Change In Percent Atheroma Volume Research Articles

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-

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.

Comparison of Intravascular Ultrasound and Quantitative Coronary Angiography for the Assessment of Coronary Artery Disease Progression

The relative merits of quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS) for the assessment of progression/regression in coronary artery disease are uncertain. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population. We investigated the relationships between QCA and IVUS at single time points (n=525) and also for the changes over time (n=432). QCA and IVUS data underwent central laboratory analyses. Statistically significant correlations were observed between the QCA coronary artery score and the IVUS-derived lumen volume (r=0.65, P<0.0001) and total vessel volume (r=0.55, P<0.0001) and between the QCA cumulative coronary stenosis score and percent atheroma volume on IVUS (r=0.32, P<0.0001) at baseline for matched segments. A similar pattern of correlations was observed for global (all segments) QCA-derived and single-vessel IVUS-derived data. There were statistically significant but weak correlations between the changes over time in lumen dimensions on QCA and IVUS (P=0.005) and between the change in cumulative coronary stenosis score on QCA and percent atheroma volume on IVUS (r=0.14, P=0.01). Nevertheless, patients with and without angiographic progression had changes in plaque volume on IVUS of 9.13 and 0.20 mm3, respectively (P=0.028). QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increases in plaque volume on IVUS compared with no angiographic progression.

Intravascular ultrasound assessment of novel antiatherosclerotic therapies: Rationale and design of the Acyl-CoA:Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Study

Inhibiting the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) has beneficial effects on foam cell formation and therefore has the potential to favorably influence the progression of coronary atherosclerosis. The aim of this study is to determine whether ACAT inhibition, when added to usual medical care, reduces atheroma progression in subjects with coronary artery disease. Five hundred thirty-four subjects with established coronary artery disease on angiography were randomized to receive the experimental ACAT inhibitor, pactimibe, 100 mg daily or matching placebo for 18 months. The primary efficacy parameter will be the nominal change in percent atheroma volume determined by analysis of pullback intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and 18-month follow-up. In addition, the effect of pactimibe on plasma lipids and inflammatory markers and the incidence of clinical cardiovascular events will also be assessed. Serial IVUS has emerged as a sensitive imaging modality to assess the impact that novel antiatherosclerotic strategies have on the arterial wall. In this study, IVUS will be used to assess whether ACAT inhibition modifies progression of atherosclerotic plaque.

Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis

Prior intravascular ultrasound (IVUS) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of regression using percent atheroma volume (PAV), the most rigorous IVUS measure of disease progression and regression. To assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging. Prospective, open-label blinded end-points trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) was performed at 53 community and tertiary care centers in the United States, Canada, Europe, and Australia. A motorized IVUS pullback was used to assess coronary atheroma burden at baseline and after 24 months of treatment. Each pair of baseline and follow-up IVUS assessments was analyzed in a blinded fashion. Between November 2002 and October 2003, 507 patients had a baseline IVUS examination and received at least 1 dose of study drug. After 24 months, 349 patients had evaluable serial IVUS examinations. All patients received intensive statin therapy with rosuvastatin, 40 mg/d. Two primary efficacy parameters were prespecified: the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also prespecified. The mean (SD) baseline low-density lipoprotein cholesterol (LDL-C) level of 130.4 (34.3) mg/dL declined to 60.8 (20.0) mg/dL, a mean reduction of 53.2% (P<.001). Mean (SD) high-density lipoprotein cholesterol (HDL-C) level at baseline was 43.1 (11.1) mg/dL, increasing to 49.0 (12.6) mg/dL, an increase of 14.7% (P<.001). The mean (SD) change in PAV for the entire vessel was -0.98% (3.15%), with a median of -0.79% (97.5% CI, -1.21% to -0.53%) (P<.001 vs baseline). The mean (SD) change in atheroma volume in the most diseased 10-mm subsegment was -6.1 (10.1) mm3, with a median of -5.6 mm3 (97.5% CI, -6.8 to -4.0 mm3) (P<.001 vs baseline). Change in total atheroma volume showed a 6.8% median reduction; with a mean (SD) reduction of -14.7 (25.7) mm3, with a median of -12.5 mm3 (95% CI, -15.1 to -10.5 mm3) (P<.001 vs baseline). Adverse events were infrequent and similar to other statin trials. Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden. Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients. Further studies are needed to determine the effect of the observed changes on clinical outcome. ClinicalTrials.gov Identifier: NCT00240318.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor