Accordingly, we designed the ASTEROID trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary. The purpose of this study is to see if 40 mg of rosuvastatin taken daily will reduce . statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound- Derived Coronary Atheroma Burden – ASTEROID. Mar 13, Share via: AddThis.
|Published (Last):||13 August 2005|
|PDF File Size:||19.52 Mb|
|ePub File Size:||18.70 Mb|
|Price:||Free* [*Free Regsitration Required]|
The top left panel illustrates the appearance of a single asterold at baseline intravascular ultrasound examination, while the top right panel shows the same cross-section after 24 months of treatment.
The bottom 2 panels illustrate the same cross-sections, but with measurements superimposed. Atheroma area was reduced from EEM indicates external elastic membrane.
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. After 24 months, patients had evaluable serial IVUS examinations.
A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also prespecified. Change in total atheroma volume showed a 6. Adverse events were infrequent and similar to other statin trials. Treatment to LDL-C rpsuvastatin 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. Atherosclerosis is generally viewed as a chronic, progressive disease characterized by continuous accumulation of atheromatous plaque within the arterial wall.
The last 2 decades have witnessed the introduction of rosuvvastatin variety of antiatherosclerotic therapies, most notably the 3-hydroxymethylglutaryl coenzyme A reductase inhibitors statins.
Although statins rank among the most extensively studied therapies in contemporary medicine, the optimal target levels for low-density lipoprotein cholesterol LDL-C remain controversial.
Recently, several active control trials have reported that more intensive statin therapy results in a greater reduction in adverse cardiovascular outcomes compared with more moderate treatment. In parallel to clinical outcomes trials, imaging studies have examined the effects of antiatherosclerotic therapies on the progression of atherosclerosis.
Initial trials used quantitative coronary angiography or carotid ultrasound to determine the progression rates.
Trials using IVUS have successfully investigated the effects of a variety of antiatherosclerotic therapies, including statins, 12161719 blood pressure—lowering drugs, 14 asterpid of inflammatory markers, 19 administration of a high-density lipoprotein HDL mimetic, 11 and novel investigative therapies. The most positive IVUS trials to date have demonstrated a slowing or halting of progression of atherosclerosis during statin eosuvastatin.
However, none of the major trials has provided convincing evidence of regression using rigorous IVUS measures of disease burden.
We hypothesized that high-intensity statin therapy, designed to reach very low levels of LDL-C, particularly if achieved in conjunction with substantial elevation of HDL-C, might result in regression of coronary atherosclerosis. Rosuvastatin is the most recently introduced statin and typically produces greater reductions in LDL-C and larger increases in HDL-C than previously available agents. The institutional review boards of all participating centers approved the protocol and all patients provided written rosuvzstatin consent.
The protocol specified enrollment of patients at least 18 years of age who required coronary angiography for a clinical indication, which typically consisted of stable or unstable ischemic chest rosuvastqtin syndromes or abnormal functional studies, such as exercise testing. All patients were statin-naive, defined as receiving no statin therapy for more than 3 months during the previous 12 months.
Patients treated with any lipid-lowering medication within the previous 4 weeks required a 4-week washout period before enrollment to obtain accurate baseline lipid values. The study sought to determine the effects of high-intensity lipid lowering on coronary asteroud progression.
Prior publications have thoroughly described the methods for IVUS interrogation. The operator was instructed to select a starting point for interrogation as far distally as could be safely reached. This procedure was designed to provide the longest possible vessel segment aateroid analysis. After selection of a starting point, the operator engaged a motor drive that progressively withdrew the transducer at a speed of 0.
During this pullback, images were obtained at 30 frames per rosuvastaatin and recorded on super-VHS videotape. The study was screened for image quality at a core laboratory at the Cleveland Clinic Foundation, Cleveland, Ohio, and only patients whose IVUS results met prespecified image quality requirements were eligible for inclusion in the study.
The ASTEROID trial: coronary plaque regression with high-dose statin therapy.
Patients were examined during scheduled clinic visits every 3 months. Lipid levels were obtained every 3 months and mean levels during treatment were computed from the time-weighted rosuvastztin of these values. After a month astdroid period, actively participating patients underwent repeat IVUS examination. If a patient required coronary angiography between 18 and 24 months following enrollment, an end-of-study IVUS examination was performed then, to avoid subjecting patients to an additional invasive procedure at the month visit.
The operator placed the IVUS catheter in the vessel originally interrogated and positioned the transducer distal to the original branch site.
A motorized pullback was repeated under conditions identical to the baseline study. This procedure was designed to obtain a series of cross-sectional images at sites identical to the original examination.
Videotapes containing baseline and follow-up pullbacks were analyzed in the Intravascular Ultrasound Core Laboratory at the Cleveland Clinic Astreoid.
All measurements were performed at the end of the study, after both the baseline and follow-up IVUS examinations were available. The baseline and follow-up pullbacks were reviewed as a pair.
However, to conceal the imaging sequence, personnel not otherwise involved in the study performed blinding and randomization. As each baseline videotape was received, the images were digitized and the date imprinted on the videotape was removed from each image using digital processing.
A similar procedure was performed for each follow-up videotape. The 2 examination results were then resequenced using random assignments generated by an outside statistician. Personnel who were unaware of the coding and were therefore blinded to the sequence subsequently analyzed both videotapes.
After the trial was concluded and all measurements were completed, the sequence coding was unblinded to enable calculation of changes from baseline to follow-up examination.
A technician selected a distal branch site as the beginning point for analysis. Subsequently, every 60th image was analyzed, representing cross-sections spaced exactly 1. Manual planimetry was used to trace the leading edges of the luminal and external elastic membrane EEM borders. Previous reports have established the accuracy and reproducibility of this method. The second prespecified primary efficacy parameter was the nominal change end of treatment minus baseline in total atheroma volume TAV in the mm subsegment of the coronary artery with the largest plaque volume at baseline the most diseased segment.
For patients without 10 contiguous evaluable cross-sections, 8 or 9 cross-sections were used and the results were normalized to compensate for the missing cross-sections.
A secondary efficacy parameter, the change in normalized TAV, was calculated by first determining the average atheroma area per cross-section as. Normalized TAV for each patient was calculated as the average atheroma area multiplied by the median number of comparable cross-sections in pullbacks for all patients completing the trial. This procedure adjusts for pullbacks of differing lengths, resulting in an equal weighting of each individual patient in computing the final efficacy results.
To allow for 2 primary efficacy parameters, a Bonferroni correction was prespecified and a significance level of. The statistical analysis plan defined tests of normality for the efficacy parameters and specified nonparametric testing if the data were not normally distributed. The efficacy results are presented as mean and SD and median and interquartile range for the change from baseline.
If IVUS data were normally distributed, analysis of covariance, with baseline as a covariate and region as a factor, was specified. Otherwise, P values were to be calculated using the Wilcoxon signed rank test. Analysis of variance, with region as a factor, was used for analysis of the percentage of change in lipid values.
Demographic and laboratory characteristics were calculated at baseline and follow-up for all patients completing the trial. A safety analysis was performed in all patients who received at least 1 dose of the study drug.
Categorical variables are described using frequencies, while continuous variables are reported as means with SDs and medians with Analyses were performed using SAS software, version 8. Between November and Octoberpatients were screened and met all inclusion and exclusion criteria, including an acceptable baseline IVUS result, and received study drug at 53 centers.
A total of patients had evaluable IVUS examinations at both baseline and after 24 months of treatment Figure 1. Of the patients who were not included in the IVUS analysis, 14 were lost to follow-up, 2 were withdrawn per investigator discretion, 3 were withdrawn for protocol violations, 32 patients withdrew consent, 63 were withdrawn for an adverse event, and 11 withdrew for other reasons. Thirty-three patients did not have a final IVUS result analyzed, 13 of whom did not undergo a final IVUS examination and 20 of whom had IVUS results that were not analyzable because of artifacts or pullbacks shorter than the prespecified mm minimum length.
Baseline demographic characteristics and concomitant medications for the patients completing the trial and the patients not completing the trial are summarized in Table 1. The characteristics of the noncompleters were very similar to those of the completers in terms of age, sex, weight, body mass index calculated as weight in kilograms divided by the square of height in metersand prevalence of hypertension and diabetes.
The disposition of these patients is summarized in Figure 1. Table 2 summarizes laboratory values obtained during the study for patients completing the trial. Baseline lipid values for the patients completing the trial and the patients not completing the trial were very closely matched. Table 3 shows the results for both the primary and the secondary efficacy parameters.
All 3 efficacy parameters showed statistically significant regression. This change represents a median reduction of 9. This change represents a median reduction of 6.
The ASTEROID trial: coronary plaque regression with high-dose statin therapy.
For the primary efficacy asferoid of PAV, For the second primary efficacy parameter, change in the mm subsegment with the greatest disease severity, Table 4 shows the results for the primary end points for prespecified subgroups.
There was no significant heterogeneity in the response to treatment for either of the 2 primary efficacy parameters for qsteroid defined by age, sex, body mass index, history of diabetes mellitus, LDL-C levels, or HDL-C levels. A post hoc sensitivity analysis was rosuvawtatin to assess the grial impact of patients not completing the trial on IVUS measures of efficacy. One approach imputed all noncompleting patients as showing no change in atheroma burden neither progression nor regression.
A second imputation method assigned the 22 patients who discontinued the study because of ischemic events to a progression rate calculated from the median value for all patients completing the trial who showed progression. Table 5 shows the treatment-emergent adverse events encountered in the trial. Rates of elevation of hepatic enzymes were comparable with those astedoid in other recent trials using maximal statin dosages.
There were no cases of rhabdomyolysis. Two patients experienced serious adverse events based on local, non—study-related laboratory values.
A year-old man had an elevated creatine kinase level following an episode of lower back pain that occurred after heavy lifting. After he received a nonsteroidal anti-inflammatory agent, renal failure developed, the family declined dialysis, and the patient died 5 days later. Postmortem examination revealed a fracture of the T11 vertebral body with local muscle hemorrhage. Multiple muscle biopsies found no evidence of rhabdomyolysis.
A second patient had an elevated creatine kinase level after a seizure but continued taking the study drug, and creatine kinase levels returned to normal during rpsuvastatin. The number of clinical events in this month trial was too small for any meaningful analysis of the relationship between progression rate and morbidity or mortality.