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Research brings out new and sometimes confusing information all the time. It can be frustrating for patients and doctors alike. You need to stay in touch with your doctor to make sure that your care is as up to date as possible.
Exactly what is a "safe" drug? Consider the ubiquitous aspirin. An aspirin-like substance made from willow bark was used by the ancient Greeks and aspirin powder became the number one drug in the world in 1899.1 Yet, it was not until the 1960s and beyond that we came to understand how it works2 and began to investigate its characteristics for disease prevention, its effect on the stomach lining and the danger it can pose when used by children.
Today, the U.S. Food and Drug Administration require that every drug undergo rigorous laboratory, animal and human clinical testing before it can be put on the market. But, FDA approval is not an unconditional endorsement. The FDA reviews research to validate ingredients and provisionally determine that a drug is effective and safe to treat a specific condition or disease. Safety is viewed in terms of its risk-to-benefit ratio – in other words, to decide if a drug's advantages outweigh the probability it will cause substantial adverse side effects. An acceptable risk/benefit ratio for a relatively benign condition will be very different than that for a life-threatening one. Pre-market clinical trials do not uncover all possible risks nor do they guarantee absolute safety. That means follow-up tests for a drug need to be done after it is in widespread use. (See the introductory page for this topic for more information.) According to a 1998 article in the Journal of the American Medical Association, 51 percent of approved drugs may have serious adverse effects not detected prior to approval".3
Furthermore, the FDA does not approve every use to which a medical product might be put.4 Once a drug is sanctioned by the FDA for one disease or condition, physicians can prescribe it for other conditions, for patient populations who were not part of the clinical trial, and in different dosages. It is called off-label prescribing and it is very common. One in five prescriptions for the 500 most commonly prescribed drugs in 2001 was for off-label use.5 As with all things, there are pros and cons. In the pro column: physicians can make use of evidence as it becomes available and patients can benefit from more options and earlier access to the newest treatments. In the con column: the absence of data can make it difficult to determine a risk/benefit ratio.
Contradictions in investigations are not unusual. In fact, surprises can happen with even the most carefully tested drugs. Side effects may appear only when a drug is used in combination with another medicine, in patients who were not represented in previous test groups or only after years of use.
There are fundamental differences in types of studies. The two major categories are observational studies and randomized trials. In an observational study, investigators observe what happens to people in their everyday lives, grouping them according to whether or not they take a drug, make certain lifestyle choices or have been exposed to something. In a randomized trial, investigators assign people to two or more study groups and then control what treatment or exposure each group receives. Usually, they compare the treated subjects to subjects who receive no treatment or standard treatment. While a controlled study is generally considered more reliable than an observational study, the two types are complementary with a legitimate role for each in optimizing scientific advancement. For example, there are instances where a randomized trial in humans can not be ethically performed, such as the identification of cigarette smoking as a cause of lung cancer. Due to stringent ethical requirements, financial limitations, and other feasibility issues, it will never be possible to address all therapeutic questions with randomized trials.6
Study validity also depends on the size of the group being studied. The smaller the study, the higher the margin of error; the bigger the group, the more reliable the conclusions. While an unnecessarily large study can be wasteful of resources and results may take longer than ideal, relatively few studies are too big.6
Second Opinion panelist, Lou Papa, MD, describes the history of hormone therapy research as an "undulating wave" leaving women with a "to use or not to use" dilemma. A few historical milestones illustrate his point:
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1940s: |
- FDA approves estrogen products for the direct symptoms of menopause: hot flashes and night sweats, vaginal dryness and atrophy.7
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1950s: |
- Study suggests hormone treatment enhances verbal memory in elderly women.8
- Study suggests estrogen protects bones; does not cause breast and cervical cancer.9
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1960s: |
- Gynecologist Robert A. Wilson claims estrogen during menopause reduces risk of breast cancer and cancers of the reproductive organs10 and publishes the book, Feminine Forever.
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1970s: |
- Studies conclusively link estrogen replacement therapy and endometrial cancer.11-12 Later studies show progesterone can be added to estrogen therapy drugs to offset those risks. 13-14
- Estrogen linked to gallbladder disease, blood clots and breast cancer.15-16
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1980s |
- The Nurses' Health Study asserts hormone therapy is cardioprotective and other studies support their findings by associating the use of estrogen with favorable lipoprotein patterns.17
- The Framingham Heart Study says women who have taken estrogen are more likely to develop heart disease.18
- The FDA announces short-acting estrogens are effective for preventing osteoporosis.7
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1990s: |
- The FDA finds that the research done to date is not adequate to support adding heart disease prevention to the list of approved uses for HRT.
- More studies tout hormone therapy for heart disease and osteoporosis prevention. 19-20
- Key studies state hormone therapy increases risk of breast cancer including:
- The Heart and Estrogen/Progestin Replacement Study (HERS) 21
- American Nurses' Health Study.22-23
- Studies show hormone therapy increases risk for blood clots.24-25
- The Heart and Estrogen/Progestin Replacement Study (HERS) finds an increase in cardiovascular events (both heart attack and stroke) in women with established cardiovascular disease after the first year of HRT with no net reduction in coronary heart disease after 4.1 years.26
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2000s |
- Women's Health Initiative (first large, randomized, placebo-controlled study on the topic) finds:
- The risks of combined estrogen and progestin hormone replacement therapy (HRT) outweigh its benefits by increasing risk for heart disease, breast cancer, stroke and blood clots.27
- Estrogen-only therapy can put women at increased risk of stroke.28
- HRT increases breast density, making breast cancer more difficult to detect.29
- Women's Health Initiative Memory Study (a sub-study of the WHI) reports HRT may double the risk of Alzheimer's disease and other dementias in women over 65.30
- The Million Women Study shows increase in breast cancer incidence for women on hormone therapy.31
- Further analysis of WHI data as well as follow-up studies are ongoing.
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1 Bayer HealthCare, Leverkusen, Germany.
2 Jeffreys, Diarmuid (August 11, 2005). Aspirin: The Remarkable Story of a Wonder Drug. Bloomsbury USA, 73. ISBN 1582346003. Jeffreys, Aspirin, pp. 226-231)
3 Moore, TJ, Psaty, BM, Furberg, CD. Time to act on drug safety. JAMA, 1998 May 20, 279(19):1571-3.
4 Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice; Richard A. Deyo, The Journal of the American Board of Family Practice 17:142-149 (2004).
5 Archives of Internal Medicine; 2006.
6 Are Observational Studies ‘Just as Effective' as Randomized Clinical Trials?; Tom Greene; Blood Purif 2000;18:317–322.
7 Synthetic generic conjugated estrogens: Timeline http://www.fda.gov/Cder/news/cetimeline.htm
8 B.M. Caldwell & R.I. Watson, An Evaluation of Psychologic Effects of Sex Hormone Administration in Aged Women: Results of Therapy After Six Months, 7 J. GERONTOLOGY 228 (1952).
9 Stanley Wallach & Philip H. Henneman, Prolonged Estrogen Therapy in Postmenopausal Women, 171 JAMA 1637 (1959).
10 Robert A. Wilson, The Roles of Estrogen and Progesterone in Breast and Genital Cancer, 182 JAMA 327 (1962).
11Harry K. Ziel & William D. Finkle, Increased risk of endometrial carcinomas among users of conjugated estrogens, 293(23) New England Journal of Medicine 1167-1170 (1975).
12D.C. Smith et al., Association of exogenous estrogen and endometrial carcinoma, 293(23) New England Journal of Medicine 1164-1167 (1975).
13 M. H. Thom et al., Prevention and Treatment of Endomtrial Disease in Climacteric Women Receiving Estrogen Therapy, 2 (8140) The Lancet 455-457 (1979).
14 R. Don Gambrell Jr. et al., Use of the Progestrogen Challenge Test to Reduce the Risk of Endometrial Cancer, 55 OBSTETRICS & GYNECOLOGY 732.1980.
15 Boston Collaborative Drug Surveillance Program, Surgically Confirmed Gallbaladder Disease, Venous Thromboembolism and Breast Tumors in Relation to Postmenopausal Estrogen Therapy, 290(1) New England Journal of Medicine 15-19 (1974).
16 Robert Hoover et al., Menopausal Estrogens and Breast Cancer, 295 NEW ENG. J. MED. 401 (1976).
17 M.J. Stampfer et al., A Prospective Study of Postmenopausal Estrogen Therapy and Coronary Heart Disease, 313(17) New England Journal of Medicine 1044-1049; 1985)
18 P.W. Wilson et al., Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50, 313(17) New England Journal of Medicine 1038-1043;1985.
19 R.L. Prince et al., Prevention of Postmenopausal Osteoporosis: A Comparative Study of Exercise, Calcium Supplementation, and Hormone-Replacement Therapy, 325 NEW ENG. J. MED. 1189 (1991).
20 The Writing Group for the PEPI Trial, Effects of Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women, 273 JAMA 199 (1995).
21 Stephen Hulley et al., Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women, 280 JAMA 605. 1998.
22Graham A. Colditz et al., Type of postmenopausal hormone use and risk of breast cancer: 12-year follow-up from the Nurses' Health Study, 3 Cancer Causes and Control 433-439 (1992).
23Graham A. Colditz et al., Hormone Replacement Therapy and Risk of Breast Cancer: Results from Epidemiologic Studies,168(5) American Journal of Obstetrics & Gynecology 1473-80 (1993).
24 Edel Daly et al., Risk of Venothromboembolism in Users of Hormone Replacement Therapy, 348(9033) The Lancet 977-980 (1996).
25 Deborah Grady et al., Postmenopausal Hormone Therapy Increases Risk for Venous Thromboembolic Disease: The Heart and Estrogen/Progestin Replacement Study, 132(9) Annals of Internal Medicine 689-696 (2000).
26 Hulley, S; Grady, D; Bush, T; Furberg, C; Herrington, D; Riggs, B; Vittinghoff, E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613. doi: 10.1001/jama.280.7.605
27 NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit; Press Release; July 9, 2002
28 NIH Asks Participants in Women's Health Initiative Estrogen-Alone Study to Stop Study Pills, Begin Follow-up Phase; Press Release; March 2, 2004.
29 HRT Doubles Breast Density, Abnormal Mammogram Possible; Healthcare in the News, October 20, 2004. Article on presentation at meeting of the American Association for Cancer Research; Lead researcher Dr. Anne McTiernan.
30 Rates of Dementia Increase Among Older Women on Combination Hormone Therapy; Press Release; May 27, 2003.
31 Emily Banks, et al., Breast Cancer and Hormone-Replacement Therapy in the Million Women Study, 362(9382) The Lancet 419-427 (2003).
Learn more about Hormone Replacement Therapy:
Key Point 2: Hormone replacement therapy is a viable option for some women. As with any other therapy, there are pluses and minuses. There is controversy around HRT. All those TV reports are not about you. You really need to talk with your doctor about your specific risks and benefits.
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