Intensive Lipid Lowering and Coronary Plaque Regression
Intensive Lipid Lowering and Coronary Plaque Regression
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.
Source: Nicholls SJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-2087.
Recent clinical trials utilizing intravascular ultrasound (IVUS) to quantify coronary artery plaque burden have demonstrated that statin therapy has the potential to arrest the progression of coronary artery disease, and even to effect a small amount of plaque regression. Rosuvastatin is more effective than atorvastatin in reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL) levels. Whether this translates into more effective plaque regression is not known. Accordingly, Nicholls and colleagues performed a large, multicenter clinical trial to compare the effects of high-dose atorvastatin vs high-dose rosuvastatin on coronary artery plaque burden.
Patients undergoing clinically indicated coronary angiography who had evidence of non-obstructive coronary plaque (< 50% stenosis) were recruited. The patients underwent IVUS analysis and were then randomized to one of two treatment arms: atorvastatin 80 mg daily or rosuvastatin 40 mg daily. Patients were excluded if they had intensive lipid lowering therapy for more than 3 months in the prior year, if they had low LDL levels (< 100 mg/dL in statin-naïve patients and < 80 mg/dL in statin-treated patients), uncontrolled hypertension, heart failure, renal dysfunction, or liver disease. The study aimed to treat for 104 weeks and then repeat the IVUS evaluation. The primary endpoint was percent atheroma volume (PAV), the percentage of the vessel wall that is occupied by atherosclerotic plaque.
A total of 1385 patients were randomized to high-dose atorvastatin (n = 691) or high-dose rosuvastatin (n = 694). After 104 weeks of treatment, 75% of patients remained in the study and underwent follow-up IVUS (n = 519 atorvastatin; n = 520 rosuvastatin). There were no differences in baseline demographic or clinical variables.
Rosuvastatin treatment resulted in lower LDL levels (62.6 ± 1.0 vs 70.2 ± 1.0 mg/dL; P < 0.001) and higher HDL levels (50.4 ± 0.5 vs 48.6 ± 0.5; P = 0.01) than atorvastatin. Both atorvastatin and rosuvastatin resulted in modest plaque regression. The primary endpoint, PAV, decreased in both the atorvastatin group (-0.99%) and the rosuvastatin group (-1.22%), but the difference between groups was not significant (P = 0.17). Both agents induced plaque regression in the majority of patients (63.2% with atorvastatin and 68.5% with rosuvastatin; P = 0.07). The side-effect profiles were similar with both medications. The authors conclude that maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower levels of LDL and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression was seen in the two treatment groups.
Coronary atherosclerosis is a progressive disease. Statins have the capacity to reduce the rate of progression of disease. This study demonstrates the ability of two intensive statin regimens to actually reverse the disease process, albeit to a modest extent. The use of IVUS at two time-points is probably the most accurate way to demonstrate small changes in plaque volume. Although there is a small risk with performing invasive IVUS, this study was important to demonstrate this effect. Clearly, serial IVUS evaluation of the coronary arteries is not warranted on an individual patient basis, but the study demonstrates an important principle of lipid-lowering therapy: intensive statin use not only prevents plaque progression over 2 years, it actually induces a small degree of plaque regression.
This study had a relatively short follow-up period, as most patients will be on statin therapy for much longer than 2 years. It remains unknown whether the longer-term effects of such intensive statin therapy on coronary plaque and cardiac event rates will differ between the two treatments. There was a trend toward greater reduction in atheroma volume with rosuvastatin that did not reach statistical significance. Perhaps over a 5- or 10-year period there may well be a difference between agents, but more studies are needed to determine this. The short follow-up, though, shows that a relatively rapid plaque regression can be achieved with current medical therapy. What are the effects of moderate lipid lowering on plaque regression (atorvastatin 40 mg or rosuvastatin 20 mg)? Are the highest statin doses actually necessary, or can lower doses of statins also lead to plaque regression? This question also remains unanswered. Concerns have been raised about the safety of statins in the long term. These concerns should be allayed by the recently published 11-year follow-up of the Anglo-Scandinavian Cardiac Outcomes Trial study,1 which showed continued benefit of atorvastatin over placebo. However, the long-term safety of rosuvastatin has not yet been demonstrated.
Although a formal cost-effectiveness analysis was not performed in this study, one could imagine that with atorvastatin going generic, there is a potential for real cost savings to the health care system with this aggressive approach to secondary prevention. This study confirms that intensive lipid lowering is beneficial in patients with established coronary artery disease, and that following the clinical guidelines, which recommend this approach, will result in better outcomes for our patients. There appears to be little difference between these two statin regimens at 2 years of follow-up.
1. Sever PS, et al. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the U.K. Eur Heart J 2011;32: 2525-2532.Recent clinical trials utilizing intravascular ultrasound (IVUS) to quantify coronary artery plaque burden have demonstrated that statin therapy has the potential to arrest the progression of coronary artery disease, and even to effect a small amount of plaque regression.
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