Rosuvastatin Slows Carotid Atherosclerosis in Low-Risk Patients

NEW ORLEANS — Rosuvastatin slowed the progression of carotid intima-media thickness in asymptomatic subjects at low risk of cardiovascular events but who nonetheless had subclinical atherosclerosis, Dr. John R. Crouse III reported at a conference sponsored by the American College of Cardiology.

The agent “basically halted progression” of intima-media thickness, Dr. Crouse said during a late-breaking clinical trials session at the meeting.

Unlike previous clinical trials of the drug involving high-risk subjects or patients with known cardiovascular disease, the METEOR (Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin) trial assessed asymptomatic people aged 45–70 years who were at low cardiovascular risk and had only moderately elevated cholesterol, but were found to have a relatively high carotid wall thickness on ultrasound examination.

The low-risk population was intentionally chosen for the study so that a placebo arm could ethically be included, said Dr. Crouse, professor of medicine and public health sciences at Wake Forest University in Winston-Salem, N.C.

A total of 984 subjects were enrolled in the study in August 2002-March 2004 at 61 medical centers in the United States and Europe and were followed with serial carotid imaging for 2 years. The study was funded by AstraZeneca Pharmaceuticals LP, maker of rosuvastatin (Crestor).

Ultrasound measurements of carotid intima-media thickness were performed at enrollment and at 6-month intervals for 2 years. Measurements were made at 12 carotid artery sites in each patient, including the near and far walls of the right and left common carotid artery, carotid bulb, and internal carotid artery.

Results were available for 252 subjects who had been randomly assigned to receive placebo and 624 who had been assigned to receive 40 mg of rosuvastatin daily. This is not the recommended starting dosage but was selected “to provide the maximum efficacy expected to slow or delay progression of atherosclerosis,” Dr. Crouse wrote in a report that was published at the time of the presentation (JAMA 2007;297:1344–53).

Carotid intima-media thickness progressed in the placebo group. It regressed in the rosuvastatin group, but the difference from baseline did not reach significance except at the common carotid artery.

The significant difference in progression between the placebo and rosuvastatin groups persisted across all clinical subgroups, regardless of subject age, sex, geo-graphical location, race, body mass index, risk factors, blood pressure levels, or lipid levels, Dr. Crouse said.

Rosuvastatin did not induce regression of carotid atherosclerosis, as it has been shown to do in previous studies involving patients with more advanced disease. “This was focused on low-risk participants without advanced atherosclerosis, and this may have limited the opportunity to achieve disease regression,” Dr. Crouse said.

LDL cholesterol declined by 49% and HDL cholesterol increased by 8% in patients taking rosuvastatin during the 2-year study. The frequency of adverse events was similar between the two groups, and most were of mild or moderate severity. Myalgia was the most commonly reported adverse effect.

In an editorial comment accompanying the published report, Dr. Michael S. Lauer of the Cleveland Clinic Heart Center said, “At first glance, the METEOR findings suggest there may be a role for routine arterial imaging” in low-risk people, and that routine rosuvastatin therapy may be warranted for those found to have increased carotid intima-media thickness.

But this would be “a radically different approach to primary prevention than that recommended by current guidelines,” and the results clearly do not justify such a change, he said (JAMA 2007;297:1376–8).

For one thing, carotid intima-media thickness is merely a surrogate end point for clinical events, and the medical literature is rife with “numerous bad experiences whereby agents that improved surrogate end points yielded no benefit or were even found to cause harm when tested for their ability to prevent clinical events. Classic examples of this include vitamin E and postmenopausal hormone therapy,” he wrote.

Moreover, there is only limited evidence that statin-induced changes in carotid intima-media thickness actually correlate with a decrease in atherosclerotic events.

The METEOR study had two additional weaknesses. “A fair number of enrolled patients failed to complete the protocol and were lost to follow-up. … [A] higher rate of follow-up clearly would have increased the credibility of the findings,” he noted.

And the study was not powered to evaluate the drug's effect on clinical events. In nearly 1,000 subjects, only six ischemic events occurred—all of them, “curiously,” in subjects taking the study drug. “Ambitious event-based randomized trials involving large numbers of patients and communities must be done,” Dr. Lauer said.

NEW ORLEANS — Rosuvastatin slowed the progression of carotid intima-media thickness in asymptomatic subjects at low risk of cardiovascular events but who nonetheless had subclinical atherosclerosis, Dr. John R. Crouse III reported at a conference sponsored by the American College of Cardiology.

The agent “basically halted progression” of intima-media thickness, Dr. Crouse said during a late-breaking clinical trials session at the meeting.

Unlike previous clinical trials of the drug involving high-risk subjects or patients with known cardiovascular disease, the METEOR (Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin) trial assessed asymptomatic people aged 45–70 years who were at low cardiovascular risk and had only moderately elevated cholesterol, but were found to have a relatively high carotid wall thickness on ultrasound examination.

The low-risk population was intentionally chosen for the study so that a placebo arm could ethically be included, said Dr. Crouse, professor of medicine and public health sciences at Wake Forest University in Winston-Salem, N.C.

A total of 984 subjects were enrolled in the study in August 2002-March 2004 at 61 medical centers in the United States and Europe and were followed with serial carotid imaging for 2 years. The study was funded by AstraZeneca Pharmaceuticals LP, maker of rosuvastatin (Crestor).

Ultrasound measurements of carotid intima-media thickness were performed at enrollment and at 6-month intervals for 2 years. Measurements were made at 12 carotid artery sites in each patient, including the near and far walls of the right and left common carotid artery, carotid bulb, and internal carotid artery.

Results were available for 252 subjects who had been randomly assigned to receive placebo and 624 who had been assigned to receive 40 mg of rosuvastatin daily. This is not the recommended starting dosage but was selected “to provide the maximum efficacy expected to slow or delay progression of atherosclerosis,” Dr. Crouse wrote in a report that was published at the time of the presentation (JAMA 2007;297:1344–53).

Carotid intima-media thickness progressed in the placebo group. It regressed in the rosuvastatin group, but the difference from baseline did not reach significance except at the common carotid artery.

The significant difference in progression between the placebo and rosuvastatin groups persisted across all clinical subgroups, regardless of subject age, sex, geo-graphical location, race, body mass index, risk factors, blood pressure levels, or lipid levels, Dr. Crouse said.

Rosuvastatin did not induce regression of carotid atherosclerosis, as it has been shown to do in previous studies involving patients with more advanced disease. “This was focused on low-risk participants without advanced atherosclerosis, and this may have limited the opportunity to achieve disease regression,” Dr. Crouse said.

LDL cholesterol declined by 49% and HDL cholesterol increased by 8% in patients taking rosuvastatin during the 2-year study. The frequency of adverse events was similar between the two groups, and most were of mild or moderate severity. Myalgia was the most commonly reported adverse effect.

In an editorial comment accompanying the published report, Dr. Michael S. Lauer of the Cleveland Clinic Heart Center said, “At first glance, the METEOR findings suggest there may be a role for routine arterial imaging” in low-risk people, and that routine rosuvastatin therapy may be warranted for those found to have increased carotid intima-media thickness.

But this would be “a radically different approach to primary prevention than that recommended by current guidelines,” and the results clearly do not justify such a change, he said (JAMA 2007;297:1376–8).

For one thing, carotid intima-media thickness is merely a surrogate end point for clinical events, and the medical literature is rife with “numerous bad experiences whereby agents that improved surrogate end points yielded no benefit or were even found to cause harm when tested for their ability to prevent clinical events. Classic examples of this include vitamin E and postmenopausal hormone therapy,” he wrote.

Moreover, there is only limited evidence that statin-induced changes in carotid intima-media thickness actually correlate with a decrease in atherosclerotic events.

The METEOR study had two additional weaknesses. “A fair number of enrolled patients failed to complete the protocol and were lost to follow-up. … [A] higher rate of follow-up clearly would have increased the credibility of the findings,” he noted.

And the study was not powered to evaluate the drug's effect on clinical events. In nearly 1,000 subjects, only six ischemic events occurred—all of them, “curiously,” in subjects taking the study drug. “Ambitious event-based randomized trials involving large numbers of patients and communities must be done,” Dr. Lauer said.

NEW ORLEANS — Rosuvastatin slowed the progression of carotid intima-media thickness in asymptomatic subjects at low risk of cardiovascular events but who nonetheless had subclinical atherosclerosis, Dr. John R. Crouse III reported at a conference sponsored by the American College of Cardiology.

The agent “basically halted progression” of intima-media thickness, Dr. Crouse said during a late-breaking clinical trials session at the meeting.

Unlike previous clinical trials of the drug involving high-risk subjects or patients with known cardiovascular disease, the METEOR (Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin) trial assessed asymptomatic people aged 45–70 years who were at low cardiovascular risk and had only moderately elevated cholesterol, but were found to have a relatively high carotid wall thickness on ultrasound examination.

The low-risk population was intentionally chosen for the study so that a placebo arm could ethically be included, said Dr. Crouse, professor of medicine and public health sciences at Wake Forest University in Winston-Salem, N.C.

A total of 984 subjects were enrolled in the study in August 2002-March 2004 at 61 medical centers in the United States and Europe and were followed with serial carotid imaging for 2 years. The study was funded by AstraZeneca Pharmaceuticals LP, maker of rosuvastatin (Crestor).

Ultrasound measurements of carotid intima-media thickness were performed at enrollment and at 6-month intervals for 2 years. Measurements were made at 12 carotid artery sites in each patient, including the near and far walls of the right and left common carotid artery, carotid bulb, and internal carotid artery.

Results were available for 252 subjects who had been randomly assigned to receive placebo and 624 who had been assigned to receive 40 mg of rosuvastatin daily. This is not the recommended starting dosage but was selected “to provide the maximum efficacy expected to slow or delay progression of atherosclerosis,” Dr. Crouse wrote in a report that was published at the time of the presentation (JAMA 2007;297:1344–53).

Carotid intima-media thickness progressed in the placebo group. It regressed in the rosuvastatin group, but the difference from baseline did not reach significance except at the common carotid artery.

The significant difference in progression between the placebo and rosuvastatin groups persisted across all clinical subgroups, regardless of subject age, sex, geo-graphical location, race, body mass index, risk factors, blood pressure levels, or lipid levels, Dr. Crouse said.

Rosuvastatin did not induce regression of carotid atherosclerosis, as it has been shown to do in previous studies involving patients with more advanced disease. “This was focused on low-risk participants without advanced atherosclerosis, and this may have limited the opportunity to achieve disease regression,” Dr. Crouse said.

LDL cholesterol declined by 49% and HDL cholesterol increased by 8% in patients taking rosuvastatin during the 2-year study. The frequency of adverse events was similar between the two groups, and most were of mild or moderate severity. Myalgia was the most commonly reported adverse effect.

In an editorial comment accompanying the published report, Dr. Michael S. Lauer of the Cleveland Clinic Heart Center said, “At first glance, the METEOR findings suggest there may be a role for routine arterial imaging” in low-risk people, and that routine rosuvastatin therapy may be warranted for those found to have increased carotid intima-media thickness.

But this would be “a radically different approach to primary prevention than that recommended by current guidelines,” and the results clearly do not justify such a change, he said (JAMA 2007;297:1376–8).

For one thing, carotid intima-media thickness is merely a surrogate end point for clinical events, and the medical literature is rife with “numerous bad experiences whereby agents that improved surrogate end points yielded no benefit or were even found to cause harm when tested for their ability to prevent clinical events. Classic examples of this include vitamin E and postmenopausal hormone therapy,” he wrote.

Moreover, there is only limited evidence that statin-induced changes in carotid intima-media thickness actually correlate with a decrease in atherosclerotic events.

The METEOR study had two additional weaknesses. “A fair number of enrolled patients failed to complete the protocol and were lost to follow-up. … [A] higher rate of follow-up clearly would have increased the credibility of the findings,” he noted.

And the study was not powered to evaluate the drug's effect on clinical events. In nearly 1,000 subjects, only six ischemic events occurred—all of them, “curiously,” in subjects taking the study drug. “Ambitious event-based randomized trials involving large numbers of patients and communities must be done,” Dr. Lauer said.