Another Study Implicates Avandia

Pharmacology Watch

In this issue: Rosiglitazone (Avandia) implicated in yet another study; Prilosec and Nexium not associated with cardiac events; Anastrozole (Arimidex) shown more effective than tamoxifen for treatment of early-stage breast cancer; antibiotics show no effect on sinusitis; FDA actions.

The handwriting may be on the wall for GlaxoSmithKline's rosiglitazone (Avandia) with yet another study implicating the drug with an increased risk of heart failure, cardiovascular events and mortality when compared to other oral hypoglycemic agents. The study was a nested case-control analysis of a retrospective cohort study using health care databases in Ontario. The patient population was nearly 160,000 older (>65 years of age) type 2 diabetics on at least one oral agent. The primary outcome was emergency visit or hospitalization for congestive heart failure, while secondary outcomes were AMI and all-cause mortality. After a mean follow-up of 3.8 years, monotherapy with rosiglitazone was associated with an increased risk of CHF (RR 1.60; 95% CI 2.10; P<.001 ami ci>P=.02), and death (RR 1.29; 95% CI, 1.02-1.62; P=.03). Thiazolidinediones in general were evaluated in the study, but the adverse effects were limited to rosiglitazone. Adverse effects were found in patients who took the drug as a single agent or in combination with other hypoglycemic drugs (JAMA. 2007;298:2634-2643). Meanwhile, two large pharmacy benefit managers, Prime Therapeutics and HealthTrans, have dropped rosiglitzone from their formularies and the Department of Veterans Affairs is severely limiting the drug's use. Sales of the drug dropped 27% in the second quarter of 2007 and 39% in the third quarter.

Prilosec and Nexium Cleared

Omeprazole (Prilosec) and esomeprazole (Nexium) are not associated with increased rates of cardiac events, according to statements on the FDA web site. Concern was raised after AstraZeneca submitted data from two long-term studies in patients with severe gastroesophageal reflux to assess treatment with either drug vs surgery. Evaluation of secondary outcomes raised the question of whether long-term use of these drugs increased risk of cardiovascular events including sudden death. In a statement published on the FDA web site ( on December 10, the agency states that it has completed a comprehensive scientific review of known safety data for both drugs. Based on review of the two studies presented by AstraZeneca and analysis of 14 comparative studies of omeprazole, no evidence of increased rate of cardiac events was seen. "Therefore, FDA continues to conclude that long-term use of these drugs is not likely to be associated with an increased risk of heart problems. The FDA recommends that health-care providers continue to prescribe, and patient's continue to use, these products as described in the labeling for the two drugs."

Anastrozole over Tamoxifen for Breast Cancer

Anastrozole (Arimidex) is more effective than tamoxifen as adjuvant treatment for early-stage breast cancer according to a study published online as an early release in the Lancet Oncology. The study looked at 6241 women with locally invasive breast cancer who were randomized to anastrozole or tamoxifen and followed for a median of 100 months. Primary endpoints were disease-free survival, and secondary endpoints were time to recurrence, incidence of new contralateral breast cancer, time to distant recurrence, overall survival, and death after recurrence. Endpoints were evaluated in the total population and in the hormone-receptor-positive subpopulation. The primary endpoint and all secondary endpoints favored anastrozole except for deaths after recurrence and overall survival for which there is no significant difference. Fracture rates were higher in patients receiving anastrozole compared to tamoxifen. There was no difference in cardiovascular morbidity or mortality between the two treatment groups. The authors conclude that the study "establishes long-term efficacy of anastrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with hormone sensitive, early breast cancer, and provide statistically significant evidence of a larger carryover effect after five years of adjuvant treatment with anastrozole." (Lancet Oncology early online publication, 50 December 2007).

Antibiotics and Steroids Not for Sinusitis

Antibiotics and topical nasal steroids are of no benefit for patients with acute maxillary sinusitis according to a new randomized controlled trial of 240 adults. Patients with acute non-recurrent sinusitis were randomized to treatment with antibiotics and nasal steroids, placebo antibiotic and nasal steroid, antibiotic and placebo nasal steroids, or placebo antibiotic and placebo nasal steroid. Amoxicillin 500 mg three times a day for seven days and budesonide spray once daily were the active drug use in the study. The main outcome was proportion of clinically cured at 10 days and the duration of symptoms. Antibiotics made no difference in the proportion of patients with symptoms lasting 10 days or more (29% with antibiotics, 33.6% with no antibiotics). Use of nasal steroid also made no difference for the same measure (31.4% with budesonide, 31.4% with no budesonide). The authors conclude that neither an antibiotic nor topical steroid alone or in combination was effective as the treatment for acute sinusitis in the primary care setting (JAMA. 2007;298:2487-2496).

FDA Actions

An expert advisory panel of the FDA has recommended against approving Merck's petition to take lovastatin (Mevacor) over-the-counter. This was the third request in 7 years for OTC status for the cholesterol-lowering drug. The advisers voted 10-2 against approval citing concerns whether patients were capable of determining if they are appropriate candidates for the medication. The FDA generally follows the advice of its advisory panels.

The FDA has approved yet another beta-blocker for the treatment of hypertension. MylanBertek's nebivolol (Bystolic) is a selective beta-1-adrenoreceptor blocker with vasodilating effects. The drug is the 19th beta-blocker approved in the United States.

Wyeth has received an approvable letter for bazedoxifene, a new selective estrogen receptor modulator (SERM) for the prevention of osteoporosis in postmenopausal women. In issuing the letter, the agency asked for more data on the risk of blood clots and stroke, problems that have plagued the other marketed SERM for this indication (raloxifene-Evista). The agency did not ask for new studies however. Wyeth is also seeking the indication for treatment of osteoporosis in postmenopausal women. When approved, bazedoxifene will be marketed as Viviant.

The FDA has issued a safety warning on fentanyl skin patches after several reports of deaths and life-threatening side effects associated with inappropriate use. The warning stresses that the patches are only for patients who are opioid-tolerant and have poorly controlled pain on other narcotic pain medications. The patches are not for postoperative pain or sudden or occasional pain. Patients who used the patch should be aware of the signs of fentanyl overdose. Patients and physicians should be aware of potential drug interactions and physicians and pharmacists need to instruct patients on appropriate use of the patch. Patients also need to be aware that heat sources such as heating pads, electric blankets, saunas, heated waterbeds, hot baths, sunbathing and even fever may result in sudden increases in blood levels of fentanyl.

The FDA has approved a new volume expander for the treatment of volume loss during surgery. German drugmaker Fresenius Kabi's Voluven utilizes a new synthetic starch that is insoluble in water. In clinical trials the product was found to be as safe and effective as Hespan, a currently approved starch solution volume expander.

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: