Pharmacology Watch

Menopausal Hormone Therapy and the Risk for VTE, AD

In this issue: Menopausal hormone therapy and risk of VTE and AD; patients' understanding of chemotherapy benefits; and FDA actions.

Hormone therapy and VTE risk

The different drug formulations of menopausal hormone therapy (HT) may determine the risk of venous thromboembolism (VTE), according to a new study. It is known that combined estrogen-progesterone therapy has a higher risk of VTE than estrogen-only therapy, and oral therapy has a higher risk than transdermal therapy. Now, a follow-up study from the Million Women Study with more than 3.3 million patient-years of follow-up looks at the varying risks of different HT combinations. The risk of VTE was again found to be significantly higher for combination estrogen-progesterone therapy compared to estrogen-only therapy (relative risks [RR] = 2.07 [95% confidence intervals (CI) 1.86-2.31] vs 1.42 [1.21-1.66]). Transdermal estrogen-only therapy resulted in no excess risk for VTE (RR 0.82 [0.64-1.06]). Among users of combination estrogen-progesterone, the risk of VTE varied by progestin type with significantly greater risk for preparations containing medroxyprogesterone compared to other progestins (2.67 [2.25-3.16] vs 1.91 [1.69-2.17]; P heterogeneity = 0.0007). The risk of VTE was significantly higher (2 times the risk) in the first 2 years after starting combination HT than later years. Five-year risks for pulmonary embolism (PE), both fatal and nonfatal, were calculated as: 1 in 664 for never users of hormone therapy, 1 in 475 for current users of oral estrogen-only, 1 in 390 for users of estrogen-progesterone containing norethisterone/norgestrel, and 1 in 250 for users of estrogen-progestin therapy containing medroxyprogesterone. The authors conclude that VTE risk varies considerably by HT formulation and is greatest in users of oral estrogen-progesterone therapy containing medroxyprogesterone. One case of PE could be avoided for every 1295 current users of oral HT if estrogen-only rather than estrogen-progesterone was used. Among combined HT users, one PE in 700 women could be avoided by use of a progestin other than medroxyprogesterone (J Thromb Haemost published online Sept. 10, 2012. doi: 10.1111/j.1538-7836.2012.04919.x). These data follow on the Women's Health Initiative, which also showed a higher risk of breast cancer for combination hormone replacement therapy vs estrogen-only therapy, but this risk is offset by the risk of endometrial cancer in women with an intact uterus on unopposed estrogen.

Hormone therapy and AD risk

Does the timing of menopausal HT affect the risk of Alzheimer's disease (AD)? Several studies have suggested the timing of postmenopausal HT is critical, especially during the first 5 years after menopause when hormones appear to be somewhat neuroprotective. The Women's Health Initiative (WHI) study clearly showed that starting HT after age 65 had no effect on cognition and in fact may be harmful. Now a new study confirms that starting HT immediately after menopause may have neuroprotective benefits. In a follow-up from the Cache County study, 1768 women provided a detailed history on age at menopause and use of HT between 1995 and 2006. During this interval, 176 women developed AD. Women who used any type of HT within 5 years of menopause were at 30% less risk of AD (95% CI, 0.49-0.99), especially if they used it for 10 years or more. By contrast, woman who started HT 5 or more years after menopause did not have a decreased rate of AD. Confirming the WHI findings, rates of dementia were nearly doubled among those who began combination estrogen-progesterone compounds later in life. The authors conclude that the association of HT and the risk of AD may depend on the timing of use. HT appears to be beneficial during the critical window near menopause, but may be associated with an increased risk if initiated later in life. (Neurology 2012;79:1846-1852). An accompanying editorial suggests that AD and coronary heart disease share common risk factors. WHI data show that women assigned to HT close to menopause had a reduction in the risk of coronary heart disease, whereas women given HT later in life had increased risk. The same seems to be true for the risk of AD. Two soon-to-be published studies will provide evidence regarding hormone effects on cognition in younger postmenopausal women (Neurology 2012;79:1840-1841). The decision to initiate HT in postmenopausal women is generally based on severity of symptoms, risk of breast cancer, risk of venous thromboembolic disease, and other factors. Benefits on cognition and potential protection against AD may now need to be added to the equation.

Chemotherapy often misunderstood

Chemotherapy for metastatic lung or colon cancer may provide palliation and prolongation of life by weeks or months, but a new study shows that most patients with these diseases erroneously think that chemotherapy is curative. Researchers studied nearly 2000 patients in the Cancer Care Outcomes Research and Surveillance study who were alive 4 months after diagnosis of stage IV lung cancer or colorectal cancer. All patients received chemotherapy. Overall, 69% of patients with lung cancer and 81% of those with colorectal cancer did not report understanding that chemotherapy "was not at all likely to cure their cancer." This misunderstanding about the benefits of chemotherapy was more prevalent among nonwhite and Hispanic patients as compared to non-Hispanic white patients (odds ratio [OR] for Hispanic patients 2.82, 95% CI, 1.51-5.25; OR black patients 2.93, 95% CI, 1.80-4.78). Patients who rated communication with their physician favorably also had a higher OR (1.90; 95% CI, 1.33-2.72). Educational level, functional status, and the patient's role in decision making were not associated with inaccurate beliefs about chemotherapy. The authors conclude that "many patients receiving chemotherapy for incurable cancers may not understand that chemotherapy is unlikely to be curative." This misunderstanding suggests that patients "have not met the standard for true ongoing informed consent" and may not accept toxic treatment with no reasonable hope of cure. The data also suggest that patients rate their doctors as better communicators if they are more optimistic. The authors suggest that honest communication is "a marker of quality of care" but may cause lower patient ratings (N Engl J Med 2012;367:1616-1625).

FDA actions

The FDA has approved a new drug for the treatment of chronic myelogenous leukemia (CML). Omacetaxine mepesuccinate is a protein translation inhibitor that was originally identified in the 1970s as a potential treatment for CML as well as other hematologic conditions and even solid tumors. It was eventually dropped from development as the tyrosine kinase inhibitors (TKIs) became the mainstay of therapy. Emerging resistance to imatinib and other TKIs has led to renewed interest in the drug. It was recently approved for chronic, accelerated, or blast-phase Philadelphia-chromosome-positive CML that is resistant or in patients who are intolerant of other therapies including TKIs. Approval was based on a study of patients in chronic or accelerated-phase CML who had been treated with two or more TKIs. Omacetaxine is administered by subcutaneous injection. It is marketed by Teva Pharmaceuticals as Synribo. It joins Pfizer's bosutinib (Bosulif), which also was recently approved for the same indication.

The FDA has approved perampanel as adjunctive treatment for partial onset seizures in patients 12 years of age and older. The drug is the first in its class of noncompetitive AMPA receptor antagonists that are taken orally once daily. Approval was based on data from three Phase 3 studies of nearly 1500 patients with partial-onset seizures which found that perampanel, when used as an adjunctive therapy with other anti-seizure medications, significantly reduced seizure frequency. The drug comes with a boxed warning regarding serious neuropsychiatric events including agitation, aggression, anxiety, paranoia, euphoria, anger, and irritably. Perampanel is marketed by Eisai Inc. as Fycompa.

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) 262-5404. E-mail: