Statin Therapy Slows Progression of Arterial Thickening in People at Low Risk for Coronary Heart Disease

Linda Brookes, MSc

Disclosures

June 12, 2007

The question of whether asymptomatic adults at low risk for cardiovascular disease should receive statin therapy was addressed, but not yet completely resolved, by the Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) trial. Treatment in people estimated to be at low (< 10%) risk, using the Framingham risk score, is usually focused on lifestyle changes.

For the METEOR study, middle-aged individuals deemed to be at low risk, but with subclinical atherosclerosis identified by B-mode ultrasound measurement of carotid intima media thickness (CIMT), were treated with rosuvastatin 40 mg or placebo over 2 years. The METEOR trial results, presented by lead investigator John R. Crouse III, MD (Wake Forest University School of Medicine, Winston-Salem, North Carolina), showed that, compared with placebo, rosuvastatin slowed progression of maximum CIMT, although it did not induce regression overall.[1]

Dr. Crouse said that he was "excited" by the demonstration that rosuvastatin can potentially slow or even stop disease progression in people with relatively modest atherosclerosis. "METEOR provides evidence that the effect of rosuvastatin on dyslipidemia translates into a beneficial effect on the progression of atherosclerosis," he said. The study was funded by AstraZeneca, the company that manufactures and markets rosuvastatin worldwide, and the results were published simultaneously in JAMA.[2]

Trial Design

Subjects were entered into the METEOR study between 2002 and 2006 at 61 sites in the United States and Europe. All were men aged 45-70 years or women aged 55-70 years who met either one of 2 criteria:

  • LDL cholesterol 120 to < 190 mg/dL (3.1 to < 4.9 mmol/L) plus age as the only risk factor for coronary heart disease (CHD), or

  • LDL cholesterol 120 to < 160 mg/dL (3.1 to < 4.1 mmol/L) and > 1 risk factor and a 10-year CHD risk (Framingham risk score) of < 10%.

A total of 984 subjects (mean age 57 years, mean LDL cholesterol 154 mg/dL; 3.99 mmol/L) were randomized to rosuvastatin 40 mg or placebo for 2 years; 738 participants completed the trial. All subjects also had HDL cholesterol ≤ 60 mg/dL (≤ 1.6 mmol/L), triglycerides < 500 mg/dL (< 5.7 mmol/L), and maximum CIMT ≥ 1.2 mm and < 3.5 mm at any site. Dr. Crouse noted that METEOR differed from previous studies using CIMT, which usually focused on either high-risk individuals or people with high levels of cholesterol, such as those with familial hypercholesterolemia or who had more marked atherosclerosis.

Results

Rosuvastatin treatment was associated with significant reductions of 49% in LDL cholesterol level, 34% in total cholesterol level, 16% in level of triglycerides, and a significant 8% increase in HDL cholesterol compared with placebo. Progression in maximum CIMT for each of 12 carotid artery sites (near and far walls of the right and left common carotid artery [CCA], carotid bulb, and internal carotid artery [ICA]), the primary endpoint of the study, was significantly slowed with rosuvastatin compared with placebo (Table).

Similar results were seen with rosuvastatin for all secondary endpoints: rate of change in maximum CIMT of individual carotid segments of the near and far walls of the right and left CCA, carotid bulb, and right and left ICA, and rate of change in mean CIMT of the near and far walls of the right and left of the right and left CCA. However, the effect of rosuvastatin on these endpoints did not represent significant regression, as the differences from baseline were not significant except in the maximum CIMT in the CCA segment.

By contrast, the placebo group showed significant progression overall and in all carotid segments. The differences between the rosuvastatin and placebo groups were consistent across participant baseline lipids, lipoproteins, and lipid ratios, and all differences were independent of sex or age.

The 40-mg dose of rosuvastatin was well tolerated during the 2-year study period and showed a safety profile similar to that of placebo. The majority of adverse events were mild to moderate in intensity and serious adverse events were infrequent. The most frequently reported adverse event was myalgia.

Discussion

 

Dr. Crouse and his colleagues concede that they may have been too optimistic in expecting rosuvastatin to produce regression of CIMT in this low-risk population, unlike that seen in the ASTEROID study (A Study To evaluate the Effect of Rosuvastatin On Intravascular ultrasound-Derived coronary atheroma burden) in patients with more advanced atherosclerosis, in which treatment with rosuvastatin 40 mg over 2 years produced regression of plaque volume, as shown by intravascular ultrasound.[3] However, they believe that larger, longer-duration randomized studies focused on clinical events will determine the practice implications of their findings.

Currently, rosuvastatin is indicated for the treatment of lipid disorders. The results from the METEOR study, supported by data from ASTEROID and including the ORION (Outcome of Rosuvastatin treatment on carotid artery atheroma: a magnetic Imaging ObservatioN) trial,[4] formed the basis of the atherosclerosis regulatory submissions filed in the European Union and the United States in January 2007. These submissions seek to expand the use of rosuvastatin to include the treatment of atherosclerosis with the purpose of affecting the progression of the disease in patients in whom lipid-lowering therapy is indicated. The 40-mg dose used in METEOR and ASTEROID is the highest registered dose of rosuvastatin. In most countries, the usual recommended starting dose of rosuvastatin is 10 mg. AstraZeneca advises that the 40-mg dose should only be used in patients who have not achieved their LDL cholesterol goal utilizing the 20-mg dose of rosuvastatin.

Commentary

 

AHA panelist Paul M. Ridker, MD, MPH (Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, Massachusetts), commenting on the "very impressive data" from METEOR, said that the study "seems to be saying that there is a core clinical message that aggressive statin therapy seems to slow progression of atherosclerosis even in people with low LDL cholesterol, no coronary disease or diabetes, few smokers (3%) and low Framingham risk scores." He continued, "This is not a group that we normally think about as having this problem," adding that "this is very exciting to me because we are running the JUPITER trial [Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin], in which we are looking for an endpoint reduction in patients with a similar set of characteristics in terms of low risk."

[JUPITER will investigate whether long-term treatment with rosuvastatin (20 mg/day) will reduce the rate of first major cardiovascular events (combined endpoint of cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina, or arterial revascularization) among individuals with LDL cholesterol levels < 130 mg/dL (3.36 mmol/L), but who have an enhanced inflammatory response as indicated by levels of high-sensitivity C-reactive protein (hsCRP; ≥ 2 mg/L).[5]]

In an editorial accompanying publication of the METEOR trial results,[6] JAMA contributing editor Michael S. Laquer, MD (Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio) pointed to the difficulties using surrogate endpoints such as CIMT in clinical trials, because evidence is limited as to whether changes in CIMT measurements induced by statin therapy translate into changes in atherosclerotic events. METEOR was not powered to assess the effect of rosuvastatin therapy on clinical events, and on the basis of the evidence to date, including the METEOR trial results, Dr. Laquer does not support routine arterial imaging of low-risk individuals followed by statin therapy in those with increased CIMT. "However, like a shooting star in the night, the METEOR findings reflect a warning of problems lurking 'out there' in the vast person-time space of the low-risk population," he warned, adding that "low-risk populations are the source of most clinical disease," but "the METEOR findings have not provided biological evidence for a plausible but unproved strategy."

Dr. Laquer went on to say that the METEOR trial should be just the beginning of a collaboration between the medical and public health communities. "Ambitious event-based randomized trials involving large numbers of patients and communities must be done. While these trials will be difficult and expensive, even greater and less desirable challenges will occur by choosing to ignore the enormous public burden of clinical atherosclerosis arising from the population of low-risk individuals," he concluded.

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