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9/17/2004

Updated Cholesterol Guidelines Can Challenge Clinicians

Kate Traynor

As part of September's National Cholesterol Education Month activities, the National Heart, Lung, and Blood Institute is urging health care practitioners to promote the updated National Cholesterol Education Program (NCEP) clinical practice guidelines on cholesterol management.

The guidelines were updated in July to address the results of recent studies of aggressive lipid lowering in patients at moderate or greater risk for cardiovascular events. Among the new recommendations for patients at very high risk for a cardiovascular event is an optional low-density-lipoprotein (LDL) serum cholesterol goal of less than 70 mg/dL.

According to the guidelines, patients for whom the 70-mg/dL goal is appropriate have at least a 20-percent risk of suffering a cardiovascular event within 10 years. These patients have coronary heart disease (CHD) or so-called CHD risk equivalents, such as peripheral atherosclerosis, abdominal aortic aneurysm, or diabetes mellitus. Also included in this group are patients with at least two CHD risk factors, such as hypertension, cigarette smoking, a low serum high-density-lipoprotein cholesterol level, or a family history of CHD.

NCEP had previously recommended that high-risk patients receive lipid-lowering therapy to maintain serum a LDL cholesterol level below 100 mg/dL, which is still the primary target for this risk group.

The new recommendations continue to describe therapeutic lifestyle modifications as a cornerstone of cholesterol management and strongly emphasize the use of hydroxymethylglutaryl-coenzyme A reductase inhibitors, or statins, to help patients reach therapeutic goals.

"Most clinicians have accepted that statins are golden drugs [as] first-line therapy for dyslipidemia," said Joseph Saseen, Pharm.D., associate professor of clinical pharmacy and family medicine at the University of Colorado Health Sciences Center in Denver.

Saseen manages lipid therapy for outpatients at a family practice office. "We treat everything from low risk to very high risk patients," he said. "We see the whole gamut."

Saseen described himself as "very much biased toward using statins" to control cholesterol and reduce cardiovascular disease. But he said that although some of the new recommendations from NCEP are firmly grounded in the literature, others "are more of an extrapolation of results or an estimation" of benefits in certain patient populations.

He said the scientific literature supporting NCEP's 70-mg/dL goal "is pretty strong for the patients who have cardiovascular disease plus acute coronary syndrome" and that he is comfortable with this goal for the few patients in his practice who meet these criteria. Additional candidates for the optional goal may be patients with diabetes mellitus and a baseline serum LDL cholesterol of around 90, he said. For other high-risk patients, Saseen said NCEP's optional target goal is based more on expert opinion than evidence.

Saseen noted that maintaining the serum LDL cholesterol level below 70 mg/dL is a challenge for many patients.

"For most people to really get to the goal, many of them require more than one drug," he explained. Appropriate therapy would most likely involve "a statin in combination with...ezetimibe, or a bile acid sequestrant, or niacin," Saseen said.

Carla Frye, director of the ASHP Section of Clinical Specialists and Scientists, said strict adherence to NCEP's updated guidelines can complicate drug-therapy decisions for patients she treats at the Lipid Clinic of the Medical Diagnostic Center at Indiana University Hospital in Indianapolis.

Frye said patients are referred to the tertiary care clinic after unsuccessfully trying to improve their lipid profile through lifestyle modifications and statin therapy. "We get these patients and see if we can do anything else" to control their cholesterol, she explained.

For some high-risk patients, Frye said, getting their LDL cholesterol level under the 100-mg/dL goal is problematic even without considering the optional below-70-mg/dL goal.

"If I have a patient that I've been treating in my clinic, and we've gotten their LDL cholesterol down to 105 from 190...we just improved their risk significantly," Frye said.

"But it's not below 100," she added. "Does that mean that I have to go ahead and try harder and put them at greater risk for drug interactions and side effects?"

Common adverse events associated with statins include gastrointestinal symptoms and muscle aches. Rarely, muscle aches may progress to myopathy or rhabdomyolysis, a potentially deadly condition. Baycol, Bayer AG's cerivastatin product, was withdrawn from the U.S. market in 2001 after it was associated with at least 31 deaths from rhabdomyolysis.

Concurrent use of a statin and gemfibrozil or niacin, both of which are used to manage lipid levels, can increase the risk of rhabdomyolysis. The risk is also raised when statins are taken with other common drugs, including erythromycin, clarithromycin, some azole antifungals, cyclosporine, and nefazodone. A 2002 joint report (PDF) from the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute discusses the association between statins and myopathy and describes how to manage patients' risk for the disorder.

Saseen noted that the risk of adverse drug interactions varies among statins, emphasizing the need for good clinical judgment.

"For those [statins] that have the potential for drug interactions, we have to be careful" with the dosage, he said.

Frye's preference when managing a patient whose lipid profile has improved substantially but has not quite reached the target goal is "to stay the course" instead of immediately intensifying therapy. Frye said she favors advising such patients that adding drugs or increasing drug dosages may increase patients' costs and adverse-event risks, which must be weighed along with the benefits of more aggressive treatment.

She noted that lifestyle modifications greatly influence cardiovascular risks but are difficult to sell to patients.

"In my clinic, probably the best thing people could do to improve their cardiovascular risk is to stop smoking," Frye said. "That has more benefit than any of the statin drugs."

A report published after the release of the NCEP update compared a high-dose regimen of simvastatin—40 mg daily for one month, beginning within days of hospitalization and followed by 80 mg daily thereafter—with four months of placebo treatment followed by 20 mg of simvastatin daily.

During the first four months of the study, simvastatin was no better than placebo for averting cardiovascular events or death. After the four-month point, the 80-mg/day simvastatin regimen reduced cardiovascular events and death by 25 percent, compared with the 20-mg daily dose.

Nine of the 2,265 patients randomized to the high-dose simvastatin group suffered myopathy or rhabdomyolisis during the 80-mg/day phase of the trial. No cases of mypathy or rhabdomyolysis occurred among these patients during the 40-mg/day phase of the study. One patient was diagnosed with myopathy while taking placebo, but none of the 2,232 patients assigned to this group suffered either complication while taking 20 mg of simvastatin per day.

In an editorial accompanying the report, Cleveland Clinic Foundation cardiologist Steven E. Nissen stated that the "increased myopathy rate applies only to a specific dose of a single agent and should not tarnish this remarkable class of drugs."

Saseen said he is comfortable with high-dose statin therapy but would not start patients on the highest dosage mentioned in the product's labeling.

"When the evidence supports starting at a higher dose, that's when I recommend it," he said. In the case of simvastatin, Saseen said he is "very comfortable" putting patients on a 40-mg-per-day regimen, but he agrees that the newly available evidence does not favor an 80-mg-per-day dosage.