ASTEROID: A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden

Linda Brookes, MSc

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

Presenter: Steven E. Nissen, MD (The Cleveland Clinic Foundation, Cleveland, Ohio)

For the first time, Dr. Nissen and his co-investigators believe, a clinical study has shown that very intensive cholesterol lowering with a statin drug can regress the buildup of plaque in the coronary arteries.[1] Previous research indicated that intensive statin therapy could prevent the progression of coronary atherosclerosis, or arterial plaque build-up, but not actually reduce disease burden. The intense statin therapy used in A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) resulted in significant regression of atherosclerosis as measured by intravascular ultrasound (IVUS), a technique in which a tiny ultrasound probe is inserted into the coronary arteries to measure plaque. The study showed that regression occurred for all 3 prespecified IVUS measures of disease burden and that the intensive statin treatment resulted in the lowest level of low-density lipoprotein (LDL)-cholesterol and the greatest increase in high-density lipoprotein (HDL)-cholesterol ever observed in a major statin outcomes trial.

The results of the ASTEROID study were published simultaneously online in JAMA.[2]

Background

Serial studies using IVUS enable assessment of the progression or regression of coronary atherosclerosis by visualizing the occurrence of atheroma in the vessel wall. A previous study using IVUS carried out by Dr. Nissen and colleagues, the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL), showed that intensive therapy with atorvastatin 80 mg/day lowered mean LDL-cholesterol to 79 mg/dL (2.04 mmol/L) and reduced disease progression compared with moderate therapy with pravastatin 40 mg/day, which lowered LDL-cholesterol to only 110 mg/dL (2.85 mmol/L) and failed to retard progression of atheroma volume.[3] As opposed to retarding or halting progression of disease, however, regression has not been convincingly demonstrated in previous IVUS studies of statin therapy.

The aim of ASTEROID, a multicenter phase 3b study, was to determine whether 24 months of treatment with rosuvastatin 40 mg would result in regression of coronary atherosclerosis as measured by IVUS. The primary hypothesis was that very intensive lipid lowering would reduce coronary atheroma burden, assessed using 2 separate IVUS parameters.[4] The trial was conducted at 53 community and tertiary care centers in Australia, Canada, Europe, and the United States.

Patients and Methods

Patients entered into the study were aged ≥ 18 years, statin-naive (defined as no use of statin therapy for > 3 months' duration within the previous 12 months), and required coronary angiography for a clinical indication, typically stable or unstable ischemic chest pain or abnormal exercise testing. Patients had to have ≥ 1 obstruction with > 20% stenosis in any major coronary artery. The target vessel for IVUS had to contain no more than 50% stenosis through ≥ 40 mm in length, with no prior infarction or angioplasty. Any baseline level of LDL-cholesterol was permitted. Patients with uncontrolled triglycerides or poorly controlled diabetes were excluded from the study.

IVUS of a single non-intervened coronary artery was carried out using a 40-MHz probe with motorized pullback at 0.5 mm/sec through the target vessel segment. Each IVUS scan was evaluated in a core laboratory, and only patients with studies meeting prespecified image quality criteria were included. A total of 507 patients had baseline IVUS examinations.

All patients received high-intensity lipid-lowering treatment with the highest authorized dose of rosuvastatin, 40 mg/day, for 24 months. There was no control group in this trial, since the investigators decided that it would be unethical to give placebo or low-intensity treatment to patients who had established coronary disease.

Patients were examined every 3 months during scheduled clinic visits. At 24 months, 349 patients had a repeat IVUS examination of the original target artery using methods identical to those used during the baseline examination. Blinding and randomization were achieved by digitizing and resequencing the IVUS images to conceal the imaging sequence from personnel analyzing the images.

Lipids

After 24 months of treatment with rosuvastatin 40 mg/day, LDL-cholesterol was reduced by 53.2% and HDL-cholesterol increased by 14.7% (Table 1). The investigators believe that the final mean LDL-cholesterol level achieved, 60.8 mg/dL (1.57 mmol/L), is "the lowest" and the increase in mean HDL-cholesterol is "the largest" ever observed. They also noted that this equated to a 58.5% reduction in the LDL-cholesterol/HDL-cholesterol ratio.

Table 1. Lipid Results (mean values)
  Baseline During
Treatment
%
Change*
Total cholesterol (mg/dL) 204 133.8 -33.8
LDL-cholesterol (mg/dL) 130.4 60.8 -53.2
HDL-cholesterol (mg/dL) 43.1 49.0 +14.7
Triglycerides (mg/dL) 152.2 121.2 -14.5
LDL-cholesterol/HDL-cholesterol ratio 3.2 1.3 -58.5
*P < .001 for all comparisons between baseline and during treatment.

HDL = high-density lipoprotein; LDL = low-density lipoprotein
Primary and Secondary Efficacy Parameters

Both of the prespecified primary efficacy parameters -- the change in percent atheroma volume (PAV) and the change in atheroma volume in the 10-mm subsegment with the greatest disease severity -- were significantly reduced (both P < .001 vs baseline) (Table 2). For PAV, 63.6% of patients showed regression and 36.4% progression, and for the most diseased 10-mm subsegment, 78.1% and 21.9% showed regression and progression, respectively -- and this is the first clinical trial to demonstrate such actual regression, the investigators assert. The secondary efficacy parameter, normalized total atheroma volume (TAV), was significantly reduced by 12.5 mm3 (P < .001 vs baseline).

Table 2. Primary and Secondary Efficacy Parameters (median values)
  Baseline Follow-up Change % Change % With Regression
Percent atheroma volume 39.9 38.5 -0.79 NA 63.6
Atheroma volume in most diseased 10-mm subsegment (mm3) 65.1 58.4 -5.6 -9.1 78.1
Normalized total atheroma
volume (mm3)
204.7 186.8 -12.5 -6.8 77.9
NA = not applicable

In a prespecified analysis, the effect of rosuvastatin on the primary endpoints was found to be consistent for subgroups defined by age (≤ or > median), gender, body mass index (≤ or > median), and history/no history of diabetes. Analysis by lipid levels showed statistically significant changes in atheroma volume in patients with baseline LDL-cholesterol levels both above and below the mean, with the extent of regression being almost 2-fold higher in those with LDL-cholesterol below the mean (Table 3). No significant regression was seen in patients with LDL-cholesterol > 70 mg/dL (1.81 mmol/L). Outcome did not appear to vary by HDL-cholesterol levels. A posthoc sensitivity analysis imputing no effect in the 158 patients did not produce any change in the main results of the study.

Table 3. Change in Percent Atheroma Volume During Treatment
Subgroup Percent Atheroma Volume
No. of
patients
Median
change (%)
P
LDL-cholesterol:
≤ mean 192 -1.1 < .001
> mean 157 -0.6 .001
< 70 mg/dL 254 -0.9 < .001
70-100 mg/dL 78 -0.3 .09
≥ 100 mg/dL 17 -0.2 .22
HDL-cholesterol:
≤ mean 197 -0.9 < .001
> mean 152 -0.7 < .001
HDL = high-density lipoprotein; LDL = low-density lipoprotein
Safety

The regimen of rosuvastatin 40 mg/day was well tolerated. Liver enzyme elevations were similar to those seen in other statin trials (Table 4). No cases of rhabdomyolysis or unusual side effects occurred. Dr. Nissen stressed that although ASTEROID was too small to answer precise safety questions about rosuvastatin, no unexpected toxicities have emerged in clinical trials to date.

Table 4. Adverse Events
Major treatment-related adverse events %
Death 0.8
Myocardial infarction 2.0
Stroke 0.6
Central laboratory abnormalities:
ALT > 3 x ULN 1.8
ALT > 3 x ULN on 2 consecutive visits 0.2
CK > 5 x ULN 1.2
CK > 5 x ULN on 2 consecutive visits 0.2
CK > 10 x ULN 0.0
ALT = alanine aminotransferase; CK = creatine kinase; ULN = upper limit of normal
Implications

"Previous similar studies with statins have shown slowing of coronary disease, but not regression. This regimen significantly lowered LDL-cholesterol, and surprisingly, markedly increased HDL-cholesterol levels," Dr. Nissen said. "We conclude that very low LDL-cholesterol levels (below current guidelines), when accompanied by raised HDL-cholesterol, can regress, or partially reverse, the plaque buildup in the coronary arteries."

Dr. Nissen acknowledged that the results of ASTEROID need to be confirmed in clinical outcome trials.

In a JAMA editorial accompanying the ASTEROID results, Roger S. Blumenthal, MD, and Navin K Kapur, MD (Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, Maryland), say that although the results of ASTEROID are exciting, they are "tempered by the lack of a control group receiving a somewhat less intensive LDL-cholesterol lowering regimen."[5] They suggest that high-dose rosuvastatin vs simvastatin would have been a good comparison, because simvastatin is significantly more potent than pravastatin, which was used in the REVERSAL trial and in the Pravastatin or Atorvastatin Evaluation and Infection Therapy -- Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial.[6] They predict that after simvastatin becomes a generic medication in the United States later this year, it is likely to become the preferred initial lipid-lowering therapy in many managed care formularies.

Drs. Blumenthal and Kapur also say that paired IVUS measurements in less diseased coronary segments in the ASTEROID patients would have demonstrated reproducibility of atheroma volume measurements, and they question exclusion of patients with coronary stenoses measuring > 50% throughout a target segment. They suggest that differences in the amount of atheroma regression might have depended on a patient being "statin naive," noting that in the REVERSAL study, patients were allowed to be on lipid-lowering therapy prior to enrollment. Drs. Blumenthal and Kapur also point out that most of the ASTEROID patients were not at extremely high risk and their baseline LDL-cholesterol was only mildly elevated, HDL-cholesterol level was average, and 17% of individuals were not taking aspirin. Current guidelines[7] would consider treatment with a less aggressive lipid-lowering regimen, with a target LDL-cholesterol of approximately 90-100 mg/dL), as standard care in these patients, they noted.

LDL and/or HDL?

The ASTEROID study does not provide definitive information regarding the relationship of LDL-cholesterol lowering and extent of coronary atherosclerosis regression to determine whether high-intensity treatment is required to achieve regression. Drs. Blumenthal and Kapur propose that since ASTEROID reported a similar magnitude of regression for patients above and below the median HDL-cholesterol and LDL-cholesterol levels, less intensive changes in LDL-cholesterol levels, non-HDL-cholesterol levels, or both, and HDL-cholesterol levels also may have led to modest regression. Comparable changes in LDL-cholesterol and HDL-cholesterol levels, which might be obtained with combination therapy, could produce similar effects on atherosclerotic coronary lesions. Dr. Nissen commented that "It is very tantalizing to speculate that the [approximately] 15% increase in HDL-cholesterol seen here was playing a big role. We are not ready to say that yet -- we have to do more analysis; we will explore these data further."

Dr. Nissen also re-emphasized that, in his opinion, "IVUS is not a surrogate for coronary atherosclerosis, it is coronary atherosclerosis. We are looking right at the disease, and when we see less plaque after a treatment period, all the limitations aside, we think it is significant. I believe that when we study these ranges of LDL-cholesterol in outcomes trials, we will find that this signal is confirmed with a morbidity and mortality benefit." Dr. Nissen believes that the level of LDL-cholesterol achieved in ASTEROID may be the "biological normal" in humans. He added that reducing LDL-cholesterol to the same level with other drugs would probably achieve the same results, although this has not been done yet.

Clinical Studies Ongoing With Rosuvastatin

As Drs. Blumenthal and Kapur pointed out in their JAMA editorial, although the ASTEROID study showed that 24 months of high-dose rosuvastatin therapy is associated with modest regression of atherosclerosis, there are no clinical trial data reporting the effect of rosuvastatin on adverse clinical events, either alone or in comparison with other, less potent statins. Several clinical studies are ongoing with rosuvastatin, including a primary prevention trial, the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER). JUPITER is a large, multinational, long-term, double-blind, placebo-controlled, randomized clinical trial of rosuvastatin 20 mg/day in individuals with low-LDL cholesterol, but elevated levels of high sensitivity C-reactive protein (hsCRP).[8]

Another phase 3 clinical trial evaluating the effects of rosuvastatin on atherosclerosis is also ongoing. The Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) trial is a 24-month, randomized, double-blind study using B-mode ultrasound to compare the effects of rosuvastatin 40 mg/day and placebo on the progression of carotid artery atherosclerosis by measuring intima media thickness of the carotid arteries in more than 800 low-risk, asymptomatic, hypercholesterolemic subjects not already on statin treatment.[9]

The preliminary results of another imaging study, the Outcome of Rosuvastatin treatment on carotid artery atheroma: a magnetic Imaging ObservatioN (ORION), presented in 2005, showed that rosuvastatin 5 and 40 mg/day given over a period of 24 months did not result in any change in carotid artery wall thickness in 35 subjects with moderate hypercholesterolemia and carotid atherosclerosis.[10] The 5-mg and 40-mg doses of rosuvastatin reduced LDL-cholesterol levels by 39% and 58%, respectively, in these patients over the course of the study, and regression of lipid cores of plaques was seen, with the greater benefit observed at the 40-mg/day dosage. Rosuvastatin also prevented the formation of new plaques with lipid-rich necrotic cores.

American Heart Association (AHA) Statement

Following presentation of the ASTEROID results, the President of the American Heart Association (AHA), Robert H Eckel, MD (University of Colorado Health Sciences Center, Denver), issued a statement that ASTEROID "was not a trial looking at end results like heart attack, but it shows that substantially reducing LDL levels can reverse the progression of atherosclerosis. This adds to the evidence that getting the LDL below 70 mg/dL in patients with coronary disease can be beneficial." The statement went on to add that the AHA recommends that all patients with CAD, other atherosclerotic vascular disease, or diabetes ensure that their LDL-cholesterol level is < 100 mg/dL. Further reduction to < 70 mg/dL is "reasonable." For those without CAD, the AHA recommends an LDL goal of < 130 mg/dL for most people with ≥ 2 risk factors and < 160 mg/dL for most people with 1 or no risk factors.

References
  1. Nissen S. Effect of very low LDL-C levels on regression of coronary atherosclerosis: Results of the ASTEROID trial. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session. Late-breaking Clinical Trials II. Abstract: 411-8.

  2. Nissen SE, Nicholls SJ, Sipahi I. et al; for the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: The ASTEROID trial. JAMA. 2006;295. [Published online ahead of print March 13, 2006]

  3. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080. Abstract

  4. Nissen S. Design and methodology of a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden: The ASTEROID study. Atheroscler Suppl 2003;4(2):27. Abstract 1P-0037.

  5. Blumenthal RS, Kapur NK. Can a potent statin actually regress coronary atherosclerosis? JAMA. 2006;295. [Published online ahead of print March 13, 2006.]

  6. Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. Abstract

  7. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. Abstract

  8. Ridker PM; JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108:2292-2297. Abstract

  9. Crouse JR III, Grobbee DE, O'Leary DH, et al. Measuring effects on intima media thickness: an evaluation of rosuvastatin - the METEOR study. Atherosclerosis Suppl. 2002;3:94. Abstract 136.

  10. Saam T, Yuan C, Zhao XQ, et al; Hatsukami TS. Rosuvastatin treatment and its effect on plaque composition of carotid atherosclerosis in moderately hypercholesterolemic subjects: a high-resolution magnetic resonance imaging trial. Poster presented at the 75th Congress of the European Atherosclerosis Society; April 23-26, 2005; Prague, Czech Republic.

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