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57th Scientific Session of the American College of Cardiology

Chicago, Illinois / March 29-April 1, 2008

Evidence confirming that progressive atherosclerosis can be reversed when LDL levels are reduced below 2.0 mmol/L has been generated by a new set of data from the previously published ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden Treatment) trial. The new quantitative coronary angiography (QCA) data, like previously reported intravascular ultrasound (IVUS) results, confirm that progression of atherosclerosis stops at a LDL level of approximately 2.0 mmol/L, and that atherosclerosis is reversed at lower levels. The QCA substudy, conducted independently of the previous analysis with IVUS, establishes unequivocally that intensive reductions in LDL shrink stenoses and enlarge the coronary lumen. These changes almost certainly explain why lipid reductions below 2.0 mmol/L produce additional protection from clinical events.

“Two imaging studies focusing on different coronary segments demonstrated concordant regression and stabilization of atherosclerosis with intensive statin therapy,” reported Dr. Christie Ballantyne, Director, Center for Cardiovascular Disease Prevention, Baylor College of Medicine, Houston, Texas. “Once again, stabilization or zero change in stenosis required a LDL of approximately 80 mg/dL [2.0 mmol/L], and one would need to go below this to see regression.”

The story of LDL lowering has been consistently summarized with the phrase “lower is better” within the confines of the potencies of tested therapies. Each incremental reduction in LDL has been associated with an incremental reduction in risk of clinical events. As of yet, no threshold of LDL has been identified at which there is no additional protection against cardiovascular events. Imaging studies are credited with providing insight into this phenomenon. REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering), which achieved a mean LDL of approximately 1.8 mmol/L on atorvastatin 80 mg, was the first to demonstrate a halt in progression of atherosclerosis (Nissen et al. JAMA 2004;291:1071-80). ASTEROID, which evaluated rosuvastatin 40 mg and achieved a mean LDL that was 10% to 15% lower than that achieved in REVERSAL, was the first to demonstrate regression (Nissen et al. JAMA 2006;295:1556-65).

ASTEROID Design

“This is a very consistent story,” remarked Dr. Ballantyne, who noted that the most recent QCA results from ASTEROID were predicted by FATS (Familial Atherosclerosis Treatment Study), which was conducted almost 20 years ago and was one of the first QCA studies to document favourable changes in atherosclerotic plaques with statin therapy (Brown et al. N Engl J Med 1990; 323:1289-98). The data accumulated over those intervening years is now overwhelming. Due to the opportunity to stop the disease process, “both the imaging and outcome studies suggest intensive statin therapy to lower LDL is warranted in high-risk patients,” he told delegates.

In the initially published ASTEROID study, serial IVUS measurements were taken in 349 patients treated with rosuvastatin 40 mg at 53 participating centres. At the end of two years, during which time there was a mean 52% reduction in LDL to lower average levels from approximately 3.35 mmol/L to 1.6 mmol/L (P<0.001), significant regression in atherosclerosis was observed by two methods of measurement. The mean change in per cent atheroma volume (PAV) for an index vessel was -0.98% (3.15%), with a median of -0.79% (97.5% CI, -1.21% to -0.53%; P<0.001 vs. baseline). There was also a median of 12.5 mm3 (6.8%) reduction in total atheroma volume (95% CI, -15.1 to -10.5 mm3; P<0.001 vs. baseline). In addition, regression was also demonstrated in the most diseased 10-mm subsegment (P<0.001 vs. baseline).

The Role of QCA

In the new ASTEROID data, QCA was employed to evaluate change in lesions producing a stenosis exceeding 25% at baseline (Figure 1). The QCA data, which evaluated both the change in stenosis and the change in median lumen diameter, generated results that were remarkably similar and highly supportive of the IVUS findings. Limited to those with a stenosis of greater than 25%, the QCA study was conducted in 292 patients (77% of those assessed in the IVUS study). A comparison of those who were included in the QCA analysis and those who were not did not reveal significant differences in most major characteristics, such as age (mean 58 years), gender (75% male), or body mass index (28). Both those who underwent QCA and those who did not were on aggressive risk management that included ASA in more than 80% of patients, beta blockers in more than 80%, and ACE inhibitors in more than 55%. As previously reported, rosuvastatin 40 mg once daily was associated with a 53.3% reduction in LDL, a 13.8% increase in HDL, a 12.3% reduction in triglycerides, and a 58.2% reduction in the LDL:HDL ratio.

Figure 1. Change in Per Cent Diameter Stenosis vs. On-Treatment LDL-C in QCA Trials

Over the two years of the study, treatment with rosuvastatin in the target vessels was associated with a 1.3% (P<0.001) median stenosis regression and a 0.03 mm increase (P<0.001) in the median coronary lumen diameter. When all lesions were evaluated, almost 60% regressed or were unchanged. However, results were even more impressive for changes considered clinically relevant, which was a progression or regression of greater than 10%. On this basis, 97% of lesions either regressed or remained stable with only 3.1% demonstrating progression over the study period. A similar finding was seen in the analysis of median lumen diameter. When clinically relevant changes were defined as an increase or decrease of greater than 0.2 mm, 94% of assessed segments remained stable or regressed and only 6% progressed.

Making the LDL-QCA Connection

The QCA analysis of ASTEROID, like the IVUS correlation, reinforces a direct correlation between reductions in LDL and protection against atherosclerosis progression. When IVUS studies are plotted for LDL reduction and change in atheroma burden, each incremental additional median reduction in LDL is associated with a lower rate of progression until REVERSAL, when the median LDL of nearly 2.0 mmol/L is associated with essentially zero progression (Figure 2). ASTEROID, which provides an additional incremental reduction in LDL, results in a regression in atherosclerosis. The QCA studies produce the same result, with stabilization once more observed when LDL reaches approximately 2.0 mmol/L. Again, ASTEROID, producing an incremental additional reduction in LDL, is the first study to demonstrate regression with QCA.

Figure 2. Change in Progression of IVUS Per Cen
LDL-C in IVUS Trials

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In the QCA and IVUS analyses, changes in HDL were not a primary focus of study even though rosuvastatin did increase HDL by a mean of nearly 14%. However, Dr. Ballantyne reported that there was a correlation between increases in HDL and favourable changes in stenosis. Although the data are not as robust with HDL as LDL, Dr. Ballantyne reported evidence of a threshold effect. Specifically, he noted that the likelihood of regression increases as HDL climbs above 1.2 mmol/L.

Lower LDL Levels Still Better

The significance of achieving LDL levels capable of producing regression rather than stabilization is supported by the clinical trials that have consistently demonstrated risk reductions as LDL levels are reduced, including reductions into ranges now demonstrated by ASTEROID that lead to regression. In a series of primary and secondary prevention studies, the treatment arm achieving the lowest reduction in LDL has consistently produced the greatest relative protection against cardiovascular events. The TNT (Treating to New Targets) trial, which is among the largest and most recent event-based trials to compare relative reductions in LDL, the more aggressive treatment arm of atorvastatin 80 mg produced a 22% relative reduction (P<0.001) in the primary composite end point of death from coronary heart disease, myocardial infarction, resuscitation after cardiac arrest or stroke when compared to atorvastatin 10 mg (LaRosa et al. N Engl J Med 2005;352:1425-35). Although the median LDL achieved on 80 mg was 2.0 mmol/L, the level now associated with plaque stabilization, stratification of event rates by LDL level revealed additional incremental reductions with each increased reduction in LDL down to a level of <1.8 mmol/L.

More Questions Remain

The results of ASTEROID provide objective data that lower is better in respect to the influence of LDL on the pathophysiology of atherosclerosis. This is critical information in regard to the goals of treatment, particularly in the context of the significance of LDL as a risk factor for events. However, there are still important questions to be addressed in defining optimal risk management with statins and adjunctive therapies for dyslipidemias. In addition to the importance of defining the relative contribution of HDL and the opportunities to treat this lipid to build on the benefits of optimally suppressed LDL, there is growing interest in C-reactive protein (CRP) as a treatable risk factor. An inflammatory marker, CRP is a predictor of events, and it can be reduced by statin therapy. Although statins are not uniformly effective in lowering CRP, which correlates poorly with LDL, a trial with rosuvastatin, which does produce substantial CRP reductions, was recently stopped early due to greater benefit in the active treatment arm.

News from JUPITER

“We just learned this morning that the JUPITER trial was halted prematurely by the data safety monitoring committee due to interim results that favoured rosuvastatin,” reported Dr. Ballantyne. “This should tell us a great deal more about risk reduction.”

In JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin), 15,000 patients with LDL-C levels <130 mg/dL (<3.36 mmol/L) and no history of cardiovascular disease were recruited on the basis of elevated CRP levels. They were randomized to rosuvastatin or placebo. The trial was stopped for “unequivocal evidence of a reduction in cardiovascular morbidity and mortality” in the active treatment arm.

Asked to comment on these developments, Dr. Subodh Verma, Canada Research Chair in Atherosclerosis, St. Michael’s Hospital, Toronto, Ontario characterized ASTEROID trial as “a landmark trial that demonstrated for the first time [now using both IVUS and QCA] that atherosclerosis regression was indeed achievable.” However, despite the importance of the ASTEROID data, he went on to comment, “I guess the most excitement is now on the remarkable news that the morbidity and mortality trial for rosuvastatin, JUPITER, has been stopped early due to clear cardiovascular benefit.” He, like others, is waiting for the published data to better understand the context of the data and its relevance to patient care.

In his comment, Dr. Jean-Claude Tardif, Director of Clinical Research, Montreal Heart Institute, and Professor of Medicine, Université de Montréal, Quebec, noted that the regression in ASTEROID, now documented through two different modalities, was not only observed at a mean LDL level of 1.57 mmol/L but also with a 14% increase in HDL, both of which may have been important to this result. According to Dr. Jacques Genest, Director, Division of Cardiology, McGill University Health Centre, Montreal, the QCA data “largely confirm the IVUS data” previously reported from ASTEROID. Although they do not change perceptions about the importance of intensive lipid lowering, they further substantiate its effect on target lesions.

Summary

New QCA data from ASTEROID have confirmed that intensive LDL lowering with rosuvastatin can produce regression of atherosclerotic lesions. Although previous studies have suggested that stabilization of atherosclerosis can be achieved at a LDL of approximately 2.0 mmol/L, a further LDL reduction reverses plaque burden, which appears to explain the association of LDL levels lower than 2.0 mmol/L with increased protection from cardiovascular events relative to higher levels. Although the level of LDL at which there is no further protection from cardiovascular events has not yet been identified, the landmark data from ASTEROID further substantiate the premise that intensive LDL lowering is appropriate for optimal protection against events.