Overview

The important role of elevated low-density lipoprotein cholesterol (LDL-C) levels in the pathogenesis of cardiovascular disease (CVD) has emerged from many clinical trials.^1,2,3 Mounting evidence indicates that statin therapy slows the progression of atherosclerosis and can induce regression of atherosclerotic lesions. Early methods of noninvasive assessment of CVD focused on diagnosing established coronary artery disease, whereas current efforts have shifted toward early identification of individuals at high risk of developing CVD; this allows aggressive early management for prevention. However, major controversy still surrounds when the treatment of dyslipidemia (in particular, LDL-C levels) should begin and how aggressive it should be.

Recently, the updated recommendation of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]),⁴ supported by strong evidence, lowered the target LDL-C level for high-risk individuals from 100 mg/dL to 70 mg/dL, which is effective in preventing cardiovascular events.^5,6,7

Clinical trials have shown that the reduction in clinical events with statin therapy in angiographic studies has been greater than would be expected from the relatively small anatomic changes produced, which suggests that statins may affect atherosclerosis not only by stabilizing plaque but also by exhibiting anti-inflammatory effects, reversing endothelial dysfunction, and decreasing thrombogenicity.^8,9 This newsletter reviews the role of statin therapy in CVD regression and plaque stabilization.

Atherosclerosis regression and plaque stabilization: Benefits of low LDL-C levels

The mechanisms of benefit with statins are incompletely understood. However, trials have consistently demonstrated the capacity of statins to delay progression and induce regression of atherosclerotic lesions in both native vessels and coronary bypass grafts. The benefit of statin therapy is seen as soon as 6 months before significant regression could occur, which implies that other factors must contribute to this benefit. A direct relationship exists between LDL-C levels and changes in carotid intimal-medial thickness (CIMT) and plaque size.^10,11 Kent et al demonstrated that lower LDL-C levels were associated with regression of CIMT.¹⁰ Of patients who achieved the target LDL-C level of less than 70 mg/dL, 61% showed regression of CIMT; only 29% of patients with LDL-C levels higher than 114 mg/dL demonstrated regression of CIMT.¹⁰ Von Birgelen et al demonstrated a positive linear relation between annual changes in plaque and media cross-sectional area and LDL-C levels; 75 mg/dL was the threshold.¹¹ This supports the revised NCEP ATP III goal of LDL-C levels less than 70 mg/dL in patients at high risk. Patients with this low level of LDL-C are more likely to have regression of atherosclerosis.

GAIN study

The German Atorvastatin Intravascular Ultrasound (GAIN) study used intracoronary ultrasound to evaluate the effect of atorvastatin on atherosclerotic progression in 131 patients. After a 12-month follow-up, atorvastatin reduced the progression of the plaque volume (1.3 mm vs 9.6 mm for placebo), with a change in plaque composition leading to greater stability and reduced tendency to rupture. The greater LDL-C level reduction with intensive therapy resulted in less increase in plaque volume.¹²

REVERSAL study

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study was a double-blind randomized trial comparing the effects of 2 different statins, administered for 18 months, on atherosclerotic burden measured by intravascular ultrasound (IVUS).⁵ This study randomized 654 patients with a previous history of CAD into 2 groups. One group used pravastatin 40 mg/d as moderate lipid-lowering therapy, and the other group used atorvastatin 80 mg/d as intensive lipid-lowering treatment. To measure atherosclerotic burden, IVUS studies were performed during the baseline catheterization and repeated after 18 months of treatment. Efficacy parameters included changes in LDL-C levels, C-reactive protein (CRP) levels, and atheroma burden (determined by IVUS).

In the group taking 40 mg/d of pravastatin, serum LDL-C levels were reduced from 150.2 mg/dL to 110 mg/dL. In the group taking 80 mg/d of atorvastatin, serum LDL-C levels were lowered to 79 mg/dL. CRP levels decreased 5.2% with pravastatin and 36.4% with atorvastatin. Using all 3 prespecified efficacy measures, the study demonstrated a complete cessation of coronary disease progression in the intensive arm compared to progression in the moderate-treatment cohort. Plaque volume was unchanged from baseline in the intensive arm, indicating absence of progression. The study concluded that, for patients with established CAD, intensive treatment with atorvastatin 80 mg/d better reduced the progression of coronary atherosclerosis than did a more moderate regimen of pravastatin 40 mg/d. The study was not designed to look for differences in mortality and had inadequate power to detect such differences.

ESTABLISH Study

This study used serial IVUS analyses in patients with acute coronary syndromes to compare the effects of early statin treatment on plaque volume. The results showed a 41.7 % reduction in LDL-C levels of patients taking atorvastatin 20 mg/d; the group taking placebo demonstrated a 0.7% increase in LDL-C levels. Statin therapy at 6 months was associated with significant change in both plaque and luminal volume; plaque volume in the atorvastatin group decreased by 13.1±12.8% compared to a 8.7±14.9% increase (P <.0001) in the control group.¹³

BELLES Study

Beyond Endorsed Lipid with Electron Beam Tomography (EBT) Scanning was a 12-month double-blind randomized trial conducted on 615 postmenopausal women with hypercholesterolemia. It compared the effect of aggressive statin therapy (atorvastatin 80 mg/d) with moderate therapy (pravastatin 40 mg/d) on slowing or halting the progression of arterial calcification. The study demonstrated a significant reduction in LDL-C levels with the intensive therapy (to 92.2 mg/dL) versus moderate treatment (to 129 mg/dL). However, this reduction was not associated with less progression of coronary calcification in the intensive therapy, and no difference was observed in median percentage increase in calcium volume score. Because of the short follow-up times and the absence of a placebo group, any slowing of atherosclerosis progression was impossible to determine.¹⁴

Ongoing regression trials

Several ongoing trials with rosuvastatin and simvastatin are expected to clarify whether aggressive LDL-C level reduction translates into less progression of atherosclerosis. The ASTEROID trial is examining the effect of rosuvastatin 40 mg/d on the change of atheroma volume after 2 years in 509 patients with angiographic evidence of CAD.¹⁵ Similarly, the Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin (METEOR) trial is evaluating the effect of 40 mg/d rosuvastatin on regression assessed by change in CIMT.¹⁶

Conclusions

The evidence appears to show a clear mortality benefit for patients treated with statins for secondary prevention. Regression of atherosclerosis in the coronary artery is a valid surrogate end point for clinical benefit of cholesterol reduction. Trials of statins have provided additional information that is related to the appropriate levels of serum LDL-C. However, the results of these trials are open to interpretation, and the ideal target LDL-C level has not yet been completely defined.

References

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2. Ballantyne CM, Grundy SM, Oberman A, et al. Hyperlipidemia: diagnostic and therapeutic perspectives. J Clin Endocrinol Metab. 2000;85:2089-112.

3. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med. 1990;322:1700-7.

4. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Circulation. 2002;106:3143-421.

5. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-504.

6. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005-16.

7. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35.

8. Vaughan CJ, Gotto AM, Basson CT. The evolving role of the statins in the management of atherosclerosis. J Am Coll Cardiol. 2000;35:1-10.

9. Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol. 2003;23:729-36.

10. Kent SM, Coyle LC, Flaherty PJ, et al. Marked low-density lipoprotein cholesterol reduction below current national cholesterol education targets provides the greatest reduction in carotid atherosclerosis. Clin Cardiol. 2004;27:17-21.

11. Von Birgelen C, Hartmann M, Mintz GS, et al. Relation between progression and regression of atherosclerotic left main coronary artery disease and serum cholesterol level as assured with serial long term (>12 months) follow-up intravascular ultrasound. Circulation. 2003;108:2757-62.

12. Schartl M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound study to compare the effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation. 2001;104:387-92.

13. Okazaki S, Yokoyama T, Miyauchi K, et al. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year coronary event: the ESTABLISH study. Circulation. 2004;110:1061-8.

14. Raggi P, Davidson M, Callister TQ, et al. Aggressive versus moderate lipid lowering therapy in hypercholesterolemic postmenopausal women: Beyond Endorsed lipid lowering with EBT Scanning (BELLES). Circulation. 2005;112:563-71.

15. Schuster H, Fox JC. Investigating cardiovascular risk reduction: The rosuvastatin GALAXY programme. Expert Opin Pharmacother. 2004;5:1187-200.

16. Crouse JR III, Grobbee DE, O’Leary DH, et al, for the METEOR Study Group. Measuring effects on intima media thickness: an evaluation of rosuvastatin in subclinical atherosclerosis- the rationale and methodology of the METEOR study. Cardiovasc Drugs Ther. 2004:18:231-8.