Two years of rosuvastatin therapy leads to clinically relevant regression of atherosclerosis in patients with baseline coronary artery disease (CAD), according to the findings of A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID).

"Until the ASTEROID trial, prior angiographic and intravascular ultrasound (IVUS) trials had shown reduced progression of coronary atherosclerosis with statin therapy, but not regression," said lead study author Christie M. Ballantyne, MD, Baylor College of Medicine, Houston, TX. "Now, both imaging and outcome studies suggest that intensive lipid therapy is beneficial in this patient population."

ASTEROID was designed to evaluate whether treatment with rosuvastatin could regress coronary atherosclerosis in statin-naïve patients with angiographic evidence of CAD. Results for the primary endpoint – regression as measured by IVUS – were published in 2006 [Nissen et al. JAMA 2006].

The analysis presented today at the American College of Cardiology focuses on the secondary endpoint of ASTEROID: the regression of discrete coronary stenoses as measured by quantitative coronary angiography (QCA). Findings were simultaneously published online in the journal Circulation [Ballantyne et al. Circulation 2008].

In ASTEROID, 507 patients received treatment with rosuvastatin 40 mg/day for 24 months. For inclusion in the secondary-endpoint analysis, patients were required to have stenosis of >25% at baseline in one of the three coronary arteries or a major branch. Of the total ASTEROID cohort, 292 patients underwent evaluation with QCA. In these patients, angiograms assessed all lesions for two measures of atherosclerosis -- minimal lumen diameter (MLD) and percent diameter stenosis -- at baseline and again at 24 months.

Patients were enrolled regardless of baseline cholesterol levels. However, after 24 months of treatment with rosuvastatin, the overall lipid profile of patients improved significantly. Between baseline and 2-year follow-up, rosuvastatin reduced low-density lipoprotein (LDL) cholesterol by 53.3% to a mean of 61.1±20.3 mg/dL (p<0.001), increased high-density lipoprotein (HDL) cholesterol 13.8% to a mean of 48.3±12.4 mg/dL (p<0.001), and decreased the LDL cholesterol/HDL cholesterol ratio by 58.2% to 1.33 (p<0.001).

After two years, rosuvastatin therapy produced measurable regression in coronary atherosclerosis. Rosuvastatin also increased the MLD – the mean MLD increased from a baseline of 1.65±0.36 mm to 1.68±0.38 mm (p<0.001) – suggesting a reversal of stenosis due to atherosclerosis. Consistent with this finding, the mean stenosis diameter decreased from 37.3±8.4% to 36.0±10.1% (p<0.001).

To provide context for these results, the study criteria defined "clinically relevant" regression and progression as a =10% reduction or increase in stenosis diameter, respectively. With these criteria, 7.5% of patients achieved a clinically relevant regression, while 3.1% of patients had clinically relevant progression of atherosclerosis over the course of the study.

"Importantly, 97% of patients had at least stable disease or had regression of atherosclerosis," according to this measurement," said Dr. Ballantyne.

Dr. Ballantyne presented similar criteria to evaluate whether MLD changes qualified as clinically relevant regression (=0.2 mm increase) or progression (=0.2 mm decrease). According to these definitions, 12.1% of patients experienced clinically relevant regression, and 6.0% showed evidence of clinically relevant progression.

In the primary ASTEROID analysis, treatment with rosuvastatin 40 mg/day for 24 months led to significant regression of all IVUS measures of atheroma volume within the wall of a major coronary artery (p<0.001). "With the addition of the QCA results, there are now two imaging modalities showing concordant regression and stabilization of atherosclerosis with intensive statin therapy," Dr. Ballantyne said.

Clinical Implications

The beneficial effects of statins on coronary atherosclerosis appear to be related to reductions in LDL cholesterol and increases in HDL cholesterol. To illustrate this relationship, Dr. Ballantyne presented a graphical analysis of the QCA findings of ASTEROID plotted with those of other large trials of statin therapy, such as the Monitored Atherosclerosis Regression Study (MARS) [Blankenhorn et al. Ann Intern Med 1993] and the Lipoprotein and Coronary Atherosclerosis Study (LCAS) [Herd et al. Am J Cardiol 1997].

Expressed graphically, the direct correlation between LDL cholesterol and atherosclerosis persists, regardless of whether LDL cholesterol is expressed as on-treatment level or percent change, or whether atherosclerosis is measured by percent change in restenosis or absolute change in MLD. In these graphs, the predicted LDL cholesterol value for zero net change in atherosclerosis (stable disease) is an on-treatment LDL cholesterol level of 80 mg/dL or a 40% reduction in LDL cholesterol. Crossing into the negative net change in atherosclerosis (regression) would require either a lower LDL cholesterol value or a greater reduction in LDL cholesterol.

In another series of graphs, Dr. Ballantyne showed an equivalent correlation between atherosclerosis and HDL cholesterol levels. In this model, the predicted HDL cholesterol value corresponding to stable disease is an on-treated HDL cholesterol level of 47-50 mg/dL or a 10% increase in HDL cholesterol. Accordingly, crossing into the "regression" area of the graph would require either a higher on-treated HDL value or a greater percent increase in HDL.

Although changes in either lipid parameter may be beneficial, "we can do best by changing both LDL and HDL cholesterol," Dr. Ballantyne said.

In his conclusion, Dr. Ballantyne shared the news – announced just this morning – that Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) was stopped early by the Data Safety Monitoring Board because rosuvastatin 20 mg/daily was shown to reduce cardiovascular morbidity and mortality in apparently healthy individuals with low LDL cholesterol levels but elevated C-reactive-protein levels, compared to placebo. JUPITER is the first trial to demonstrate a reduction of clinical events with rosuvastatin.

"Large outcome studies are the only way to know definitively whether changes in LDL and HDL cholesterol can change cardiovascular outcomes," Dr. Ballantyne said. "Given the news about JUPITER, we are optimistic that this will be the case," he concluded.