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55th Annual Scientific Sessions of the American College of Cardiology

Atlanta, Georgia / March 11-14, 2006

Cardiovascular disease (CVD) was once described as a progressive narrowing of the arteries by accumulation of stenotic lesions causing ischemia and eventually leading to thrombosis and myocardial infarction (MI). In this traditional view, angiography, which shows the lumen of the artery, was widely considered the best method of measuring disease burden. Intravascular ultrasound (IVUS) has profoundly modified this view. IVUS, which measures both the lumen and the arterial wall, has demonstrated that atherosclerotic plaques only extend into the lumen in very late stages of disease. Instead, most atherosclerosis that leads to CV events resides in the wall, where it is unseen on angiography.

Atherosclerosis, Disease of the Arterial Wall

“CVD has long been considered a disease of the lumen, but it is really a disease of the vessel wall. The lumen does not really change very much over time. Rather, the atherosclerotic plaque grows diffusely throughout the arterial tree, and when there is a rupture in this plaque, it leads rapidly to a CV event,” explained Dr. Steven Nissen, Medical Director, Cleveland Clinic Cardiovascular Coordinating Center, Ohio. The newly elected president of the American College of Cardiology (ACC), Dr. Nissen has been an innovator in the use of IVUS, and his studies have contributed to a major evolution in the conception of atherosclerosis and how IVUS can be used to evaluate the effects of anti-atherosclerotic treatments.

IVUS yields cross-sectional images of the artery that permit precise measurements of the lumen and the arterial wall. As the transducer-equipped catheter is pulled through the artery, it takes images at fixed and reproducible intervals. In exploratory studies, this tool permitted Dr. Nissen to show that there can be dramatic progression of atherosclerosis with essentially no change in the lumen diameter (Nissen et al. Circulation 2001; 103:604-16). When investigators at other centres confirmed that the arterial wall carried a heavy plaque burden before it advanced into the lumen of the artery, it led to a major evolution in the perception of how this disease develops. Importantly, the findings explained why the majority of MIs occur in patients without significant arterial stenosis.

Dr. Nissen addressed delegates, “In the early 1990s, IVUS gave us the first chance to see and measure plaque. Although we already knew by that point that most MIs were not the result of rupture of large stenotic lesions, what we saw was a surprise. The remodelling of the artery from atherosclerosis was found to be taking place almost entirely in the vessel wall.”

REVERSAL: IVUS Demonstrates Change in Atheroma

Results of the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial suggested that controlling atherosclerotic disease progression in the vessel wall may be the source of the major reductions in clinical events observed in statin trials. In REVERSAL, two statins with different potencies for lowering LDL levels were compared for their effects on atherosclerosis with IVUS. Published in the Journal of the American Medical Association (Nissen et al. JAMA 2004; 291:1071-80), the study evaluated 502 patients at 34 centres over 18 months. In the patient group randomized to 80 mg atorvastatin, mean LDL was reduced to approximately 2.05 mmol/L. In the group randomized to 40 mg pravastatin, mean LDL over the study period was approximately 2.85 mmol/L. When compared to baseline, IVUS demonstrated a slight and non-significant reduction in the average thickness of the atherosclerotic plaque in the atorvastatin group but a significant progression in the pravastatin group.

“The more intensive regimen reduced the progression of atherosclerosis to zero. This was a very exciting result. It was the first evidence that it was possible to stop progression if LDL levels were lowered sufficiently. However, despite the name of the trial, we did not show reversal of disease,” Dr. Nissen stated.

Results of REVERSAL explained the findings of PROVE-IT/TIMI-22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22), which was published about the same time (Cannon et al. N Engl J Med 2004; 350:1495-504). PROVE-IT compared the same two lipid-lowering strategies at the same doses as in REVERSAL in 4162 patients hospitalized for an acute coronary syndrome. Although the trial hypothesis was that the two strategies would provide benefits, the more aggressive lipid-lowering regimen was significantly more effective in reducing CV events. At the end of two years, those randomized to more aggressive lipid lowering achieved a highly significant 16% reduction (P=0.005) in the composite end point of death from any cause, MI, documented unstable angina requiring hospitalization, revascularization, or stroke.

TNT: Lower LDL Is Better

The message that lower is better in high-risk patients has been supported by several subsequent trials, particularly TNT (Treating to New Targets), which randomized 10,001 patients and found a 22% relative reduction in major CV events when LDL levels were reduced to an average level of 2.0 mmol/L when compared to an average level of 2.6 mmol/L, the recommended target at the time of the trial (LaRosa et al. N Engl J Med 2005;352:1425-35). According to lipid trial data analyzed by the Cholesterol Treatment Trialists Collaborators, each 1.0 mmol/L reduction in LDL produces a 21% reduction in vascular events (Baigent et al. Lancet 2005; 366:1267-78). Moreover, no analysis of lipid trial data, including those generated by PROVE-IT and TNT, was able to show any threshold at which no further benefit was associated with additional LDL lowering.

The importance of lipid lowering created the basis for ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma), which was to explore whether even lower LDL levels demonstrated improvement in atherosclerosis as measured with IVUS. Although Dr. Nissen acknowledged that there was considerable doubt that actual regression of atherosclerotic plaques could be achieved even with maximal lipid lowering, ASTEROID was designed to answer this question. The results have broken new ground. “Over the course of the trial, very intensive lipid lowering produced highly statistically significant regression, and it was surprisingly large,” Dr. Nissen indicated. “This is the first study to demonstrate that you can remove atherosclerotic plaque with a lipid-lowering agent and do so at substantial levels.”

ASTEROID: Multicentre Participation

In ASTEROID, 507 patients at 53 centres in the US, Canada, Europe and Australia were evaluated with IVUS before starting a regimen of rosuvastatin 40 mg q.d. All patients were required to have more than 20% stenosis in at least one major coronary artery but no more than 50% stenosis in the target vessel. Patients, who were statin-naïve (defined as having had less than three months of statin therapy within the past 12 months), were excluded if they had a prior revascularization in the target vessel or MI.

Average LDL levels at baseline were 3.35 mmol/L. On treatment, average levels were reduced to 1.50 mmol/L, a reduction of 53.2%. HDL levels were raised from an average of 1.1 mmol/L to 1.3 mmol/L, an increase of 14.7%. The increase in HDL was uncommonly large for a statin trial. The average LDL levels were the lowest ever reported in a large treatment study.

When IVUS was repeated at the end of two years, atheroma volume was reduced by 7% to 10% (P<0.001). The absolute reduction in the atheroma volume of the entire target artery was 12.5 mm3, a 6.8% decrease (P<0.001). When all IVUS measures at the end of the study were compared to baseline measures, regression of atheroma volume was observed in 63.6% and progression was observed in 36.4%. In the most diseased 10 mm segment of the target artery, regression was observed in 78.1% of the measures, and progression was observed in 21.9%. The reductions were consistent across all prespecified subgroups, which included age below or above the median, gender, and body mass index above or below the median.

Improving Regression with Lower LDL

“When we stratified by LDL level, there was improving regression with lower vs. higher LDL levels with significant differences between those at the lowest levels compared to the highest,” Dr. Nissen reported. Consistent with REVERSAL, there was no significant regression observed when LDL levels were greater than 1.8 mmol/L, but there was significant regression when LDL levels less than 1.8 mmol/L were achieved.

The regimen was well tolerated. There were no cases of rhabdomyolysis over the two years of evaluation, and abnormal liver function tests occurred in less than 2% of patients, a rate that might be expected in an untreated population. According to Dr. Nissen, the adverse event rate was no different than what has been previously reported with other high-intensity statin regimens, despite the far lower level of LDL achieved in this trial.

ASTEROID did not have a control arm, a design element that was criticized by commentators who spoke after the data were presented, but Dr. Nissen countered that the study had powerful internal controls that protected the integrity of the data. Most importantly, IVUS images were read blind to sequence so that observers were unaware whether images were obtained at baseline or after treatment. Dr. Nissen also noted that there were several reasons not to include a control arm, including concern that a placebo arm or a low-dose statin arm would be unethical in a population with established coronary artery disease. Most importantly, the purpose of the study was to evaluate the effect of LDL lowering on atheroma volume rather than compare treatment strategies.

The ASTEROID study is important because it demonstrates that highly, intensive lipid lowering can not only slow atherosclerosis, but also effectively reverse the disease process, according to Dr. Nissen. However, he emphasized that a clinical end point study is now needed to confirm whether regression reduces death and CV events. Specifically, he reported, “We did not show a change in morbidity or mortality with this study. We think it will follow, but we now need the clinical data.”

The study also did not yet reveal a target LDL. Although the data imply that LDL should be lowered more than the current goals, a preliminary evaluation of the ASTEROID data did not show LDL levels beyond which there was no further favourable effect on atheroma volume. Dr. Nissen speculated that 1.3 mmol/L will prove superior to 1.5 mmol/L, but he suggested that target LDL levels might no longer be the best way to conceptualize lipid lowering. Citing evidence that LDL levels of near 1.0 mmol/L might be physiologic in Homo sapiens, he suggested that if clinical event data corroborate the benefits in ASTEROID, “it may be more important to get LDL to the lowest levels achievable without serious adverse events rather than aim for any single target.”

HDL: The Next Main Therapeutic Target?

After more than 10 years of major trials showing the benefit of aggressively treating hypercholesterolemia to reduce CV risk, the LDL story is nearing completion. The “lower is better” premise has held up through several adjustments in treatment guidelines, but further protection from CVD may require targeting of other lipid subfractions, particularly HDL. In new data taken from the TNT trial, HDL and the LDL:HDL ratio were identified as important independent predictors of CV events. While the major results of TNT demonstrated a tight correlation between reductions in LDL and reductions in clinical events, HDL levels remain predictive of major CVD in those with low or high LDL levels.

“The LDL level is certainly important, but it does not explain all CVD,” reported the senior author of this TNT substudy, Dr. Philip Barter, The Heart Institute, Sydney, Australia. “I think that our next big opportunity for treating CV risk will be in raising HDL, and there are several studies underway to tell us whether this is true.”

In the TNT substudy, the 10,001 patients were stratified by HDL and compared for CV events. A highly significant inverse correlation between HDL and major CV events was observed (P<0.0001). For every 0.025 mmol/L increase in HDL, there was a 2% reduction in the relative risk of a CV event. Although these results are consistent with previous studies, the persistence of HDL as a predictor of CV risk even in patients with very low LDL levels emphasizes its potential as a therapeutic target.

LDL is not only a well established marker of risk but is also now a proven factor in the pathogenesis of CVD. The IVUS data showing that lowering LDL not only halts progression but can also reverse the process of atherosclerosis completes a circle leading from clinical observations to objective evidence of effect on basic disease mechanisms.

Summary

IVUS has been instrumental in revealing how atherosclerosis affects the vascular tree over time and how lipid-lowering therapies affect this process. While statin trials have associated LDL lowering with large reductions in clinical events, IVUS has been able to explain the mechanism of benefit. While REVERSAL demonstrated that reducing average LDL levels to 2.0 mmol/L halts progression of atherosclerosis, the most recent IVUS study, ASTEROID, has demonstrated that even greater LDL reductions actually produce regression. These data are a major step toward identifying optimal LDL levels for producing concrete reductions in CV risk.