Reversal of Atherosclerosis Via Intensive Statin Therapy

Pharmacology Watch

Aggressive LDL lowering with statins, so-called "very intensive statin therapy," leads to reversal of coronary atherosclerosis, according to a new study. The ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) trial, a perspective, open label, blinded end-points trial, utilized the potent statin rosuvastatin in evaluating whether very intensive statin therapy resulting in LDL cholesterols in the low 60s associated with increases in HDL cholesterol could reverse atherosclerosis. Five hundred and seven patients were initially evaluated with intravascular ultrasound (IVUS) to determine baseline atheroma burden. Patients were then treated with intensive statin therapy with rosuvastatin 40 mg daily for 24 months, which resulted in an average LDL cholesterol of 60.8 mg/dL (mean reduction, 53.2%) and increased HDL cholesterol by 14.7%. IVUS was performed again at 24 months. The mean change in atheroma volume in the most diseased 10 mm sub segment was -6.1 (10.1) mm3, with a median of -5.6 mm3 (P < .001 vs baseline). Change in total atheroma volume showed a 6.8% median reduction. Adverse events were infrequent. Specifically there were no cases of rhabdomyolysis.

The authors conclude that lowering LDL-C to levels below currently accepted guidelines, when accompanied by significant increases HDL-C, can regress atherosclerosis in coronary disease patients, and is indicated for high-risk patients with established coronary disease (JAMA. 2006;295:1556-1565). An accompanying editorial notes that the study had several limitations, including lack of a control group or a comparator drug. They also note that the modest plaque reduction noted in this study "may not be the best measure of the treatment's effect on hard cardiovascular end points", however, they do applaud the pioneering work using intravascular ultrasound to help understand the anatomy and pathophysiology of coronary atherosclerosis and the effect of medical therapy on atheroma (JAMA. 2006;295:1583-1584).

Alternative Therapy for Depression?

Patients who fail SSRI treatment for depression may respond to an alternative medication, or the addition of a second medication, according to 2 studies in the March 23 New England Journal of Medicine. In the first study, 727 adults with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram (Celexa) were randomized to receive sustained release bupropion (Wellbutrin) in a maximal daily dose of 400 mg, sertraline (Zoloft) at a maximum daily dose of 200 mg, or extended release venlafaxine (Effexor-XR) at a maximal daily dose of 375 mg for up to 14 weeks. The primary outcome was remission of symptoms based on the Hamilton Rating Scale of Depression (HRSD-17). Secondary outcomes included scores on the Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR-16). Remission rates, as assessed by the 2 scales, respectively, were bupropion - 21.3% and 25.5%, sertraline - 17.6% and 26.6%, venlafaxine - 24.8% and 25.0%. Response rates based on the QIDS-SR-16 were bupropion 26.1%, sertraline 26.7%, and venlafaxine 28.2%. There was no significant difference with respect to outcomes, tolerability, or adverse effects among the 3 drugs.

The authors conclude that after unsuccessful treatment with an SSRI, 1 in 4 patients have a remission after switching to another antidepressant, and all 3 drugs in the trial were reasonable choices (N Engl J Med. 2006;354:1231-1242). Another option for treating patients who failed treatment with citalopram was explored in the second study in the same issue. In the study, 565 adults who had a nonpsychotic major depressive disorder without remission after 12 weeks of citalopram therapy were randomized to receive add-on therapy with sustained release bupropion up to 400 mg per day, and 286 were randomized to receive buspirone (Buspar) at a dose of up to 60 mg per day. The same depression rating scales were used in this study as in the previous study. For bupropion and buspiron, respectively, HRSD-17 remission rate was 29.7% vs 30.1%, QIDS-SR-16 remission rate was 30.9% vs 32.9%, and QIDS-SR-16 response rate was 31.8% vs 26.9%. Bupropion was associated with a greater change in QIDS-SR-16 score, as well as the overall lower QIDS-SR-16 score at the end of the study and a lower dropout rate to due to intolerance (12.5% vs 20.6%, P < 0.009).

The authors conclude that the addition of bupropion or buspirone to citalopram is useful; however, the addition of bupropion may have some advantages, including a greater reduction in the severity of symptoms in fewer side effects (N Engl J Med. 2006;354:1243-1252).

FDA Actions

The FDA has approved the first generic HIV/AIDS drug for use in the United States. Zidovudine, manufactured under the trade name Retrovir by GlaxoSmithKline, was initially approved in 1987, and the company has had exclusive manufacturing rights until the drug's patent expired in September 2005. The generic is made by Aurobindo Pharma LTD of India. This is the same company that recently received approval from the FDA to co-package 3 antiretroviral drugs for the treatment of HIV/AIDS outside the United States. The regimen consists of lamivudine/zidovudine combination tablet along with efavirenz tablets. The co-packaging of these products has met the clinical safety, efficacy, and manufacturing quality standards required by the FDA. The approval is part of the Presidents Emergency Plan for offering full HIV treatment regimens for targeted areas of the world that are at risk to prevent HIV transmission and to treat AIDS and associated conditions. Patents and exclusivity prevent marketing of this combination in United States.

The FDA has approved a transdermal patch for the treatment of children with attention-deficit hyperactivity disorder. The patch delivers methylphenidate, the same ingredient found in Ritalin, in a daily patch that is applied early in the morning and removed 9 hours later. Methylphenidate patch is manufactured by Shire Pharmaceuticals and Noven Pharmaceuticals under the trade name Daytrana.

Salix pharmaceuticals has received approval to market a new tablet bowel prep for colon cleansing prior to colonoscopy. The virtually tasteless sodium phosphate tablets are an alternative to traditional liquid PEG bowel preps. The recommended dose is 32 tablets taken orally with a total of 2 quarts of clear liquids, administered as 4 tablets with 8 ounces of liquid every 15 minutes. Twenty tablets are given on the night prior to the procedure, with the remaining 12 tablets administered 3 to 5 hours prior to colonoscopy. Sodium phosphate tablets will be manufactured under the trade name OsmoPrep.

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) 262-5416. E-mail: