New Clinical Guidelines on Cholesterol Management

Pharmacology Watch

The National Cholesterol Education Program (NCEP), a product of a collaboration of the National Heart, Lung, and Blood Institutes, the American College of Cardiology, and the American Heart Association, has updated its clinical practice guideline on cholesterol management. Based on several recent studies, that suggest that aggressive lowering of LDL cholesterol benefits high-risk patients, the new guidelines recommend aggressive treatment for patients who are at risk for coronary artery disease. Specifically, patients who are defined as "very high-risk" should be considered for aggressive treatment. Very high-risk patients are defined as those who have cardiovascular disease together with multiple risk factors (especially diabetes), severe and poorly controlled risk factors (such as continued smoking), or metabolic syndrome. The guideline had previously recommended drug therapy in these patients only if the LDL cholesterol was greater than 130 mg/dL, with a goal of 100 mg/dL. The new guideline recommends a treatment threshold of 100 mg/dL, with a goal of 70 mg/dL. "High-risk patients" are defined as those who have coronary heart disease, cerebrovascular disease, peripheral vascular disease, diabetes, or 2 or more risk factors (such as smoking or hypertension) that give a greater than 20% chance of having heart attack within 10 years. The LDL goal for these patients remains 100 mg/dL or less, and the new guideline now recommends drug treatment for those high-risk patients with an LDL > 100 mg/dL. Moderately high-risk patients are defined as those with 2 or more risk factors for coronary heart disease and a 10-20% risk of heart attack within 10 years. For these patients, drug therapy is recommended to lower LDL cholesterol under 130 mg/dL, and the option is given to treat to levels under 100 kg/dL. For lower-risk patients, the guideline was not changed. Drug therapies recommended by the NCEP include statins, bile acid resins, nicotinic acid, and ezetimibe. As in previous NCEP guidelines, the role of lifestyle modification is stressed. The full guideline can be viewed in the July 13th issue of Circulation, and highlights can be reviewed on-line at www.nhlbi.nih.gov.

Hypothyroidism and Pregnancy

A new study clarifies thyroid replacement therapy during pregnancy. Researchers at Harvard followed 19 women with hypothyroidism through 20 pregnancies, of which 17 resulted in full-term births. Thyroid function, HCG levels, and estradiol were measured before conception, every 2 weeks for the first trimester, and monthly thereafter. Oral doses of levothyroxine were increased during pregnancy to maintain preconception levels. The mean levothyroxine requirements increased 47% during the first half of pregnancy, plateaued by week 16, and remained stable until delivery. The authors recommend that hypothyroid women, who become pregnant, should increase their levothyroxine dose by 30% as soon as pregnancy is confirmed, and should be monitored carefully throughout the duration of their pregnancy (N Engl J Med. 2004;351:241-249). Although simple in its design, this is an important study because it is estimated that 1 to 2% of all pregnant women are hypothyroid and need replacement therapy. Hypothyroidism during pregnancy is associated with poor fetal outcomes including impaired cognitive development and increased mortality. Clinicians now have a clear guide to levothyroxine dosing changes during pregnancy.

Anti-Depressants and the Risk of Suicide

The risk of suicidal behavior is relatively high after starting anti-depressants, however, there is no statistical difference between anti-depressants used, according to a new study. Researchers reviewed data from the UK General Practice Research Database from 1993 to 1999, and compared nearly 160,000 users of 4 anti-depressant drugs, 2 SSRIs and 2 tricyclics; fluoxetine, paroxetine, amitriptyline, and dothiepin (a trycyclic anti-depressant not marketed this country). The outcome was first-time non-fatal suicidal behavior, or suicide in treated patients vs comparable patients who did not exhibit suicidal behavior. The relative risks for non-fatal suicidal behavior were 0.83 for amitriptyline (95% CI, 0.61-1.13), 1.16 for fluoxetine (95% CI, 0.90-1.50), and 1.29 for paroxetine (95% CI, 0.97-1.70), compared to those using dothiepin. Perhaps the most startling finding in this study was the 4.07 relative risk for suicidal behavior within 9 days of starting any anti-depressant (95% CI, 2.89-5.74), compared to patients prescribed an anti-depressant 90 days or more before their suicidal behavior. Even more concerning, was a relative risk for fatal suicide among new users of anti-depressants of 38.0 (95% CI, 6.2-231). The authors found no significant associations between use of the various anti-depressants and the risk of suicide (JAMA. 2004;292:338-343, ed 379-380). The accompanying editorial points out the timeliness of the study, with regard to current congressional hearings in the use of anti-depressants in young adults. The authors point out that the data on patients aged 10 through 19 is limited however, and further study may be needed in this group.

FDA Actions

The FDA has approved acamprosate (Campral-Merck) for the maintenance of abstinence in patients in alcohol recovery programs. The drug, which has been available in Europe for several years, may not work if patients are still drinking or abusing other drugs when initiating therapy. Acamprosate’s mechanism of action is unknown, but it appears to act in the central nervous system. Common side effects include diarrhea, nausea, vomiting, and abdominal pain.

The FDA has approved Merck and Schering-Plough’s Vytorin for the treatment of hypercholesterolemia. The drug combines Merck’s simvastatin (Zocor) with the jointly developed ezetimibe (Zetia), and is touted to be as potent as the so-called "super statins" atorvastatin (Lipitor) and rosuvastatin (Crestor). The new drug, which is expected to garner a hefty market share, will be priced at $2.30 a pill and should be available this fall.

Imiquimod (Aldera-3M) has received the expanded indication for treatment of superficial basal cell carcinoma. The drug, which is a topical immune modulator, was recently approved for treatment of actinic keratosis, and was initially approved for the treatment of venereal warts.

Brief Notes

The over-the-counter cough medications, dextromethorphan and diphenhydramine, are no better than placebo in suppressing cough in children (Pediatrics. 2004;114:e85-e90).

Many women are turning to phytoestrogens in lieu of hormone replacement therapy. The most commonly used of these, isoflavone soy protein, does not improve cognitive function, bone mineral density, or plasma lipids in healthy postmenopausal women (JAMA. 2004;292:65-74).

Ginseng reduces the effectiveness of warfarin in healthy volunteers. Patients on warfarin should be questioned as to their herbal supplement use (Ann Intern Med. 2004;141:23-27).


This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Telephone: (404) 262-5416. E-mail: leslie.hamlin@thomson.com. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.