Women’s health: The good, the bad, the maybe

CV disease, breast cancer, HIV care, compounding all in the news

Recently published data focusing on women’s health issues have been generally—but not always—positive.

A range of therapeutic areas have been covered in journals and news articles in recent months. These provide new information about cardiovascular risks with oral contraceptives, use of antidiabetic drugs to reduce the risk of invasive breast cancer in women with diabetes, use of two-drug regimens to prevent perinatal transmission of HIV from mothers to infants, safety of compounded formulations of hydroxyprogesterone caproate, and risks of cardiovascular events in women using calcium supplements with or without vitamin D.

Hormonal contraceptives: Stroke, MI

Numerous studies have evaluated the risks of venous thromboembolism associated with the use of oral contraceptives, but few have assessed the risks of arterial complications such as thrombotic stroke and myocardial infarction (MI). Data assessing arterial risks were published in the June 14 issue of the New England Journal of Medicine.

Lidegaard and colleagues performed a 15-year Danish historical cohort study in which nonpregnant women 15 to 49 years old with no history of cardiovascular disease or cancer were followed and data on the use of hormonal contraceptives, clinical endpoints, and potential confounders were collected.

The study cohort included 1,626,158 women with 14,251,063 person–years of observation. Overall, 3,311 women had a stroke and 1,725 had an MI. When comparing the rates among those who used oral contraceptives compared with nonusers, the crude incidence rates for thrombotic stroke and MI were similar: 21.4 and 10.1 per 100,000 person–years, respectively, in users, and 24.2 and 13.2 per 100,000 person–years, respectively, in nonusers.

The investigators also assessed the arterial risks according to the estrogen dose, progestin type, and route of administration. The relative risks of thrombotic stroke and MI were increased approximately 1.3- to 2.3-fold among users of estrogen–progestin oral contraceptives with a low dose of ethinyl estradiol (i.e., 30–40 µg) regardless of the type of progestin in the formulation. For patients taking estrogen–progestin oral contraceptives with a very low dose of ethinyl estradiol (i.e., 20 µg), risks were increased by 0.9- to 1.7-fold, again regardless of the progestin type. A higher risk of thrombotic stroke was observed with use of transdermal patches (3.2-fold) and for the vaginal ring (2.5-fold).

The risk of arterial thrombosis with use of hormonal contraceptives is low, wrote Diana Petitti, MD, MPH, in an accompanying editorial. The probability of an event is quite small in an individual woman, she wrote, adding: “The research shows that the small risk could be minimized and perhaps eliminated by abstinence from smoking and by checking blood pressure, with avoidance of hormonal contraceptive use if blood pressure is raised.” She concluded that the overall body of evidence is convincing enough that low and very low doses of ethinyl estradiol in combination estrogen–progestin contraceptives given orally or by other routes may not be risk free but are safe enough to use.

Calcium supplements, cardiovascular events

The role of calcium supplements in the management of osteoporosis in women needs to be reassessed, given the findings published recently in BMJ that these supplements may increase a woman’s risk for cardiovascular events. Bolland and colleagues analyzed data from the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study) and incorporated these data into a meta-analysis with other published studies to determine the association between calcium supplement use and cardiovascular risk.

In 16,718 women who were not taking personal calcium supplements at the time of randomization, calcium and vitamin D therapy increased hazard ratios for cardiovascular events by 13% to 22% (P = 0.05 for clinical MI or stroke, P = 0.04 for clinical MI or revascularization). In addition, when these data were added to data from eight clinical trials of calcium supplementation, a meta-analysis showed that calcium or calcium and vitamin D supplementation increased the relative risk of MI by 24% (P = 0.004) and a composite of MI or stroke by 15% (P = 0.009).

Although these increases are modest, substantial numbers of people could be affected, given the widespread use of calcium supplements alone or with vitamin D, the investigators noted. They suggested that the risk–benefit profile for calcium supplements is unfavorable and wrote, “In our analysis, treating 1,000 patients with calcium or calcium and vitamin D for 5 years would cause an additional six MIs or strokes (number needed to harm of 178) and prevent only three fractures (number needed to treat of 302).” They concluded that a reassessment of the use of these supplements, especially in older patients, is warranted at this time.

Metformin lowers breast cancer risk

In postmenopausal women with diabetes, use of metformin is associated with a lower incidence of invasive breast cancer, according to a study published online June 11 by the Journal of Clinical Oncology. Chlebowski and colleagues assessed data from the WHI clinical trials to determine the relationships among diabetes, metformin use, and breast cancer. Previous research has suggested that use of metformin may lower cancer risks and cancer-associated mortality, and this provided the rationale for the study.

Among 68,019 women who were followed for a mean of 11.8 years, 3,401 had diabetes at study entry. Over the follow-up period, 3,273 invasive breast cancer cases were diagnosed. Compared with women without diabetes, those with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio 1.16 [95% CI 0.93–1.45]), while those given metformin had a lower breast cancer incidence (0.75 [0.57–0.99]). The beneficial effects of metformin were observed in women with breast cancers that were positive for both estrogen and progesterone receptors, and in those negative for human epidermal growth factor receptor 2.

The investigators concluded that their findings are most applicable to women with diabetes, most of whom were overweight or obese during their participation in WHI. In addition, the authors noted that consideration should be given to performing additional clinical trials with metformin for prevention.

Stopping perinatal HIV transmission

For infants of mothers with HIV who did not receive antenatal antiretroviral therapy because of late identification of their disease, treatment with a two- or three-drug regimen reduced transmission more effectively when compared with zidovudine alone, according to study results published by Nielsen-Saines and colleagues in the June 21 issue of the New England Journal of Medicine.

Within 48 hours of birth, formula-fed infants of mothers who tested positive for HIV were randomized to one of three treatment groups: zidovudine monotherapy for 6 weeks (n = 566), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (n = 562), or zidovudine for 6 weeks plus nelfinavir (Viracept—ViiV Healthcare) and lamivudine for 2 weeks (n = 556).

Intrapartum transmission occurred in 24 infants in the zidovudine monotherapy group (4.8%) compared with 11 infants (2.2%) in the two-drug group and 12 infants (2.4%) in the three-drug group (both P = 0.046 compared with monotherapy). Although more effective, the three-drug regimen was associated with a significantly higher rate of neutropenia compared with the other two groups (P < 0.001 for both group comparisons).

These results are important because zidovudine monotherapy has been the standard of care for some time. Administration of additional agents may further reduce transmission of HIV during the intrapartum period. The investigators concluded, “Ease of use, reduced toxicity, availability, and low cost suggest that zidovudine plus nevirapine is an attractive option for prophylaxis in infants at high risk for perinatal HIV-1 infection.”

Compounded progesterone found safe

Based on analysis of a limited sample of compounded hydroxyprogesterone caproate products and active pharmaceutical ingredients, FDA reported that it did not identify any major safety problems. The agency stressed that approved drug products such as Makena (Ther-Rx Corporation) provide a greater assurance of safety and effectiveness than do products compounded in pharmacies.

This saga began in February 2011, when FDA approved Makena for reduction of risk of certain preterm births in women who have had at least one prior preterm birth. Before the product’s approval, patients who needed this agent were able to acquire it from compounding pharmacies with a physician’s order. When the commercially available product was launched, its cost was substantially higher than the compounded version.

In March 2011, FDA issued a statement that although greater assurance of safety is provided by an approved product, under certain conditions a licensed pharmacist may compound a drug product using ingredients that are components of FDA-approved drugs if the compounding is for an identified individual patient based on a valid prescription for a compounded product that is necessary for that patient. This left the door open for compounding pharmacies to continue making the drug.

In October 2011, FDA received information from K-V Pharmaceuticals regarding the potency and purity of samples of bulk hydroxyprogesterone caproate active pharmaceutical ingredients and compounded hydroxyprogesterone caproate products, noting that there was variability in the purity and potency of both the bulk active pharmaceutical ingredients and compounded hydroxyprogesterone caproate products that were tested. Based on this information, FDA conducted its own analysis.

On June 15, FDA released its findings. The agency tested 16 samples of hydroxyprogesterone caproate active pharmaceutical ingredients, and all 16 samples passed United States Pharmacopeia tests for potency (97% to 103%) and purity as well as the potency tests in the Makena New Drug Application (NDA). In addition, FDA tested 13 samples of compounded hydroxyprogesterone caproate prepared by eight pharmacies. Of 13 samples, 1 was subpotent (in the range of 80% of declared potency). All 13 samples met the Makena NDA standard for total purity. Two of the 13 samples failed to meet the standard for unidentified impurities in the Makena NDA.

Time for education

Given the widespread media attention around the studies presented here, women may have questions about the current findings and how the implications of these trials affect them. Pharmacists are in an ideal position to educate women on the recently published findings.