In large clinical trials, therapy with HMG-CoA reductase inhibitors (statins) has been shown to prevent recurrent coronary events in patients with coronary artery disease.1-3 Recent clinical trials have also shown that early treatment with statins could reduce recurrent coronary events after onset of acute coronary syndrome (ACS), even during the immediate follow-up period.4,5 Although the pleiotropic effects, such as anti-inflammatory effects and improvement of endothelial function, were suggested in these trials, the means by which improvement occurred was not clear. The reduction in low-density lipoprotein (LDL) cholesterol levels did indeed correlate well with event reduction in some clinical studies.
To determine whether early LDL cholesterol—lowering therapy (within 24 hours of emergency percutaneous coronary intervention [PCI]) with atorvastatin (Lipitor) could result in a marked decrease in plaque volume as shown on volumetric intravascular ultrasound (IVUS) analysis, we conducted an open-label prospective study. We also examined whether the percent change in plaque volume correlated with the percent of LDL cholesterol reduction.
Patients and methods
In the Early Statin Treatment in patients with Acute coronary syndrome: Demonstration of the Beneficial effect on atherosclerotic Lesions by Serial volumetric Intravascular ultrasound Analysis during Half a year after coronary event (ESTABLISH) study, 70 patients were randomly assigned after PCI either to a control group or to an atorvastatin treatment group. To control for diabetes mellitus, total cholesterol level at baseline, culprit vessel, and sex, minimization methods were used. The study included ACS patients with severe stenosis as shown on coronary angiography (CAG) who had received PCI and who had undergone IVUS examination. Patients who were given certain other lipid-lowering drugs, who had cardiogenic shock, who were referred for coronary artery bypass graft surgery, or who had unsuccessful PCI were excluded from the study. Those in the atorvastatin group (n = 35) received 20 mg of atorvastatin once daily within 24 hours after emergency PCI. Patients in the control group (n = 35) were given usual care, which consisted of following a diet designed to reduce lipids and, for those whose LDL cholesterol levels did not decrease to less than 150 mg/dL, a cholesterol absorption inhibitor was prescribed for ethical reasons.
IVUS images were obtained at the start of the study and after 6 months. Changes in plaque volume of one target point in a nonculprit lesion were compared between the two groups during the 6-month follow-up period. The primary end point of the study was
the change in plaque volume measured by volumetric IVUS analysis. The secondary end point was the association between the percent change in LDL cholesterol level and plaque volume. Continuous variables were analyzed using the Mann-Whitney rank sum test or unpaired Student’s t test. The chi-square test was used to analyze the differences in categorical variables between the two groups. Linear regression analysis was used to assess associations. The Kaplan-Meier method was used to evaluate event-free survival. A probability value of less than .05 was considered to indicate statistical significance.
Baseline and follow-up IVUS examinations were performed using the same equipment for both groups. Following intracoronary injection of 0.2 mg of nitroglycerin, the ultrasound catheter was placed 10 mm distal to the PCI location. At a speed of 0.5 mm/sec, auto-pullback was performed. S-VHS videotape was used to document the results of the IVUS examination. Quantitative analysis was performed by individuals at our IVUS laboratory. One target segment was selected in each patient more than 5 mm from the PCI site. The target segment was required to have a reproducible index side branch. To achieve accurate an-alysis, we did not use vessels that
were tortuous or significantly calcified.
The Netra volumetric analysis system (ScImage) was used to analyze the plaque volume. This system provides 100 cross-sectional sliced images that permit analysis of a 10-mm length of plaque. The plaque volume is calculated from these 100 sliced images using Simpson’s method. All volumetric analyses were evaluated by an experienced independent IVUS observer unaware of the patient’s group and angiographic data.
A total of 35 patients were enrolled in the control group and 35 were enrolled in the atorvastatin group. As shown in Table 1, the two groups were similar with regard to baseline data, procedural characteristics, and lesion attributes. Because they refused follow-up CAG, two patients in the atorva-statin group were withdrawn from the study. Three patients in the control group did not complete the study: one refused follow-up CAG, one moved to another location, and one died of noncardiac causes. The 65 remaining patients received follow-up IVUS and CAG evaluation. Of these, 17 patients were excluded because of poor-quality IVUS images that could not provide for accurate analysis. We therefore analyzed IVUS images for 24 patients in each group.
As shown in Table 2, the LDL cholesterol level was markedly reduced in the atorvastatin group compared with the control group, which showed an increase in LDL level (47.1% reduction for the atorvastatin group versus 0.7% increase for the control group). Plaque volume was also markedly decreased in the atorvastatin group compared with baseline measurements (69.6 ± 49.0 mm3 at baseline versus 61.4 ± 44.9 mm3 at 6 months; P < .001), with an average reduction of 13.1%. There was an increase in plaque volume, however, in the control group (59.5 ± 38.6 mm3 at baseline versus 63.7 ± 40.1 mm3 at 6 months; P = .0276), with an average increase of 8.7% (P < .001 for the atorvastatin group versus the control group at follow-up). The lumen volume was also increased by an average of 5.8% in the atorvastatin group.
No matter what the baseline LDL cholesterol level was, there was a marked association between the percent LDL cholesterol level reduction and the percent change in plaque volume. As shown in Figure 1, in the atorvastatin group, there was no association between percent change in plaque volume and baseline LDL cholesterol level (R = 0.154), but the percent change in plaque volume was positively associated with the LDL cholesterol level at follow-up (R = 0.456; P = .001). As shown in Figure 2, although there was no association between the percent change in plaque volume and the percent gain in high-density lipoprotein cholesterol level (R = 0.206), the percent change in plaque volume was positively associated with the percent LDL cholesterol reduction (R = 0.612; P < .001). Figure 3 shows that, after dividing patients into two groups based on the median LDL cholesterol level
(> 125 mg/dL and < 125 mg/dL), both groups showed a similar significant positive correlation between the percent change in plaque volume and percent LDL cholesterol reduction (R = 0.685, P < .001 in patients with baseline LDL cholesterol < 125 mg/dL; R = 0.462, P = .023 in patients with baseline LDL cholesterol > 125 mg/dL).
Cardiac events in both groups were similar; 25.0% of patients in the control group and 24.2% of patients in the atorvastatin group had target-vessel revascularization.
Significant plaque regression by intensive lipid-lowering therapy with a statin had not previously been shown using volumetric IVUS analysis. In this study, plaque regression was evident with only 6 months of pharmacologic intervention after onset of ACS. The percent change in plaque volume was also strongly associated with the LDL cholesterol level at 6 months and percent LDL cholesterol reduction, no matter what the baseline LDL cholesterol level was. Plaque regression was not shown after 12 months of follow-up in some studies.6,7 We think this occurred because of differences in the conditions and populations in each study. The German Atorvastatin Intravascular Ultrasound (GAIN) study and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study were designed for patients with stable coronary artery disease, whereas our study populations were ACS patients. In the recent pathological studies, as well as clinical studies using CAG, intravascular angioscopy, and IVUS, ACS patients usually had multiple vulnerable plaques.8-12 These studies suggest that coronary plaques are prone to regress with intensive statin treatment in patients with ACS. We speculate that the plaque regression seen in our study was related to the stabilization of vulnerable plaque in the nonculprit lesion as a result of aggressive LDL-lowering in patients with ACS.
The results of our study showed that intensive early therapy with atorvastatin could reduce the plaque volume in patients following the appearance of ACS. The beneficial effect of atorvastatin was evident whether patients had a high baseline LDL cholesterol level (> 125 mg/dL) or not, indicating that this lipid-lowering therapy would achieve favorable results for patients with ACS no matter what their LDL cholesterol levels were. This efficacy can be an important mechanism for event reduction using early statin treatment in ACS patients.