METEOR: Rosuvastatin Slows Progression of CIMT in Low-Risk Subjects

Susan Jeffrey

March 26, 2007

March 26, 2007 (New Orleans, LA) - Results of a randomized trial of rosuvastatin (Crestor, AstraZeneca) in low-risk individuals--those with a Framingham risk score of less than 10%--show that treatment slowed progression of carotid intima-media thickness (CIMT) compared with placebo, although it did not produce disease regression [ 1].

The findings, from the Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) trial, are published online March 25, 2007 in the Journal of the American Medical Association to coincide with their presentation here at the American College of Cardiology 2007 Scientific Sessions.

Dr John R Crouse III (Wake Forest University School of Medicine, Winston-Salem, NC) presented the findings and was first author on the paper.

"METEOR provides new evidence of effects of rosuvastatin on atherosclerosis," Crouse told attendees here. "It supports and extends the results of [ A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound] ASTEROID, the previous [intravascular ultrasound] IVUS study that showed regression of atherosclerosis in high-risk patients with established coronary artery disease, in contrast to the METEOR population, which was low risk and asymptomatic with early signs of atherosclerosis. In this group there was no evidence of disease progression across a two-year period."


METEOR vs ASTEROID

Last year at this meeting, researchers reported results from the ASTEROID trial [ 2], showing that intensive lipid lowering with rosuvastatin over 24 months resulted in a significant regression of coronary atherosclerosis as measured by intravascular ultrasound. IVUS measures showed significant decreases in mean percent atheroma volume and mean atheroma volume in the most diseased 10-mm vessel segment. The study was uncontrolled, however, and did not have clinical end points.

The aim of the METEOR trial was to investigate whether rosuvastatin therapy could slow progression or even cause regression of carotid intima-media thickness (CIMT). The study was a randomized, double-blind, placebo-controlled trial comparing treatment with 40 mg/day of rosuvastatin with placebo in 984 individuals, randomized in a 5:2 ratio.

Subjects included were chosen for low risk, with either age as the only risk factor or with a 10-year Framingham risk score of less than 10%. All had mild to moderate CIMT thickening, with a maximum IMT of at least 1.2 mm at a single site and less than 3.5 mm at all sites. Subjects with one risk factor had to have an LDL level of less than 190 mg/dL and those with multiple risk factors had to have an LDL level of less than 160 mg/dL. The mean LDL level at study baseline was about 155 mg/dL.

Investigators used B-mode ultrasound to follow the change in maximum CIMT for 12 carotid sites as the primary end point over two years of follow-up; they also measured changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery, as well as the mean CIMT of the common carotid artery sites. Regression was also assessed, but only in the rosuvastatin-treated patients.

LDL levels showed a mean reduction of 49% in the rosuvastatin group, declining from 155 mg/dL to 78 mg/dL, a statistically significant reduction vs placebo. HDL increased with rosuvastatin by 8% with treatment.

At two years, treatment with rosuvastatin was associated with a statistically significant reduction in the rate of progression of CIMT thickening both overall and for the individual carotid segments, while the placebo group showed progression. However, there was no regression of atherosclerosis burden seen with treatment in this trial.

METEOR: Change in maximum CIMT with rosuvastatin vs placebo

Change in maximum CIMT Rosuvastatin (mm/y) Placebo (mm/y) p
For 12 sites -0.0014 0.0131 <0.001
Common carotid sites -0.0038 0.0084 <0.001
Carotid bulb sites -0.0040 0.0172 <0.001
Internal carotid artery sites 0.0039 0.0145 0.02


Ischemic cardiovascular events were infrequent in this low-risk group and not specifically adjudicated. Over two years, six participants in the rosuvastatin group (0.86%) had eight events vs no events in the placebo group. None of the events was considered related to treatment. One death occurred, a 64-year-old man who was diagnosed with Creutzfeldt-Jakob disease, and the death was not considered related to treatment.

Rosuvastatin was well tolerated, the authors report. Myalgia was the most common adverse event, occurring in 12.7% and 12.1% of the rosuvastatin and placebo groups, respectively.

"Larger longer-term randomized studies focused on clinical events are needed and are ongoing, to evaluate the clinical implications of these findings," Crouse concluded.

That there was no regression seen on end points in this trial may relate to the lower overall risk in these patients, the authors speculate.

"Presumably, the presence of more advanced disease in ASTEROID allowed detection of regression that was not observed in METEOR," Crouse and colleagues write. "Although a reduction in clinical events by rosuvastatin has not yet been demonstrated, increased CIMT has been linked to increased cardiovascular risk in asymptomatic adults, and a reduced progression of CIMT in statin trials is congruent with a reduction in cardiovascular events."

Another study in the "Galaxy" series of trials with rosuvastatin, JUPITER, involving 15 000 patients with elevated C-reactive protein levels but normal LDL cholesterol, is under way.

Principal investigator of the JUPITER trial, Dr Paul Ridker (Brigham and Women's Hospital and Harvard Medical School, Boston, MA), was part of a panel discussing these late-breaking trials during the session. He called the results of METEOR "impressive data" that underline the importance of placebo controls in any study of disease progression.

"The core clinical message is that aggressive statin therapy seems to slow progression of atherosclerosis even in people where the LDLs are low," Ridker said. These low-risk patients, he added, "are not a group we normally think about with this problem, and of course that's very exciting to me, in trying to run our JUPITER trial where we're looking for end-point reduction in patients who have actually quite a similar set of characteristics."

Crouse emphasized, though, that their findings do not mean that low-risk patients should be screened for and treated. "I think that we need more information, such as is going to come from your study, to make those kinds of extrapolations."

Rethinking assumptions

In an editorial accompanying the paper, Dr Michael Lauer (Cleveland Clinic Foundation, OH), a contributing editor for JAMA, points out that, currently, those with a 10-year Framingham risk of less than 10% usually receive conservative management focused on lifestyle interventions. These findings raise the question of whether low-risk individuals with evidence of asymptomatic disease should undergo routine arterial imaging followed by statin therapy.

"On the basis of the current evidence, includingthe METEOR trial, the answer is clearly no," Lauer writes. "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."

"I think what this means is that we should rethink our blanket rejection of the medical approach to low-risk people, and we should probably do some large-scale trials," Lauer said. "I don't think the message we should take away from this is that we should put everyone over the age of 57 or low-risk people on rosuvastatin."

While the scale of the trials needed to answer this question would be exceptionally large, he said, the risk of diagnosing "nondisease" with screening has been seen in other clinical settings--melanoma rates, for example, have gone up steeply, while death rates from melanoma have remained stable.

Dr Roger Blumenthal (Johns Hopkins University School Medicine, Baltimore, MD) called this a "very important and helpful study."

"One of the main limitations with ASTEROID was that there was no placebo group," he said. "Here they were able to show more convincingly that aggressive lipid-lowering does have a meaningful effect on the progression of atherosclerosis, and while they weren't able to show regression or reversal, this significant slowing of progression I think is very meaningful and supports the idea that raising HDL in a more traditional way with rosuvastatin and aggressively lowering triglycerides and LDL does have a clear impact over a relatively short period of time on atherosclerotic vascular disease."

The METEOR study was funded by AstraZeneca. Crouse reports receiving grant or salary support from Merck, Merck-Schering Plough, Pfizer, AstraZeneca, and Kos Pharmaceuticals and has given lectures for Merck, Merck-Schering Plough, Pfizer, AstraZeneca, Abbott, and Kos Pharmaceuticals.

Disclosure information for other coauthors are outlined in the paper.

  1. Crouse JR, Raichlen JS, Riley WA, et al for the METEOR Study Group. Effect of Rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: The METEOR trial. JAMA 2007; 297:1344-1353, 1376-1378. Available at: http://jama.ama-assn.org .

  2. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295:1556-1565.

  3. Lauer MS. Primary prevention of atherosclerotic cardiovascular disease: The high public burden of low individual risk. JAMA 2007: DOI:10.1001/jama.297.12.1376. Available at: http://jama.ama-assn.org .

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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