Higher HDL Cholesterol in Statin Therapy, Key to Slowing Atherosclerosis?

Pharmacology Watch

Aggressive statin therapy is associated with slowed progression and even regression of atherosclerosis. A new study suggests that, when monitoring statin therapy, increases in HDL cholesterol may be as important as decreases in LDL cholesterol in preventing disease progression. Researchers from the Cleveland Clinic reviewed 4 large studies from United States, North America, Europe and Australia in which 1,455 patients with angiographic coronary disease underwent serial intravascular ultrasonography while receiving aggressive statin therapy for 18 or 24 months. During therapy, mean LDL levels dropped from 124.0 mg/dl to 87.5 mg/dl, and mean HDL levels increased from 42.5 mg/dl to 45.1 mg/dl, and LDL to HDL ratios were reduced from a mean of 3 to 2.1 (P < 0.001 for all). These changes were accompanied by a small, but statistically significant decrease in atheroma volume as measured by intravascular ultrasound. The largest decrease in atheroma volume was associated with patients with LDL cholesterol less than the mean of 87.5 mg/dl, and percentage increases in HDL cholesterol of greater than 7.5%. The authors conclude that when treating with statins, decreases of LDL cholesterol and increases in HDL cholesterol are independently associated with regression of atheroma volume. They also note that these changes were not associated with reductions in clinical events or improved clinical outcomes and that more research is needed (JAMA. 2007; 297:499-508).

Citalopram Useful for Depression in CDA Patients

Major depression affects up to one quarter of patients hospitalized with coronary artery disease and these patients have a worse prognosis than non-depressed patients. A new study from Canada compares the efficacy of citalopram vs interpersonal psychotherapy in reducing depressive symptoms among these patients. The study randomized 284 patients with CAD and major depression to 12 weeks of interpersonal psychotherapy plus clinical management vs clinical management only, and a second randomization compared 12 weeks of citalopram 20-40 mg/day vs placebo. The main outcomes were scores on objective depression scales. Citalopram was superior to placebo in reducing depression scores (P = 0.005), but interpersonal psychotherapy was ineffective, being no better than clinical management. The authors conclude that citalopram administered in conjunction with weekly clinical management was effective in treating depression whereas there was no evidence of value for interpersonal psychotherapy. The authors suggest that citalopram or sertraline (based on previous studies) should be considered as first-step treatment for patients with CAD and major depression (JAMA. 2007;297:367-379). An accompanying editorial agrees that citalopram and sertraline are safe and effective for treatment of depression in patients with coronary heart disease, and suggests physicians should actively screen for signs and symptoms of depression in these patients. However, there is not yet any evidence that treating depression in this patient population reduces subsequent cardiac events (JAMA. 2007;297:411-412).

When to Stop Anticoagulation Before Surgery?

For patients on warfarin who have been bridging therapy with low molecular weight heparin (LMWH) prior to surgery, when is the best time to stop anticoagulation? A new study suggests that the evening before surgery is too late. Researchers in Ontario, Canada, looked at 80 patients who were scheduled for surgery or invasive procedures and were bridged with LMWH. All 20 patients had normal renal function and were given enoxaparin 1 mg/kg of body weight twice daily with the last dose administered the evening before surgery. Blood anti-factor Xa heparin levels were measured shortly before surgery, an average of 14 hours after the last dose. Two-thirds of patients had anti-Xa heparin levels of 0.5 U/ml or higher shortly before their invasive procedure. Patients with higher BMIs were more likely to have higher levels as were patients with lower creatinine clearances. The authors conclude that preoperative bridging with twice daily enoxaparin results in high residual anti-Xa heparin levels if the last dose is given the evening before surgery. They recommend that the last dose be given the morning on the day prior to surgery (Ann Int Med. 2007;146:184-187).

Drug Warnings: Ranibizumab and Bevacizumab

Both of Genentech's anti-angiogenic agents, ranibizumab (Lucentis) and bevacizumab (Avastin), have been the subject of new warnings from the company and the FDA. Ranibizumab, which is used for the treatment of neovascular (wet) macular degeneration, has been associated with increased risk of stroke in elderly patients. The drug, which is administered as an monthly intraocular injection, was found to be associated with a 1.2% risk of stroke at the recommended dose of 0.5 mg compared to a 0.3% risk associated with the lower-than-recommended 0.3 mg dose (P = 0.02) at an average follow-up of 230 days. Patients who had a history of stroke were at the highest risk. Bevacizumab, which is approved for treatment of non-small cell lung cancer and metastatic colorectal cancer, was recently found to be associated with increased risk of gastrointestinal perforation and potentially fatal pulmonary hemorrhage. Gastrointestinal perforation was seen as a complication of patients treated for colorectal cancer, while pulmonary hemorrhage was seen in patients receiving chemotherapy plus bevacizumab for lung cancer. Other bleeding complications seen in bevacizumab-treated patients including GI hemorrhage, subarachnoid hemorrhage and hemorrhagic stroke.

Growth Hormone Treatment, More Harm Than Good

The January 16, 2007, Annals of Internal Medicine includes a review of the safety and efficacy of growth hormone in the healthy elderly. The review was undertaken because growth hormone is widely recommended and sold as an anti-aging agent in this population. The authors reviewed 31 articles, which included a total of 220 participants who received growth hormone. The mean age was 69 and patients were generally overweight. Treatment duration mean was 27 weeks. Growth-hormone-treated patients compared to placebo- treated patients were noted to have decreases in overall fat mass and increases in overall lean body mass, but weight did not change significantly. Total cholesterol decreased, although not significantly, after adjustment for body composition changes. Bone density and other lipid levels did not change. Those treated with growth hormone were significantly more likely to experience soft tissue edema, and arthralgias, carpal tunnel syndrome, and gynecomastia as well as a slightly increased rate of diabetes and impaired fasting glucose. The authors conclude that growth hormone use in the elderly is associated with small changes in body composition and an increased rate of adverse events and cannot be recommended (Ann Int Med. 2007; 146:104-115).

FDA Actions

The FDA has warned against unsupervised use of topical anesthetic products for cosmetic procedures. The agency has received multiple reports of adverse events associated with patients applying excess amounts of topical agents containing lidocaine, tetracaine, benzocaine, and prilocaine. Two women who used topical anesthetics with lidocaine and tetracaine died after applying the creams to their legs and wrapping their legs in plastic to increase absorption. Healthcare professionals are cautioned to prescribe topical anesthetics with caution in the lowest concentration consistent with pain relief goals and to advise patients in their safe use.

The FDA has approved Roche's orlistat for over-the-counter use to facilitate weight loss. The drug, available in prescription form under the trade name "Xenical," blocks absorption of fat by inhibiting pancreatic lipase thus preventing triglyceride absorption in the small bowel. The over-the-counter version will be available as a 60 mg dose, half the prescription dosage. Orlistat over-the-counter will be marketed as "Alli."

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. 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. Questions and comments, call: (404) 262-5431. E-mail: jennifer.corbett@ahcmedia.com.