the 2 groups. However, follow-up IVUS showed significantly decreased TAV and percent change in PAV in the olmesartan group (5.4% vs. 0.6 % for TAV and 3.1% vs. -0.7% for percent change in PAV, control vs. olmesartan, p < 0.05 for all).These observations suggest a positive role in a potentially lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent, for patients with stable angina pectoris.

Seeking Alternatives to Hard End Points

Patients with diabetes mellitus are at increased risk of death resulting from cardiovascular disease, but the best strategy to control excess cardiovascular risk is not yet clear. Although the use of statins and angiotensin antagonists has been successful, treatment of diabetes mellitus itself, especially from the standpoint of degree of glycemic control and type of antidiabetic agents, remains an area of ongoing investigation. Once touted as having the potential for atheroprotection because of their favorable effects on inflammatory biomarkers, endothelial function, carotid intimal-medial thickness, and even macrophage and lipid deposition, the thiazolidinediones (TZD) have become substantially controversial after a meta-analysis suggested an increase in the risk of myocardial infarction in patients treated with rosiglitazone.1 Although this notion was not confirmed in an interim analysis of the prospective study Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD), owing to several serious limitations of this report and several unanswered questions,2 studies such as Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes Patients with Cardiovascular History (APPROACH)3 become important. Taking a leaf from the statin playbook, the APPROACH was to see whether imaging the atheroma in the coronary vasculature could explain some of the outcome data with rosiglitazone. This prospective, multicenter, double-blind, randomized study compared potentially glucose-independent effects of rosiglitazone with those of a sulfonylurea (glipizide) on progression of coronary atherosclerotic disease in 672 patients with type 2 diabetes mellitus. Patients underwent baseline intravascular ultrasound (IVUS) of the longest and least angulated nonintervened epicardial artery with noncritical plaque at baseline and 18 months later. Atheroma, as measured by IVUS, did not progress significantly in either arm over time; the primary end point of the trial—change in percent atheroma volume (ΔPAV)—in individuals treated with rosiglitazone (−0.21%) was not significantly different from …

Effect of Rosiglitazone on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (-0.64%; 95% confidence interval, -1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (-5.1 mm(3); 95% confidence interval, -10.0 to -0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (-1.7 mm(3); 95% confidence interval, -3.9 to 0.5; P=0.13). Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00116831.

Stabilization and Regression of Coronary Plaques Treated With Pitavastatin Proven by Angioscopy and Intravascular Ultrasound - The TOGETHAR Trial -

Few studies have serially monitored the change of coronary plaque after statin therapy using multiple plaque imaging modalities. A prospective open-label trial was performed to assess coronary plaque regression and stabilization following 52 weeks of pitavastatin treatment (2 mg/day). Coronary segments that included the most diseased plaque of 90 patients determined on angioscopy were analyzed using intravascular ultrasound (IVUS). The yellow grade of each plaque of 46 patients who had matched angioscopy and IVUS data was evaluated on angioscopy. Low-density lipoprotein-cholesterol (LDL-C) was reduced 34.5% (145.0+/-24.0 mg/dl to 93.6+/-22.6 mg/dl, P<0.001), and high-density lipoprotein cholesterol increased 17.8% (44.9+/-11.1 mg/dl to 51.9+/-11.7 mg/dl, P<0.001). Yellow grade decreased (2.9+/-0.8 to 2.6+/-0.7, P=0.040) during 52 weeks. The reduction of yellow grade was not correlated with the LDL-C level at 52 weeks or its change. The change of yellow grade was inversely correlated with maximum yellow grade at baseline. Percent atheroma volume on IVUS did not change during 52 weeks, but its change for 52 weeks was significantly correlated with LDL-C level at 52 weeks (Spearman's rank correlation coefficient 0.312, P=0.035). Fixed dose pitavastatin stabilized vulnerable coronary plaques by the reduction of yellow grade without significant reduction of plaque volume. The stabilization and regression of atherosclerotic plaques by statin may differ, but both nonetheless contribute to the reduction of cardiovascular events (UMIN Clinical Trials Registry UMIN000001107).

New evidence in cardiovascular medicine, general practice and public health

Scientific evidence is available with reference to the major role of both blood pressure and low-density lipoprotein cholesterol (LDL-C) in the promotion of coronary artery disease, yet the effect of the concomitant correct control of blood pressure and LDL-C in human beings has not been clarified. A group of US researchers has therefore studied the progression of coronary atheroma in subjects with low LDLC and variable values of systolic blood pressure. The changes in the burden of atheroma were investigated by means of intravascular ultrasound in 3,437 patients affected by coronary artery disease subdivided into four groups: individuals with LDL-C B 70 mg/dl and systolic blood pressure B120 mmHg, individuals with LDL-C B 70 mg/dl and systolic blood pressure[120 mmHg, individuals with LDLC [ 70 mg/dl and systolic blood pressure B120 mmHg, individuals with LDL-C [ 70 mg/dl and systolic blood pressure [120 mmHg. People with very low LDL-C (B70 mg/dl) and normal systolic blood pressure (B120 mmHg) showed a more frequent plaque regression (P = 0.01), less progression in percentage atheroma volume (P 0.001) and total atheroma volume (P 0.001), and a less frequent plaque progression (P 0.001). In subjects with systolic blood pressure[120 mmHg, very low LDL-C was linked to less progression of percentage atheroma volume (?0.30%, 95% confidence interval between -0.17 and 0.77% versus ?0.61%, 95% confidence interval between 0.17 and 1.05%, P = 0.01) and total atheroma volume (-3.9 mm, 95% confidence interval between -7.24 and -0.63 mm versus -1.2 mm, 95% confidence interval between -4.31 and 1.92 mm, P = 0.001). In coronary patients with LDL-C [ 70 mg/dl, normal systolic blood pressure was not associated with less progression of percentage atheroma volume or total atheroma volume. The authors conclude that normal systolic blood pressure and very low low-density lipoprotein cholesterol are linked to the slowest progression of coronary atherosclerosis.

Low Levels of Low-Density Lipoprotein Cholesterol and Blood Pressure and Progression of Coronary Atherosclerosis

We investigated coronary atheroma progression in patients with low levels of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP). Low LDL-C and SBP beneficially impact coronary atherosclerosis. However, the association between intensive control of both risk factors and coronary plaque progression remains unclear. Changes in atheroma burden monitored by intravascular ultrasound were studied in 3,437 patients with coronary artery disease (CAD) who were stratified according to on-treatment LDL-C and SBP. Patients with very low LDL-C (< or =70 mg/dl) and normal SBP (< or =120 mm Hg) had less progression in percent atheroma volume (PAV) (p < 0.001) and total atheroma volume (TAV) (p < 0.001), more frequent plaque regression (p = 0.01), and less frequent plaque progression (p < 0.001). In patients with SBP >120 mm Hg, very low LDL-C was associated with less progression of PAV (+0.30%, 95% confidence interval [CI]: -0.17% to 0.77% vs. +0.61%, 95% CI: 0.17% to 1.05%, p = 0.01) and TAV (-3.9 mm3, 95% CI: -7.24 to -0.63 mm3 vs. -1.2 mm3, 95% CI: -4.31 to 1.92 mm3, p = 0.001). In patients with LDL-C >70 mg/dl, normal SBP was not associated with less progression of PAV (+0.51%, 95% CI: 0.04% to 0.99% vs. +0.61%, 95% CI: 0.17% to 1.05%, p = 0.159) or TAV (-2.3 mm3, 95% CI: -5.59 to 1.05 mm3 vs. -1.2 mm3, 95% CI: -4.31 to 1.92 mm3, p = 0.617). Very low LDL-C and normal SBP are associated with the slowest progression of coronary atherosclerosis. Although a greater beneficial association is observed in patients with very low LDL-C, these findings suggest the need for intensive control of global risk in patients with CAD.

Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis

Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis. Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P =0.02), and lowered serum potassium (0.11±0.02 mmol/L, P &lt;0.0001). Despite substantial increases in HDL-C, no effect was found of torcetrapib on percent atheroma volume. In torcetrapib-treated patients, an inverse relationship was observed between changes in HDL-C and percentage atheroma volume ( r =−0.17, P &lt;0.001). Participants with regression had greater increases in HDL-C (mean±SE, 62.9±37.4% versus 54.0±39.1%, P =0.002). Compared with the lowest quartile, torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (−0.31±0.27 versus 0.88±0.27%, P =0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (−0.69±0.27%, P =0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression ( P =0.001). Conclusions— The majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression.

Leapfrogging Data

Properly designed and conducted randomized controlled clinical trials (RCTs) are the premier tool for both testing mechanistic hypotheses and critically ascertaining the risks and benefits of a therapy or strategy for clinical care. The sample size of a trial is mainly a function of the rates of its primary objectives and the presumed influence of the intervention. Trials focusing on a primary outcome variable that can be readily quantified in each subject, such as blood pressure or plasma cholesterol levels, require substantially fewer participants and shorter durations to determine whether their predefined measurement is altered compared with a morbidity and mortality trial. Trials designed to determine whether clinical prognosis is altered by an intervention depend on the proportion of patients experiencing the predefined adverse clinical event(s) and often require 100s-fold–greater patient-time exposures to test their primary hypothesis and provide even modest information about safety. These resource-intense morbidity and mortality trials are generally only performed when information from observational studies as well as smaller mechanistic and surrogate- outcomes RCTs are so highly supportive of a favorable outcome that they justify the effort. Despite this understandable stacking of the cards with the best available information, many of the morbidity and mortality trials conducted to test for a potential favorable impact of an intervention conclude by not supporting the prestudy hypothesis-generating data.1 The lessons in humility offered by these neutral or negative outcomes trials underscore the importance of obtaining crucial risk–benefit data before widespread adoption of even an apparently favorable therapy.2 Articles pp 2506 and 2515 For rational therapeutic decision making, we would ideally like to have both a framework of reliable mechanistic information and robust clinical outcomes and safety data. Sometimes major clinical outcomes trials are designed with a complement of embedded ancillary trials to generate a more complete picture …

Abstract 3211: Diabetes is Associated with Greater Progression of Coronary Atherosclerosis than the Metabolic Syndrome: Insights from Serial Intravascular Ultrasound Studies

Background: While the metabolic syndrome (MetS) and diabetes (DM) share many pathophysiological features it remains to be determined if they influence coronary atherosclerotic disease progression to a similar degree. Methods : A systematic review of subjects participating in 7 clinical trials that monitored coronary atheroma progression with intravascular ultrasound was performed. Clinical characteristics, baseline atheroma burden and disease progression were compared in patients with the MetS (n=1119), DM (n=201) or their combination (n=878). Results: Patients with the MetS were younger, more likely to be female and had a greater risk factor burden than diabetics. At baseline the presence of DM was associated with a greater percent atheroma volume (PAV 41.0+/−8.5 vs 37.6+/−8.9 %, p&lt;0.001) and total atheroma volume (TAV 202.5+/−84.1 vs 190.73+−84.9 mm 3 , p&lt;0.001) than observed in patients with the MetS. Greater progression of PAV (+0.71+/−0.3 vs 0.28+/−0.2 % p=0.04) and TAV (−3.3+/−1.8 vs −1.0+/−2.1 mm 3 , p=0.1) was observed in the presence of DM compared with the MetS. The combination of MetS and DM was not associated with greater PAV (+0.82+/−0.2 vs +0.71+/−0.3 %, p=0.59) or TAV (−1.0+/−1.8 vs −1.0+/−2.1 mm 3 , p=0.98) than DM alone. Substantial progression rate were not differ between three groups (Table ). However, the combination of DM and the MetS did result in the lowest rate of patients undergoing substantial plaque regression (&gt;.0 % chg in PAV, 14.9% vs 18.4%, p=0.01) when compared with patients with DM, not meeting the criteria for the MetS. Conclusions: Despite the presence of more risk factors, meeting the criteria for the MetS is not associated with a greater rate of progression of coronary atherosclerosis in patients with DM. This highlights the accelerated nature of disease in the setting of established DM. Table. Baseline and changes in IVUS disease burden according to metabolic syndrome and diabetes

Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in diabetes patients with Cardiovascular History (APPROACH): Study design and baseline characteristics

Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitazone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitazone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease.

Rimonabant and Progression of Atherosclerosis in Obese Persons

sion of atherosclerosis in patients with abdominal obesity and coronary artery disease. We would like to raise a number of issues about this trial. From an ethical perspective, new treatments should be tested when possible against an established treatment with proven benefits, rather than against placebo. Medications other than rimonabant have been shown to be superior to placebo for weight reduction in obese patients, 2,3 but in the STRADIVARIUS trial the interventions studied were either rimonabant (20 mg daily) or placebo. The primary end point used was percent atheroma volume (PAV), determined using intravascular ultrasound. Decrease in body weight is associated with favorable changes inthemetabolicprofile,whichmayreduceprogressionofatheroscleroticdisease.Thestrategyofusingaprimaryendpoint of PAV rather than weight reduction in this study seems to be a way to avoid the need for comparing rimonabant with anactiveantiobesitymedication.IntheSTRADIVARIUStrial, morethan80%oftheincludedpatientswereobese(BMI30). In addition, PAV is a nonvalidated surrogate end point for cardiovascular outcomes, and measurement of PAV requires an invasive procedure. Diagnostic cardiac catheterization is not a risk-free procedure, with 1 study finding a 1.9%majorcomplicationrateandamortalityrateof0.12%. 4 It is not clear how many cardiac catheterizations were conducted solely to evaluate PAV, and no data were presented about complications resulting from the procedure. The high rates of adverse events resulting from rimonabant itself were discussed in the accompanying Editorial by Drs Rumsfeld and Nallamothu. 5 Our main concerns are whether it is acceptable to compare an active drug against placebo when another therapy has already shown proven benefits for the condition, and whether it is ethical to submit patients to a risky invasive procedure to evaluate a nonvalidated end point.

Effect of Diabetes on Progression of Coronary Atherosclerosis and Arterial Remodeling: A Pooled Analysis of 5 Intravascular Ultrasound Trials

Our goal was to characterize coronary atherosclerosis progression and arterial remodeling in diabetic patients. The mechanisms that underlie adverse cardiovascular outcomes in diabetic patients have not been well characterized. A systematic analysis was performed in 2,237 subjects in randomized controlled studies of atherosclerosis progression. The pattern of arterial remodeling, extent of coronary atherosclerosis, and disease progression was compared in subjects with and without diabetes. In association with more risk factors, diabetic patients demonstrated a greater percent atheroma volume (PAV) (40.2 +/- 0.9% vs. 37.5 +/- 0.8%, p < 0.0001) and total atheroma volume (TAV) (199.4 +/- 7.9 mm(3) vs. 189.4 +/- 7.1 mm(3), p = 0.03) on multivariate analysis. A stronger correlation was observed between PAV and glycated hemoglobin (r = 0.22, p = 0.0003) than fasting glucose (r = 0.09, p < 0.0001), although the difference just failed to meet statistical significance after controlling for study. Diabetic patients exhibited a smaller lumen (291.1 +/- 104.8 mm(3) vs. 306.5 +/- 108.2 mm(3), p = 0.005) but no difference in external elastic membrane (494.9 +/- 166.9 mm(3) vs. 498.8 +/- 167.2 mm(3), p = 0.61) volumes. More rapid progression of PAV (0.6 +/- 0.4% vs. 0.05 +/- 0.3%, p = 0.0001) and TAV (-0.6 +/- 2.5 mm(3) vs. -2.7 +/- 2.4 mm(3), p = 0.03) was observed in diabetic patients on multivariate analysis. Smaller external elastic membrane (482.5 +/- 160.7 mm(3) vs. 519.9 +/- 166.9 mm(3), p = 0.03) and lumen (276.0 +/- 100.3 mm(3) vs. 310.1 +/- 105.6 mm(3), p = 0.001) volumes were observed in diabetic patients treated with insulin despite the presence of a similar TAV (206.5 +/- 88.6 mm(3) vs. 209.9 +/- 90.2 mm(3), p = 0.84). Intensive low-density lipoprotein cholesterol lowering in patients improved the rate of plaque progression, but only to the level observed in nondiabetic patients with suboptimal lipid control. Diabetes is accompanied by more extensive atherosclerosis and inadequate compensatory remodeling. Accelerated plaque progression, despite use of medical therapies, supports the need to develop new antiatherosclerotic strategies in diabetic patients.

Relationship Between Biomarkers of Oxidized Low-Density Lipoprotein, Statin Therapy, Quantitative Coronary Angiography, and Atheroma Volume: Observations From the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Study

This study was designed to test the hypothesis that circulating biomarkers of oxidized low-density lipoprotein (OxLDL) are affected by statin therapy and predict changes in atheroma volume. Oxidative stress is thought to play an important role in atherogenesis but the relationship between OxLDL, statin therapy, and atheroma volume in humans is not known. In a subgroup of 214 patients from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, oxidized phospholipids (OxPL) and malondialdehyde (MDA) epitopes per apolipoprotein B-100 (apoB), immunoglobin (Ig) G and IgM apoB immune complexes, and OxLDL autoantibodies were measured at baseline and after 18 months of treatment with atorvastatin or pravastatin. Relationships between changes of OxLDL biomarkers and quantitative coronary angiography (QCA), total atheroma volume, and percentage atheroma volume were analyzed. There were no differences in QCA parameters or atheroma volume in the 2 groups at baseline. Compared with baseline values, OxPL/apoB and MDA/apoB, and lipoprotein (a) levels increased 21% to 48% (p < 0.001 for all) in response to atorvastatin and 17% to 39% (p < 0.001 for all) in response to pravastatin. In contrast, IgG apoB immune complexes, IgM apoB immune complexes, and IgM OxLDL autoantibodies were significantly reduced by both atorvastatin and pravastatin (p value range 0.003 to <0.001). There were no significant differences between the atorvastatin and pravastatin groups. In the entire cohort, there were no correlations between changes in any OxLDL biomarkers and changes in QCA parameters or atheroma volume. Statin therapy results in significant increases in OxPL/apoB, MDA/apoB, and lipoprotein (a) levels and decreases in apoB immune complexes and OxLDL autoantibodies. However, these measures did not correlate with changes in QCA parameters or atheroma volume.

Effect of Rimonabant on Progression of Atherosclerosis in Patients With Abdominal Obesity and Coronary Artery Disease

Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n = 839) and study completion (n = 676). The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P = .22), respectively, and TAV decreased 2.2 mm3 (-4.09 to -0.24) vs an increase of 0.88 mm3 (-1.03 to 2.79) (P = .03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P = .13), and TAV decreased 1.95 mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P = .02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P < .001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (-35.4 to -17.3) (20.5%) vs 8.9 mg/dL (-14.2 to -1.8) (6.2%) (P < .001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11% [0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P < .001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P < .001). After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. clinicaltrials.gov Identifier: NCT00124332.

Does PERISCOPE Provide a New Perspective on Diabetic Treatment?

CARDIOVASCULAR EVENTS, PARTICULARLY ACUTE myocardial infarction and stroke, are the main causes of death in patients with diabetes. Whether stringent glucose control and use of specific glucose-lowering drugs reduce this risk has remained a controversial issue for decades. Thus, adequately powered randomized clinical trials are now required to study the effect of new antidiabetic drugs on cardiovascular death, myocardial infarction, and stroke. One of these studies was the Proactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) trial, which compared pioglitazone with placebo in addition to standard glucose-lowering drugs in more than 5000 patients. In the Proactive trial, treatment with pioglitazone failed to reduce significantly the primary composite end point of death, myocardial infarction, stroke, revascularization, and amputation, even though the secondary end point of death, myocardial infarction, and stroke was reduced (hazard ratio [HR]; 0.84, 95% confidence interval [CI], 0.72-0.98; P=.027). A patient-level meta-analysis of the 19 randomized, double-blind controlled trials of pioglitazone showed consistent results for reducing cardiovascular events, with an HR of 0.82 (95% CI, 0.72-0.94; P=.005) but at the price of an excess of serious heart failure (HR, 1.41; 95% CI, 1.14-1.76; P=.002). Given the role of coronary and cerebrovascular atherosclerosis in the genesis of cardiovascular events, reducing or at least slowing progression of atherosclerosis in the coronary or carotid arteries appears to be an important pathway for preventing cardiovascular events. In this issue of JAMA, Nissen and colleagues report the results of a randomized trial comparing pioglitazone with glimepiride in 543 patients with type 2 diabetes and coronary artery disease. Patients in whom coronary angiography had identified a segment with mild coronary stenosis ( 20% but 50% diameter stenosis) were evaluated with intravascular ultrasound (IVUS) at baseline and 18 months later. The primary end point of the trial—change in percent atheroma volume— increased by 0.73% (95% CI, 0.33% to 1.12%) in the glimepiride group and decreased by 0.16% (95% CI, −0.57% to 0.25%) in the pioglitazone group (P=.002). The results of this study therefore suggest that for patients with type 2 diabetes pioglitazone has the potential to slow or prevent progression of coronary atherosclerosis better than glimepiride, a widely used sulfonylurea. Several aspects of the PERISCOPE trial must be considered in interpreting the findings. First, IVUS exquisitely delineates changes in coronary atherosclerosis; the PERISCOPE investigators are among the champions of this approach, which they have applied effectively in several previous studies. Second, the effects observed were on the background of excellent contemporary therapy with statins, reninangiotensin blockers, and aspirin. However, more than a third of the patients did not complete the study end point assessment, primarily because a repeat IVUS was not obtained. Although the authors used a sophisticated imputation algorithm to reanalyze their results and found essentially consistent outcomes, this high rate of noncompletion raises caution against overinterpreting the results. Another factor is that the target segments selected for ultrasound study were, by definition, segments with apparent mild disease, with exclusion of segments in which a stenosis exceeding 50% was present. Because patients who underwent repeat IVUS also underwent repeat coronary angiography, it would be important to know about the evolution of more severe coronary lesions that may have been present in patients at baseline but were not subjected to percutaneous coronary intervention. Third, the clinical relevance of the difference achieved, which appears minimal ( 1% change in atheroma volume), is unclear, although this effect is well within the range of what is achieved with some therapies demonstrated to improve cardiovascular outcomes, such as high-dose statins. However, the results from the PERISCOPE trial are consistent with those from several small previous studies suggesting that pioglitazone may have favorable effects on carotid intimal-medial thickness progression or neointima formation after coronary stenting. Given the small differences in glycemic control and the fact that there is still no evidence that more intense glycemic control is associated with cardiovascular benefits, the authors as-

Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes

No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. Change in percent atheroma volume (PAV) from baseline to study completion. Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) with pioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. clinicaltrials.gov Identifier: NCT00225277.

The Effects of Rosuvastatin on Plaque Regression in Patients Who Have a Mild to Moderate Degree of Coronary Stenosis With Vulnerable Plaque

Background and Objectives: Intensive lipid-lowering therapy with statins improves the clinical outcomes and patient survival and it reduces the progression of atherosclerosis. Intravascular ultrasound (IVUS) has been used for calculating the plaque volumes to evaluate the mechanisms that may be involved in the progression or regression of coronary artery disease. We used serial IVUS exams to assess the efficacy of rosuvastatin on plaque regression in angina patients who had a mild to moderate degree of vulnerable plaque burden. Subjects and Methods: This study was a prospective, randomized, comparative study for lipid lowering therapy with using rosuvastatin 20 mg or atorvastatin 40 mg. IVUS was performed during the baseline coronary angiography and it was repeated after 12 months of treatment. The efficacy parameters included the changes in the atheroma volume and the lipid pool size as determined by IVUS. A total of 45 lesions in 30 patients were analyzed (rosuvastatin: 24 lesions in 16 patients vs. atorvastatin: 21 lesions in 14 patients). Results: The low density lipoprotein (LDL)-cholesterol level was reduced from 121±45 mg/dL to 65±25 mg/dL in the rosuvastatin group (a 46% decrease, p<0.001), and from 127±37 mg/dL to 72±26 mg/dL in the atorvastatin group (a 43% decrease, p<0.001). The total atheroma and vessel volumes were significantly decreased, whereas the lumen volume was significantly increased from baseline to follow-up in both groups (for the rosuvastatin group: the total atheroma volume, 252±80 to 246±79 mm 3 , p<0.001; the vessel volume, 555±158 to 553±130 mm 3 , p<0.001; the lumen volume, 303±91 to 307±92 mm 3 , p<0.001, and for the atorvastatin group: the total atheroma volume, 288±98 to 283±98 mm 3 , p<0.001; the vessel volume, 607±165 to 604±166 mm 3 , p<0.001; the lumen volume, 319±71 to 321±73 mm 3 , p<0.001). The follow-up LDL-cholesterol level was correlated with the change in the total atheroma volume (r=0.577, p< 0.001), the change in the percent atheroma volume (r=0.558, p<0.001) and the change in the lipid pool size (r=0.470, p=0.001). Conclusion: Both rosuvastatin 20 mg and atorvastatin 40 mg could contribute to the regression of lipid-rich plaque. The follow-up LDL-cholesterol level is related to the regression and stabilization of vulnerable coronary plaque. (Korean Circ J 2008;38:366-373)

Abstract 684: Changes in Levels of High Density Lipoprotein Cholesterol Predict the Impact of Torcetrapib on Progression of Coronary Atherosclerosis: Insights from ILLUSTRATE

Background: Administration of the CETP inhibitor torcetrapib does not slow the rate of progression of coronary atherosclerosis. The reason for the lack of therapeutic efficacy remains unknown. This analysis investigated the relationship between changes in HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) and atheroma volume in patients treated with torcetrapib. Methods: 910 patients with angiographic coronary artery disease underwent IVUS imaging within a single coronary artery before and during 24 months of treatment with torcetrapib (n = 464) or placebo (n = 446) on a background of atorvastatin therapy. The relationship between changes in levels of HDL-C and LDL-C and both percent atheroma volume (PAV) and total atheroma volume (TAV) was evaluated in patients treated with torcetrapib. Results: Administration of torcetrapib raised HDL-C by 61% and lowered LDL-C by 20% when compared to atorvastatin alone. An inverse relationship was observed between changes in HDL-C and both PAV (r = −0.17, p &lt; 0.001) and TAV (r = −0.17, p &lt; 0.001). Patients with the highest level of HDL-C (&gt; 87 mg/dL) had the lowest rate of progression of PAV (−0.7 v +0.7%, p = 0.0003) and TAV (−9.2 v −4.6 mm 3 , p = 0.09). The greatest elevation in level of HDL-C (&gt; 80%) was associated with the lowest progression of PAV (−0.3 v +0.9%, p = 0.002) and TAV (−12.6 v −3.4 mm 3 , p = 0.0006). Patients undergoing regression (any reduction in PAV) had greater absolute levels (73 v 66 mg/dL, p = 0.02) and changes (59.5 v 48.3%, p = 0.02) of HDL-C. No difference in the impact of torcetrapib on changes in PAV (+0.3 v +0.1%, p = 0.34) and TAV (−9.1 v −9.3 mm 3 , p = 0.95) was observed in patients with baseline levels below or above 40 mg/dL. No relationship was observed between changes in LDL-C and either PAV (r = 0.06, p = 0.20) or TAV (r = 0.07, p = 0.12) in torcetrapib treated patients. On multivariate analysis, changes in levels of HDL-C independently predicted the impact of torcetrapib on progression of PAV (p = 0.007) and TAV (p = 0.004). Conclusion: Increasing levels of HDL-C from torcetrapib treatment were associated with a beneficial impact of torcetrapib on plaque progression. This is consistent with the generation of functional HDL particles and suggests other effects to be responsible for the lack of benefit of torcetrapib.