Improving outcomes in established coronary artery disease
Improving Outcomes in
Established Coronary Artery Disease
LDL Cholesterol
Pathologist’s Summary
Coronary artery disease (CAD) is the leading cause of death and is a major cause of morbidity in the United States. The American Heart Association reports that approximately 12.2 million people in the United States have CAD. Approximately 1% of the population dies each year from this disease. Five- and 10-year cumulative costs (in 1995 dollars) for all patients with CAD are estimated to be $71.5 and $126 billion respectively. Despite these dismal numbers, rates of recurrent myocardial infarction have decreased over the past several years, and survival after myocardial infarction has improved. This is likely due, in part, to efforts targeted at secondary prevention of cardiovascular events. Identifying patients with hyperlipidemia and initiating therapy, when indicated, is an important component in these efforts.
Supporting Evidence
The role of increased concentrations of serum cholesterol and low-density lipoprotein (LDL) cholesterol in the development of CAD has been established through a variety of study types. As a result of these studies, the Adult Treatment Panel of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) published recommendations for lipid-lowering therapy for secondary prevention of coronary artery disease. Subsequently, even more compelling evidence of the effectiveness of lipid-lowering therapy in secondary prevention of coronary artery events was provided in three major trials with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins).
Recently, the Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol (Adult Treatment Panel III) stressed the need for early and aggressive therapy for increased LDL cholesterol in established CAD.
Cholesterol reduction is cost-effective when it is used for the secondary prevention of coronary artery disease. Goldman et al estimated that 20 mg/d of lovastatin saves lives and saves costs in younger men with cholesterol levels above 250/dL (6.47 mmol/L). Its use is associated with a favorable cost-effectiveness ratio regardless of the cholesterol level except in young women with cholesterol levels below 250 mg/dL (6.47 mmol/L) (Goldman et al. JAMA 1991;265:1145-1161). Despite the proven benefit of lipid-lowering therapy and the inclusion of lipid analysis and therapy in several major secondary coronary disease guidelines, utilization remains low (Suerta CA, et al. Am J Cardiol 1999;83:1303-1307 and EUROASPIRE I and II Group. Lancet 2001;357:995-1001).
Current Guidelines
The National Cholesterol Education Program (NCEP), American College of Cardiology, American Heart Association, American College of Physicians - American Society of Internal Medicine, and the Agency for Health Care Policy and Research Guidelines have developed guidelines for management of patients with coronary artery disease. All recommend annual lipid profiles for patients with CAD and therapy for those with elevated LDL cholesterol levels. The National Committee for Quality Assurance (NCQA) has also sanctioned the use of LDL cholesterol-lowering therapy in patients with CAD.
Recommendations for Screening
For secondary prevention in adults with evidence of CAD or other clinical evidence of atherosclerotic disease, a fasting lipid panel should be performed as an initial laboratory test. The lipid profile should include total cholesterol, HDL cholesterol, triglycerides and LDL cholesterol (AMA Current Procedural Terminology code 80061). A fasting specimen is recommended as recent food intake produces transient increases in plasma triglycerides of 50% or more and decreases of up to 10 to 15% in LDL and high-density lipoprotein (HDL) cholesterol, depending on the fat content of the meal.
The patient should be as close to metabolic “baseline” as possible. In the patient with unstable angina or acute myocardial infarction, a lipid panel should be performed within 24 hours of admission; otherwise, a minimum four-week waiting period is recommended to allow lipid fractions to stabilize. Normal physiologic variations occur and it is difficult to evaluate a patient based on a single measurement. NCEP guidelines recommend that the average of two to three serial specimens be used as the parameter for risk assessment.
While the importance of recognizing and treating elevated LDL cholesterol in patients with CAD is known, optimal management cannot be provided without a reliable, accurate measurement of its blood level. In most of the large-scale clinical and epidemiological studies that established the relationship between lipids, lipoproteins, risk for CAD and the efficacy of cholesterol lowering, the measurements were traceable to CDC reference methods. Laboratories do not necessarily need to use identical analytic methods; however, other methods should be capable of giving values equivalent to those on which the relationships between lipids, lipoproteins, and risk for coronary heart disease were established. Participation in consensus standardization processes such as the NHCBI/CDC Lipid Standardization Program and in proficiency testing programs such as those offered by the College of American Pathologists (CAP) are useful methods of documenting equivalent findings between local laboratories and epidemiological databases.
Most laboratories use enzymatic methods for cholesterol measurement, as they are accurate, precise, and easy to use. If appropriate reagents, instruments, and calibration material with assigned values that are traceable to CDC reference methods are used, interlaboratory variation is reduced. If used appropriately, a 1998 College of American Pathologists Q-probes study showed that few out-of-control events occur using current methods of cholesterol testing. These events are usually resolved rapidly with little impact on laboratory operation.
Methods of LDL cholesterol measurement assume that total cholesterol is composed primarily of very low-density lipoprotein (VLDL), LDL, and HDL. Commonly, LDL cholesterol is determined using an indirect method in which cholesterol, triglyceride, and HDL cholesterol are directly measured and LDL cholesterol is calculated from the primary measurements by the Friedewald equation:
[LDL chol] = [Total chol] – [HDL chol] – [Triglyceride]/5
where all concentrations are given in milligrams per deciliter (triglyceride/2.22 is used when LDL cholesterol is expressed in millimoles per liter). Very low-density lipoprotein cholesterol is estimated in the factor [triglyceride]/5 based on the average ratio of triglyceride to cholesterol content in VLDL. The NCEP has supported the use of this equation in appropriate clinical situations, and, in practice, the Friedewald equation can be used in most cases.
Situations in which the Friedewald equation should not be used do exist. In these situations, lipid particles are present which have triglyerides: cholesterol content ratios different than 5:1. In the nonfasting state, triglyceride-rich chylomicrons are present in the blood, which lead to an overestimation of VLDL cholesterol and an underestimation of LDL cholesterol (as much as 20%). When the triglyceride level is greater than 250 mg/dL (2.8 mmol/L), triglyceride-rich chylomicrons, chylomicron remnants, and VLDL remnants are present which also lead to an overestimation of VLDL cholesterol and an underestimation of LDL cholesterol. Conversely, in patients with Type III hyperlipoproteinemia, the presence of relatively cholesterol-rich ß-VLDL in the blood leads to an underestimation of VLDL cholesterol and an overestimation of LDL cholesterol. The impact on therapeutic intervention is obvious. Those patients with nonfasting cholesterol levels or hypertriglyceridemia are at risk for undertreatment while those with Type III hyperlipoproteinemia are at risk for overtreatment.
The ultracentrifugation-polyanion precipitation method (AMA Current Procedural Terminology code 83721) is often used in samples for which the Friedewald equation is inappropriate. This procedure determines LDL cholesterol as the difference between total cholesterol and HDL cholesterol after removal of VLDL and chylomicrons by ultracentrifugation. This is the CDC reference method used to standardize the epidemiological data that formed the basis for the NCEP recommendations. Utilization of this method is limited by its required prolonged centrifugation. In the past few years, several new direct assay systems have been developed to estimate LDL cholesterol under nonfasting conditions and in the setting of elevated triglycerides. However, even with direct assays, post-prandial LDL cholesterol measured values will be slightly lower than fasting samples. This is due to mobilization of cholesterol out of LDL and HDL into chylomicrons and VLDL as they are synthesized. The decreases are moderate, usually 3-5%, but can be higher in some individuals. This may be of significance in borderline cases of elevated LDL cholesterol. Direct LDL cholesterol measurement does not assess triglyceride and HDL cholesterol levels that also provide useful information for risk of secondary cardiovascular events.
Recommendations for Therapy
When a patient with CAD has an LDL cholesterol level 130 mg/dL (3.36 mmol/L), the Adult Treatment Panel III recommends immediate initiation of drug therapy. Many authorities recommend a trial of maximum diet therapy if the LDL cholesterol is 100-129 mg/dL (2.59-3.33 mmol/L). If LDL cholesterol remains within this range, clinical judgment must be used as to whether to use cholesterol-lowering drugs. Other authorities recommend immediate drug therapy for this group. If one drug brings the LDL cholesterol to this range, clinical judgment is required as to determine if a second drug should be added.
Future
The laboratory will likely play an increasing role in identifying patients at risk for CAD events. Recent meta-analysis of prospective studies indicates that elevated triglycerides are also an independent risk factor for CAD. The Adult Treatment Panel III also stresses the need to identify patients with low HDL levels. The role of ApoB, homocysteine, C-reactive protein, LDL and HDL lipoprotein subspecies in the development of CAD needs to better defined in future prospective studies.
Outcome Study
Given the compelling evidence that lowering LDL cholesterol improves outcomes in patients with established coronary artery disease, the effectiveness of health care providers in screening for elevated LDL cholesterol and providing therapy when indicated can be a useful outcome measure. A collaborative effort between clinicians and laboratories can produce meaningful outcome data. As a result, the effectiveness of interventions such as lipid clinics, case management, collaboration with pharmacists, and numerous other modalities can be assessed.
Using current information systems, patients with known coronary artery disease can be recognized by ICD-9 billing codes. Patients with acute myocardial infarction can be identified by hospital laboratories as those patients with elevated troponin levels. Laboratory information systems can then search for lipid panel and LDL cholesterol values in the selected patient group. Data can be displayed on a spreadsheet. For screening outcomes, this alone provides useful utilization information. Chart reviews may be required to assess utilization of drug therapy in those CAD patients with elevated LDL cholesterol levels. If desired, additional outcomes of those not receiving therapy can be further characterized by such factors as: a) no recommendation for therapy, b) therapy recommended but refused by patient, c) contraindication to therapy. For those patients started on therapy, success in reaching target LDL cholesterol can also be assessed. Data can then be summarized for a reference time period. For a single practitioner or a health-care entity, data from serial time periods can be compared to judge the usefulness of various interventions. Data obtained can also used to meet Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and NCQA expectations.
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