Achieving Target Goals in Dyslipidemia Management

With the release in May 2001 of the third Adult Treatment Panel (ATP-III) by the National Cholesterol Education Program (NCEP), lipid control for the prevention and treatment of heart disease has become more aggressive. As the result of the new evidence-based treatment standards encompassing criteria such as peripheral arterial disease and risk equivalents such as diabetes, some 36 million Americans merit lipid-lowering intervention, approximately triple the number estimated under the standards of ATP-II. The new diagnostic criteria and treatment goals for dyslipidemia arise from new clinical trial data indicating that control of low-density lipoprotein cholesterol (LDL-C) improves survival. The vast majority of patients tolerate HMG-CoA reductase inhibitors, or “statin” medications, well. At present, however, only about 20% of candidates for statin therapy do receive treatment; and because many of them take only standard starting doses, not all achieve established goals. Physician assistants practicing in primary care settings can play a pivotal role in identifying, educating, and treating individuals with dyslipidemia, and thus reduce their risk for adverse cardiovascular events.

This program was supported by an unrestricted educational grant from AstraZeneca LP.

NCEP Guidelines: Implications for the Expanding Treatment Population

Peter Libby, MD (Brigham and Women’s Hospital and Harvard Medical School) outlined the similarities between ATP-II and ATP-III. Both begin with three risk strata, each with a different intensity of therapy. The primary objective is control of low-density lipoprotein cholesterol (LDL-C). The target serum LDL-C level is adjusted according to the patient’s risk stratum.

Under ATP-III, however, approaches to screening and treatment address the entire “lipoprotein menagerie.”

LDL-C remains the primary therapeutic target because it is strongly associated with the development atherosclerosis and coronary heart disease. It is known, for example, that a 10% increase in serum LDL-C results in a 20% increase of risk for coronary heart disease. The relationship between high-density lipoprotein cholesterol (HDL-C) and heart disease is the opposite: the lower the HDL-C, the higher the risk for coronary heart disease and atherosclerosis. Under ATP-II, the minimum HDL-C goal was 35 mg/dL. This has been adjusted to 40 mg/dL under ATP-III. Triglycerides are an independent risk factor for coronary heart disease. ATP-II defined the normal triglyceride level as 200 mg/dL. Under ATP-III, this has been reduced to 150 mg/dL, with readings between 151 and 199 defined as borderline high and those above 200 mg/dL as high. Levels above 200 mg/dL increase the risk for pancreatitis.

One of the innovations of the ATP-III guidelines is the introduction of the concept of non-HDL cholesterol, which consists of the total cholesterol minus HDL-C. Thus non-HDL cholesterol includes all of the atherogenic lipoprotein particles: LDL, lipoprotein A, intermediate-density lipoprotein, and very-low-density lipoprotein (VLDL). VLDL is a secondary target of therapy in patients with triglyceride levels above 200 mg/dL. Quantitatively, the treatment goal is the LDL-C goal plus 30 mg/dL.

LDL-C treatment goals under the ATP-III guidelines differ according to risk stratification. Patients with established coronary heart disease have a 10-year risk of 20% for having a cardiovascular event. Their LDL-C treatment goal is less than 100 mg/dL. Patients with two or more risk factors but no symptomatic atherosclerosis have a 10-year risk of myocardial infarction of less than 20%. (The individual patient’s risk can be calculated from a standard algorithm involving typical risk factors including age, blood pressure, hypertension treatment, lipid profile, smoking, and obesity. The formula is available on the ATP-III website: www.nhlbi.nih.gov/ guidelines/cholesterol.toc.pdf). For them, the LDL-C treatment goal is 130 mg/dL or less. Asymptomatic patients who have zero or one risk factors have an LDL-C goal of 160 mg/dL.

Importantly, the ATP-III guidelines now define coronary risk equivalents. Individuals with diabetes, even when well controlled, have a 10-year risk of myocardial infarction equivalent to that of individuals who have established coronary heart disease. Consequently, ATP-III assigns patients with diabetes to the highest risk stratum whether or not they have established coronary heart disease (e.g., myocardial infarction, angina), atherosclerosis, or other risks. The LDL-C treatment target for this category is less than 100 mg/dL. In addition to diabetes, coronary risk equivalents include all forms of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease.

Although therapeutic lifestyle change including moderate exercise and nutritional intervention is important in lipid management, most patients require pharmacologic intervention to meet their LDL-C targets. Interpretation of the mechanism by which lipid-controlling drugs decrease coronary risk is based on the evolving understanding of the pathophysiology of coronary artery disease. A decade ago, 50% stenosis of a coronary artery was not considered clinically significant. More recently, however, studies of coronary angiograms taken after thrombolytic therapy for acute occluding coronary syndromes have indicated that approximately two-thirds of acute myocardial infarctions occur in coronary arteries with stenoses of less than 50%. Moreover, for about one-third of patients, the first manifestation of coronary artery disease is sudden death. These observations contradict the traditional notion that the progression of atherosclerosis from its chronic, asymptomatic, stable phase to acute manifestations in the various circulatory beds results from intimal thickening leading to pinpoint narrowing. We now understand that the atherosclerotic lesion usually grows in an outward direction initially, preserving the lumen for an extended period. Encroachment of the vessel occurs only in advanced stages of the disease.

Studies using intravascular ultrasound indicate that because atherosclerosis is a disease not of the lumen but of the arterial wall, angiography markedly underestimates its prevalence. Furthermore, postmortem evidence makes it clear that the ultimate cause of myocardial infarction is the physical disruption of vulnerable atherosclerotic plaque. A tear in the fibrous cap puts blood in contact with thrombogenic material in the lipid core of the plaque, thus setting off a potentially fatal thrombus. Intense lipid accumulation and multiple inflammatory cells in plaque indicate an important inflammatory process.

Traditionally, therapies for coronary heart disease have targeted lesions that cause stenoses, angina, and myocardial infarction: anti-anginal medication and either surgical or percutaneous revascularization. Although these maneuvers provide symptomatic relief, there is little evidence that they either prevent cardiovascular events or prolong life. In sharp contrast, rigorous lipid control has been demonstrated in multiple studies to achieve these objectives in many patients with dyslipidemia. The largest of these, with almost 20,000 high-risk patients with diabetes and/or established coronary heart disease, is the landmark Heart Protection Study. Both women and men were included, and the trial population contained a large number of elderly patients. In the study, patients were randomized to statin therapy, a cocktail of antioxidant vitamins, or placebo. Patients treated with statin medication experienced a 17% reduction in all vascular events, a 27% reduction in stroke, and a 12% reduction in all-cause mortality. In the same trial, antioxidant vitamins showed no benefits.

The mechanism by which statin therapy reduces coronary events remains under study. Fourteen published lipid-lowering trials monitored angiographically indicate that statin therapy reduces arterial stenosis by only 1 to 2%. Because the reduction in adverse events exceeds this small improvement by far, regression of stenosis alone cannot explain the benefit. Dr. Libby postulated that a more important mechanism may be an anti-inflammatory effect of lipid lowering. Rabbits maintained on high cholesterol diets accumulate large numbers of arterial inflammatory cells expressing enzymes that digest collagen. When these animals are shifted to a low cholesterol diet for 16 months, there is a marked decrease in the number of inflammatory cells and a corresponding increase in collagen. It appears, therefore, that a high cholesterol diet destabilizes plaque, whereas a low cholesterol diet stabilizes it. Stable plaque resists rupture and is associated with reduced thrombogenicity.

C-reactive protein (CRP) is a surrogate marker for these changes in humans. CRP has been shown to increase in plasma concentration during the inflammatory stages of plaque vulnerability and myocardial infarction to the extent that it is a prognostic indicator of myocardial infarction. In a retrospective analysis of data from large lipid-lowering trials, Dr. Libby’s colleagues found that patients randomized to statin therapy experienced a decrease in plasma CRP over 5 years, while there was no change in this indicator of inflammation among patients randomized to placebo. The decrease among treated patients corresponded with the degree of clinical benefit. Every statin drug that has been tested lowers inflammation as measured by CRP. Thus, these agents benefit patients by influencing the biology of atherosclerosis.

Cholesterol Management: The Tip of the Iceberg

Robert M. Guthrie, MD (Ohio State University) opened by citing prosperity as the principal reason for the increased prevalence of weight gain and diabetes, a very serious metabolic trend, in the United States. Despite the availability and general tolerability of statin medications, only about 20% of individuals in need of lipid-lowering therapy are currently under treatment. Furthermore, only 30% of patients in the intermediate risk stratum and 17% of patients in the highest risk stratum are achieving the recommended target levels of LDL-C. The proportion is higher in the lowest risk strategy, because less aggressive treatment is required to reach the goal.

Although myocardial infarction places an individual in the highest risk stratum, recent studies of initial myocardial infarction hospitalizations among individuals with abnormal lipid profiles observed that only 31% to 42% of patients were discharged with prescriptions for statins. Data from the Swedish national database reveal that the 1-year mortality rate was 4.0% for patients discharged with statin prescriptions compared with 9.3% for those who were not given statins. Similarly, in the Quality Assurance Program involving 48,000 patients with coronary heart disease from 140 medical practices, 80% of which were cardiology practices, 39% of patients were on lipid-lowering medications with only 25% reaching the recommended target levels. All of these figures indicate that, at present, only the tip of the dyslipidemia iceberg is being addressed. Because the primary reason for the failure of treated patients to achieve the recommended lipid targets is clinician reluctance to titrate doses upward from standard introductory levels, Dr. Guthrie urged the audience “to be afraid of the disease, not of the drugs.”

In the years immediately following the introduction of statin medications, it was common to treat patients first with nutritional intervention and activity prior to initiating drugs. Studies of individuals in isolated environments with highly controlled diets have demonstrated, however, that dietary control of lipid abnormalities is of limited value. Consequently, patients with abnormal lipid profiles need to be treated “right out of the gate.”

Currently there are five FDA-approved statins: lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin. Cerivastin was removed from the market. While these agents have many common characteristics, there are subtle but important differences among them.

One of the pivotal primary prevention studies, AFCAPS/TexCAS, enrolled 6,605 low-risk primary care patients with modest LDL-C elevations and mid-range to low HDL-C levels (Downs JR et al. JAMA 1998;279:1615). Treatment with lovastatin was associated with a 37% overall risk reduction (cardiovascular death and other cardiovascular events), primarily because of improved HDL-C. The control of LDL-C had little influence on clinical outcomes except for levels above about 160 mg/dL. Thus the main contribution of this study is its clarification of the importance of maintaining adequately high HDL-C levels.

The West of Scotland Coronary Prevention Study (WOSCOPS), another primary care trial, randomized 6,595 men with a mean baseline LDL-C of
192 mg/dL to placebo or pravastatin (Shepherd J et al. N Engl J Med 1996; 333:1301). The relative risk reduction associated with the statin was 31%. The risk associated with elevated triglycerides was eliminated in patients treated with pravastatin.

The Scandinavian Simvastatin Survival Study (4S) and the Cholesterol and Recurrent Events (CARE) study conducted in the United States were both secondary prevention trials. The 4S study, which enrolled 4,444 high-risk patients with histories of angina or acute myocardial infarction and a mean LDL-C level of 188 mg/dL, was the first to demonstrate a total mortality reduction owing to a 42% reduction in coronary events (Scandinavian Simvastatin Survival Study Group. Lancet 1994; 344:1383). CARE enrolled 4,159 patients undergoing revascularization following myocardial infarction. The average LDL-C was 139 mg/dL. Pravastatin was associated with a 24% reduction in fatal and nonfatal myocardial infarction at 5.5 years, although there was no difference between treatment and placebo through year 2 (Sacks FM et al. N Engl J Med 1996;335:1001).

The Comparison of Statin Efficacy Study (CURVES) was the first to compare statins (atorvastatin, simvastatin, pravastatin, and fluvastatin) at varying doses for mean percentage change in LDL-C (Jones P et al. Am J Cardiol 1998;81:582). The most marked reductions were with atorvastatin.

Pitavastatin, rosuvastatin, and nicostatin are investigational agents that induce large reductions in LDL-C levels, the largest with rosuvastatin, and increases in HDL-C levels. In a comparison trial using atorvastatin and two doses of rosuvastatin, the percent change from baseline in HDL-C levels at 12 weeks was significantly higher for both doses of rosuvastatin than for atorvastatin. The higher dose of rosuvastatin was comparable to atorvastatin, which is marketed as an anti-triglyceride drug, with respect to reduction in triglycerides from baseline at the same time point. Eighty-four percent of patients treated with each dose of rosuvastatin achieved ATP-II LDL-C goals compared with 73% of patients taking atorvastatin and 13% of the placebo arm. However, in the highest risk category, 42% of patients taking rosuvastatin 5 mg and 47% of patients treated with rosuvastatin 10 mg met the LDL-C goal compared with 19% taking atorvastatin and 0% taking placebo (Davidson M et al. Am J Cardiol 2002; 89:268). In a European trial studying the short-term and long-term benefits of the same two drugs on LDL-C reductions and HDL-C increases, rosuvastatin was also superior (Olsson A et al. XIV International Symposium on Drugs Affecting Lipid Metabolism, New York, 2001). In a European trial comparing rosuvastatin with pravastatin and simvastatin for benefits with respect to ATP-II goals at 12 and 52 weeks, rosuvastatin performed significantly better than the other two drugs in both the short and long terms (Brown W et al. XXIII Congress of the European Society of Cardiology, Stockholm, 2001).

Ezetimibe is an investigational cholesterol absorption inhibitor that will probably have a role as a niche drug.

John R. White, Pharm D, PA-C (Washington State University) noted that cholesterol awareness among the public remains a barrier to effective intervention. A survey taken 6 years ago indicated, for example, that 78% of individuals knew that cholesterol is involved in cardiac health, 70% knew their total cholesterol values, and only 46% knew their LDL-C levels. Less than 50% of individuals with abnormal lipid profiles made a diligent effort to abandon unhealthy lifestyles. Additionally, a survey reported in 1996 observed marked differences in physician cholesterol monitoring habits (Figure 1).

Although awareness levels may be somewhat higher today, it remains important for physician assistants in primary care settings to identify candidates for lipid-lowering therapy, and to be certain that patients are treated optimally in order to achieve the ATP-III target guidelines for LDL-C, HDL-C, total cholesterol, and triglycerides.

In addition to initiating and monitoring pharmacologic intervention, Dr. White emphasized the role of lifestyle modification including physical activity, smoking cessation, weight loss, and nutritional intervention. He also emphasized the importance of blood pressure and blood glucose control in preventing heart disease. He cited evidence that intervention at the pre-diabetic stage can significantly reduce progression to type-2 diabetes. Patient and family education about the role of lipids in arterial health should be an integral part of the treatment strategy, as should enlisting family support. He placed special importance on the value of prescribing once-a-day medications to improve compliance. If a patient does not meet lipid-lowering targets within 12 weeks of initiating therapy, the treatment should be intensified.

Following his formal presentation, Dr. White presented two case studies designed to identify and initiate treatment, in two very different sets of circumstances, based on medical histories, family histories, physical examination, and laboratory findings including electrocardiogram and lipid profile.