College of American Pathologists
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One year later, cholesterol guidelines sinking in

One option for a more complete profile

July 2002
Anne Paxton

The first National Cholesterol Education Program guidelines for cholesterol testing and treatment, released in 1988, created a minor sensation, with the public immediately embracing the link they established between lowering cholesterol levels and lowering the risk of heart disease.

Following the 1993 release of the second version of the NCEP guidelines, people were almost as quick to catch on to the notion of "good" cholesterol versus "bad" cholesterol.

Because heart disease continues to be the leading cause of death in the United States, and because other cholesterol-related diseases are reaching epidemic status, the latest revision of the guidelines known as the Adult Treatment Panel III, or ATP III,1 could prove at least as significant. Released a year ago, it substantially changed laboratory testing and treatment recommendations, bringing millions of new patients into the cholesterol-testing fold and expanding the cardiac risk-factor menu.

For laboratories, it means conducting many more lipid tests, changing reporting formats, and paying even closer attention to accurate, standardized lipoprotein measurements, says G. Russell Warnick, MS, director of the Pacific Biometrics Research Foundation, Issaquah, Wash.

Warnick says the 2001 guidelines nearly tripled the number of patients expected to qualify for drug treatment, increasing it from 13 million to 36 million, or 18 percent of all adults.2 The number of persons qualifying for lifestyle intervention will rise to 65 million, fully one-third of the adult population. "The treatment net falls on a much higher proportion of the population," he says.

Warnick is the former director of the lipoprotein laboratory at the University of Washington’s Northwest Lipid Research Clinic—one of 12 research centers in the United States and Canada that participated in the Coronary Primary Prevention Trial, reported in 1984. This was the first major study to demonstrate that lowering cholesterol could lower the risk of heart disease.

"That was really the watershed study that focused attention on treating cholesterol and led to the formation of the NCEP, which has been the leader in promoting improvements in lowering cholesterol and reducing risk," Warnick says.

Studies dating back to the 1950s show cholesterol’s link with heart disease, says Gerald R. Cooper, MD, PhD, medical research director of the Clinical Chemistry Branch, Centers for Disease Control and Prevention. "The thing that really made a difference was the Lipid Research Clinics Trial. They knew that cholesterol changed whenever you eat a lot of fat or didn’t watch your diet, but they did not know whether increased serum cholesterol levels caused an increase in death. But the Lipid Research Clinics Trial between 1972 and 1982 definitely proved that lowering cholesterol actually lowered death."

Warnick, who co-edits a series called The Handbook of Lipoprotein Testing, describes the shifts in NCEP recommendations over the three reports since 1988. "The major change from 1988 to 1993 was to elevate the status of HDL [high-density lipoprotein] cholesterol as a protective or inverse risk factor for coronary artery disease, and NCEP began recommending measuring HDL whenever total cholesterol is measured."

The 2001 guidelines took a new tack by substantially expanding the range of disease that cholesterol testing can address as well as the indications for treatment. ATP III recommended categorizing people with diabetes and multiple risk factors but who did not have heart disease to the risk level of "CHD risk equivalent." It called for identifying patients with multiple metabolic risk factors (metabolic syndrome) as candidates for intensified therapeutic lifestyle changes. These changes increase the number of patients who qualify for treatment and mean that much more laboratory testing is likely to be required.

ATP III also calls for a complete lipoprotein profile, as the preferred initial test, rather than simply screening for total cholesterol and HDL alone. "Basically what they’re saying is that anybody 20 or over should have a profile consisting of total cholesterol, HDL, LDL [low-density lipoprotein], and triglycerides once every five years," says Gary Myers, PhD, chief of the Clinical Chemistry Branch at the CDC. "And then if total cholesterol is greater than 200, or HDL is less than 40, a followup lipoprotein profile would be appropriate."

The guidelines have also increased the number of patients to be selected for treatment by modifying the classification of lipids and lipoprotein levels. "There were three big changes," Warnick says. "The first is that the cutpoint for LDL cholesterol has been lowered—particularly for LDL levels that would trigger drug treatment." Identifying LDL cholesterol of less than 100 mg/dL as optimal in part reflects the success of the statins. These not only can lower cholesterol, he adds, but can reduce the risks of coronary disease and may alleviate the risk of type 2 diabetes and Alzheimer’s disease and mitigate bone loss contributing to osteoporosis.

"So far, the benefits of these drugs have far outweighed the side effects, so the Adult Treatment Panel was comfortable about pushing drug treatment into the lower categories," Warnick says.

The second change was raising the risk cutpoint for HDL from less than 35 mg/dL to less than 40 mg/dL, which the panel called a better measure of a depressed HDL. The third change—lowering the risk cutpoints for triglycerides to include moderate elevations—"has probably not gotten as much attention but is very dramatic," he says. The triglycerides cutpoint at which followup is triggered went from 400 in the original guidelines, to 200 in 1993, to 150 in 2001.

"The underlying rationale is that there’s more and more evidence that high triglycerides are also associated with increased risk of coronary disease, and triglyceride levels should be treated as well as high cholesterol levels," Warnick says.

In some cases, both analytes may be elevated, "but there are instances or conditions that elevate cholesterol without elevating triglycerides and vice versa," he adds. When both are elevated, "it can indicate a metabolic syndrome, a new buzzword emphasized more strongly in the latest guidelines. It’s a somewhat complicated constellation of symptoms that can include high blood pressure, insulin resistance, high triglycerides, low HDL, and central obesity, or the so-called ’apple’ shape. So those conditions, as well as diabetes itself, were given a lot more attention in 2001."

The wider net called for by ATP III is well-founded on the science, he says. "Studies have shown that treating a person with a moderate cholesterol elevation is as effective as treating a person with a high cholesterol elevation. Regardless of initial LDL level, if you lower LDL there’s a proportionate reduction of risk."

In 1993, treatment was recommended for people who had already had a heart attack or heart disease symptoms, but "now the cost-effectiveness of treatment has become better established, so the guidelines justify treatment over a higher proportion of the population," Warnick says.

Science aside, the time frame for widespread adoption of the ATP III recommendations is hard to predict. "When the first guidelines came out," Warnick says, "there was a lot of skepticism both in the popular press and among many medical professionals who did not accept the lipid hypothesis or did not accept that high cholesterol was a major contributor to heart diseases. So there was some resistance. But over the subsequent 14 years, I think the skepticism has largely faded."

In 1996, "a group of us did a survey after the release of the ATP II guidelines,"3 he says. "We found that about three years after release of the guidelines, very few clinical laboratories had actually adopted the recommended cutpoints for all lipids and lipoprotein analytes. But I would think, as time goes by, laboratories will be somewhat more aggressive in getting up to speed and implementing the new guidelines."

Warnick notes that professional organizations generally have supported the NCEP guidelines. Among those supporters have been the American Heart Association, American Association for Clinical Chemistry, and American College of Cardiology. "When they put out followup reports, it has been more in the sense of fine-tuning or updating the recommendations of NCEP," he says.

Laboratories primarily are hindered by a lack of communication and inertia, he adds. "Cholesterol, LDL, and HDL are only three of hundreds of analytes that clinical laboratories have to deal with." With labs having to keep abreast of so many analytes, "simply getting up to speed on the information is probably one factor," Warnick says. "The second issue would be figuring out how to incorporate the guidelines into a standard reporting format."

Triglycerides, which now have four cutpoints and five categories of risk, exemplify the difficulty. "When I go out and talk to laboratory people," Warnick says, "I ask them, can you actually make these fit into your laboratory information system? And it sometimes requires some juggling, streamlining, or simplifying to get complicated cutpoints to fit into the system."

An NCEP working group informally suggested that laboratories streamline reports by categorizing patients based on the three treatment targets of 100, 130, and 160 mg/dL for low-density lipoprotein cholesterol, rather than the five categories of medical decision value—optimal, near optimal, borderline high, high, and very high. For patients at highest risk, treatment is designed to bring LDL-C values below 100 mg/dL, while the target for patients with two or more risk factors is less than 130, and for all others is less than 160.

Sometimes, Warnick says with a chuckle, the guidelines have become so complicated that no one can figure out how to follow them to the letter. One example is the ATP III guidelines recommendation to use Framingham projections of 10-year absolute CHD risk—that is, the percent probability of having a CHD event in 10 years—through a formula based on the patient’s gender, age, total cholesterol, high-density lipoprotein cholesterol, blood pressure, and cigarette smoking. "So you can go to the National Institutes of Health and order a risk calculation and load it into a Palm Pilot or a computer, or go online and calculate it,4 but the process is somewhat cumbersome to go through, and I’ve heard some professionals question whether doing the calculations is really worth the trouble," Warnick says.

The Framingham Heart Study, a well-known Massachusetts research project that has followed a large sample of patients for more than 50 years, "has provided a huge and long-term base of data," he adds. "They have not only sampled the original cohort but the offspring of that original cohort as well, and the statisticians and cardiovascular epidemiologists associated with the study have been quite astute in continually mining the data for information."

Nevertheless, while cholesterol has proved to be a powerful marker, one sign of its limitations is that half the Framingham cohort that developed heart disease had not been identified with traditional lipid panels. Total cholesterol is obviously missing a lot of people, the CDC’s Dr. Myers says. "There are a percentage of individuals that have what are considered to be normal lipids, or slightly elevated lipids, but still suffer from some cardiovascular event like a myocardial infarction. We estimate that 50 percent of people with MI are individuals who may have normal or slightly elevated cholesterol."

ATP III did not make detailed recommendations about the measurement of emerging biochemical risk markers. "You can consider the NCEP Adult Treatment Panel recommendations more or less the tip of the iceberg," Warnick says. "It is only advocating measurements and conclusions that have been very well proven over years of research." ATP III, however, recognized that cardiac risk is influenced by other factors, such as Lp(a), homocysteine, high fasting glucose, and prothrombic and proinflammatory markers.

Expert laboratory panels of the NCEP had, earlier, recommended developing alternative methods to the routine LDL calculation approach using the Friedewald formula. This method, Warnick says, has been shown to be reasonably reliable for triglycerides of less than 200 mg/dL and marginal but acceptable up to 400 mg/dL. The diagnostics industry responded to this by developing fully automated tests for LDL, the so-called homogeneous assays.

Opinion differs on whether measuring LDL directly is better than calculating it. A recent study compared four of five new methods against each other and against the reference method at the CDC, says Dr. Myers. It found that because there are some specificity problems, these methods "didn’t really do much better than the Friedewald estimation that’s been used for years.5 There is pretty much a general feeling that the estimation triad is quite appropriate and good for triglyceride levels below 300 milligrams," he says.

Warnick points out that a draft policy from the Centers for Medicare and Medicaid Services could induce more clinicians to choose the direct LDL-C assay over calculation. CMS is proposing that the number of reimbursed lipid panels would drop from four to one while the number of ancillary individual tests would rise to six. The agency, therefore, would reimburse for any combination of total cholesterol, HDL-C, LDL-C, or triglycerides up to six tests.

A research review by Warnick and colleagues,6 published this year, found evidence to support using the homogeneous assays for LDL-C to supplement the Friedewald calculation in cases where the calculation is known to be unreliable, such as when triglycerides exceed 400 mg/L. But in routine practice, the authors call for more evaluation before recommending that the assays replace the calculation.

Atherotech, Liposcience, and Berkeley Heart Laboratories, says Warnick, are "fairly aggressively promoting" the measurement of lipoprotein subclasses, especially of small/dense LDL, as superior measures of risk (see "One option for a more complete profile," page 80). Noting that ATP III acknowledges the lipoprotein subclasses but does not recommend measuring them, Warnick says, "The idea is that by measuring not just the major lipoprotein classes but also the subclasses, one can get a better prediction. However, these tests are relatively new, and the jury is still out on their routine use."

But other emerging markers that might improve the cardiac risk detection rate have been a hot topic throughout the standard-setting world, especially homocysteine and the proinflammatory acute-phase reactant high-sensitivity C-reactive protein. Recent prospective epidemiological studies have shown that CRP is a strong and independent predictor of future coronary events in apparently healthy men and women.

"It’s quite a controversial question whether the lipoprotein subclasses are really helpful in improving prediction," says Warnick, maintaining that the evidence is not yet strong. "If one had to make a choice, the inflammatory marker is probably more useful than lipoprotein subclasses. The evidence has been accumulating in recent years that the CRP may be as important as HDL and LDL in identifying patients at risk."

Herbert Naito, PhD, asserts that both markers are helpful in assessing patient risk. "We need more studies on both to observe the outcome," says Dr. Naito, chief of ancillary testing and satellite facilities, Veterans Affairs Medical Center, Cleveland. "The next stage is whether there is evidence that if you lower the high-sensitivity C-reactive protein the outcome is more positive, and there’s some evidence for that, although we need more."

The CDC and the American Heart Association, he adds, recently held a conference to develop a position paper on emerging markers, particularly inflammatory markers, and the paper is expected to be issued soon.

Much is at stake as the medical community awaits further consensus on emerging markers. For example, a coverage policy bulletin on Aetna’s Web site says the "medical literature does not support the effectiveness" of C-reactive protein, homocysteine testing, intermediate and small density lipoproteins, or lipoprotein(a) enzyme immunoassay.

Even taking into account the ATP III recommendations, the insurer maintains that there is insufficient evidence to warrant covering these tests, either because they are only theoretically linked to CHD, there are conflicting study results, or the test methods "are not applicable to clinical practice."

Dr. Myers warns against putting too much credibility into the favorite "new risk factor of the month."

"I think where we are is we have new risk factors that have the potential of adding more information for assessing individuals at risk for coronary heart disease," he says. "These will all be supplemental to the traditional lipids and lipoprotein profile that’s recommended by the NCEP ATP. I don’t see any of these new risk factors taking the place of the traditional ones, but I do see them as possible adjuncts." The new risk factors would not be used in screening but would be used to supplement the lipid and lipoprotein profile. "In other words, if someone presents a certain risk classification, then we may look at them," he adds.

Dr. Myers emphasizes the need for more clinical trials, however. "Before these emerging markers can make the transition from research into clinical practice, we have to have clinical data to support their associations," he says.

Dr. Naito concurs. "However," he says, "about 18 percent of the patients undergoing bypass surgery have normal lipid and lipoprotein profiles. Obviously there are other etiologic factors that are contributing to the coronary artery disease process." These individuals and other high-risk persons, such as persons with type 2 diabetes or a family history of premature deaths due to CAD, "may benefit from assessing the presence of the emerging risk factors," he says.

Lipoprotein(a) standardization will be the topic of a workshop sponsored by the National Heart, Lung and Blood Institute later this year, and the CDC has finished the first phase of a project to standardize commercial methods for CRP.

While a few cardiologists now order tests like these, they are not widely performed in routine clinical practice and are still being transitioned from the medical research environment. Because of this, and because ATP III lowers and narrows the gap between cutpoints, the need for precise cholesterol testing has increased, highlighting the central importance of standardization, according to many experts. Fortunately, that’s an area in which cholesterol has been the leader, says Warnick, who has been active in standardization issues for years. "We don’t try to make everyone use the same method, but we put programs in place so that hopefully all the methods will give equivalent results."

It was the Framingham project leaders who approached the CDC nearly 45 years ago about standardizing cholesterol test results, says the CDC’s Dr. Cooper. "They said the cardiovascular epidemiologists had been swapping specimens and didn’t agree on the results, and everybody thought their own answers were right. So they wanted a neutral laboratory to set up a standardization methodology research laboratory and a standardization office."

Today, CDC’s cholesterol reference methodology laboratory network works with manufacturers to calibrate their instruments and ensure they give accurate results with the right coefficient of variation. "Right now, over 90 percent of the manufacturers are participating in that program," Dr. Cooper says.

Having a common cutpoint is necessary "so the whole country is on the same page," says Dr. Naito. "I’m pleased that CDC is stepping forward to standardize the country. It’s extremely important from analytical and chemical standpoints. They’ll also set up guidelines on preanalytical and postanalytical issues."

But Warnick worries that the emphasis on standardization could suppress innovation. "CDC has provided an invaluable service in allowing the entire world to tie into a common gold standard, but on the other hand, an overly rigid demand that every new test demonstrate agreement with the reference method could stifle innovation and basically lock practice into a 30-year-old technology," he contends.

The reference methods have never been proved to fractionate the lipoproteins in a way that gives the best prediction of risk, he says. "This has to do with the subclasses and, depending on how a particular method cuts those subclasses, it can affect the association with cardiovascular disease," Warnick says. An example is the "convenient and precise fully automated methods for HDL and LDL, the so-called homogeneous assays. The assays for HDL have been quite well accepted, but those for LDL have encountered resistance—and part of that is they don’t exactly separate the lipoproteins the way the reference method does," he says.

To address the problem, Warnick has outlined ways manufacturers could demonstrate that their methods are as good as or better than the reference methods in predicting risk. "I have long been an advocate of standardization, but when I talk to people about the concept, many of them seem to agree that we have been so fixed on standardization and making everyone agree with reference methods, there’s been a tendency to throw the baby out with the bathwater, to discourage access to some of the newer and more innovative methods, or even to create a disincentive for manufacturers to innovate."

Says Dr. Myers: "So much rests on the measurement of total cholesterol and LDL and HDL that it’s still very important that we have good reliable measurement. We can’t take it for granted that we’ve solved cholesterol measurement problems and everything’s okay. It’s still something that needs to be watched and maintained. We’re still basing intervention decisions on a very specific number, and because of that, reliability, accuracy, and precision in those measurements are still very important."

As to the impact of ATP III, Dr. Cooper believes laboratories are well-equipped to handle the new parameters of cholesterol testing. Managing analytical performance guidelines and finding ways to report easily interpretable results will be the chief concerns. "I think with the help of the manufacturers in developing really excellent equipment, and with the programs like CDC’s and CAP’s and those of other quality assurance groups, laboratories as well as cardiologists have been sensitized to expect accurate results," he says. So adjusting to ATP III "will be a question of replanning what they’re doing. All it takes is for them to be a little flexible and recognize what’s going to happen-and get in there."

1.  National Cholesterol Education Program Expert Panel. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication. Bethesda, Md.: National Heart, Lung, and Blood Institute; 2001.

2.  Warnick GR, Myers GL, Cooper, GR, et al. Impact of the third cholesterol report from the Adult Treatment Panel of the National Cholesterol Education Program on the clinical laboratory. Clin Chem. 2002;48:11-17.

3.  Kroll MH, Cole TG, Rifai N. Standardization of lipoprotein reporting. Am J Clin Pathol. 2000;114:696-702.

4.  See

5.  Miller WG, Waymack PP, Anderson FP, et al. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem. 2002;48:489-498.

6.  Nauck M, Warnick GR, Rifai N. Methods for measurement of LDL-cholesterol: a critical assessment of direct measurement by homogeneous assays versus calculation. Clin Chem. 2002;48(2):236-254.

Anne Paxton is a writer in Seattle.