Managing Cholesterol: Achieving Lower LDL-C Levels

Elevated Cholesterol Is a Risk Factor for Cardiovascular Disease Elevated serum cholesterol is associated with increased risk of CHD Reinfarction CVD mortality All-cause Stroke Multiple Risk Factor Intervention Trial (N=350,977) 50 40 30 CVD mortality rate* 20 10 Large-scale epidemiologic studies have demonstrated a strong link between elevated serum cholesterol and cardiovascular morbidity and mortality. In the Framingham study, hypercholesterolemia was associated with increased risks of coronary heart disease (CHD), reinfarction, overall mortality, and mortality due to CHD.1-3 The Multiple Risk Factor Intervention Trial (MRFIT) also confirmed the positive relationship between high serum cholesterol and cardiovascular disease.4 > <160 160–199 200–239 240 Serum cholesterol (mg/dl) *Crude death rate (per 10,000 person-years) Adapted from Kannel WB Am J Cardiol 1995;76:69C–77C; Anderson KM et al JAMA 1987;257:2176–2180; Kannel WB et al Ann Intern Med 1971;74:1–12; Neaton JD et al Arch Intern Med 1992;152:1490–1500.

Pathologic Consequences of High Cholesterol Atherosclerosis Increased plasma LDL-C may injure endothelial cells High LDL-C levels facilitate progression of endothelial injury Endothelial cell injury leads to plaque formation, which reduces lumen size and limits blood flow Plaque rupture leads to thrombosis Human coronary artery in which there is large, lipid-rich plaque Atherosclerosis progresses from fatty streaks to fibrous plaques that reduce lumen size and limit blood flow. Disruption or rupture of fibrous plaques may result in thrombotic episodes and sudden death. The development and progression of atherosclerotic lesions are associated with elevated levels of low-density lipoprotein cholesterol (LDL-C). In atherosclerotic lesions, the accumulation of lipids with proliferated smooth-muscle cells and macrophages is common; modified or oxidized lipoproteins are key in the development of atherosclerosis. Increased plasma levels of LDL-C may injure endothelial cells, a process that initiates and exacerbates the central response to the formation of fibrous plaques that characterize atherosclerosis.5,6 Adapted from Ross R. In Hurst’s The Heart, Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1139–1159; Davies MJ. In Hurst’s The Heart, Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1161–1173.

European Guidelines for CVD Prevention: Lipid Management Treatment Goals Patient group LDL-C Total-C General population <115 mg/dl <190 mg/dl (3 mmol/L) (5 mmol/L) Clinical CVD <100 mg/dl <175 mg/dl (2.5 mmol/L) (4.5 mmol/L) Diabetes <100 mg/dl <175 mg/dl Recent guidelines (2003) from the Third Joint Task Force of The European Society on Cardiovascular Disease Prevention recommend that patients with clinically established CVD and patients with diabetes should maintain total cholesterol levels <175 mg/dl (4.5 mmol/L) and LDL-C levels <100 mg/dl (2.5 mmol/L). The guidelines specifically recommend lower target levels in patients with CVD and diabetes; in the general population, recommended levels are <115 mg/dl (3 mmol/L) for LDL-C and <190 mg/dl (5 mmol/L) for total cholesterol (total-C).7 These guidelines suggest the use of drug therapy in asymptomatic patients who have a high multifactorial risk of developing cardiovascular disease and have total cholesterol levels near 190 mg/dl (5 mmol/L) and LDL-C levels near 115 mg/dl (3 mmol/L). The use of lipid-lowering therapy is recommended in patients whose 10-year risk of cardiovascular death remains 5% after dietary modifications (10-year risk of fatal CVD is based on gender, age, systolic blood pressure, total cholesterol, and smoking status). Adapted from DeBacker C et al Eur Heart J 2003;24:1601–1610.

Lipid Management in Clinical Practice What is an appropriate therapeutic target for LDL-C? For patients with CHD or diabetes, a new, lower optimal goal for LDL-C is <70 mg/dl (1.8 mmol/L)—NCEP Coordinating Committee Circulation 2004;110:227–239 Optimal LDL-C is 50–70 mg/dl (1.3 to 1.8 mmol/L): “Lower is better and physiologically normal”—O’Keefe JH J Am Coll Cardiol 2004;43:2142–2146 Two recent publications have summarized the evidence for even lower LDL-C goals. In one of these, the National Cholesterol Education Program (NCEP) Coordinating Committee has proposed modifications to the Adult Treatment Panel (ATP) III guidelines based on results from five major new clinical trials of statin therapy: Heart Protection Study (HPS), Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Treat (ALLHAT-LLT), Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22). One of the proposed modifications to ATP III goals for very-high-risk patients (risk factors include obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) includes an optimal lower LDL-C goal of <70 mg/dl (1.8 mmol/L) for patients with CHD or CHD risk equivalents. This new recommendation is based on results from HPS and PROVE IT, which demonstrated that high-risk patients with low LDL-C levels at baseline benefit from additional lowering of LDL-C.8 Accumulating data consistently show that the optimal LDL-C level is approximately 50 to 70 mg/dl (1.3 to 1.8 mmol/L).8 Although this LDL-C range seems low by current standards, it is physiologically normal, that is, the range associated with the lifestyle and diet for which we are genetically programmed. In addition, this range represents a threshold for development of atherosclerosis.9 Adapted from Grundy SM et al Circulation 2004;110:227–239; O’Keefe JH et al J Am Coll Cardiol 2004;43:2142–2146.

Changes to NCEP ATP III LDL-C Goals Risk Category Publication LDL-C Goal CHD or CHD risk equivalents (10-year risk >20%) ATP III <100 mg/dl (2.5 mmol/L) Modification Optional goal of <70 mg/dl (1.8 mmol/L) 2+ risk factors (10-year risk 20%) <130 mg/dl (3.4 mmol/L) Optional goal of <100 mg/dl (2.5 mmol/L) for 10%–20% risk group Investigators from the NCEP Coordinating Committee assessed data from recent trials that provide the rationale for further lowering of LDL-C levels. Modifications to ATP III recommendations have been proposed on the basis of that review.8,10 In patients with CHD or CHD risk equivalents (10-year risk >20%), an optional LDL-C goal of <70 mg/dl (1.8 mmol/L) is now proposed, especially in those with CHD plus diabetes, poorly controlled risk factors (e.g., cigarette smoking), multiple risk factors for metabolic syndrome (high triglycerides 200 mg/dl [2.6 mmol/L] plus non–HDL-C [high-density lipoprotein cholesterol] 130 mg/dl [3.4 mmol/L] with low HDL-C [<40 mg/dl (1.0 mmol/L)]), and acute coronary syndrome. In patients with a 10-year risk from 10% to 20% and LDL-C of 130 mg/dl (3.4 mmol/L), there is a new optional LDL-C goal of <100 mg/dl (2.5 mmol/L); those with LDL-C levels from 100 to 129 mg/dl (2.5 to 3.3 mmol/L) at baseline or on lifestyle therapy should also be considered for drug therapy. NCEP=National Cholesterol Education Program; ATP III=Adult Treatment Panel III Adapted from Grundy SM et al Circulation 2004;110:227–239; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486–2497.

Rationale for Lower LDL-C Goals Both HPS and PROVE IT suggest that additional benefit may be obtained by reducing LDL-C levels to substantially less than 100 mg/dl (2.5 mmol/L) Recent trials indicate that for every 1% reduction in LDL-C level, the relative risk for major CHD events is reduced by approximately 1% No threshold below which lower LDL-C concentrations provide no further benefit Data from both HPS11 and PROVE IT12 suggest that reducing LDL-C to levels that are substantially below 100 mg/dl (2.5 mmol/L) may be associated with additional benefits: In HPS, reducing LDL-C from <116 to <77 mg/dl (<3.0 to <2.0 mmol/L) decreased vascular risk by approximately 25%. In PROVE IT, reducing median LDL-C to 62 mg/dl (1.6 mmol/L) instead of 95 mg/dl (2.5 mmol/L) reduced the combined endpoint (death from any cause/major cardiovascular event) by 16% (p=0.005). Based on data from clinical trials, it is estimated that for every 1% reduction in LDL-C levels, the relative risk for major CHD events is reduced by approximately 1%.8 This may be true even when LDL-C levels are <100 mg/dl (2.5 mmol/L). In fact, there is no definite threshold beyond which lower LDL-C levels are no longer associated with reduced cardiovascular risk.9,13,14 HPS=Heart Protection Study; PROVE-IT=Pravastatin or Atorvastatin Evaluation and Infection Therapy Adapted from Grundy SM et al Circulation 2004;110:227–239; HPS Study Group Lancet 2002;360:7–22; Cannon CP et al N Engl J Med 2004;350:1494–1502; O’Keefe JH et al J Am Coll Cardiol 2004;43:2142–2146; Stamler J et al JAMA 2000;284:311–318; Chen Z et al BMJ 1991;303:276–282.

Lower LDL-C Reduces Risk for CHD 3.7 2.9 –30% CHD risk 2.2 –30 mg/dl Relative risk for CHD (log scale) 1.7 The log-linear relationship between LDL-C levels and the relative risk for CHD is consistent with a large body of epidemiological data and the available clinical trial data of lipid-lowering therapy. These data suggest that for every 30 mg/dl (0.8 mmol/L) change in LDL-C, the relative risk for CHD is correspondingly changed by about 30%, (assuming the relative risk is 1.0 for an LDL-C of 40 mg/dl [1.0 mmol/L]).8 1.3 1 40 70 100 130 160 190 LDL-C (mg/dl) Adapted from Grundy SM et al Circulation 2004;110:227–239.

Current Treatment Often Fails to Achieve LDL-C Goals Proportions of patients achieving NCEP ATP II target LDL-C in L-TAP n=861 Low risk* (p=0.001) High risk** (p<0.001) CHD (p=0.004) All patients (p<0.004) n=1924 Drug therapy n=1352 n=4137 According to the Lipid Assessment Treatment Project (L-TAP) and phase 2 of the third National Health and Nutrition Examination Survey (NHANES III), many individuals do not meet NCEP LDL-C goals.15,16 In L-TAP,16 which included 4888 patients with dyslipidemia who were receiving lipid-lowering therapy, only 39% of patients in the drug therapy group (n=4137) achieved NCEP-specified LDL-C target levels. The percentage of patients who reached treatment goals17 was 68% among low-risk patients (fewer than two risk factors; goal of <160 mg/dl [<4.1 mmol/L]), 37% among high-risk patients (two or more risk factors; goal of <130 mg/dl [3.4 mmol/L]), and 18% among patients with CHD (goal of 100 mg/dl [2.5 mmol/L]). Thus, in many patients, lipid-lowering therapy does not achieve target LDL-C levels. 10 20 30 40 50 60 70 Patient success (%) Note: p values based on univariate analysis comparing success rates among patients who did and did not receive lipid-lowering drug therapy. *Fewer than two CHD risk factors **Two or more CHD risk factors Adapted from Pearson TA et al Arch Intern Med 2000;160:459–467.

EUROASPIRE II: Only 51% of Patients on Lipid-Lowering Therapy Achieved Goal* BEL/GHE 39 CZE/PP 31 FIN/KUO 70 FRA/LLRT 44 GER/MUNS 41 GRE/ATCI 42 HUN/BUD 48 IRE/DUB 55 Center ITA/TV 49 NET/ROT 66 POL/CRA 49 SLO/LJU 41 The second European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE II) survey was conducted in 15 European countries to provide systematic information on patient management for cardiovascular disease. Among patients using lipid-lowering medication, a total of 51% reached their total cholesterol goal at interview. The values ranged from a low of 31% to a high of 70%.18 SPA/BAR 52 SWE/MAL 65 UK/HL 54 All 51 20 40 60 80 100 % Patients *Total cholesterol <5 mmol/L (190 mg/dl) Adapted from EUROASPIRE II Study Group Eur Heart J 2001;22:554–572.

% Patients not reaching goal Percentage of Patients Not Reaching Goal with Starting Dose and after First Dose Adjustment Initial dose First dose adjustment 99 100 90 90 83 78 80 68 69 66 61 60 47 % Patients not reaching goal 40 Although statins lower plasma LDL-C levels, many patients do not achieve treatment goals, even at high doses.19 In one randomized, 54-week study of statin therapy in 318 patients with atherosclerosis, 66% of all patients failed to reach NCEP ATP II target LDL-C levels after the first dose adjustment. In addition, the first dose adjustment of statins above starting dose, which typically provides only an additional 6% LDL-C reduction, only brought an additional 17% of patients to goal.20-22 20 Atorvastatin (n=78) Simvastatin (n=76) Lovastatin (n=78) Fluvastatin (n=76) Overall (n=308) Adapted from Brown AS J Am Coll Cardiol 1998;32:665–672.

The New “Lower Is Better” Approach Requires More Intensive Therapy LDL-C of 100 mg/dl (2.5 mmol/L) was a minimal goal of treatment in high-risk patients in NCEP ATP III Standard doses of statins achieve LDL-C <100 mg/dl (2.5 mmol/L) in little more than half of high-risk patients In high-risk patients who require more LDL-C lowering than a standard statin dose provides, potential options include Increase to high-dose statin Coadminister another lipid-lowering drug, such as ezetimibe In establishing the LDL-C goal at <100 mg/dl (2.5 mmol/L), ATP III guidelines implicitly recognized 100 mg/dl as a minimum goal of treatment and not the maximum level of clinical benefit.8 Lipid-lowering therapy with standard statin doses will achieve LDL-C <100 mg/dl (2.5 mmol/L) in little more than half of high-risk patients. In patients who are receiving a standard statin dose but require greater LDL-C reduction, possible options for more efficacy include high-dose statin therapy or coadministering another LDL-C–lowering drug such as ezetimibe.8 The following slides evaluate the benefit of both options. Adapted from Grundy SM et al Circulation 2004;110:227–239.

Limitations in Efficacy of LDL-C–Lowering Therapy ATP III established a minimal goal of 100 mg/dl (2.5 mmol/L) Limit of efficacy supported by then available data Practical limit achievable by standard statin therapy ATP III acknowledged the “Rule of 6” limitation of statins For every doubling of the statin dose, LDL-C is lowered only by another 6% –6% –6% –6% Statin 10 mg 20 mg 40 mg 80 mg ATP III established an LDL-C goal of <100 mg/dl (2.5 mmol/L) because that goal was as low as could be supported by the clinical trials conducted up to that time. A goal of <100 mg/dl (2.5 mmol/L) was also considered the practical limit that could be achieved with standard statin therapy.8 For example, the ATP III report referred to the limitation of statin therapy recognized in the Rule of 6: each time the dose of a statin is doubled, LDL-C is reduced by only another 6%.21-23 In view of the need for better lipid-lowering therapy to achieve the lower goals now recommended, it has been suggested that combination therapy with agents such as ezetimibe plus a statin is an effective approach to reach goals.9 Ezetimibe coadministered with a statin provides innovative dual inhibition of cholesterol absorption from the intestine (ezetimibe) and cholesterol synthesis in the liver (statin).24 The result is greater lipid lowering versus the statin alone.24 10 20 30 40 50 60 % Reduction in LDL-C Adapted from Grundy SM et al J Am Coll Cardiol 2004;43:2142–2146; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Circulation 2002;106:3143–3421; Knopp RH N Engl J Med 1999;341:498–509; Stein E Eur Heart J Suppl 2001;3(Suppl E):E11–E16.

Dual Inhibition for Greater Efficacy There are two main sources of cholesterol: biosynthesis of cholesterol from the liver and extrahepatic tissues, and absorption of cholesterol in the intestines. The cholesterol pool in the intestines is composed of both dietary and biliary cholesterol, with the biliary cholesterol source being the major contributor.25 Approximately 50% of this intestinal cholesterol pool is absorbed by the intestines and recirculated through the body, whereas the remainder is excreted through the feces.26 Coadministration of ezetimibe with a statin achieves dual inhibition of two sources of cholesterol.19,24 On the one hand, ezetimibe inhibits intestinal absorption of dietary and biliary cholesterol, resulting in decreased delivery of cholesterol to the liver.27 On the other hand, statins inhibit cholesterol biosynthesis.28 Adapted from Shepherd J Eur Heart J Supple 2001;3(Suppl E):E2–E5; Bay H Expert Opin Invest Drugs 2002;11:1587–1604.

Conclusions Elevated serum cholesterol is associated with an increased risk of cardiovascular morbidity and mortality. Results from landmark clinical studies suggest that the risk of cardiac endpoints decreases as LDL-C levels decrease. Many patients need more intensive LDL-C–lowering therapy, according to the clinical trial evidence that “Lower Is Better.” Standard doses of statins may not be sufficient to achieve LDL-C levels <70 mg/dl (1.8 mmol/L). Dual inhibition of two sources of cholesterol via coadministration of ezetimibe with a statin provides greater efficacy than statin therapy alone to get patients to a lower LDL-C goal. Epidemiologic studies reveal that elevated serum cholesterol is associated with an increased risk of cardiovascular morbidity and mortality.1-4 Moreover, as cholesterol levels decrease, the risk of cardiac endpoints decreases.29-32 However, based on the evidence that lower is better, it is apparent that growing numbers of patients require more intensive lipid-lowering therapy.9 Because standard doses of statins provide a 30% to 40% reduction in LDL-C levels,8 a statin alone may not be sufficient to achieve optimal LDL-C goals (<70 mg/dl [1.8 mmol/L]) in patients with CHD and/or diabetes. Dual inhibition of two sources of cholesterol provides greater LDL-C lowering versus a statin alone24 and provides an effective approach that is consistent with the new “lower is better” treatment paradigm. Adapted from Kannel WB Am J Cardiol 1995;76:69C–77C; Anderson KM et al JAMA 1987;257:2176–2180; Kannel WB et al Ann Intern Med 1971;74:1–12; Neaton JD et al Arch Intern Med 1992;152:1490–1500; Lipid Research Clinics Program JAMA 1984;251:351–364; Scandinavian Simvastatin Survival Study Group Lancet 1994;344:1383–1389; Shepherd J et al N Engl J Med 1995;333:1301–1307; Sacks FM et al N Engl J Med 1996;335:1001–1009.

References Please see notes page. References Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol 1995;76:69C–77C. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 Years of follow-up from the Framingham Study. JAMA 1987;257:2176–2180. Kannel WB, Castelli WP, Gordon T et al. Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham Study. Ann Intern Med 1971;74:1–12. Neaton JD, Blackburn H, Jacobs D et al. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Arch Intern Med 1992;152:1490–1500. Davies MJ. Pathology of atherosclerosis. In: Alexander RW, et al, eds. Hurst's The Heart, Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1161–1173. Russ R. Factors influencing atherogenesis. In Alexander RW et al, eds. Hurst's The Heart, Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1139–1159. DeBacker C, Ambrosioni E, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003;24:1601–1610. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227–239. O’Keefe JH, Cordian L, Harris W et al. Optimal low-density lipoprotein is 50 to 70 mg/dl. Lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142–2146. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001;285:2486–2497. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7–22. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1494–1502. Stamler J, Daviglus ML, Garside DB et al. Relationship of baseline serum cholesterol levels in three large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA 2000;284:311–318. Chen Z, Peto R, Collins R et al. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ 1991;303:276–282. Hoerger TJ, Bala MV, Bray JW et al. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults. Am J Cardiol 1998;82:61–65. Pearson TA, Laurora I, Chu H et al. The Lipid Treatment Assessment project (L-TAP): A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459–467. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;69:3015–3023. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Eur Heart J 2001;22:554–572. Leitersdorf E. Cholesterol absorption inhibition: Filling an unmet need in lipid-lowering management. Eur Heart J Suppl 2001;3(Suppl E):E17–E23. Brown AS, Bakker-Arkema RG, Yellen L et al. Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin. J Am Coll Cardiol 1998;32:665–672. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498–509. Stein E. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J Suppl 2001;3(Suppl E):E11–E16. References Please see notes page.

References (continued) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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). (Final Report) Circulation 2002;106:3143–3421. Summary of Product Characteristics, EZETROLTM, MSP. Shepherd J. The role of exogenous pathway in hypercholesterolaemia. Eur Soc Cardiol 2001; 3(Suppl E):E3–E5. Bays H. Ezetimibe. Expert Opin Invest Drugs 2002;11:1587–1604. Miettinen TA. Cholesterol absorption inhibition: A strategy for cholesterol-lowering therapy. Int J Clin Pract 2001;55(10):710–716. Ginsberg HN, Goldberg IJ. Disorders of lipoprotein metabolism. In: Fauci AS et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138–2149. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351–364. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study Group (4S). Lancet 1994;344:1383–1389. Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301–1307. Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med 1996;335:1001–1009. References (continued) Please see notes page.

Managing Cholesterol: Achieving Lower LDL-C Levels Before prescribing, please consult the manufacturers’ prescribing information. MSP does not recommend the use of any product in any different manner than as described in the prescribing information. Before prescribing, please consult the manufacturers’ prescribing information. MSP does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2004 MSP Singapore Company, LLC. All rights reserved. 8-06 EZT 2004-W-6167-SS Printed in USA. VISIT US ON THE WORLD WIDE WEB at http://www.ezetrol.com Copyright © 2004 MSP Singapore Company, LLC. All rights reserved. 8-06 EZT 2004-W-6167-SS Printed in USA. VISIT US ON THE WORLD WIDE WEB AT http://www.ezetrol.com