Historical Perspectives on Hypercholesterolemia

The importance of hypercholesterolemia in the development of atherosclerosis can be traced historically as a medical controversy, as atherosclerosis was considered an inevitable part of aging. Studies on rabbits demonstrating the impact of high-cholesterol diets on atherogenesis, published in 1913 by Anitschkow and Chalatov, substantiated the role of hypercholesterolemia, yet it took a decade of research to confirm that the findings from experimental atherosclerosis in animals could be extrapolated to humans.

The Framingham Heart Study and other prospective epidemiologic investigations demonstrated that risk for myocardial infarction, stroke, and death was proportional to serum cholesterol levels. In the Seven Countries Study, a direct relationship was found between serum cholesterol and risk for CHD among 12,763 middle-aged men. This relationship has been confirmed and extended in cohorts from 26 nations in the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study. The Ni-Hon-San study evaluated the impact of migration and progressive westernization of the diet among Japanese men residing in Nippon, Japan, or in Honolulu and San Francisco. As the intake of animal fat increased, serum cholesterol and risk for CHD mortality both increased. In the Multiple Risk Factor Intervention Trial (a cohort of 356,222 men), there was a clear gradient of continuously rising risk for CVD as serum cholesterol levels increased. Whereas the majority of total cholesterol is composed of LDL-C in most patients, it was important to evaluate whether LDL-C is an independent predictor of CHD. The Cooperative Lipoprotein Phenotyping study, the Atherosclerosis Risk in Communities study, and the Framingham study all demonstrated a direct and independent relationship between LDL-C and risk for cardiovascular morbidity and mortality. These relationships between total cholesterol and LDL-C and risk for CVD are remarkably consistent in populations studied throughout the world.

Acceptance of the lipid hypothesis that dyslipidemia is a causative factor in the development of atherosclerosis and CHD did not begin until the early 1960s, when research findings as well as the release of the American Heart Association’s recommendation for dietary modification as a first step toward implementation of a cholesterol-lowering strategy refocused attention on hypercholesterolemia. Advances in knowledge that ultimately validated the lipid hypothesis including understanding of the pathogenesis of atherosclerosis, large-scale clinical trial results including the Lipid Research Clinics Coronary Primary Prevention Trial, establishment of the National Cholesterol Education Program, and development and use of statins all led to confirmation of the role of dyslipidemia in the development of CHD.

Lipoprotein Metabolism

Cholesterol derived from both biliary and dietary sources is transported into jejunal enterocytes from the intestinal lumen by a sterol translocase known as Niemann-Pick C1-like 1 protein. Cholesterol, triglycerides, and phospholipids are packaged together with apoprotein B48 to form chylomicrons. Chylomicrons enter the enteric lymphatic system and are secreted into the central circulation through the lymphatic duct. The triglycerides in chylomicrons can be hydrolyzed by lipoprotein lipase in serum, yielding chylomicron remnant particles. Both chylomicrons and chylomicron remnants are taken up by hepatocytes. Intrahepatic cholesterol and lipids can be repackaged with apoprotein B100 into very-low-density lipoproteins (VLDL) and secreted into the central circulation.

The triglycerides in VLDL particles are hydrolyzed by lipoprotein lipase to yield, in sequence, intermediate-density lipoproteins (IDL) and then low-density lipoproteins (LDL). LDL particles tend to be highly enriched with cholesterol. All of the apo B100–containing lipoproteins are atherogenic. The sum of all atherogenic lipoproteins (VLDL + IDL + LDL) is defined as non–high-density lipoprotein (non-HDL). Non-HDL is a fairly sensitive measure of the total atherogenic lipoprotein burden in serum. LDL particles can be taken up into arterial walls. Alternatively, LDL particles are cleared from serum by the LDL receptor (LDLR) and LDLR-related protein expressed on the surface of hepatocytes. The cholesterol in LDL particles can then be shunted toward bile acid formation (rate-limiting step catalyzed by 7α-hydroxylase), it can be secreted into bile, or it can be repackaged into VLDL.

In patients with loss-of-function mutations in lipoprotein lipase, serum VLDL and triglyceride levels tend to be elevated. This impairs the conversion of VLDL into smaller, triglyceride-depleted lipoproteins. With this excess availability of triglyceride in VLDL, cholesteryl ester transfer protein catalyzes a 1 : 1 stoichiometric exchange for cholesterol between VLDL and LDL. This leads to progressive enrichment of the LDL particles with triglyceride, rendering them more vulnerable to lipolysis by the enzyme hepatic lipase. Hepatic lipase converts large buoyant LDL particles into smaller, denser and more numerous particles. Smaller LDL particles also tend to be more atherogenic: (1) biophysically, they can gain access into the subendothelial space more easily because they are smaller; (2) they are more easily oxidized than their larger counterparts; and (3) they have a lower affinity for the LDLR and hence reduced systemic clearance.

Some patients have a genetic predisposition to elevated serum levels of LDL-C. Hereditary hypercholesterolemias are frequently associated with premature multivessel coronary artery disease (CAD). Patients with familial hypercholesterolemia harbor a variety of mutations (these are indexed at www.ucl.ac.uk/fh/ ) in the gene for LDLR, resulting in reduced capacity for LDL clearance from serum. Heterozygotes often present with serum LDL-C of 250 to 350 mg/dL. Homozygotes can have LDL-C levels of 500 mg/dL or more and usually require LDL apheresis to control their serum levels of this lipoprotein.

Loss-of-function mutations in cholesterol 7α-hydroxylase are also associated with elevations in LDL-C and decreased bile acid biosynthesis. Patients with familial defective apo B100 have impaired capacity for LDL-C clearance secondary to polymorphisms in apo B100 (henceforth apo B), which reduce the affinity of this apoprotein for the LDLR. Another fascinating group of mutations linked to hypercholesterolemia localizes to the gene coding for the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9). This enzyme modulates the activity of the LDLR. Gain-of-function mutations lead to increased degradation of the LDLR, whereas loss-of-function mutations allow increased expression of the LDLR; these mutations are associated with increased and decreased risk for CAD, respectively.

Low-Density Lipoprotein Cholesterol and Atherosclerotic Vascular Disease

Atherogenesis is a complex disease whose etiology and progression are strongly influenced by the severity of a large number of risk factors. LDL is an apo B–containing particle ( Fig. 14-1 ) and as such contributes to high levels of atherogenic lipoproteins ( Fig. 14-2 ). In addition, low serum levels of high-density lipoprotein cholesterol (HDL-C), hypertension, impairments in glucose metabolism, heightened systemic inflammatory tone, cigarette smoking, and other risk factors induce progressive arterial wall injury. An early event in atherogenesis is the development of endothelial cell dysfunction. Under normal physiologic conditions, the endothelium serves as an efficient barrier between blood and the arterial wall. The endothelium produces nitric oxide (a potent vasodilator) and maintains an antithrombogenic surface by producing prostacyclin and tissue plasminogen activator. As the endothelium becomes stressed in response to risk factors, it becomes dysfunctional, resulting in a maladaptive inflammatory response ( Fig. 14-3 ).

The structure of low-density lipoprotein. Nuclear magnetic resonance (NMR) spectroscopy of the LDL surface structure has enabled identification of a surface monolayer of phospholipids and free cholesterol and a hydrophobic core of triglyceride and cholesteryl esters. Phosphatidylcholine and sphingomyelin are tightly bound to apo B and therefore NMR invisible.

(From Murphy HC, Burns SP, White JJ, et al: Investigation of human low density lipoprotein by H nuclear magnetic resonance spectroscopy: mobility of phosphatidylcholine and sphingomyelin headgroups characterizes the surface layer . Biochemistry 39:9763, 2000. Reproduced with permission.)

The atherogenicity of apo B–containing lipoproteins is related to their diameter and density. Chylomicrons are the largest lipoproteins and are produced by jejunal enterocytes. VLDL is secreted by the liver and progressively converted into IDL and then LDL by the activity of serum lipases. Atherogenic lipoproteins include chylomicron remnants, VLDL, VLDL remnants, IDL, and LDL particles. Remnants represent particles that are incompletely hydrolyzed. Lipoprotein(a) [Lp(a)] is a variant of LDL that is also atherogenic. Dyslipoproteinemia with low concentrations of HDL-C and elevated serum triglycerides with increased concentrations of small, dense LDL particles is associated with a particularly high incidence of coronary vascular disease.

(From Segrest JP, Garber DW, Brouillette CG, et al: The amphipathic alpha helix: a multifunctional structural motif in plasma apolipoproteins . Adv Protein Chem 45:303, 1994. Reproduced with permission.)

The continuum of developing atherosclerotic disease over a lifetime. Atherogenesis involves a complex interplay between inflammation, apo B–containing lipoproteins, and histologic components of blood vessel walls. Atherogenesis is potentiated by apo B lipoprotein retention by subendothelial extracellular matrix molecules (e.g., proteoglycans), which initiates a series of biologic reactions that develop into a maladaptive inflammatory response. As depicted in this figure, early response to lipoprotein retention begins in the preteen years and continues to accelerate in the 20s and beyond. Green arrows indicate progression; orange arrows indicate the potential for regression. The earliest stages are the most easily reversible by lowering of plasma apo B lipoproteins (large orange arrows). The complexity of advanced lesions, including accelerated lipoprotein retention, renders them less reversible (small orange arrows) as the severity of atherosclerosis advances.

(From Tabas I, Williams KJ, Borén J: Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications . Circulation 116:1832, 2007. Reproduced with permission.)

Endothelial dysfunction is highly associated with atherosclerosis. Dysfunctional endothelial cells increase expression of adhesion molecules, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and different types of selectins. These cell surface receptors interact with counterreceptors on the surface of inflammatory white blood cells, such as monocytes, T cells, and mast cells. These receptor-counterreceptor interactions facilitate the binding, rolling, and stable arrest of these cells along the endothelial surface.

Under normal conditions, endothelial cells maintain appropriate intercellular contacts through gap junctions, which allow these cells to communicate with one another and to maintain tight contacts among themselves. These gap junctions also become dysfunctional and allow the transmigration of inflammatory white cells into the subendothelial space by following a gradient of monocyte chemoattractant protein 1 down into the subendothelial space. Once they are in the subendothelial space, monocytes can transform into resident macrophages in response to macrophage colony-stimulating factor. As gap junctions and endothelial cells become more dysfunctional, their barrier function becomes progressively more compromised, allowing greater influx of atherogenic lipoproteins into the arterial wall. Lipoproteins can be trapped in the vessel wall by intercellular matrix proteins such as proteoglycans, fibronectin, and vitronectin, among others.

In the subendothelial space, LDL particles can be oxidized by such enzymes as myeloperoxidase, 5′-lipoxygenase, lipoprotein-associated phospholipase A ₂ , NADPH oxidase, and others. T cells can present oxidized LDL to macrophages. The macrophages are activated and increase expression of families of scavenging receptors (e.g., CD36, scavenging receptor A). Scavenging receptors take up oxidized LDL, leading to foam cell formation. Foam cells can coalesce to form fatty streaks, and fatty streaks are the progenitors to the formation of atherosclerotic plaque. Macrophages can maintain a certain level of lipid homeostasis as long as there is adequate availability of HDL particles. HDL particles interact with macrophages and foam cells to promote the mobilization and externalization of intracellular lipid.

If there is inadequate availability of HDL in the face of excess LDL in the extracellular milieu, there is continued net accumulation of lipid by the macrophage, ultimately resulting in apoptosis or programmed cell death. As cellular debris and more lipid accumulate, and as the capacity to phagocytose and clear this debris is progressively more compromised, the volume of the atherosclerotic plaque increases and develops a lipid core ( Fig. 14-4 ).

The role of macrophage apoptosis and atherosclerotic lesion progression. In the setting of endothelial dysfunction, atherogenic lipoproteins enter the subendothelial space, where they can aggregate and become oxidatively modified by a variety of enzymes. Oxidized LDL induces the upregulation of scavenging receptors on the surface of macrophages resident in the subendothelial space. Progressive macrophage lipid uptake results in the formation of foam cells. There is a limit to lipid uptake. Excess lipid is toxic to the cell and can result in apoptosis. Early in the course of atherogenesis, apoptotic debris is phagocytosed by other macrophages, a process that can modulate the cellularity and rate of progression of an atherosclerotic lesion. As depicted in this figure, in late lesions (right), macrophages also undergo apoptosis but are no longer cleared as efficiently. This leads to the formation of the necrotic core, which promotes inflammation, plaque instability, and acute lesional thrombosis secondary to loss of architectural integrity and rupture.

(From Tabas I: Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency . Arterioscler Thromb Vasc Biol 25:2255, 2005. Reproduced with permission.)

National Cholesterol Education Program Guidelines

A high serum level of LDL-C is an established risk factor for the development of CHD. For this reason, LDL-C reduction is the primary goal of therapy in patients with dyslipidemia. This recommendation is emphasized by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the American Heart Association/American College of Cardiology guidelines for secondary prevention of CHD, and the European Guidelines on Cardiovascular Disease Prevention. NCEP ATP III defines an LDL-C of <100 mg/dL as optimal. Among patients in the primary prevention setting, it is recommended that 10-year projected risk for sustaining a CHD-related event be estimated with the Framingham risk score. Non–HDL-C is a surrogate measure of total atherogenic lipoprotein burden in serum and represents the sum of VLDL, IDL, LDL, and lipoprotein(a) as well as remnant particles. It is calculated by subtracting HDL-C from total cholesterol. Among patients with baseline triglycerides >200 mg/dL, non–HDL-C is the secondary target of therapy. Non–HDL-C has been shown to be a better predictor than LDL-C of risk for cardiovascular events in both men and women. Goals for both LDL-C and non–HDL-C are risk stratified, and the goals for both of these lipoprotein fractions decrease as risk increases ( Table 14-1 ). Among patients with CAD or a CAD risk equivalent (diabetes mellitus, abdominal aortic aneurysm, peripheral arterial disease, symptomatic carotid artery disease, or 10-year Framingham risk score >20%), it is recommended that patients achieve LDL-C <100 mg/dL and non–HDL-C <130 mg/dL. Among patients defined as very high risk (CAD complicated by a recent acute coronary syndrome, diabetes mellitus, or multiple poorly controlled risk factors), it is a therapeutic option to reduce LDL-C below 70 mg/dL and non–HDL-C below 100 mg/dL. In a more recent advisory statement from the American Heart Association, it was recommended that an LDL-C target of <70 mg/dL be an option for any patient with established CAD.

Evidence from clinical trials has established the merits of aggressive LDL-C risk reduction therapies for patients with CHD and other atherosclerotic vascular diseases in improving survival, reducing recurrent coronary events and need for revascularization, and improving quality of life. Data from studies including the Framingham Heart Study, Multiple Risk Factor Intervention Trial, and the Lipid Research Clinics trial established the direct relationship between levels of LDL-C and the rate of development of CHD in asymptomatic patients. Other studies including the Heart Protection Study (HPS), the Treating to New Targets (TNT) trial, and the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) established the benefits of aggressive statin therapy in secondary prevention.

However, despite the substantial body of research establishing the benefit of LDL-C reduction, only a small percentage of patients with CHD are reaching lipid goals. In the National Cholesterol Education Program (NCEP) Evaluation Project Utilizing Novel E-Technology (NEPTUNE) survey of physicians regarding the care of 4885 patients with dyslipidemia, 75% of patients with CHD met the definition of “very high risk,” yet only 18% had an LDL-C level <70 mg/dL and only 4% had an LDL-C level <70 mg/dL and a non–HDL-C level <100 mg/dL when triglycerides were >200 mg/dL.

In a retrospective study from a national outpatient electronic medical record data base of 10,637 patients with a diagnosis of atherosclerosis, 57% of the 4067 patients with a baseline LDL-C ≥100 mg/dL were not prescribed statin treatment after diagnosis. Among patients receiving statin or any other cholesterol-lowering therapy after diagnosis who had baseline and follow-up LDL-C values (n = 682), 43% had a post-diagnosis LDL-C ≥100 mg/dL. The proportion of patients with LDL-C <100 mg/dL at baseline was 46.8%, and 12% of patients had LDL-C cholesterol <70 mg/dL. Less than 5% of patients were currently receiving hypercholesterolemia therapy at the time of diagnosis, and 25% had hypercholesterolemia treatment after their condition had been diagnosed. Among patients receiving hypercholesterolemia therapy, LDL-C levels in 12 months after diagnosis of atherosclerosis were similar to levels at the time of diagnosis. These data substantiate the need for more aggressive statin therapy and implementation of combination therapy to reduce residual risk for cardiovascular events and highlight the importance of monitoring and managing lipid levels in patients with atherosclerosis.

Metabolic Syndrome and Cardiometabolic Risk

In the United States, it is estimated that 35% to 40% of adults have the metabolic syndrome, a cluster of lipid and nonlipid disorders. The metabolic syndrome is characterized by a set of five risk factors: abdominal obesity; elevated blood pressure, triglycerides, and fasting glucose concentration; and low HDL-C ( Table 14-2 ). The presence of any three or more of the following risk factors in a single individual is diagnostic of the metabolic syndrome according to the revised ATP III/American Heart Association/National Heart, Lung, and Blood Institute definition : triglycerides ≥150 mg/dL, HDL-C <40 mg/dL in men and ≤50 mg/dL in women, serum glucose concentration ≥100 mg/dL, blood pressure ≥130/85 mm Hg (can be either systolic or diastolic or on therapy with antihypertensive medication), and waist circumference ≥40 inches in men and ≥35 inches in women. Metabolic syndrome develops secondary to the effects of insulin resistance and obesity. Although the metabolic syndrome significantly increases risk for atherosclerotic disease and diabetes mellitus, it is not defined as a CAD risk equivalent.

The primary goal of clinical management of the metabolic syndrome is to reduce CHD risk and diabetes mellitus. This focuses on intensified LDL-C lowering and modification of the underlying risk factors including obesity, physical inactivity, and other risk factors associated with the metabolic syndrome, such as blood pressure control ( Table 14-3 ). The NCEP ATP III guidelines emphasize the modification of metabolic syndrome risk factors through lifestyle changes, especially because both weight loss and exercise reduce insulin resistance and favorably modify risk factors for the metabolic syndrome.

Therapeutic Lifestyle Changes

A number of preventive strategies can be used to target reductions in LDL-C to decrease the burden of CHD. The NCEP ATP III guidelines identify therapeutic lifestyle changes (TLC) as the initial intervention for lowering of LDL-C with a focus on smoking cessation, weight loss, total calories, physical activity to maintain desirable weight, and moderate alcohol intake (see Table 14-3 ). The NCEP guidelines outline TLC as a multifaceted lifestyle approach for LDL-C lowering. The recommendations for TLC include a reduction in saturated fat intake to <7% of total calories and cholesterol to <200 mg/day, weight reduction, increased physical activity, therapeutic options to enhance LDL lowering such as the use of plant stanols or sterols (2 g/day), and increased viscous (soluble) fiber (10 to 25 g/day) to reduce cholesterol absorption. The aim of primary prevention is to reduce long-term risk (>10 years) as well as short-term risk (≤10 years). Whereas TLC is the basis of clinical primary prevention, pharmacologic therapy is often indicated in the management of elevated LDL-C to achieve risk-stratified target goals.

Statin Therapy

Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been the most widely used therapy for the treatment of dyslipidemia to reduce the risk of CHD. Statins are used to target the reduction of elevated LDL-C and to improve the lipid level profile. The statins are recognized as the first-line treatment of dyslipidemia. Statins are used to target the reduction of elevated LDL-C and to improve all components of the lipid level profile.

Data from the major statin trials including the Scandinavian Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE), HPS, Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), and TNT have established that LDL-C reduction correlates with cardiovascular event reduction in a linear fashion. The HPS, the largest statin trial, demonstrated the benefits of aggressive statin therapy with simvastatin 40 mg/day, with a 24% reduction in CVD events compared with placebo ( Table 14-4 ). The beneficial effects of LDL-C reduction were demonstrated even in patients with baseline LDL-C levels below 100 mg/dL and in persons with diabetes.

TABLE 14–4

Prospective Randomized Statin Trials in Both Primary and Secondary Prevention

Primary Prevention Studies
Study	Drug	Design	Outcomes
AFCAPS/TexCAPS	Lovastatin 20 to 40 mg/day versus placebo	6605 men and women	40% reduction in fatal and nonfatal MI; 37% reduction in first ACS; 33% reduction in coronary revascularizations; and unstable angina reduced by 32%
ASCOT	Atorvastatin 10 mg/day versus placebo	10,305 hypertensive men (n = 8463) and women (n = 1942) with treated high blood pressure and no previous CAD	36% reduction in total CHD/nonfatal MI; 27% reduction in fatal and nonfatal stroke; total coronary event reduced by 29%; fatal and nonfatal stroke reduced by 27%
CARDS	Atorvastatin 10 mg/day versus placebo	2838 patients with type 2 diabetes mellitus and 1 CHD risk factor	37% reduction of major cardiovascular events; 27% reduction of total mortality; 13.4% reduction of acute cardiovascular events; 36% reduction of acute coronary events; 48% reduction of stroke
Heart Protection Study	Simvastatin 40 mg/day versus placebo	20,536 high-risk individuals (previous CHD, other vascular disease, hypertension among men aged >65 years, or diabetes)	25% reduction in all-cause and coronary death rates and in strokes; need for revascularization reduced by 24%; fatal and nonfatal stroke reduced by 25%; nonfatal MI reduced by 38%; coronary mortality reduced by 18%; all-cause mortality reduced by 13%; cardiovascular event rate reduced by 24%
PROSPER	Pravastatin 40 mg/day versus placebo	5804 men (n = 2804) and women (n = 3000) aged 70 to 82 years	15% reduction in combined endpoint (fatal/nonfatal MI or stroke); 19% reduction in total/nonfatal CHD; no effect on stroke (but 25% reduction in TIA)
WOSCOPS	Pravachol therapy 40 mg/day versus placebo	6595 men	CHD death of nonfatal MI reduced by 31%; CVD death reduced by 32%; total mortality 22% reduction
Secondary Prevention Studies
Study	Drug	Design	Outcomes
4S	Simvastatin 20 mg/day versus placebo	4444 patients with angina pectoris or history of MI	Coronary mortality reduced by 42%; myocardial revascularization reduction of 37%; all-cause mortality reduced by 30%; nonfatal major coronary event reduced by 34%; fatal and nonfatal stroke reduced by 30%
AVERT	Atorvastatin 80 mg/day versus angioplasty + usual care	341 patients with stable CAD	36% reduction in ischemic event; delayed time to first ischemic event reduced by 36%
CARE	Pravastatin 40 mg/day versus placebo	3583 men and 576 women with history of MI	Death from CHD or nonfatal MI reduced by 24%; death from CHD reduced by 20%; nonfatal MI reduced by 23%; fatal MI reduced by 37%; CABG or PTCA reduced by 27%
IDEAL	Atorvastatin 80 mg/day versus simvastatin 20-40 mg/day	8888 men and women with CHD	Major cardiac events reduced by 13%; nonfatal MI reduced by 17%; revascularization reduced by 23%; peripheral arterial disease reduced by 24%
JUPITER	Rosuvastatin 20 mg/day versus placebo	17,802 men (>50 years) and women (>60 years) with no history of CAD or diabetes mellitus, entry LDL <130 mg/dL, and CRP >2.0 mg/L	44% reduction in primary endpoint of major coronary events; 65% reduction in nonfatal MI; 48% reduction in nonfatal stroke; 46% reduction in need for revascularization; 20% reduction in all-cause mortality
LIPID	Pravachol 40 mg/day versus placebo	9014 patients	Coronary mortality reduced by 24%; stroke reduced by 19%; fatal CHD or nonfatal MI reduced by 24%; fatal or nonfatal MI reduced by 29%
LIPS	Fluvastatin 40 mg/day versus placebo	1667 men and women aged 18-80 years after angioplasty for CAD	22% lower rate of major coronary events (e.g., cardiac deaths, nonfatal MI, or reintervention procedure)
MIRACL	Atorvastatin 80 mg/day versus placebo	3086 patients with ACS	Reduction in composite endpoint by 16%; ischemia reduced by 26%; stroke reduced by 50%
PROVE IT	Atorvastatin 80 mg/day versus pravastatin 40 mg/day	4162 patient with ACS	16% reduction of composite endpoint; 14% reduction in CHD death, MI, or revascularization; revascularizations reduced by 14%; unstable angina reduced by 29%
REVERSAL	Atorvastatin 80 mg/day versus pravastatin 40 mg/day	654 patients with CAD	Atheroma: atorvastatin −0.4%, pravastatin 2.7%, difference of −3.1%, P = 0.02
TNT	Atorvastatin 10 mg/day versus 80 mg/day	10,003 patients with CHD and LDL cholesterol 130-250 mg/dL	22% reduction in composite endpoint; MI reduced by 22%; stroke reduced by 25%

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