Pathophysiology, Diagnosis, and Management of Dyslipidemia

Pathophysiology, Diagnosis, and Management of Dyslipidemia Gerald T. Gau, MD, and R. Scott Wright, MD, FACC, FAHA, FESC Abstract: Atherosclerosis is a systemic diffuse disease that may manifest as an anglographically localized coronary, cerebral, mesenteric, renal, and/or peripheral arterial stenosis or as diffuse atherosclerosis. While relief of organ ischemia is frequently possible with percutaneous or surgical revascularization, this in itself does not alleviate the long-term risks of disease recurrence or modify the metabolic derangements that promote atherosclerosis. It is critically important to recognize the need for treatment of dyslipidemia and to institute necessary therapies. The complex role of lipoprotein abnormalities is well understood and the use of lipid-lowering agents (90% statins) is reviewed in both primary and secondary prevention. The clinical interaction with novel risk factors and the practical problems in patient management are discussed. (Curr Probl Cardiol 2006;31:445-486.)

Introduction he enhanced understanding of the pathophysiology of atherosclerosis and the introduction of statin drugs over the past decade have dramatically altered the management of atherosclerotic vascular disease. Statin drugs have surpassed all other classes of medicines in reducing the incidence of major adverse outcomes of death, heart attack, and stroke.1 The five major statin trials beginning with the Simvastatin

T

Disclosures: Gerald T. Gau, MD, Principle investigator in the COURAGE Trial and a member of the Executive Committee, was supported by the Department of Veterans Affairs Cooperative Studies Program, in collaboration with the Canadian government CIHR. R. Scott Wright, MD, received research support from Bayer, Bristol-Myers Squibb, Merck, and Johnson & Johnson and worked as a consultant for Pfizer and Merck-Schering Plough. Curr Probl Cardiol 2006;31:445-486. 0146-2806/$ – see front matter doi:10.1016/j.cpcardiol.2006.03.001

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FIG 1. Table listing currently available agents utilized to treat dyslipidemia.

Survival Study (4S), the West of Scotland Trial (WOSCOPS), the Cholesterol and Recurrent Events (CARE) Trial, Long-Term Intervention with Pravastatin in Ischemic Disease trial (LIPID), and the AFCAPS/ TEXCAPS all demonstrated improved survival, decreased cardiovascular disease, decreased cardiovascular events, and decreased need for intervention [angioplasty and coronary artery bypass grafting (CABG) surgery]. Current treatment paradigms for the prevention of coronary heart disease strongly suggest that initiation of therapy with 3-hydroxy-3methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (statins) is warranted for the attainment of low-density lipoprotein cholesterol (LDLc) goals.2 These statin drugs have been called “miracle drugs” and have become popular the world around.3 The focus of therapy has been LDLc reduction for the most part. Guidelines have been established around the world for drug therapy to lower dyslipidemia. These drugs have been said to be underutilized and new, more aggressive, goals have recently been suggested.4 We will discuss the basic pathophysiology of dyslipidemia and its role in atherosclerosis. We will review the role of established risk factors, novel risk factors, and other new diagnostic tools used in the diagnosis of atherosclerotic vascular disease. Effective lipid-lowering therapy is now widely available to all medical personnel and statin drugs are the most widely used (90%) (Fig 1). 446

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Worldwide, consumers spend 15 to 20 billion dollars annually for these agents with generally good results in coronary disease prevention. There are many nonstatin agents available that complement the effect of statins or target different pathways altogether, such that it should be rare in today’s environment to have a patient whose dyslipidemia cannot be adequately managed. We will focus on the treatment of dyslipidemia in patients with and without established coronary artery disease.

Pathophysiology of Dyslipidemia and Atherosclerosis The understanding of the role of dyslipidemia in atherosclerosis has slowly evolved over the past 30 years. From the 7 Countries Study, it was clear that cardiovascular disease mortality was highest in countries that had the highest cholesterol and LDLc levels and lowest in Greece (Mediterranean) and Asian populations.5 This focus on cholesterol and LDLc as a causative factor in atherosclerosis has pushed research and clinical trials which have demonstrated significant benefit with cholesterol and LDLc lowering. In the early understanding, the role of cholesterol was only one of the risk factors considered and documented by the Framingham Studies. It soon became clear that this process was complicated and affected by multiple cardiovascular risk factors including smoking, hypertension, diabetes, age, gender, triglycerides, and high-density lipoprotein cholesterol (HDLc). This mix of factors when present led to atherosclerotic plaque development. There was a definite interaction when more than one of these risk factors were abnormal. The Framingham risk assessment was constructed using these data and was used in early patient management. Atherosclerosis is a chronic inflammatory disorder in the vessel wall with monocytes (macrophages), T-lymphocytes, proliferation, and migration of smooth muscle cells, production of extracellular matrix, and neovascularization.6 There has been an explosion of data in the last two decades that has now created a new reality. We now understand the cellular, biochemical, genetic, enzymatic, and inflammatory processes that affect the vessel wall.7 The cellular and biochemical development of the atherosclerotic plaque has been clearly outlined and illustrated by Dr. Peter Libby.7 The role of the endothelium (the largest endocrine organ in our body) is central to this process. Normal endothelial function can be altered by traditional risk factor abnormalities. With altered endothelial function a cascade of events occur that cause plaque formation with subsequent inflammation, altered thrombosis, altered vessel tone, and biochemical Curr Probl Cardiol, July 2006

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FIG 2. This figure depicts the process of atherosclerosis and the role of inflammation in the progression. (Color version of figure is available online.)

interactions. Plaque enlargement leads to vascular shear stresses plaque fissure or rupture, platelet adhesion, and vessel thrombosis.8 The work of Dr. Valentin Fuster has clearly helped us to understand this clinical picture presenting as angina, unstable angina, and myocardial infarction.9 Macrophages became activated in the vessel wall and take in the LDLc leading to foam cell formation. These macrophages also secrete metalloproteinases that can weaken the plaque cap. They also secrete plateletderived growth factor (PDGF), which induces mitogenesis and promotes plaque neovascularization. Macrophages also elaborate cytokines, which stimulate smooth muscle cell and lymphocyte proliferation with enhanced inflammation. In the presence of plaque and altered endothelial function, there is decreased nitrous oxide production, decreased endothelial-derived relaxation factor, and enhanced platelet activation leading to thromboxane production, which promotes platelet aggregation and vasoconstriction. Platelets also secrete PDGF, which is a potent mitogen (Figs 2 and 3).10 This process is further complicated in the presence of lipoprotein(a) elevation and the presence of C-reactive protein stimulated by the ongoing inflammatory process.6 Cholesterol (LDL cholesterol) is a strong player in the process but not the only one and control of the multiple causes for this inflammatory process is necessary if we are to control this process. 448

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FIG 3. This figure depicts platelet deposition on an unstable plaque and the role of inflammation in the process. (Color version of figure is available online.)

Classification of Dyslipidemia Dyslipidemia is a heterogeneous disorder with multiple etiologies. The definition of dyslipidemia has undergone revision,11 and a practical clinical application of the current definitions is depicted in Fig 4. In western societies, the majority of dyslipidemia is secondary to lifestyle and dietary habits. Physiological LDLc is probably in the range of 50 to 70 mg/ml as determined by findings in non-westernized primitive societies where atherosclerosis is unknown.12 Thus, modern diet and lifestyle (tobacco use, obesity, high fat intake, sedentary activity) are probably the largest contributors to the current epidemic of atherosclerosis. There are primary causes of dyslipidemia (Fig 5) that occur rarely and demand the attention of a consulting lipidologist. There are many secondary causes of dyslipidemia that may exist in clinical practice (Fig 6) and should be addressed concurrently with initiation of pharmacotherapy. The great majority of cases encountered during the daily practice of medicine will be secondary etiologies of dyslipidemia. S. C. Smith: Low HDLc and hypertriglyceridemia along with hypertension, central obesity, and impaired fasting glucose are the five components of the metabolic syndrome, an increasingly common clustering of risk factors which Curr Probl Cardiol, July 2006

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FIG 4. Definitions of dyslipidemia.

is associated with increased risk of diabetes and cardiovascular disease. Recognition of this syndrome by the clinician and modification of patient dietary habits, exercise programs, along with appropriate medical therapy are high priorities in national programs to reduce the incidence of cardiovascular disease.

It is the rare patient who presents with an isolated pattern of dyslipidemia. Most patients will present with a mixed picture of dyslipidemia, such as an elevated LDLc in combination with a low HDLc or elevated triglycerides. In addition, may patients with dyslipidemia have multiple confounding medical issues such as diabetes or metabolic syndrome, obesity, hypertension and, on occasion, obstructive sleep apnea, all of which necessitate treatment. One can also encounter on a rare occasion the patient with an isolated low HDLc or isolated hypertriglyceridemia. The majority of patients can have significant success in managing their dyslipidemia with intensive dietary modification. Reductions in saturated fat and total caloric content will typically reduce LDLc values 10 to 15%, and even better in some situations. Plasma triglycerides can fall 20 to 40% once dietary changes are instituted. Weight loss can result in similar improvements in dyslipidemia. Initiation of a regular, vigorous exercise 450

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FIG 5. Primary mechanisms of dyslipidemia.

FIG 6. Secondary mechanisms of dyslipidemia.

program can raise HDLc values by 10 to 15% comparable to changes induced by pharmacological therapy yet without any of the potential side effects and economic costs of pharmacologic therapy. Diet therapy, while undoubtedly effective in the highly motivated individual, fails to achieve Curr Probl Cardiol, July 2006

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FIG 7. Pathways for cholesterol biosynthesis and prenylated protein formation.

goal LDLc levels in the majority of patients and often requires the addition of pharmacological therapies.

Pharmacological Treatment of Dyslipidemia Drug treatment of dyslipidemia is effective and has been demonstrated to reduce long-term cardiovascular risks.11 The first line of therapy in most patients should be a statin agent. However, many patients may suffer from mixed dyslipidemias and require combination pharmacotherapy. The approach to the pharmacological treatment of dyslipidemia should be tailored to correct as much of the total dyslipidemia as possible without inducing drug-related side effects.

Statin Agents Statin agents work through at least two mechanisms in patients with dyslipidemia. First, statins inhibit the enzyme responsible for the ratelimiting step of cholesterol biosynthesis, HMG-CoA reductase, and, thus, directly inhibit cholesterol biosynthesis (Fig 7).13 Second, statins promote 452

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FIG 8. Dose-dependent reductions in LDL cholesterol by statin agent.

LDL receptor upregulation on hepatocytes and, thus, promote the biochemical clearance of LDLc. Finally, recent work has suggested that statins can work by inhibiting the synthesis of prenylated proteins such as geranyl– geranyl pyrophosphate and farnesyl–farnesyl pyrophosphate, and by this inhibition, indirectly mediate intracellular processes that involve cell signal trafficking and protein synthesis.13 Blocking the production of phrenylated proteins stops the activation of certain regulatory proteins via prenylation (the addition of a specific carbon structure to a protein).13 These proteins are regulatory proteins such as Ras, Rac, and Rho, which promote cell maintenance, cell growth, and cell communication and attenuate apoptosis. Apoptosis caused by statins could reduce the enlargement of atherosclerotic plaques by regulating smooth muscle cell proliferation, which would be a positive benefit. This same process in skeletal muscle with statin use, however, could theoretically produce skeletal muscle damage observed with statins (see later discussion of myositis). The six commonly used statins (Fig 1) have varying crystallographic differences that may explain some of the potency difference. The different potency of the statins are shown as the dose of each agent sufficient to decrease cholesterol by 20%, as illustrated in Fig 8. Lovastatin and pravastatin are both about equal with about 10 mg achieving this effect. Zocor is about twice as potent and only 5 mg is needed for this. Atorvastatin and rosuvastatin are much more potent with rosuvastatin being significantly greater in its potency effect, requiring only a small Curr Probl Cardiol, July 2006

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FIG 9. Pharmacokinetic metabolism of various statin agents.

amount of this agent to produce a similar effect. Fluvastatin, on the other hand, requires 20 mg and is the least potent of all the statin agents. The statin pharmacogenetics can be seen in Fig 9. Hepatic metabolism utilizes the cytochrome P450 system and the 3A4 pathway for lovastatin, simvastatin, and atorvastatin. Fluvastatin uses the 2C9 and rosuvastatin uses 3A4, as well as the 2C9 pathway. Pravastatin does not require these pathways and, therefore, is metabolized differently than the other statins. The statins are all highly protein-bound with the exception of pravastatin, which is less so. They tend to be lipophilic with the exception of pravastatin and, to some degree, rosuvastatin, which are more hydrophilic. The significance of this has not been proven. Their half-life also varies differently with the statins and the more potent the statin the longer the half-life with 19-hour half-life for rosuvastatin and 14-hour half-life for atorvastatin as compared to 2-hour half-life for simvastatin. All of these characteristics lead to the different clinical potency of these agents. Statins typically lower LDLc 25 to 55% depending on the agent one chooses to utilize (Fig 10) lower total cholesterol similarly in magnitude to that observed with LDLc. Statins also raise HDLc by 5 to 15% and reduce plasma triglycerides 15 to 45%. The reduction in triglycerides is dose-related and also related to the baseline triglyceride values. Patients with higher baseline triglyceride levels have a greater lowering than ones with lower baseline values. The five major megatrials using statin drugs in high-risk patients were all large trials with 4000 to 9000 patients enrolled. These trials had both 454

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FIG 10. Relative risk reduction in total mortality by statin megatrial.

men and women enrolled with the exception of the West of Scotland (WOS) trial,14 which looked at 6595 men at high risk without prior heart attacks in primary prevention. These trials evaluated high-risk secondary prevention (4S with 4444 men and women),15 the CARE16 trial with 4159 men and women, and the LIPID17 trial with 9014 men and women, and high-risk primary prevention (WOS and the AFCAPS/TexCAPS trial),18 a trial of 6,605 men and women with normal cholesterol values and lower HDL cholesterol values. The results of these trials are summarized in Fig 11 in the order in which they appeared in publication. All of these trials showed improved patient survival and decreased coronary death, decreased coronary events, and decreased need for coronary intervention with percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. All five of these trials support the need for aggressive treatment in primary and secondary prevention consistent with the NCEP Adult Treatment Panel III (ATP-III) Guidelines. We know from the statin trials that those over 65 years of age, as well as those under 65 years of age, showed similar benefit.19 Both men and women derived equal benefit from these trials. Diabetic populations seem to have a much greater drop in event rate primarily because of the higher baseline event rates. It is clear that secondary prevention with statin use is proven and therapy should be aggressively used in these patients without delay. There are strong treatment guidelines that have been established and these will be reviewed. In primary prevention, there is a Curr Probl Cardiol, July 2006

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FIG 11. Currently recommended management goals of lipid-lowering therapy.

similar potential for therapy but there is still some controversy over the variable risk and whom to treat. It is these elements that have been actively addressed by the ATP-III guidelines.11 These ATP-III guidelines use a risk assessment in defining the need for lipid management. They divided patients into three risk factor groups: first, those with coronary disease and coronary disease risk equivalents; second, those with greater than two risk factors for coronary disease; and third, those with zero to one risk factors. The category of coronary disease and coronary disease risk equivalents includes people with established coronary artery disease, people with peripheral arterial atherosclerosis, abdominal aortic aneurysm, or symptomatic carotid disease, diabetics,20 and people with multiple risk factors that confer a 10-year risk of greater than 20% coronary risk by the new Framingham Heart Risk Score calculation. In the ATP-III primary prevention guidelines, risk factors are counted first. In those who have multiple (greater than two) risk factors, the Framingham risk calculator is used to determine the 10-year cardiovascular risk. The Framingham risk calculator has been readjusted to more accurately calculate those that have a 10-year risk of greater than 20%, those who have risk between 10 and 20%, and those who have a risk less than 10%. Finally, in those with zero to one risk factors, the Framingham Risk Calculator is not needed because they virtually all have a 10-year risk of less than 10% and should be treated more conservatively. 456

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FIG 12. Integration of lipid lowering goals stratified by 10-year risk assessment.

The Framingham Risk Calculator was redesigned at the time of publication of ATP-III. In this redesign, age was adjusted and diabetes was removed, and in its place the treatment of blood pressure was added in. The new Framingham Risk Calculator now uses age, HDLc, total cholesterol, systolic blood pressure, treatment of blood pressure, and smoking status. The new Framingham Risk Calculator gives a very close risk of the approximate 10-year risk of coronary events. In the ATP-III guidelines, risk assessment is the first step in primary prevention. LDLc remains the primary target and metabolic syndrome is a secondary target. It was pointed out that therapeutic lifestyle changes in the presence of elevated LDL cholesterol remain the main standby in lipid management. The therapeutic lifestyle diet reduces the intake of cholesterol very similar to the previous Step 2 diet with saturated fats being less than 7% of the calories and a greater shift to the mono- and polyunsaturated fats within the diet. Dietary cholesterol is below 200 mg per day and LDLc lowering is enhanced by the use of plant stanols 2 grams per day and viscous soluble fiber 10 to 25 grams per day. Weight reduction and increased physical activity are integral parts of this dietary program. The ATP-III treatment management guidelines are shown in Figs 11, 12, and 13. The ATP-III guidelines also pointed out that an LDLc goal of less than 100 mg/dL is considered optimal now and we should all strive for this. An HDLc of less than 40 mg/dL is now considered high risk and is a categorical risk factor in the new guidelines. There were lower triglycerides classifications made within these guidelines with normal triglycCurr Probl Cardiol, July 2006

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FIG 13. Lipid management goals in primary prevention.

erides being less than 150 mg/dL, borderline high 150 to 199 mg/dL, high cholesterol 200 to 499 mg/dL, and very high greater than 500 mg/dL. The metabolic syndrome was defined and discussed in the ATP-III guidelines and was brought to attention because of the prevalence and significance for this as a cause for coronary death in the United States. The prevalence in the United States at the present time is estimated at 24% by the NHANES data published between 1988 and 1994 but current estimates are that it is approximately 35 to 40% of the population. It is associated with 2.6 to 3 times higher coronary disease mortality. The characteristics of the metabolic syndrome include abdominal obesity, atherogenic dyslipidemia, elevated serum triglycerides (small dense LDLc particles, low HDLc), raised blood pressure, insulin resistance, prothrombotic state, increased fibrinogen, and a proinflammatory state with elevated high sensitive C-reactive protein. The clinical diagnosis of metabolic syndrome can be made with any three of the five main components: abdominal obesity (waist ⬎40 inches for men and 35 inches for women), elevated triglycerides ⱖ150 mg/dL, low HDLc (men ⬍40 mg/dL and women ⬍50 mg/dL), elevated blood pressure (ⱖ130/ⱖ85 mmHg), fasting glucose ⬎110 mg/dL. S. C. Smith: Controversy exists about the criteria for waist circumference. ATP-III deals with the United States and the cut-points are higher than those published for other regions. For example, South Asian residents become at risk at much lower waist circumference. As the ethnic composition of the United States continues to expand, I expect we will see adaptation of the waist circumference criteria based on ethnicity.

The metabolic syndrome in this country is predominantly acquired because of overweight, obesity, and physical inactivity. High carbohy458

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drate diets providing greater than 60% of the energy intake are responsible in some patients, and there are genetic causes as well. The therapeutic intervention in the metabolic syndrome is to reduce the underlying causes, particularly addressing the overweight, obesity, and physical inactivity by eating less and exercising more. At the same time that this activity is commenced, however, it is important to treat the lipid and nonlipid risk factors aggressively (the prothrombotic state, hyperlipidemia, hypertension, and insulin resistance). For patients with triglycerides greater than 200 mg/dL, LDLc still remains the primary target for therapy but non-HDLc is a secondary target. Non-HDLc is the total cholesterol minus the HDLc. It is a surrogate estimate of atherogenic particles in LDLc, VLDL, remnants, and Lipoprotein(a) [Lp(a)]. It is not a calculated value such as LDL, which is calculated from the Friedwald equation and is more accurate. Triglycerides greater than 400 mg/dL do not preclude its calculation and can be determined in a nonfasting state. Apo-B lipoprotein measurement would be even more accurate but there is not a good reliable readily available standardized assay for clinical use at present. Apo-B lipoprotein is more predictive of cardiovascular risk and Apo-B/AI ratio also is more predictive than cholesterol/HDL ratio.21 These are not recommended at present due to measurement and standardization concerns. NMR particle numbers with assessment of large and small particle sizes show great promise as perhaps the best future risk assessment but are under study at this time and not in wide clinical use.22

S. C. Smith: The assays for Apo-B have improved with regard to their reliability. Many feel that they provide a more accurate assessment of risk. For the present, the non-HDLc advocated by ATP-III appears to be very useful.

The agents used in cholesterol (LDLc) reduction include the six present statins on the market—lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, and rosuvastatin. Vytorin is new but is a combination of simvastatin and ezetimibe. Advicor is a combination of lovastatin and niacin (Fig 14). Any one of these statins can be used to lower LDLc. Some of these have long-term use with greater experience and proven outcomes, whereas others are new, such as rosuvastatin, and without any long-term outcomes yet published. Statin drug interactions do occur, particularly in combination with gemfibrozil, Niacin, Verapamil, Amiodarone, and much less rarely, with fenofibrate. Atorvastatin and fluvaCurr Probl Cardiol, July 2006

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FIG 14. Lipid-lowering agents: generic names and expected side effects.

statin have minimal renal excretion, and dose adjustment of these statins in patients with renal insufficiency is therefore unnecessary.23 There are also intestinal-acting agents used for LDLc lowering (cholesevalam, cholestyramine, Colestipol, ezetimibe) and agents to reduce non-HDLc (the fibric agents and Niacin) (Fig 14). Although it was initially suspected that gemfibrozil increased statin levels by inhibiting the CYP450 enzymes, it is now thought that its inhibition of glucuronidation of statins may be the mechanism.24 Gemfibrozil undergoes extensive glucuronidation by the UPD-glucuronosyltransferase (UGT) isoforms, which also mediate glucuronidation of statins. Glucuronidation is now recognized as the major pathway for elimination of active hydroxy-acid metabolites of statins. Fenofibrate does not appear to interfere with these enzymes that mediate statin glucuronidation. Fenofibrate is glucuronidated by a different pathway and does not compete with statins.25 This suggests that statin combination with fenofibrate would be less risky than with the use of gemfibrozil. Other variables that may increase the likelihood of side effects with statins include advanced age, small body size, female gender, renal and hepatic dysfunction, perioperative periods, hypothyroidism, multisystem disease especially diabetes, and alcohol abuse.13,26 The higher the dose of statin, the greater the risk of toxic effects seen with statins. Statin cytochrome P450 3A4 metabolism is also inhibited by 460

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inhibitors of the CYP3A4 system such as cyclosporine, itracanozole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, Nefazodone, and grapefruit juice (greater than 1 quart per day) taken at the same time as the statin is used. This increases myopathy risk and you should consider an alternative statin not metabolized by the CYP3A4 system or decreasing the dose of statin by 50% to avoid these complications. The mechanism of muscle toxicity in statins remains controversial to some degree but clearly is an entity that is recognized in a small percentage of patients receiving statins. It has been suggested that the statin depletion of cholesterol production may alter myocyte cell membranes causing membrane instability and predispose to myopathy (Fig 8).27,28 The failure of repairing squalene and enhancing cholesterol production to reverse myopathy makes this less likely a significant cause of myopathy. There are several other theories proposed that the effects on the skeletal muscle may be due to depletion of intermediates in the cholesterol biosynthetic pathway. The most clearly defined of these is the pathway using the farnesyl pyrophosphate leading to ubiquinone (CoEnzyme-Q10) production. Ubiquinone blood level in patients that are stated on statins drops about 50%. It is felt that perhaps this response may be what is leading to the myositis. Ubiquinone (CoEnzyme-Q10) participates in electron transport in mitochondria of muscle. The muscle levels of ubiquinone are not depleted29 but lactate/pyruvate ratios are increased, suggesting mitochondrial dysfunction. Mitochondrial dysfunction has been found in muscle biopsies with normal creatine kinase blood values.30 In four patients biopsied with myositis (CPK normal), all demonstrated electron microscopy evidence of myopathy showing cytochrome oxidase-negative staining fibers and ragged red fibers. These cell changes improved with stopping the statin in the three patients who had a repeat biopsy. Increased lipid stores, cytochrome oxidase-negative myofibers, and ragged red fibers are all features of mitochondrial respiratory chain dysfunction consistent with a metabolic abnormality. This same pattern has been seen in a drug reaction31 and as a consequence of coenzyme-Q10 deficiency.32 The role of coenzyme-Q10 alteration has not been clearly defined but may still play some role. The depletion of prenylated small GTP-binding proteins (Rho, Ras, and Rac) formed by farnesyl pyrophosphate and geranyl– geranyl pyrophosphate has also been implicated in statin-associated myopathy. These GTP-binding proteins play integral roles in cell proliferation and growth.33 Curr Probl Cardiol, July 2006

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Blocking these small GTP-binding proteins (Rho, Ras, and Rac) that promote cell maintenance and growth and attenuated apoptosis can have a beneficial effect by decreasing smooth cell proliferation and helping the vascular plaque, which could be a beneficial effect from statins.33,34 At the same time, this apoptosis produced by statins could cause muscle damage in peripheral muscles. Exercise can induce myopathy symptoms in people on statins possibly unmasking the effects of these GPT proteins’ absence.35 Stimulating cholesterol production using squalene or replacing CoEnzyme-Q10 does not solve the problem in the majority of these patients. It may well be that decreasing the production of these prenylated proteins is the main cause for statin-induced myositis. A further mechanism for myopathy may be through interruption of isopentenylation of selenocysteine-tRNA by statins.36 Statin-induced myopathy is varied in severity but skeletal muscle pain, muscle tenderness, and fatigue are the main features. Biopsy shows ragged red fibers and loss of mitochondrial markers and dystrophic signs and necrosis in severe cases. Moosmann and Behl suggest the hypothesis that statin blocking of the production of isopentenyl sec-tRNA will deplete the selenoproteins necessary in muscle cell metabolism and regeneration.36 The myopathy associated with nutritional selenium deficiency is similar to statin-induced myopathy with similar biopsy findings, elevation of CPK, and abnormal mitochondrial changes. The question as to the benefit of selenium substitution remains to be studied but is an interesting hypothesis.36 Myopathy related to statins is more common in our experience and usually mild. Stopping statins and using an alternative statin may well work for many patients. More frequently, these patients react to all the statins and alternative lipid-lowering drugs are used. Severe myopathy with CPK elevations is rare and usually with the higher doses of statins. In the pravastatin pooling project with over 112,000 patient-years of therapy, pravastatin was withdrawn in only three patients due to elevated CPK levels.37 Clinically significant rhabdomyolysis with statin use is rare with an overall reported incidence of fatal rhabdomyolysis of 0.15 deaths per 1 million prescriptions.38 Less serious muscle pain and weakness, however, is more common and may be inasmuch as 1 to 5% of patients.38 It is this population that we tend to see in the office and deal with the skeletal muscle complaints. The management of this problem would seem worthy of a few comments. Prevention is still the best approach rather than managing statin-related myopathy. This includes using the lowest dose of statin required to achieve a therapeutic goal and by avoiding the higher doses as outlined in the warnings in the drug labeling. Avoiding 462

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concomitant therapy of drugs known to inhibit the pharmacokinetic metabolism of statins would be of benefit, as well. Patients should be instructed in the symptoms of myositis and encouraged to discontinue the medication promptly and report unexpected muscle pain or weakness if they notice this or any discoloration of the urine. If the patient is warned of these symptoms, to allow early discontinuation, more serious side effects from statin use are less likely to occur. It is possible that patients can tolerate one statin better than another and may get myositis with one and then restart another statin and not get myositis with it. There are a number of factors including the degree of physical activity that may cause some of these symptoms from time to time in patients. Patients complaining of myalgias without any elevated CK elevations can be watched and, if the symptoms increase, then clearly the statin should be discontinued and alternative therapy for lowering the cholesterol using resins, bile acid sequestrants, Niacin, and ezetimibe should be considered. It is also clear that staying away from a combination of statins and gemfibrozil should be avoided and, if a fibric acid is to be used, then switching to Tricor, which is less likely to cause this reaction, would be a prudent additional clinical maneuver. S. C. Smith: The above discussion of statins and myositis by the authors is excellent. Although the risk is generally very low, patients should be advised about the symptoms. When at all possible, higher doses of statins, especially when used in combination with other lipid-lowering agents, should be monitored carefully.

Myositis is a major concern as manifested by Baycol (cerivastatin) introduced in 1997 and withdrawn from the market 4 years later due to significant rhabdomyolysis and patient death problems. These data were not clearly recognized by the FDA but, in retrospect, were present at the time of the drug release for patient use. The toxic effect when noted in clinical use caused this drug to be voluntarily withdrawn.35,39 The latest released statin, rosuvastatin (Crestor), introduced to the market in 2003, is the most potent statin with clinical doses of 10 to 40 mg. Risk– benefit studies were carried out looking at doses 10 to 80 mg. These data showed only a 2% additional LDLc decrease as the doses increased from 40 to 80 mg. This differs from the other statins which result in LDLc decreasing about 6% with doubling the statin dose 40 to 80 mg. These studies also noted adverse events (hepatic enzyme increase and myositis) in the 80-mg dose. The safety data were reviewed in April 2003 in 12,569 patients (14,231 patient-years of treatment at doses up to Curr Probl Cardiol, July 2006

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80 mg).40 In doses 10 to 40 mg, the adverse profile was similar to atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg.40 Myopathy (CPK ⬎10⫻ upper limit of normal) for rosuvastatin 10 to 40 mg was ⱕ0.03%. No cases of rhabdomyolysis were reported under 40-mg dose. AST elevations occurred in 0.2% of patients similar to all other statins.40 Limited clinical comparison trials and short-term safety trials have been published.41-45 There are no long-term outcome studies with rosuvastatin and long-term safety has not yet been determined. However, rosuvastatin has been used in ⬎10,000 subjects before approval in the USA. Rosuvastatin is relatively hydrophilic like pravastatin, while other studies are highly lipophilic with cerivastatin the most lipophilic. The amount of bioavailability of statin in the bloodstream was greatest with cerivastatin (60%), while rosuvastatin was 20% and all other statins ⬍20%. These data suggest that rosuvastatin is likely to be safe and useful in clinical practice in doses 5 to 40 mg. The dosing in studies for rosuvastatin suggests that the 40-mg dose is a titration dose for patients not able to reach goal with doses of 5 to 20 mg. For Asian or North American patients of Asian descent, there is a twofold elevation in exposure risks with rosuvastatin and 5 mg has been suggested as the starting dose in this population. Myopathy risk with all statins is low, 0.1 to 0.2%, in reported trials.35 The rise in CPK in statins of comparable doses per degree of LDLc lowering confirms the observation that 80-mg equivalent doses are associated with increased myositis and are dose-dependent.35 In our own practice, we see frequent myositis occurring many months after statin use at doses of 20- to 40-mg and more often at 80-mg doses. Hypothyroidism predisposes to myopathy and a thyroid-stimulating hormone level should be obtained in any patient with muscle symptoms.35 With present available data, the present statins including rosuvastatin seem to be safe and effective in present clinical doses approved by the FDA. We also recognize that myositis is dose-related in all statins with a higher symptom rate with higher doses (10 to 80 mg). Avoiding the highest dose would seem a wise consideration and using combination therapy with a lower dose statin would seem the best advice (statin ⫹ Zetia). Increasing statin doses (doubling the dose, ie, 20 to 40 mg) decreases the LDLc by only 6%, a small payoff for increased myositis risk. When another agent is added (Zetia, cholesevelam), the drop in LDLc is 15 to 20% at lower myositis risk. We must not forget that statins, in combination with gemfibrozil, also have an increased myositis risk and 464

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should be used with care or not at all. Tricor (fenofibrate) and Niacin in combination have a lower risk but can cause myositis in some patients. In ATP-III, LDLc lowering is the primary target. Recent publications of the Heart Protection Study (HPS),46 PROVE-IT,47 and Reversal Trial have shown that, no matter what the baseline LDLc is, a drop of LDLc of 25 to 40% is associated with cardiovascular benefit. The recent publication by the NCEP updating the ATP-III guidelines has suggested an LDLc goal of 70 mg/dL for high-risk patients based on recent trials.4 This article also suggested that if this goal cannot be achieved, then at least a 30 to 40% drop in LDLc should be accomplished.

S. C. Smith: This is an important point in the ATP-III Update that is frequently overlooked. For those who cannot achieve the optional target LDLc of ⬍70 mg/dL, at least 30 to 40% reduction in LDLc should be the goal.

Statins have many potential pleiotropic effects that can add to cardiovascular benefit including anti-inflammatory (decrease hs-CRP and other inflammatory markers), antithrombotic, improved endothelial function, improved bone metabolism, and possible cognitive benefits. However, it appears from recent studies that LDLc lowering is the main benefit and should be our primary goal.4,46-48 We have no outcome data with Zetia and statins at present but given the benefit noted with other resins in combination use it seems prudent at present to consider combination treatment and avoid high-dose statin use. The cost– benefit effect of statin therapy continues to be a concern. The ATP-III guidelines have cost– benefit designs built in with less aggressive statin treatment for lower risk patients. We do need to understand the costs of these medications to gain the deserved LDLc goal, whether it is higher dose statins or combination therapy. Compassionate use from drug companies, drugs from Canada and Mexico, and understanding the importance of weight loss, exercise, fiber, and soy products are important. When considering statin or other drug use in lipid-lowering, it is very important to look at the patient’s alcohol use because of the potential liver problems that may cause some of these drug interactions. Is there a history of hepatitis? What other drugs is the patient taking, in terms of immunosuppressants, antifungal agents, etc., and what is the patient’s renal function given some of these agents have significant renal excretion are all important considerations. Always check the thyroid status to avoid treating with statin the lipid abnormalities seen in hypothyroidism. Also, Curr Probl Cardiol, July 2006

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look at other comorbid conditions such as diabetes and treatment with steroids when selecting these agents.

Adverse Events Statins are generally well tolerated.35 Elevation of hepatic transaminases occur in 0.5 to 2.0% of cases and are dose-dependent.49,50 Progression to liver failure due to statins is exceedingly rare if it ever occurs.51 Transaminase reduction occurs with decreasing the dose and elevations may not recur with either rechallenge or use of a different statin. Statins have not been shown to worsen the outcome in persons with chronic transaminase elevations due to hepatitis B or C and may actually improve transaminase elevations in people with fatty liver.52 Transaminase measurement should be obtained prior to initiation of statin treatment and be rechecked 6 to 12 months later. It can be rechecked then periodically as clinically indicated. When titrating up the dose, this needs to be rechecked again.

Other Lipid-Lowering Drugs Additional lipid-lowering drugs can be used in combination with statins or singly.

Niacin Nicotinic acid has been a medication that has been used for over 35 years. Niacin comes in three different forms. One is an immediate release crystalline form that is associated with significant flushing as a major side effect. This agent has to be started at a low dose and titrated upward to get the desired effect and is a three times a day medication. This requires a lot of counseling to get the patient to continue this and, therefore, is difficult to use. The flushing is caused by prostaglandin release and can be blocked by using aspirin prior to taking the niacin. After 2 to 3 weeks, the flushing is less and aspirin may not be needed. With each increase in the niacin dose, the flushing will return for a short time and aspirin use will again be helpful. Slow-release niacins are available on the market and some are better than others in terms of side effects. These can be taken one to two times a day depending on the brand that is used. They have less flushing. They are more potent and, therefore, if taken in larger doses, can cause significant liver toxicity. Rarely should you use more than 2 grams per day. Niaspan is an agent that is used once a day and is a time-release medication having less flushing side effects and is taken at bedtime. 466

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Niacin lowers LDLc 20 to 30%, total cholesterol 20 to 30%, triglycerides 30 to 40%, and raises HDLc 20 to 30%. Niacin has the strongest effect on raising low HDLc and is primarily used in hypertriglyceridemia and low HDLc settings. Niacin also shifts small dense LDL cholesterol over to large fluffy LDLc, which is then more easily cleared by the liver. This may have a significant effect particularly in the metabolic syndrome and in treating patients with high Lp(a). Niacin can be used safely in combination with statins, fibrates, and ezetimibe.

Fibrates The fibric acid agents, gemfibrozil and fenofibrate, have also been available for a long period of time. These are the agents of choice in hypertriglyceridemia and have a major effect in lowering triglycerides 40 to 60% when utilized with appropriate dietary modifications. As mentioned earlier, gemfibrozil is glucuronidized with statin drugs utilizing the same pathway. Since gemfibrozil competes with statins, there is a greater tendency to produce myositis in combination use.53 Fenofibrate is glucuronidized by a different pathway than statins and is safer when used in combination with statin drugs and less likely to cause myositis. Fibrates raise HDLc 10 to 20% and are generally less effective than niacin in this situation. Fibrates lower LDLc 10 to 15%. When fibrates are utilized in combination with statins, clinicians must exercise caution and judgment. Rare, but serious, cases of rhabdomyolysis have been reported with combination therapy. Reducing the statin dose prior to starting combination therapy is advised as a safeguard.

Ezetimibe Ezetimibe is a new agent that has recently come on the market in 2003 available only in a 10-mg dose. This localizes and appears to act at the brush border of the small intestine and inhibits cholesterol absorption and phytosterol absorption.54 It results in a decrease in the delivery of intestinal cholesterol to the liver and a reduction in hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe has a distinct mechanism of action that differs from the other classes of cholesterol-lowering compounds, namely the statins, bile acid sequestrants, folic acid derivatives, fenofibrates, niacin, as well as plant stanols and sterols. Ezetimibe, as monotherapy, decreases LDLc about 18%, cholesterol 13%, and triglycerides 8%, and has little effect on HDLc.55-58 When combined with a statin drug, its effect is increased with a 25% decrease in LDLc, 14% decrease in triglycerides, and mild increase in HDLc of 3%. Ezetimibe works in combination with the statin drugs Curr Probl Cardiol, July 2006

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dropping the LDLc another 25% with an amplified effect. This effect in combination with statins (10- to 20-mg doses) results in a greater than 50% reduction in LDLc. Because only 20% of Ezetimibe in the small intestine is absorbed into the enterohepatic circulation, the drug has no major side effects. This combination use would allow easy LDLc reductions of ⬎50% with resultant clinical benefit.59 This has been documented with all of the available statins that are used at present. It is of interest that ezetimibe does not decrease high-sensitive C-reactive protein and statins do.60

S. C. Smith: Exetimibe has been a valuable addition to the lipid-lowering therapies available for patients. The combination with statin therapies provide impressive reduction of LDLc at lower doses. Data are needed to determine whether patient outcomes are improved with use of Ezetimibe.

Resin Binding Agents The resins, bile acid binding sequestrants, Cholestyramine and Colestipol, are well established in the treatment of dyslipidemia. Resin agents reduce total cholesterol and LDLc by binding bile acids in the intestine to interrupt the enterohepatic circulation of bile acids. This action stimulates a secondary increase in hepatic LDL receptors, which in turn remove LDLc from the circulation. Resins have no significant effect on HDL but will raise plasma triglycerides. As expected from their mode of action, the major side effects associated with these agents are gastrointestinal (GI) intolerance with gas, bloating, constipation, nausea, and esophageal reflux. These agents work well in bringing down LDLc and, if the dose is slowly incremented, can be reasonably tolerated by patients. A problem with resins is their effect on absorption of Vitamin K, especially in patients on Coumadin. Resins also inhibit the absorption of digoxin, Coumadin, thyroxine, and diuretics if given simultaneously.

Cholesevalam (WelChol) WelChol, unlike the resin powder, is a binding gel that comes in tablet form and is easier to use. The tablets are large and the dose is three tablets twice daily. This product lowers cholesterol 20 to 30% and is well tolerated with less GI side effects than the other resins. When used in combination therapy with Zetia, the LDLc reduction can exceed 40% and be used in patients who do not tolerate statins to get the desired LDLc 468

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lowering.61 Cholesevalam, when combined with 10 mg Atorvastatin, produces LDLc reduction of 48% similar to 80-mg dose of Atorvastatin alone.

Additional Intestinal Cholesterol Blocking Agents ● Benacol ● Take Control ● B-sestosterol These agents block cholesterol and bile absorption in GI tract and result in 10 to 15% decrease in LDLc values.62 These are available over-thecounter, are nonprescription, and are widely used. Increased diet fiber intake also can decrease cholesterol values ⫾10%.

Cholesterol Ester Transfer Protein Blockers The new cholesterol ester transfer protein blockers are interesting potential anti-atherosclerotic drugs.63 These blockers work by blocking the transfer of cholesterol esters from HDLc to VLDLc, LDLc, and SD LDLc. This results in increased large HDL particles, which may well be beneficial with an increased HDLc number in the blood. By blocking the transfer of cholesterol esters to VLDLc, LDLc, and small dense LDLc, this results in decreasing the presence of oxidized small dense LDLc with potential beneficial effects. It has shown that small dense LDLc particles can be cleared from the bloodstream using these agents. This effect has a remarkable potential for atherosclerosis control particularly with the increase in metabolic syndrome with high triglycerides and small dense LDLc. Dr. Brian Brewer demonstrates that the rise in the large HDLc particles would allow transport of cholesterol from arterial wall macrophages to the HDLc particles without passing it along to LDLc and small dense LDLc (Fig 15).63 This would allow a greater number of HDLc particles to move these lipid particles back to the liver where they are taken up. There is some controversy that still exists as to whether or not this will be cardioprotective but, at present, it remains very promising.

AI Milano The infusion of AI milano phospholipids with a super-efficient Apo AI protein does raise the HDLc and holds the promise of possible future clinical use.64 This unusual variation of Apo-lipoprotein AI was discovered in Northern Italy in 40 carriers. They have low HDLc levels, Curr Probl Cardiol, July 2006

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FIG 15. Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (arrows). Apolipoprotein A-1 (apoA-1) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-1 (arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-1 interacts with ABCA1, removing excess cellular cholesterol and forming pre-␤-HDL is converted into mature ␣-HDL by lecithin-cholesterol acyltransferase (LCAT, arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type 1 (SR-B1, arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL-LDL, with uptake by the liver through the LDL receptor (arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-1 Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC, free-cholesterol; PL, phospholipids; LRP, LDL-related protein; LPL, lipoprotein lipase. (Color version of figure is available online.)

apparent longevity, and less evidence of any atherosclerosis. The genetic variant is due to a cysteine substituted at position 173 for arginine. A recombinant Apo A1 milano that mimics the properties of milano Apo A1 has been studied in 57 randomized patients (47 completed 470

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studies). The required weekly IV infusion for 5 weeks randomized to placebo versus treatment. Ultrasound studies in the coronary arteries showed regression in coronary atherosclerosis. This showed larger HDLc particles and a rapid effect in 5 weeks. There were some significant side effects with patient reactions and it required IV infusion. This does, however, show promise and will need further study. Previous work demonstrated that use of this synthetic protein mediated reductions in arterial thrombosis and clotting time.65 It is expected that this compound will emerge with a central role in the treatment of dyslipidemia, perhaps for hospitalized patients such as those with ACS.

Important Subgroups for Lipid-Lowering Treatment Acute Coronary Syndromes. There is a growing body of literature that indicates that use of statin therapy during hospitalization or at discharge from hospitalization for an acute coronary syndrome (unstable angina, non-STEMI, or STEMI) is beneficial. Multiple observational studies have demonstrated an association between statin use and improved outcomes.66-74 Two of the observational studies demonstrated improved outcomes by hospital discharge.66,67 There have been at least eight randomized clinical trials testing the use of statin therapy in ACS, including the Pravastatin Turkish Trial (PTT),75 the FLuvastatin On RIsk Diminishing after Acute myocardial infarction (FLORIDA) Trial,76 the Myocardial Ischemia Reduction by Aggressive Cholesterol Lowering (MIRACL) Trial,77 the LCAD Trial,78 the Prevention of Recurrent Ischemia with Cerivastatin Study (PRINCESS),79 the Aggrastat to Zocor Trial with simvastatin (A to Z),80 the Pravastatin Acute Coronary Trial (PACT),81 and the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) TIMI-22 Trial.47 The first study, the PTT, randomized 164 patients with STEMI to pravastatin (40 mg) or placebo at the time of intravenous fibrinolytic therapy. The investigators reported on a subset of their original cohort who had undergone PCI during hospitalization for STEMI.75 The 80-patient subset revealed that those randomized to pravastatin had fewer recurrent coronary events (32.5%) at 6 months compared to the placebo group (75.6%) (P ⫽ 0.0001). The FLORIDA Trial randomized 540 patients with STEMI to fluvastatin or placebo within 14 days of the index AMI, examining a primary endpoint of reduction in cardiac ischemia on ambulatory Holter monitoring by 6 and 12 weeks following AMI. No differences in ambulatory ischemia were observed and there were no Curr Probl Cardiol, July 2006

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differences in death or major adverse cardiac events at 1 year. The MIRACL Trial randomized patients with unstable angina, STEMI, and non-STEMI to atorvastatin (80 mg) or placebo for 16 weeks and observed a 16% relative reduction in the combined endpoint of death, recurrent non-fatal AMI, resuscitated cardiac arrest, or recurrent ischemia requiring repeat hospitalization (Atorvastatin group, 14.8%; placebo group, 17.4%; P ⫽ 0.048, RR 0.84, 95% CI 0.70 to 1.00, P ⫽ 0.048). The L-CAD trial took patients who had undergone percutaneous coronary revascularization for acute myocardial infarction (MI) or unstable angina and randomized the participants to aggressive lipid lowering with pravastatin (20 to 40 mg) ⫾ cholestyramine and/or nicotinic acid, or to usual care. The group randomized to aggressive lipid lowering had fewer recurrent coronary events at 2 years compared to the usual care group. The PROVE-IT Trial took patients with recent hospitalization for AMI and randomized them to pravastatin (40 mg daily) or atorvastatin (80 mg daily) and followed them for cardiovascular outcomes for 2 years. The group randomized to atorvastatin experienced few recurrent coronary events (26.3%) compared to the pravastatin group (22.4%) (P ⫽ 0.005). Of interest, subgroup analysis demonstrated that patients with STEMI or those on prior statin therapy did not benefit from the aggressive use of atorvastatin. A subsequent publication from the PROVE-IT investigators demonstrated that achievement of an LDL ⬍70 mg/dL and a CRP of ⬍1 g/dL was most predictive of lowest risk of recurrence. Indeed, the achievement of these tandem goals was more predictive of lowest clinical risk than was randomization to either atorvastatin or pravastatin.68 The difference in on-treatment LDLc (62 mg/dL atorvastatin) versus (95 mg/dL pravastatin) was part of the support data leading to the recommendations by of the NCEP, suggesting the aggressive treatment goal for LDLc of 70 mg/dL in high-risk patients. The PACT Trial randomized patients with STEMI and non-STEMI to pravastatin or placebo prior to hospital discharge and examined outcomes as early as 1 month following discharge. The results from PACT have been reported to show an 8% reduction in death, reinfarction, and recurrent coronary ischemia.81 It is not known if the enrollment in PACT was completed or prematurely terminated. The A to Z Trial is treatment with simvastatin 80 mg daily compared to usual care with study randomization occurring at 120 hours after admission with ACS, switching to open-label simvastatin treatment (20 mg daily versus 80 mg daily). In this trial, the placebo ⫹ 20 mg simvastatin achieved LDLc of 122 mg/dL at 1 month and 77 mg/dL at 8 months. In the treatment arm, the 1-month LDLc on 40 mg simvastatin 472

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was 68 mg/dL and 63 mg/dL on 80 mg at 8 months. The primary endpoint in the placebo was 16.7% versus 14.4% in the treatment group. There was no change in the first 4 months with increasing change noted later. Myopathy was seen in nine patients on an 80-mg dose (0.4%). Only a favorable trend was noted, in part due to the potent lipid reductions achieved in the two treated groups. Initiation of lipid-lowering agents during hospitalization for ACS will result in achievement of NCEP lipid treatment targets at a much earlier time. Several reports have suggested that patients who start lipid-lowering therapy during hospitalization are much more likely to achieve target LDL goals at 6 and 12 months following hospital discharge and are more likely to have excellent long-term compliance.82-84 In summary, there is a growing body of evidence that use of statin agents at time of hospitalization for ACS/AMI may offer benefit beyond the role of lipid lowering. Statin agents have a variety of pleiotropic actions that may favorably modify the vulnerable plaque, the vulnerable plasma, and the vulnerable patient.85-87 Additionally, patients who are started on these agents before hospital discharge demonstrate better shortand long-term compliance and have better LDL values during the first year of hospital follow-up.

PCI Patients There are two studies examining periprocedural statin use which may have direct relevance to the practice of interventional cardiology. The L-CAD study, described above, randomized patients post-PCI for AMI to statin ⫹ cholestyramine/niacin therapy or to usual care.78 Those who were randomized to statin therapy experienced far fewer recurrent coronary events compared to the usual care group. The lesson from L-CAD is that patients should be aggressively treated for dyslipidemia before they leave the care of the interventional cardiologist, as those randomized to usual care did not have success with lipid lowering or with reductions in coronary events. The second study is one by Hermann and coworkers who demonstrated that use of a statin agent for 1 week prior to PCI resulted in fewer PCI-related infarcts as determined by elevations of cardiac biomarkers.87 Patients were stratified by whether they had been “pretreated” with a statin agent prior to elective PCI. Of interest, those who were pretreated had a significantly lower risk of periprocedural rise in CK-MB compared to those not pretreated (Fig 16). The data from Hermann and coworkers are consistent with recent data revealing that statin therapy at the time of hospitalization for AMI is associated with reduced levels of Curr Probl Cardiol, July 2006

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FIG 16. Reduction in cardiac biomarker release during PCI by pretreatment with statin therapy.

CK-MB release.88 Work from experimental models of ischemia– reperfusion injury has demonstrated that statin pretreatment can reduce infarct size. This action appears mediated through modulation of expressible nitric oxide synthase, which can be quickly upregulated by statin pretreatment.89 It is unlikely that randomized trials will be conducted to test the hypothesis advanced by Hermann and coworkers, and in the absence of trial data, it would seem reasonable to pretreat patients undergoing PCI with statin agents unless clinically contraindicated.

Lipid Management in Hypertensive Patients Two important studies have demonstrated the importance of lipidlowering therapy in patients with hypertension.90,91 The AngloScandinavian Cardiac Outcomes Trial (ASCOT) with its accompanying lipid-lowering arm (ASCOT-LLA) along with the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized patients with hypertension to statin or placebo to examine if aggressive lipid-lowering therapy was associated with improved secondary prevention. Patients in ASCOTLLA were randomized to atorvastatin (10 mg/day) or placebo, while patients in ALLHAT were randomized to pravastatin (40 mg/day) or placebo. The ASCOT-LLA Trial was reported before completion of the prespecified amount of time of follow-up since patients randomized to the LLA enjoyed a 36% reduction in nonfatal AMI and 474

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coronary heart disease related deaths compared to the placebo group. The ALLHAT trial followed patients for at least 6 years, during which time nearly 27% of the placebo group was on open-label statin treatment. This resulted in a mean LDL value of 104.0 mg/dl in the pravastatin group and 121.2 mg/dl in the placebo group. The group randomized to pravastatin had reductions in nonfatal myocardial infarction and CHD deaths of 95 (P ⫽ 0.16). Nonetheless, these data emphasize the importance of aggressive lipid lowering in patients with hypertension, who otherwise are at increased risks for myocardial infarction, coronary death, and stroke. Emerging Risk Factors. There are over 200 emerging risk factors or markers that play some role in atherosclerosis and coronary events. The five main factors that are commonly measured at present are lipoprotein(a), high-sensitive C-reactive protein, homocysteine, fibrinogen, and small dense LDLc. Lipoprotein(a). Lp(a) has emerged as one of the most useful and important of these markers.92,93 This marker has been known for over 30 years but only in the last 3 to 5 years has its importance been recognized. This marker is determined by a genetic variation in Apo(a) production and is transmitted as a dominant gene in families. These families usually, but not always, have premature onset of atherosclerosis with accelerated malignant coronary artery disease, cerebrovascular disease, and peripheral vascular disease. The lipoprotein (LDL particle) attaches to the LDL particle via a disulfide bond and promotes atherosclerosis.94 The apo-A protein interferes with plasmogen and inhibits fibrinolysis. This apo-A can vary in patients from a very short protein (14 kringles) to a very large protein. The shorter the protein, the more inflammatory and dangerous is the effect. The LDLc protein is usually oxidized and, when this enters the vessel wall into a plaque it becomes inflammatory, causing the plaque to become unstable. The history of premature family history of coronary artery disease (CAD) is very frequently related to this Lp(a) and these patients should be screened for its presence. When it is found, other family members need screening as this Lp(a) factor is dominantly transmitted. When patients with hyperlipidemia treated with statin therapy do not get their LDLc ⬍100 mg/dL with moderate to high doses of statin, this suggests the presence of an elevated Lp(a). Lp(a) ⬎30 mg/dL was compared to other risk factors and was found to be more significant than a cholesterol ⬎240 mg/dL, HDLc ⬍35 mg/dL, and elevated blood pressure. Only diabetes and smoking had a higher relative risk for coronary artery disease.95 Curr Probl Cardiol, July 2006

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The treatment of Lp(a) is difficult as there is nothing that consistently lowers Lp(a).96 There is a wide oscillation in the Lp(a) baseline and prior studies with Niacin and fenofibrate did not take this into effect. The work of Maher and coworkers is the best, and they pointed out that the risk associated with an elevated Lp(a) is attenuated by aggressive lowering of the LDLc.97 The present first management recommendation is to lower LDLc to the 60- to 80-mg/dL range. This frequently requires high statin dose and combination therapy. No therapy alters the Lp(a) number to any degree over time (personal experience). The (a) protein prefers oxidized small dense LDLc to bind with and is more inflammatory with this association. The second recommendation is to treat with Niacin, which decreases small dense LDLc by one-third or more and in combination with a statin drops the small dense LDLc up to 60 to 70%. At the present time, it appears that the risk of an elevated Lp(a) can be controlled with LDLc reduction and management of small dense LDLc. In the HERS Trial, hormone therapy did not lower Lp(a) but it attenuated the heart disease risk in patients with high Lp(a) values.98 It is important to remember to be careful with combination therapy using vigilance to watch for side effects using combination therapy. There are new tests being developed to look at the kringle length that will give us more understanding of the nature of individual Lp(a) proteins. The location of this gene defect has been studied and it has the potential to be a target for future gene therapy. Hyperhomocysteinemia. Plasma homocysteine has been epidemiologically linked with increased CAD risk in certain groups of patients.99-101 Recent work has suggested that CAD risk may be dependent upon which genetic subtype of dihydrofolate reductase is present within the individual.102 This disorder is usually not identified unless specialized testing is ordered. Elevations of plasma homocysteine should be treated equally in patients with CAD and those without CAD given the epidemiological evidence linking it to advanced CAD development. Treatment consists of a daily B-complex vitamin and folic acid (400 to 1000 mg). The B-complex vitamin is necessary to avoid precipitating pernicious anemia in individuals who have a B12 deficiency and take folic acid as monotherapy. Rare cases of B12 deficiency dementia have been reported when folic acid monotherapy has been administered over a long-term basis in patients with asymptomatic pernicious anemia. With renal insufficiency up to 10 to 12 grams, daily folic acid may be needed. Because this test is expensive, many clinicians just empirically treat with B vitamins. 476

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S. C. Smith: The authors correctly note the epidemiologic association between increased plasma homocysteine and CAD. What is now needed are studies demonstrating that treatment with folic acid actually improves cardiovascular outcome when homocysteine levels are reduced.

C-Reactive Protein. Work by Ridker and coworkers first recognized the importance of an elevated C-reactive protein (CRP) with risk of first time and/or recurrent MI.103-105 It has become apparent that statin therapy is quite effective in patients with elevations of both LDLc and CRP. Treatment of the combined dyslipidemia should result in potent reductions in LDLc and CRP values. Less is known about what the proper treatment decision is with patients who have an elevated CRP but normal LDLc values. Data from the AFCaps/TexCaps Trial suggest that an elevated CRP in the setting of an LDLc less than median represents an atherogenic risk.104 Patients who were treated with lovastatin in that study had risk reductions of a similar magnitude to that observed in the LDL ⬎ median population. There is an ongoing randomized clinical trial testing whether treatment with statin therapy in patients with elevations of CRP but with low LDLc is beneficial. Elevated hs-CRP values in patients experiencing acute coronary syndromes is a recognized predictor of increased risk of recurrent coronary events. There are data from ST elevation AMI patients, non-STE AMI patients, and patients with unstable angina. The largest study to date to examine this hypothesis has been the PROVE-IT trial, where patients with a CRP ⬎1 mg/L had nearly double the risk of those with CPR ⬍1 mg/L at time of randomization. When higher CRP cutoffs were used, those with CRP ⬎2 mg/L had 150% of the risk of those with CRP ⬍2 mg/L. These data are sufficient to suggest that the treatment paradigm following ACS must take into account both LDL and CRP values.106 The statin agents are ideally suited for this dual treatment role. The role of ezetimibe ⫹ statin remains to be tested but offers promise. We should remember that hxl-CRP is an indicator of cardiovascular risk, in part because of its association with obesity, insulin resistance, dyslipidemia, and hypertension. Measuring the patient’s waist may be just as useful and less expensive. S. C. Smith: The evolving evidence for CRP as a predictor of risk for cardiovascular events is indeed impressive. Greatly needed are clinical trials that demonstrate that therapeutic strategies based on hs-CRP levels actually improve cardiovascular outcomes.

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Pharmacologic Treatment of Hyperlipidemia—What Agent(s) for What Patients? In patients with elevated triglycerides, gemfibrozil, fenofibrate, and niacins are the treatments of choice. Statins reduce triglycerides 30 to 40% in general and fish oils in large quantities of 2 to 6 grams per day can also be effective in lowering triglycerides. In patients with low HDLc, Niacin will raise the HDLc approximately 25 to 30%. Gemfibrozil would raise the HDLc about 10 to 15%, as would Tricor. In the VA-HIT study, HDLc rose 6% with the use of gemfibrozil and there was a 22% decrease in clinical events showing significant effect related to the HDLc rise.106 Statins will generally raise HDLc between 5 and 15% but usually less than 10% as seen in most patients. Elevated LDL-Cholesterol Values. Statin therapy is the preferred first line of therapy for any patient with an elevated LDLc. Most patients can be brought to LDL goal with aggressive statin therapy. There may be a need for up titration of the dose of a particular statin to get the LDL cholesterol to target. In the rare patient in whom you cannot achieve LDL goal with statin monotherapy, it is often necessary to add a second pharmacological agent. We favor use of ezetimibe in most patients. It is well tolerated, has few side effects, and is potent when added to statin therapy. Combination therapy with moderate statin dose and ezetimibe results in ⫾50% reduction in LDLc at low side effect risks. The side effects of statins at low dose are similar to placebo and myositis risk does increase with increasing statin dose. At the present time, the selection of which statin to use must take into consideration the long safety records of the established statins and watch with caution the new agents until time use and safety records assure its utility. We do prefer the combination approach over high-dose monotherapy. Other choices include sitostanol esters and/or resin-binding agents. These agents can be used when the patient does not have elevated triglycerides or a low HDLc. Niacin and fibric acid derivatives are the appropriate choices for addition to statin therapy when the patient has significant elevation of triglycerides (⬎150 mg/dl) or a low HDLc (HDL ⬍40 mg/dl). In aggressive treatment of low HDLc, the following recommendations are useful. Exercise, smoking cessation, and achieving ideal body weight are all initial steps to begin management. Aerobic exercise has a strong effect on increasing HDLc. Alteration in the diet with a decrease in polyunsaturated oil (which lowers HDLc) and increasing monounsaturated oils with help. Reduction of the soluble fiber in the diet and decreasing the free sugars in the diet will also raise HDLc. More fish and 478

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fish oils will also help. As the triglyceride values drop, the HDLc will rise. Niacin has the strongest HDLc rising effect by decreasing the catabolism of HDLc. Gemfibrozil and Tricor are also beneficial by increasing the secretion rate of nascent HDLc. In some patients, the combination of these drugs can increase the HDLc in refractory low HDLc problems. When all of these steps do not work, using a statin to lower the LDLc and improve the cholesterol/HDLc ratio should be considered. Normal LDL-Cholesterol but Low HDL-Cholesterol Values. In secondary prevention, when LDLc is at goal but HDLc remains low (⬍40 mg/dL), combination therapy with niacin will increase HDLc approximately 25 to 30%. Gemfibrozil will raise HDLc 10 to 15%, as well as fenofibrate. In the VA-HIT Study, HDLc rose 6% with gemfibrozil therapy, resulting in a 22% decrease in clinical events.107 Statins will generally raise HDLc 5 to 15%. Elevated Triglycerides and Elevated LDL-Cholesterol. A significant number of patients with CAD will have elevations of both LDLc and plasma triglycerides. A search should be made for metabolic stressors (diabetes, obesity, hypothyroidism), dietary imbalances (excess ethanol ingestion, excessive simple carbohydrate intake), and medication-triggered triglyceride elevations. When medication and dietary and lifestyle modifications fail to correct the triglyceride elevations, it is necessary to institute pharmacological therapy. The first line of treatment should be one of the FDA-approved statin agents with potent triglyceride-lowering properties. If the triglycerides remain elevated above 150 mg/dl, it will be necessary to use niacin or a fibrate agent. Both niacin and the fibrates are potent triglyceride-lowering agents, often achieving 40 to 60% reductions in patients with hypertriglyceridemia. Resin-binding agents must be avoided in patients with hypertriglyceridemia as these agents will worsen hypertriglyceridemia. Remember that gemfibrozil and statins have an excess risk of myositis when used in combination therapy and should be avoided. Primary High Triglycerides. In patients with primary hypertriglyceridemia, gemfibrozil, fenofibrate, and niacins are the treatments of choice. The fibric acid agents lower triglycerides 40 to 60%, while niacin will lower triglycerides 30 to 40%. Fish oils in large quantities of 2 to 6 grams/day can also be effective in lowering triglycerides. Remember, the sugar intake drives the triglycerides elevation and alcohol abuse is often a major cause. Diabetic control, weight loss, and exercise all need to be addressed. Do not forget to check the thyroid status as hypothyroidism can present in this way. Curr Probl Cardiol, July 2006

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S. C. Smith: In patients with elevated triglycerides it is very important to repeat the fasting sample before initiating therapy specific for lowering triglycerides. Nonfasting samples, poorly controlled diabetes, and excessive ethanol intake are frequent causes of elevated triglycerides.

Statin agents in moderate dose will also decrease triglycerides 15 to 45%. The more potent statins have a larger triglycerides-lowering effect. In mixed hyperlipidemia, statin is the initial drug of choice to decrease LDLc and triglycerides. If triglycerides remain ⬎150 mg/dL on treatment, then combination therapy should be considered. S. C. Smith: The past decade has seen an impressive increase in the therapies available for the treatment of dyslipidemia. Coupled with the development of these new drugs have been numerous clinical trials defining their benefit. The authors have provided a thoughtful and thorough summary of the pathophysiology, diagnosis, and management of dyslipidemia, which should be of great value to the practicing clinician.

REFERENCES 1. Topol, E. Intensive statin therapy—a sea change in cardiovascular prevention. New Engl J Med 2004;350:15. 2. Wright RS, Kottke TE, Gau GT. Lipid-lowering Agents. In: Murphy J, editor. Mayo Clinic Cardiology Review, 2nd Ed., Philadelphia, PA, Lippincott Williams & Wilkins, 2000. p. 1301-18. 3. Roberts WC. The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infection disease. Am J Cardiol 1996;78:377-8. 4. Grundy SM, Cleeman JL, Bairey Mertz N, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39. 5. Kromhout D. On the waves of the Seven Countries Study: a public health perspective on cholesterol. Eur Heart J 1999;20:796-802. 6. Vaughn CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996;348(9034):1079-82. 7. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91(11):2844-50. 8. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 1995;92(5):1355-74. 9. Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994;90:2126-46. 10. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell 2001;14:503-16. 11. 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 (ATP-III). JAMA 2001;285:2486-97. 480

Curr Probl Cardiol, July 2006

12. Kromhout D. On the waves of the Seven Countries Study—a public health perspective on cholesterol. Eur Heart J 1999;20:796-802. 13. Vaughn CJ, Gotto AM. Update on statins 2003. Circulation 2004;110:886-92. 14. Shepherd J, Cobbe SM, Ford I, et al. West of Scotland Coronary Prevention Study Group. Prevention of coronary artery disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-7. 15. Randomized trial of cholesterol lowering in 4444 patients with coronary artery disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:138389. 16. Sacks FM, Pfeffer MA, Moye LA, et al. Cholesterol and recurrent trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1000-9. 17. Long-term intervention with pravastatin in ischemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57. 18. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615-22. 19. Pedersen TR, Kjekshus J, Pyorala K, et al. Presented at American Heart Association Annual Meeting. Circulation 1995;92(8):1-672, abstract no. 3225. 20. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34. 21. Sniderman AD, Furberg CD, Keech A, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003;361:777-80. 22. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90(8A):22i-9i. 23. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35:1096-107. 24. Prueksaritanont T. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos 2002;30:505-12. 25. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002;30:1280-7. 26. Pastermak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002;106:1024-8. 27. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003;289:1682-90. 28. Rosenson RS. Current overview of statin-induced myopathy. Am J Med 2004;116:408-16. 29. Laaksonen R, Jokelainen K, Sahi T, et al. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther 1995;57:62-6. 30. Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137:581-5. 31. Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic and therapy. Ann Pharmacother 2003;34:630-8. Curr Probl Cardiol, July 2006

481

32. Ogasahara S, Engel AG, Frens D, et al. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci USA 1989;86:2379-82. 33. Coleman ML, Olson MF, Rho GT. Pase signaling pathways in the morphological changes associated with apoptosis. Cell Death Differ 2002;9:493-504. 34. Olson MF, Ashworth A, Hall A. An essential role for Rho, Rad, and Cdc42 GTPases in cell cycle progression through G1. Science 1995;269:1270-2. 35. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI Clinical Advisory on the use of safety of statins. Circulation 2002;1024-8. 36. Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins. Lancet 2004;363:892-4. 37. Pfeffer MA, Keech A, Sacks FM, et al. Safety and tolerability of pravastatin in long-term clinical trials: prospective pravastatin pooling (PPP) project. Circulation 2002;105:2341-6. 38. Thompson PD, Clarkson P, Karas RH. Stating-induced myopathy. JAMA 2003;289:1682-90. 39. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002;346:539-40. 40. Data file—personal communication and package insert data. AstraZeneca LP, Alderley Park, Macclesfield, Cheshire, UK; 1998-2003. 41. Jones PH, Davidson MH, Stein EA, et al. STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92(2):152-60. 42. Hunninghake DB, Stein EA, Bays HE, et al. Rosuvastatin improves the atherogenic and atheroprotective lipid profiles in patients with hypertriglyceridemia. Coron Artery Dis 2004;15:115-23. 43. Schneck DW, Knopp RH, Ballantyne CM, et al. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol 2003;91(1):33-41. 44. Stein EA, Strutt K, Southworth H, et al. Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 2003;92:1287-93. 45. Berry DA, Berry SM, McKellar J, et al. Comparison of the dose-response relationships of two lipid-lowering agents: a Bayesian meta-analysis. Am Heart J 2003;145(6):1036-45. 46. The Heart Protection Study Investigators. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360:7-22. 47. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipidlowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504. 48. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071-80. 49. Hsu I, Spinler SA, Johnson NE. Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacother 1995;29:743-59. 50. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of 482

Curr Probl Cardiol, July 2006

51. 52. 53. 54.

55. 56.

57.

58.

59. 60.

61.

62.

63. 64. 65.

66. 67.

68.

69.

Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991;151:43-9. Pedersen TR, Tobert JA. Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal. Drug Saf 1996;14:11-24. Angelo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-31. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Am Soc Pharm Exp Ther 2002;30(11):1280-7. Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003;24:729-41. Sudhop T, Lutjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002;106:1943-8. Gagne C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with hypercholesterolemia. Am J Cardiol 2002;90:1084-91. Dujovne CA, Ettinger MP, McNeer JF. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, in ezetimibe, in patients with primary hypocholesterolemia. Am J Cardiol 2002;90:1092-7. Davidson MT, McGarry T, Bettis R, et al. Ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125-34. Roberts WC. Two more drugs for dyslipidemia. Am J Card 2004;93:809-11. Sager PT, Melani L, Lipka L, et al. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity c-reactive protein. Am J Cardiol 2003;92:1414-8. Zema MJ, Chan E. Ezetimibe and colesevelam are additive in the management of hypercholesterolemia. Presented at the American College of Chest Physicians meeting 2004, abstract. Nguyen TT, Dale LC, vonBergmann K, et al. Cholesterol-lowering effect of stanol ester in a US population of mildly hypercholesterolemic men and women: a randomized controlled trial. Mayo Clin Proc 1999;74(12):1198-206. Brewer HB. Increasing HDL cholesterol levels. N Engl J Med 2004;350:15:1491-4. Brousseau ME, Schaefer EJ, Wolfe ML, et al. N Engl J Med 2004;350(15):1505-15. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant Apo A1 milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-300. Li D, Weng S, Yang B, et al. Inhibition of arterial thrombus formation by Apo A1 milano. Arterioscler Thromb Vasc Biol 1999;19:378-83. Bybee KA, Wright RS, Williams BA, et al. Effect of concomitant or very early statin administration on in-hospital mortality and reinfarction in patients with acute myocardial infarction. Am J Cardiol 2001;87:771-4. Schiefe R, Gitt AK, Heer T, et al. Early statin use in acute myocardial infarction is associated with a reduced hospital mortality: results of the Mitra-2. Circulation 2000;102:II-435. Stenestrand U, Wallentin L, for the Swedish Registry of Cardiac Intensive Care. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001;285:430-6.

Curr Probl Cardiol, July 2006

483

70. Bybee KA, Wright RS, Powell BD, et al. Differential benefit from treatment with a statin agent at hospital discharge in non-ST elevation MI compared to ST elevation MI. Circulation 2000;102(suppl 2):II-614 [Abstract 2977] 71. Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357:1063-8. 72. Giugliano RP, Antman EM, Thompson SL, et al. Lipid lowering drug therapy initiated during hospitalization for acute MI is associated with lower post-discharge 1-year mortality. J Am Coll Cardiol 2001;37(suppl A):316A[Abstract 1053-91]. 73. Cannon CP, McCabe CH, Bentley J, et al. Early statin therapy is associated with markedly lower mortality in patients with acute coronary syndromes: observations from OPUS-TIMI 16. J Am Coll Cardiol 2001;37(suppl A):334A[Abstract 831-2]. 74. McGuire DK, Kristinsson A, Bhapkar MV, et al. Early statin use after acute coronary syndromes (ACS) and outcomes at 90 days. Circulation 2001;104:II-343. 75. Kayikcioglu M, Can L, Kultursay H, et al. Early use of pravastatin in patients with acute myocardial infarction undergoing coronary angioplasty. Acta Cardiol 2002;57:295-302. 76. Van Boven AJ, Liem A. Effects of fluvastatin administration immediately after an acute myocardial infarction on myocardial ischemia (FLORIDA). Presented at: American Heart Association Scientific Session 2000; November 12-15, 2000; New Orleans, LA. Available at: http://www.acc.org/education/online/trials/aha00/ florida.htm 77. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study. JAMA 2001;285(13):1711-8. 78. Arntz HR, Agrawal R, Wunderlich W, et al. Beneficial effects of pravastatin (⫹/⫺colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study). Am J Cardiol 2000;86:1293-8. 79. Wright RS, Murphy JG, Bybee KA, et al. Statin lipid-lowering therapy for acute myocardial infarction and unstable angina: efficacy and mechanism of benefit. Mayo Clin Proc 2002;77:1085-92. 80. Blazing MA, de Lemos JA, Dyke CK, et al. The A-to-Z Trial: methods and rationale for a single trial investigating combined with use of a low-molecularweight heparin with the glycoprotein IIb/III inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy. Am Heart J 2001;142:211-7. 81. Ross AM, Coyne KS, Reiner JS, et al. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial. PACT investigators. J Am Coll Cardiol 1999;34(7):1963-5. 82. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes. JAMA 2004;292(11):1307-16. 83. Fonarow GC, French WJ, Parsons LS, et al. Use of lipid-lowering medications at discharge in patients with acute myocardial infarction: data from the National Registry of Myocardial Infarction 3. Circulation 2001;103(1):38-44. 84. Bybee KA, Powell BD, Williams BA, et al. Superior short-term cholesterol control and achievement of the adult treatment panel III low-density lipoprotein goals with 484

Curr Probl Cardiol, July 2006

85. 86. 87.

88. 89. 90.

91.

92.

93.

94. 95.

96.

97.

98.

99. 100. 101.

initiation of statin therapy by the time of hospital discharge following acute myocardial infarction. Am J Cardiol 2004;93:776-9. Rosenson RS, Tangey CC. Antiatherothrombotic properties of statins. Implications for cardiovascular event reduction. JAMA 1998;279:1643-50. Vaughan CJ, Murphy MB, Buckley BM. Statins do more than lower cholesterol. Lancet 1996;348:1079-82. Herrmann J, Lerman A, Baumgarat D, et al. Preprocedural statin medication reduces the extent of periprocedural non-Q wave myocardial infarction. Circulation 2002;106:2180-3. Bybee KA, Kopecky SL, Williams BA, et al. Reduced creatine kinase release with statin use at the time of myocardial infarction. Intl J Card 2004;96(3):461-6. Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Circulation 1998;97:1129-35. Sever PS, Dahlof B, Poulter NR, et al. for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet 2003;361:1149-58. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care. The antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT-LLT). JAMA 2002;288:2998-3007. Kim C, Gau GT, Allison TG. Relation of high lipoprotein(a) to other traditional atherosclerotic risk factors in patients with coronary heart disease. Am J Cardiol 2003;91:1360-3. Marcovina SM, Koschinsky ML, Albers JJ, et al. Report of the National Heart, Lung, and Blood Institute Workshop on lipoprotein(a) and cardiovascular disease: recent advances and future directions. Clin Chem 2003;49:1785-896. Deb A, Caplice N. Lipoprotein A. New insights into mechanisms of atherogenesis and thrombosis. Clin Cardiol 2004;27:258-64. Bostrom LA, Cupples JL, Jenner L, et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger—a prospective study. JAMA 1996;276:544-8. van Wissen S, Smilde TJ, Trip MD, et al. Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia. Heart 2003;89:893-6. Maher VM, Brown BG, Marcovina LA, et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 1995; 274(22):1771-4. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 2000;283:1845-52. Gauthier GM, Keevil JG, McBride PE. The association of homocysteine and coronary artery disease. Clin Cardiol 2003;26:563-8. Wald DS, Law M, Morris J. Serum homocysteine and the severity of coronary artery disease. Thromb Res 2003;111:55-7. Matetzky S, Freimark D, Ben-Ami S, et al. Association of elevated homocysteine

Curr Probl Cardiol, July 2006

485

102.

103.

104.

105.

106. 107.

486

levels with a higher risk of recurrent coronary events and mortality in patients with acute myocardial infarction. Arch Intern Med 2003;163:1933-7. Weisberg IS, Park E, Ballman KV, et al. Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease. Atherosclerosis 2003;167:205-14. Ridker PM, Rifai N, Pfeffer MA, et al, for the Cholesterol and Recurrent Events (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998;98:839-44. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100(3):230-5. Ridker PM, Rifai N, Clearfield M, et al, for the Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959-65. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-8. Rubins HB, Robins SJ, Collins J, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-8.

Curr Probl Cardiol, July 2006