Pharmacology Watch: WHI Trial Arm Stopped Due to Increase in Breast Cancer
September 2, 2002
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Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women" is the stunning conclusion from the Women’s Health Initiative published in the July 17 Journal of the American Medical Association. The trial, which randomized 16,608 healthy postmenopausal women to conjugated equine estrogen/medroxy-progesterone or placebo, was stopped just 5.2 years into the 8.5 year study when the risk for invasive breast cancer exceeded the stopping boundary. Excess coronary heart disease (CHD), stroke, and pulmonary embolism (PE) were also noted; however, the combination reduced the risk of colorectal cancer, endometrial cancer, and hip fracture. The findings were front-page news coast-to-coast as well as the subject of cover stories in Time and Newsweek. Important aspects of the study include:
Although there is a higher risk of adverse events with the combination of conjugated estrogen and medroxyprogesterone, the absolute risk is low. The hazard ratios were: CHD 1.29, breast cancer 1.26, stroke 1.41, PE 2.13, colorectal cancer 0.63, endometrial cancer 0.83, hip fracture 0.66, and death due to other causes 0.92. Per 10,000 person-years, estrogen/progestin resulted in 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, but 6 fewer colorectal cancers and 5 fewer hip fractures. All- cause mortality was no different between the 2 groups.
This study, which enrolled healthy women with an intact uterus, was designed as a primary prevention trial of CHD. When combined with the results from HERS II published just one week earlier (JAMA. 2002;288:49-57) (a secondary prevention trial in women with known CHD), the notion of estrogen/progestin being cardioprotective is essentially eliminated.
Another wing of WHI is looking at nearly 11,000 women who have had hysterectomies and are on estrogen alone. So far, that study has not shown an increase in the rate of breast cancer, and the study will continue. The WHI group also admits that other estrogen/progestin combinations may result in different outcomes.
What to do with women on HRT who are doing well? The authors and editorialists of WHI suggest that there is no urgency, but that all women should be moved away from HRT as a strategy for preserving health and preventing disease. New patients should look for alternatives, and women currently on HRT should reevaluate the reason the drugs are being used and consider other options (JAMA. 2002;288:321-333; JAMA. 2002;288:366-367).
Side Effects Overrated in Beta Blockers
The side effects of beta blockers may be over- rated by most physicians according to a new study. This leads to underuse of these important drugs, especially in cardiac patients. The authors performed a quantitative review of 15 trials, which included more than 35,000 patients. Beta blockers were not associated with an increased risk of depression, and only a small risk of fatigue (18/1000 patients 95% CI, 5-30) or sexual dysfunction (5/1000 95% CI, 2-8). There was no difference in these side effects with the lipid solubility of the various drugs; however, late-generation beta blockers were associated with less fatigue than the older drugs (JAMA. 2002;288[3]:351-357).
Aranesp Approved in Cancer Treatment
Aranesp (darbepoetin alpha), Amgen’s long-acting erythropoietin, has been approved for use in cancer patients undergoing chemotherapy. The drug was initially approved for treatment of anemia associated with renal failure and dialysis. Aranesp maintains blood levels about 3 times longer than previous available erythropoietin (Procrit), allowing for dosing every 2-3 weeks as compared to weekly dosing for Procrit.
Zelnorm to Provide IBS Relief
The FDA has approved tegaserod maleate (Zelnorm—Novartis) for the treatment of women with irritable bowel syndrome (IBS) whose primary symptom is constipation. The drug is a serotonin-4 receptor agonist that is been shown to reduce constipation, bloating, and abdominal discomfort.
The approval was based on results of 3 randomized, double-blind, placebo-controlled trials each lasting 12 weeks. The efficacy of tegaserod was greater at 1 month than at 3 months, suggesting a decrease in efficacy over time. The drug is approved for short-term treatment, as long-term efficacy as well as safety is not established. The efficacy in men with constipation-predominant IBS has also not been established. Not surprisingly, the primary side effects of tegaserod are diarrhea. The approval has already come under criticism by the consumer watchdog group Public Citizen calling the approval "reckless." The group contends that users of tegaserod were more likely to need surgery in clinical trials and were also more likely to develop ovarian cysts. Public Citizen has also been critical of the FDA for reapproving alosetron (Lotronex) for the treatment of women with diarrhea predominant IBS.
FluMist Delayed for Second Time
The FDA approval of FluMist has been delayed for a second time. The intranasal, live attenuated influenza vaccine was first delayed 1 year ago when the agency requested more safety data. The current delay is due to the FDA’s need for additional information regarding the manufacturer’s biologics license application. FluMist may someday provide an alternative to injection based flu vaccines.
Elderly Patients: Keep Taking Your Statins!
Elderly patients frequently discontinue statin therapy on their own according to 2 new studies in JAMA. A large group of elderly patients enrolled in a New Jersey Medicaid and pharmaceutical assistance program were followed to assess their compliance with statin therapy over time. Based on the quantity of drugs dispensed, only 60% of patients were adhering to therapy at 3 months and only 32% at 120 months. Factors predicting poorer adherence with therapy included nonwhite race, low income, older age, less cardiovascular morbidity at the start of therapy, depression, dementia, and coronary events after starting treatment. Patients who started therapy more recently were more likely to continue therapy compared with those who started the statin therapy in 1990. In the second study, researchers in Canada looked at patients age 66 and older who were on statin therapy and fell into 1 of 3 groups: those with recent acute coronary syndrome, those with chronic coronary artery disease, and those without coronary disease who were taking statins for primary prevention. Patients older than the age of 66 had 2-year adherence rates of 40.1% for patients with recent acute coronary syndromes, 36.1% among patients with chronic CAD, and only 25.4% among those taking statins for primary prevention. As pointed out in an accompanying editorial, both studies are based on pharmacy databases, which are only a surrogate for compliance; however, the sheer size of the studies and the magnitude and consistency of the trends noted make the findings likely be correct. In light of the recent National Cholesterol Education Program recommendations, which dramatically increases the number of elderly patients eligible for statin therapy, compliance programs in this population are needed (JAMA. 2002;288:455-461; 462-467; 495-497).
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) 262-5517. E-mail: [email protected]. 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.
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