Frankfurt, Germany - A new study comparing high-dose atorvastatin with a standard dose has shown that the more intensive lipid-lowering therapy was unable to attenuate the progression of coronary artery calcification (CAC) as measured by electron-beam computed tomography (EBCT) over 12 months. In fact, no relationship between on-treatment LDL-cholesterol levels and the progression of coronary calcification was observed in the study, report investigators.

"More intensive lipid lowering will prevent a greater number of cardiovascular events—there is no doubt about this, as this has been shown by a number of recent studies," said lead investigator Dr Axel Schmermund (Cardioangiologisches Centrum Bethanien, Frankfurt, Germany). "On the other hand, at least over the course of one year, if you give intensive lipid-lowering therapy as opposed to standard lipid-lowering therapy, the progression of calcium is practically the same in both treatment groups."

The results of the study are published online January 16, 2006 in Circulation.

In an interview with heartwire, Schmermund said the progression of coronary atherosclerosis is frequently used as a surrogate end point in clinical trials and that previous studies have shown that increased progression of coronary calcification is an important predictor of future coronary events. The purpose of this study, he said, which was designed around the time the other major high-dose statin therapy trials were getting under way, was to test whether therapy with atorvastatin 80 mg/day would slow the progression of CAC over 12 months compared with atorvastatin 10 mg/day.

In this multicenter, randomized, double-blind clinical trial, men and women between ages 32 and 80 years with at least two cardiovascular risk factors, without high-grade coronary stenoses (>50% diameter lumen narrowing), and a coronary artery calcification score >30 (according to the Agatston method) were screened for study inclusion.

Before randomization, there was a four-week open-label run-in phase in which all participants received atorvastatin 10 mg. The first EBCT examination was performed within 14 days before or after screening. Patients with a CAC score >30 and LDL cholesterol levels <130 mg/dL at the end of the run-in phase were randomized to receive atorvastatin 80 mg or 10 mg once daily for 12 months. In total, slightly more than 1000 patients were screened in Germany, England, and Russia, and 471 patients entered into the randomized treatment phase. Most patients not randomized after screening were excluded due to low CAC scores.

Compared with standard lipid-lowering therapy, treatment with atorvastatin 80 mg further reduced LDL-cholesterol levels by approximately 20%, down to 87 mg/dL, after 12 months. Yet despite the difference in LDL-cholesterol levels, the primary end point—the percent change in EBCT-determined total CAC volume between baseline and 12 months—did not differ between the two treatment arms.

There was no difference in CAC progression whether determined by Agatston scores or by volume, and CAC progression showed no relationship with on-treatment LDL-cholesterol levels.

Schmermund said the observed progression of coronary calcification is considered moderate but noted that patients with progression of coronary calcification between 15% and 20% are known to have more cardiovascular events.

Asked why high-dose atorvastatin failed to attenuate the progression of coronary calcification, Schmermund said it is possible that 12 months is too short a time frame to detect changes in CAC progression. He also pointed out that patients in this study achieved a final LDL-cholesterol level of 87 mg/dL, higher than the on-treatment LDL-cholesterol levels observed in the Treating to New Targets (TNT) and Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction (PROVE-IT TIMI-22) studies. However, failure to halt CAC progression in this trial is likely due to other factors, said Schmermund.

"My personal interpretation is simply that the relationship between lipid-lowering therapy, the total amount of atherosclerosis, and the influence of LDL cholesterol on total atherosclerosis and coronary calcium, as well as the progression of disease, is much more complex than we currently understand," said Schmermund.

"To me, one of the most important things to make clear is that coronary calcium in and of itself has a great predictive value. If you have a lot of calcium, that's bad news. Also, an increasing amount of calcium over time is bad news, too," continued Schmermund. "On the other hand, you cannot expect EBCT to track whether treatment is successful, not in an individual patient or even in a group of patients. This was something we had hoped for, as we would like to see whether our attempts to prevent cardiac events with lipid lowering are working or if we need to be more aggressive in our treatment. However, over the course of one year, that does not appear to be possible with calcium scanning."

Like the study authors, Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD), who commented on the results of the study for heartwire, noted that the findings are supported by the previously published Beyond Endorsed Lipid Lowering with Electron Beam Tomography Scanning (BELLES) study. In that study, treatment with atorvastatin 80 mg/dL resulted in greater LDL reductions than pravastatin 40 mg/dL, but these lipid changes did not translate into less CAC progression.

"EBCT doesn't seem to be as good as carotid IMT for following the progression of CAD," noted Blumenthal. "Perhaps the results would be somewhat different if the follow-up were 24 or 36 months."

Regarding the future role of EBCT in clinical trials and practice, said Schmermund, the question remains open. One prospective trial with antihypertensive therapy did find a difference with calcium progression and treatment, but there are now at least three studies, including BELLES, that did not find a difference in calcium progression in randomized treatment groups.

"I wouldn't say that EBCT has no value because it does image the coronary arteries and is noninvasive," he said. "It's very interesting, but we need to figure out what we can expect to gain from it."