Long-term safety of intravascular ultrasound in nontransplant, nonintervened, atherosclerotic coronary arteries

OBJECTIVES: The goal of this study was to demonstrate that intravascular ultrasound (IVUS) examination of native coronary arteries does not result in an acceleration of the atherosclerotic process. BACKGROUND: Intravascular ultrasound is increasingly used to assess the effects of pharmacologic agents on atherosclerosis. METHODS: Intravascular ultrasound examinations of one coronary artery and coronary angiography were performed in 525 patients at baseline. Patients then underwent a follow-up angiogram 18 to 24 months later. All end points were evaluated in IVUS-related and non-IVUS arteries using quantitative coronary analysis. The study end points were the coronary change score (per-patient mean of minimum lumen diameter changes for all lesions measured), occurrence of new coronary lesions, and progression of preexistent lesions at follow-up. Acute angiographic and clinical complications were also analyzed. RESULTS: Coronary change score was -0.06 ± 0.23 mm and -0.05 ± 0.21 mm for IVUS-related and non-IVUS arteries, respectively (p = 0.35). The increase in percent diameter stenosis from baseline to follow-up was 0.8 ± 6.7% and 1.2 ± 7.0% in the IVUS-related and non-IVUS arteries (p = 0.29). New lesions occurred in 3.6% and 3.9% of IVUS-related and non-IVUS arteries, respectively (p = 0.84). When all coronary lesions were considered, the incidence of lesion progression was not significantly different between IVUS-related (11.6%) and non-IVUS (9.8%) arteries. Coronary spasm occurred in 1.9% of IVUS procedures, and there was one case of acute occlusion with no long-term sequelae. CONCLUSIONS: Intravascular ultrasound does not significantly accelerate atherosclerosis in native coronary arteries and can be used safely to assess progression/regression in clinical trials. © 2005 by the American College of Cardiology Foundation

Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis - A randomized controlled trial

Context: High-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression. Objective: To investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS). Design and Setting: A randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2 to 3 weeks after the last study infusion. Patients: Between July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks. Intervention: Sixty patients were randomly assigned to receive 4 weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. Main Outcome Measures: The primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points. Results: The higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was −3.4% with CSL-111 and −1.6% for placebo (P = .48 between groups, P<.001 vs baseline for CSL-111). The nominal change in plaque volume was −5.3 mm3 with CSL-111 and −2.3 mm3 with placebo (P = .39 between groups, P<.001 vs baseline for CSL-111). The mean changes in plaque characterization index on IVUS (−0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (−0.039 mm for CSL-111 and −0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = .01 and P =.03, respectively). Administration of CSL-111 40 mg/kg was associated with mild, self-limiting transaminase elevation but was clinically well tolerated. Conclusions: Short-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography. Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted

Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial

Background Oxidative stress and inflammation are involved in the pathophysiology of atherosclerosis. Our aim was to assess the effects of the antioxidant succinobucol (AGI-1067) on cardiovascular outcomes in patients with recent acute coronary syndromes already managed with conventional treatments. Methods After an acute coronary syndrome occurring 14–365 days before recruitment, 6144 patients were randomly assigned with a computer-generated randomisation list, stratified by study site, to receive succinobucol (n=3078) or placebo (n=3066) in addition to standard of care. Enrolment began in July, 2003; this event-driven trial was stopped in August, 2006, after the prespecified number of primary outcome events had occurred. The composite primary endpoint was time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularisation. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00066898. Findings All randomised patients were included in the efficacy analyses. Succinobucol had no effect on the primary endpoint (530 events in succinobucol group vs 529 in placebo group; hazard ratio 1·00, 95% CI 0·89–1·13, p=0·96). The composite secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke occurred in fewer patients in the succinobucol group than in the placebo group (207 vs 252 events; 0·81, 0·68–0·98, p=0·029). The tertiary endpoint of new-onset diabetes developed in fewer patients without diabetes at baseline in the succinobucol group than in such patients in the placebo group (30 of 1923 vs 82 of 1950 patients; 0·37, 0·24–0·56, p<0·0001). New-onset atrial fibrillation occurred more often in the succinobucol group than in the placebo group (107 of 2818 vs 55 of 2787 patients; 1·87, 1·67–2·09, p=0·0002). Although the number of patients who reported any treatment emergent adverse event was much the same in the two groups, more patients in the succinobucol group than in the placebo group reported bleeding episodes or anaemia (32 vs 18 and 37 vs ten, respectively) as serious adverse events. Relative to treatment with placebo, succinobucol increased LDL cholesterol and systolic blood pressure, and decreased HDL cholesterol and glycated haemoglobin (p<0·0001 for all). Interpretation Although succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes—both beneficial and harmful—will need to be further assessed before succinobucol is used in patients with atherosclerosis or as an antidiabetic agent

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial

Aims In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis.Methods and results dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P= 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98).Conclusion Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.[GRAPHICS]