The NIH has halted the estrogen-alone wing of the Women’s Health Initiative (WHI) a year before its scheduled end. The 11,000 postmenopausal women who have had a hysterectomy and were enrolled in the estrogen-alone trial recently received a letter informing them of the preliminary results of the study and asking them to stop their study medication. After nearly 7 years of follow-up it appears that estrogen alone does not affect the rates of heart disease or breast cancer (either positively or negatively), both key findings of the estrogen/progesterone wing of the study, which was halted in July 2002. The researchers did find, however, that estrogen alone led to a slightly higher incidence of stroke (8 per 10,000), similar to the rate found in the estrogen/progesterone wing. Estrogen alone was also found, however, to decrease the risk of hip fracture. The NIH statement also says that older women (65 and older) showed a trend toward increase risk of probable dementia or mild cognitive impairment with estrogen-alone treatment. All of the women in the study were taking Wyeth & Co.’s conjugated estrogen product, Premarin. The full results of the trial will be published in a major peer-reviewed journal in the next 2 months. The NIH statement concurs with the guidance from the FDA, which states that hormone use should be limited to treatment of moderate-to-severe menopausal symptoms, vulvovaginal atrophy, and prevention of osteoporosis (as a second-line drug). The NIH statement is available on its web site at www.nih.gov/news.

Antibiotics Associated With Cancer Risk

Is antibiotics use associated with an increased risk of breast cancer in women? The question, which was first raised decades ago, has been the subject of much debate, but now a new study suggests that the answer may be yes. Researchers looked at data from more than 10,000 female members of the Group Health Cooperative in Washington state and identified 2266 women with invasive breast cancer and 7953 randomly selected controls without breast cancer. The variable evaluated was cumulative days of antibiotic use over the study period from January 1993 to June 2001. Increasing cumulative days of antibiotic use was associated with increased risk of breast cancer. The categories were 0 days, 1-50, 51-100, 101-500, 501-1000, and > 1001 days. The odds ratios (95% CI) for breast cancer were, respectively, 1.00 (reference), 1.45 (1.24-1.69), 1.53 (1.28-1.83), 1.68 (1.42-2.00), 2.14 (1.60-2.88), and 2.07 (1.48-2.89) (P < .001 for trend). Increased risk was seen in all antibiotic classes, including women taking tetracycline or macrolides for treatment of acne or rosacea. After adjusting for age, length of enrollment, and use of postmenopausal hormones, the death rate from breast cancer also increased with cumulative days of antibiotic use. The authors conclude that use of antibiotics was associated with an increased risk of incidence of breast cancer and death from breast cancer; however, it cannot be determined from the study whether antibiotic use is causally related or whether the indication for use of antibiotics was the primary factor (JAMA. 2004; 291:827-835). The link between antibiotics for breast cancer is plausible since antibiotics affect intestinal microflora, thus affecting phytochemical metabolism in the gut. Phytochemicals are thought to play an inhibitory role in the carcinogenesis pathway. Antibiotics also affect immune and inflammatory responses, which may lead to mammary carcinogenesis. An accompanying editorial reviews the possible mechanisms of the antibiotic/breast cancer connection and suggests that this study provides more questions and answers but that further research is needed. In the mean time, antibiotic use in women should be scrutinized, especially when other treatment options are available (JAMA. 2004;291:880-881).

Topiramate Effective Against Migraine

Topiramate is an effective agent for migraine prevention, according to a new double-blind study of 483 migraine patients. The drug, which is approved for prevention of seizures, was used in maximal doses of 50, 100, or 200 mg for 18 weeks in patients aged 12-65, who had at least a 6-month history of migraine and averaged 3-12 migraines per month. Mean monthly migraine frequency decreased significantly in the 100-mg (P = .008) and 200-mg (P < .001) doses, and the benefit was seen within the first month of therapy. Migraine days and use of rescue medication were also significantly reduced in the 100-mg and 200-mg groups. Adverse events included paresthesia, fatigue, and nausea (JAMA. 2004;291:965-973). Johnson & Johnson has already received conditional approval from the FDA for topiramate for the indication of migraine prevention pending additional safety information.

Statin Therapy For Heart Failure

Statin therapy has been found to be beneficial for a number of chronic illnesses; now add 2 more to the list. Statins have been found to benefit patients with advanced ischemic and non-ischemic heart failure. Researchers from UCLA reviewed the records of 551 patients with systolic heart failure with ejection fractions of 40% or less. After risk adjustment, statin use was associated with improved survival without the necessity of urgent transplantation in both non-ischemic and ischemic heart failure patients (91% vs 72% [P < .001] and 81% vs 63% [P < .001], at 1-year follow-up, respectively) (J Am Coll Cardiol. 2004;43:642-648). A new, large, randomized trial shows statins may also reduce the risk of stroke. As part of the Heart Protection Study in the United Kingdom, 3280 adults with cerebrovascular disease and an additional 17,256 patients with other occlusive arterial disease or diabetes were randomized to simvastatin 40 mg per day or placebo. Over the 5-year treatment period, there was a significant 25% proportional reduction in the rate of first stroke (4.3% simvastatin vs 5.7% placebo; P < .0001). The entire benefit was found in reduction in ischemic stroke. There was no difference found in the rate of hemorrhagic stroke, either increase or decrease. Simvastatin also reduced the number of TIAs (P = .02) and requirement for carotid endarterectomy or angioplasty (P = .0003). Among patients with pre-existing cerebrovascular disease, there is no apparent reduction in the stroke rate, but there was a highly significant 20% reduction in the rate of any vascular event (P = .001). Interestingly, benefit was seen in all levels of LDL, even in patients with LDL levels less than 116 mg/dL. The authors conclude that statin therapy reduces the risk of ischemic stroke by one-quarter to one-third in these at-risk patients (Lancet. 2004;363:757-767).

FDA Actions

The consumer watchdog group Public Citizen is calling for the FDA to ban AstraZeneca’s new statin, rosuvastatin (Crestor), because of the risk of myositis and rhabdomyolysis. The drug, which was introduced to the American market in September, has been associated with 7 cases of rhabdomyolysis, 9 cases of renal failure, and 1 death. Myositis is a class affect of statins, especially the high-potency statins like Crestor. AstraZeneca states that the drug has been used in more than 1 million patients and that its benefits outweigh the risks. The FDA banned Bayer’s cerivastatin (Baycol) in 2001 because of more than 100 deaths associated with the drug due to rhabdomyolysis.

Drug Approved to Target Angiogenesis

The FDA has approved the first monoclonal antibody that targets tumor angiogenesis. Genentech’s bevacizumab (Avastin) is approved for the treatment of metastatic colorectal cancer. The drug works by binding vascular endothelia growth factor, thus inhibiting the formation of new blood vessels in tumors. In clinical trials the drug was found to extend survival time in patients with metastatic colorectal cancer by several months. 

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) 262-5413. E-mail: christie.petrone@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.