The results of A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound (ASTEROID) were presented here today during a late-breaking clinical-trials session at the American College of Cardiology 2006 Scientific Sessions. With large reductions in LDL cholesterol, as well as a significant 15% increase in HDL cholesterol, investigators say the findings should change the way clinicians think about coronary atherosclerosis. Other experts, however, cautioned that, as an uncontrolled study without clinical end points, ASTEROID is highly interesting but should not be used to change practice.

Speaking to the press during a media briefing today, lead investigator Dr Steven Nissen (Cleveland Clinic, OH) noted that atherosclerosis has been viewed traditionally as a progressive disease for which even the most active therapies can merely slow advancement. More recent studies, however, most notably the REVERSAL trial, showed that high-dose statin therapy could halt progression to almost zero. The ASTEROID study, published online today in the Journal of the American Medical Association to coincide with the late-breaking-trials session, showed that there is potential for a more optimistic treatment strategy.

"We concluded that if you lower LDL cholesterol to these very low levels and keep it there for two years, particularly if accompanied by an increase in HDL cholesterol, you could partially reverse coronary disease," said Nissen. "You could remove plaque from the coronary arteries in fairly large quantities. We think it is very good news for patients."

Dr James Stein (University of Wisconsin Medical School, Madison, WI), who commented on the results of the study for heartwire, praised the ASTEROID investigators, saying the "take-home message of this study—that lower LDL-cholesterol levels can regress atherosclerosis—is undeniable." However, the trial has important limitations, he said.

"In 2006, the standard of cardiology research is a prospective randomized, placebo-controlled clinical trial," said Stein. "This study was not controlled by a placebo or by a comparator. So the magnitude of the benefit that we're seeing is not interpretable. Although we're seeing large reductions in atheroma burden here, we don't know what would have been seen with any of the other drugs on the market or other approaches, such as statins, niacin, or lifestyle changes, in this group of patients."

Also speaking with heartwire, Dr Roger Blumenthal (Johns Hopkins University School Medicine, Baltimore, MD), who wrote an editorial in JAMA with Dr Navin Kapur (Johns Hopkins University School of Medicine) to accompany the published study, said the trial is unique, as it changes the treatment paradigm. However, despite the regression, "future studies will be needed as we look to see whether there is any benefit, in terms of hard cardiovascular end points, with really low levels of LDL cholesterol accompanied by increases in HDL cholesterol."

Rosuvastatin jumped into the market in August 2003 after receiving approval from the Food and Drug Administration in doses ranging from 5 mg to 40 mg once daily, with a recommended starting dose of 10 mg once daily. The drug earned the nickname "superstatin" or "gorilla statin" early on as it emerged from clinical trials with evidence it provided greater reductions of LDL cholesterol than any other statin.

In ASTEROID, a 24-month study examining the effects of statin therapy on IVUS-derived measures of coronary-disease progression, investigators hypothesized that high-intensity statin therapy, with the intention of achieving very low levels of LDL cholesterol, coupled with significant increases in HDL cholesterol, might actually regress coronary atherosclerosis.

Patients enrolled in the study required coronary angiography for a clinical indication, typically stable or unstable chest pain or an abnormal functional test. To be included in the trial, patients required one obstruction with more than 20% luminal diameter narrowing in any coronary vessel as long as the IVUS-targeted vessel had not undergone angioplasty. Patients with lesions with >50% luminal narrowing throughout the segment were excluded. All patients enrolled in the study were statin-naive.

In total, 507 patients met the inclusion and exclusion criteria, including a baseline IVUS result, and were treated with rosuvastatin 40 mg. Of these, 349 patients underwent a second IVUS study at 24 months. Reasons for not being included in the follow-up IVUS analysis included withdrawn consent or withdrawal for other reasons. Overall, 63 were withdrawn for an adverse event.

Not surprisingly, treatment with the drug resulted in significant reductions in LDL cholesterol, as well as increases in HDL cholesterol. In fact, the LDL-cholesterol levels at 24 months were the lowest ever achieved in a statin trial, said Nissen.

In terms of the two primary end points—change in PAV and change in atheroma volume in the 10-mm subsegment with the greatest disease—there was a significant reduction in both IVUS-derived end points when compared with baseline. In addition, there was also a significant reduction in total atheroma volume, a prespecified secondary end point, when compared with baseline.

The investigators point out that the regression of coronary atherosclerosis occurred in nearly all subgroups, including men and women, older and younger patients, and most subgroups defined by lipid levels. They also report that the drug was well tolerated, with rates of elevated hepatic enzymes comparable to other trials using maximum doses. There were no cases of rhabdomyolysis.

According to Nissen and colleagues, the observed increases in HDL cholesterol in ASTEROID suggest that therapies "designed to simultaneously lower LDL cholesterol while raising HDL cholesterol have the potential to substantially reduce lesion burden in patients with established disease." Moreover, the investigators add that the findings further support the "lower-is-better" cholesterol premise. In terms of the PAV end point in this and other statin trials, including REVERSAL, the investigators contend there is no apparent LDL-cholesterol level beyond which the benefit of statins is no longer evident.

Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) said the study reinforces the importance of getting LDL-cholesterol levels low in patients with coronary artery disease. He noted that while previous data have suggested the predominant benefit derived from statins is through stabilization of lipid-rich plaque, rather than the regression of atherosclerosis, these new findings really "push past the old idea."

"My patients ask all the time, 'Is there anything I can take to shrink my heart-artery blockages?' " said Cannon. "Until now the answer was no, but for the first time we can say yes. The difference of this regimen is the potency; 40-mg Crestor is known to be the most potent in lowering LDL—even more so, although just slightly, than atorvastatin 80 mg. It also is known to raise HDL more than the others. Thus, the combination of better LDL reduction and raising HDL appears to be what makes this regimen able to push into the ability to regress plaques."

With the data in his hands just three weeks ago, Nissen said that his group has not had time to analyze the role of HDL in reversing atherosclerosis. However, in terms of achieving ultralow levels of LDL cholesterol and the incremental benefit on end points people care the most about, like mortality, Nissen suspects they "have not yet exhausted what this molecule can do."

Commenting on the study design in JAMA, the ASTEROID investigators argue that because the guidelines and practice patterns require intensive treatment of secondary-prevention patients, randomizing patients with established coronary disease to placebo or low-dose statin therapy was considered "ethically unacceptable." Because of this, the authors say, there are limitations to the study, but they point out that they compensated for the absence of placebo controls by the extensive blinding of pertinent information, as well as the resequencing of examinations to avoid observer bias.

According to Blumenthal, a comparison with simvastatin would have helped clinicians who will soon have to make tough decisions about generic medications.

"The results of this trial, as well as some of the other statin trials, really make a case for low levels of LDL cholesterol," Blumenthal told heartwire. "In 2007, however, simvastatin is coming off patent and will be available in the US. While there are good outcome data with simvastatin 40 mg, the drug typically does not achieve these ultralow levels of LDL cholesterol. It would have been interesting to compare rosuvastatin 40 mg with simvastatin 40 mg, as this information will be most relevant to clinicians in practice."

Stein told heartwire that the regression of disease in this trial, as well as the benefit observed in other statin trials, is the result of changes to the whole lipid panel and not just LDL lowering. He also noted that this is not the first trial to show regression, with atherosclerotic disease regression shown almost two decades ago in the FATS study, as well as in the STARS study and the Lifestyle Heart Study. The recent HATS trial, a study testing niacin and simvastatin, also demonstrated regression and event reduction, said Stein. The ASTEROID study, he added, simply has a more sensitive tool in IVUS for detecting changes in disease progression/regression.

During the late-breaking-trials discussion, Nissen disagreed, telling the audience that such trials, utilizing angiography to measure percent stenosis, did not demonstrate a reversal of disease but simply measured the regression of the most severely diseased vessel segment. In these trials, such regression is merely the measurement of regression to the mean, he said.

In their editorial, Blumenthal and Kapur write that the ASTEROID study has revolutionized the current approach to understanding the anatomy and pathophysiology of coronary atherosclerosis and its response to treatment, but they also urge caution when interpreting the ASTEROID findings [2].

"While IVUS-documented atherosclerotic regression is an intriguing finding, clinicians must remember that this may not be the best measure of the treatment's effect on hard cardiovascular end points," write the editorialists. While there is a major primary-prevention trial with rosuvastatin ongoing, known as JUPITER, "future studies are needed to determine whether at-risk patients derive more clinical benefit from treatment with rosuvastatin than other statins and whether these benefits are attributable to the extent of atherosclerotic progression," Blumenthal and Kapur write.

Importantly, the editorialists also note that several high-profile statin trials—REVERSAL, the Heart Protection Study, PROVE-IT, and TNT—have already shown that intensive lipid lowering with atorvastatin or moderate-dose simvastatin reduces hard clinical end points and slows the progression of atherosclerosis.

Nissen agrees, stressing that the findings from this study are not sufficient to alter guidelines and physicians will individually determine how compelling the argument is for going to ultralow levels of cholesterol, such as the achieved LDL of 60 mg/dL in this study.

"We did not show that these fairly low levels reduce morbidity and mortality," said Nissen. "We think that will follow. If you go back over 20 years, whenever we have developed regimens that have improved the progression rate of disease, affected the plaque directly, this is ultimately translated into a morbidity and mortality advantage."

In terms of a clinical implication, Nissen said he intends to recommend that clinicians treat "patients to as low as LDL-cholesterol level as can be safely achieved." Regarding IVUS-measures as a surrogate end point, Nissen told the audience that what they were observing in the IVUS images "is not a marker of coronary atherosclerosis, it is coronary atherosclerosis."