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Lipid management of cardiovascular disease
S20
ISCNM/IHFS 2008, Hong Kong / International Journal of Cardiology 125 Suppl. 1 (2008) S1–S37
Lipid management of cardiovascular disease J.K. Liao. Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA Atherosclerosis is the underlying disorder in the majority of patients with cardiovascular disease. Although the development of atherosclerosis is dependent upon many factors and processes, a clear association has been established between elevated serum cholesterol levels and increased atherosclerotic disease. Indeed, lipid-lowering trials with statins have shown substantial reduction in cardiovascular events. Consequently, the 2001 NCEPT/ATP III guidelines indicate that high-risk patients should have their LDL lowered to less than 100 mg/dL. However, since 2001, results from PROVE-IT/TIMI-22 and TNT trials indicate that further reduction in LDL-C to levels perhaps less than 70 mg/dL may provide even greater cardiovascular protection for high-risk patients. Interestingly, half of the benefits in PROVE-IT were related to the reduction in the inflammatory marker, C-reactive protein (CRP), suggesting that both lipid lowering and anti-inflammation contribute to the therapeutic benefits of statin therapy. Indeed, recent studies indicate that some of the cholesterolindependent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. These vascular effects of statins are thought to contribute to some of the beneficial effects of statin therapy in cardiovascular disease. Although lipid lowering contributes to the benefits of statin therapy, the exact mechanism by which lipid lowering with statins alters the biology of atherosclerosis is not known. In the REVERSAL trial, intensive lipid lowering with atorvastatin to a LDL of 77 mg/dL (2 mmol/L) did not produce significant changes in coronary regression by IVUS (−0.4% total atheroma volume [TAV], +0.2% percent atheroma volume [PAV], P = NS for both). Similar findings were observed in carotid intima-media thickness with rosuvastatin in low-risk patients in the METEOR trial. Based upon these findings, intensive LDL lowering therapy appears to halt atherosclerotic lesion progression, but does not cause substantial regression. However, regression of atherosclerosis in high-risk patients with coronary artery disease was observed in the HATS trial with simvastatin and niacin and the recent ASTEROID trial with rosuvastatin. Of note, HDL was increased by 14% and 35% in HATS and ASTEROID, respectively, whereas HDL was unchanged with atorvastatin in REVERSAL. Indeed, infusion of a mutant ApoA1 (Milano) for 5 weeks resulted in a −4.2% decrease in TAV and −1.1% decrease in TAV in patients
with acute coronary syndromes. These findings indicate that aggressive LDL lowering (<88 mg/dL) coupled with HDL raising (>7.5%) as represented by LDL:HDL ratio of <1.5, is required for reversing atherosclerosis. Indeed, the TC:HDL ratio and the apoB:apoA1 ratio are the most significant markers which predict future cardiovascular events in the Framingham Heart Study and InterHeart Study, respectively. Finally, the ability to achieve target lipid goals has been rather difficult. In the REALITY trials of Europe and Asia, most individuals at risk for cardiovascular events do not reach their lipid goals. For example, approximately 24−40% of all patients achieve their lipid goals and less than 20% of high-risk patients achieve LDL goal of less than 100 mg/dL. The difficulty in achieving LDL target goals partly stems from the wide use of low efficacy statins as initial therapy, the reluctance of physicians to titrate statins to a higher dose due to side effects, and the costs associated with titration. Consequently, about 75% of patients on statin therapy are on their original starting dose. Therefore, achieving LDL goals at a starting dose of an efficacious statin would greatly improve healthcare costs and adherence to lipid guidelines, while minimizing potential adverse effects. Reference(s) [1] The multiple risk factor intervention trial (MRFIT). A national study of primary prevention of coronary heart disease. J Am Med Assoc 1976;235:825−7. [2] Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–504. [3] Brown, B.G., et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2004;345:1583−92. [4] Nissen SE, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. J Am Med Assoc 2004;291:1071−80. [5] Nissen SE, et al. Effect of recombinant ApoA-1 Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. J Am Med Assoc 2003;290:2292–2300. [6] Nissen SE, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID Trial. J Am Med Assoc 2006;295:1556−65. [7] Crouse JR, et al. The effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. J Am Med Assoc 2007;297:1344−53. [8] Nicholls SJ, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. J Am Med Assoc 2007;297:499–508.
ISCNM/IHFS 2008, Hong Kong / International Journal of Cardiology 125 Suppl. 1 (2008) S1–S37
Lipid management of cardiovascular disease J.K. Liao. Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA Atherosclerosis is the underlying disorder in the majority of patients with cardiovascular disease. Although the development of atherosclerosis is dependent upon many factors and processes, a clear association has been established between elevated serum cholesterol levels and increased atherosclerotic disease. Indeed, lipid-lowering trials with statins have shown substantial reduction in cardiovascular events. Consequently, the 2001 NCEPT/ATP III guidelines indicate that high-risk patients should have their LDL lowered to less than 100 mg/dL. However, since 2001, results from PROVE-IT/TIMI-22 and TNT trials indicate that further reduction in LDL-C to levels perhaps less than 70 mg/dL may provide even greater cardiovascular protection for high-risk patients. Interestingly, half of the benefits in PROVE-IT were related to the reduction in the inflammatory marker, C-reactive protein (CRP), suggesting that both lipid lowering and anti-inflammation contribute to the therapeutic benefits of statin therapy. Indeed, recent studies indicate that some of the cholesterolindependent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. These vascular effects of statins are thought to contribute to some of the beneficial effects of statin therapy in cardiovascular disease. Although lipid lowering contributes to the benefits of statin therapy, the exact mechanism by which lipid lowering with statins alters the biology of atherosclerosis is not known. In the REVERSAL trial, intensive lipid lowering with atorvastatin to a LDL of 77 mg/dL (2 mmol/L) did not produce significant changes in coronary regression by IVUS (−0.4% total atheroma volume [TAV], +0.2% percent atheroma volume [PAV], P = NS for both). Similar findings were observed in carotid intima-media thickness with rosuvastatin in low-risk patients in the METEOR trial. Based upon these findings, intensive LDL lowering therapy appears to halt atherosclerotic lesion progression, but does not cause substantial regression. However, regression of atherosclerosis in high-risk patients with coronary artery disease was observed in the HATS trial with simvastatin and niacin and the recent ASTEROID trial with rosuvastatin. Of note, HDL was increased by 14% and 35% in HATS and ASTEROID, respectively, whereas HDL was unchanged with atorvastatin in REVERSAL. Indeed, infusion of a mutant ApoA1 (Milano) for 5 weeks resulted in a −4.2% decrease in TAV and −1.1% decrease in TAV in patients
with acute coronary syndromes. These findings indicate that aggressive LDL lowering (<88 mg/dL) coupled with HDL raising (>7.5%) as represented by LDL:HDL ratio of <1.5, is required for reversing atherosclerosis. Indeed, the TC:HDL ratio and the apoB:apoA1 ratio are the most significant markers which predict future cardiovascular events in the Framingham Heart Study and InterHeart Study, respectively. Finally, the ability to achieve target lipid goals has been rather difficult. In the REALITY trials of Europe and Asia, most individuals at risk for cardiovascular events do not reach their lipid goals. For example, approximately 24−40% of all patients achieve their lipid goals and less than 20% of high-risk patients achieve LDL goal of less than 100 mg/dL. The difficulty in achieving LDL target goals partly stems from the wide use of low efficacy statins as initial therapy, the reluctance of physicians to titrate statins to a higher dose due to side effects, and the costs associated with titration. Consequently, about 75% of patients on statin therapy are on their original starting dose. Therefore, achieving LDL goals at a starting dose of an efficacious statin would greatly improve healthcare costs and adherence to lipid guidelines, while minimizing potential adverse effects. Reference(s) [1] The multiple risk factor intervention trial (MRFIT). A national study of primary prevention of coronary heart disease. J Am Med Assoc 1976;235:825−7. [2] Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–504. [3] Brown, B.G., et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2004;345:1583−92. [4] Nissen SE, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. J Am Med Assoc 2004;291:1071−80. [5] Nissen SE, et al. Effect of recombinant ApoA-1 Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. J Am Med Assoc 2003;290:2292–2300. [6] Nissen SE, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID Trial. J Am Med Assoc 2006;295:1556−65. [7] Crouse JR, et al. The effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. J Am Med Assoc 2007;297:1344−53. [8] Nicholls SJ, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. J Am Med Assoc 2007;297:499–508.