Screening for Diseases: Ethical and Medical Considerations



UCSD Biomedical Ethics Seminar Series

Hormone Replacement Therapy: What Went Wrong?

Jan. 21, 2003

Cynthia A. Stuenkel, MD,

Clinical Professor of Medicine, Endocrine and Metabolism

Mary Devereaux, Ph. D.,

Ethicist and Director for the Biomedical Ethics Seminars, UCSD Research Ethics Program

What follows is a synopsis of the discussion that followed Dr. Stuenkel and Dr. Devereaux’s Jan. 21st, 2003 presentation. It aims to summarize the range of views expressed following their talk. Not all of these views represent Dr. Stuenkel or Dr. Devereaux’s own thinking on the topic. Nor of course do they necessarily represent the views of everyone present at the discussion.

1) PRESENTATION: Cynthia A. Stuenkel

Key points in Hormone Replacement Therapy Trials History:

• PEPI: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial was the first large randomized trial conducted on HRT, which results were published in 1995: HRT was found to have beneficial effects on bone mineral density and heart disease risk factors. However, the study also found estrogen had negative effects on the uterine lining, unless progesterone was used in combination.

• HERS: Heart and Estrogen-Progestin Replacement Study was the first large-scale randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy of HRT on postmenopausal women with coronary heart disease over a period of 4 to 5 years. It unexpectedly found that hormone therapy presented no overall benefit over placebos in preventing heart attacks and that women in the first year of the study were actually at increased risk for heart attacks and blood clotting.

• The results of HERS called into question the conclusions of observational studies and brought to the foreground issues of hierarchies of evidence for therapeutic studies.

If the ideal is evidence-based medicine, what are the ideal research methods to prove the efficacy of therapy regimens?

• The Oxford Centre for Evidence-based Medicine defines the ‘Levels of Evidence’ that can be assigned to therapeutic studies as follows: (May 2001)



HIGHEST: Meta-Analysis of RCTs Systematic Review of RCTs

↓

Individual RCT Individual RCT

↓

Observational Studies (Cohort and Case-Control Studies)

↓

Basic Research (Test Tube, Animal, Human Physiology)

↓

WEAKEST: Clinical Experience Expert Opinions, Consensus Opinions

• WHI: The Women's Health Initiative (WHI) is a large-scale, 5-year NIH research program on cardiovascular disease, cancer, osteoporosis, mental health and quality of life related factors in postmenopausal women. It studied the effects of HRT on Fracture Risk and Bone Mineral Density (October 2003), Gynecologic Cancers and Diagnostic Procedures (October 2003), Coronary Heart Disease Risk (August 2003), Breast Cancer Risk (June 2003), Dementia and Cognitive Function -- WHI Memory Study (May 2003), Stroke Risk (May 2003) and Quality of Life (March 2003.)

o The ‘Combination Therapy’ part of the study was stopped in July 2002 by the investigators, when it was found that HRT put healthy women at an increased risk for breast cancer and heart disease and lacked overall benefit for prevention. The estrogen-only study is still ongoing. (Addendum: On March 4, 2004, WHI participants in the estrogen only arm were notified that the study had been halted due to an increase in stroke risk. According to the press release, there was also a trend for an increase in dementia, a reduction in fractures, and no increase or decrease in coronary heart disease, and no increase in breast cancer).

o For fracture risk and bone mineral density, HRT was found to have positive effects. However the associated risks outweighed the benefits, even in the subgroup of women at increased risk for bone fracture.

o For gynecologic cancers, women taking HRT were found at similar or slightly smaller risk of endometrial cancer than women taking placebo, and at similar risk for ovarian cancer.

o For coronary heart disease and breast cancer, HRT in combination was found to have no positive effects and to increase their incidence.

o HRT was found to increase the risk for probable dementia and contributed to a significant decline in the score used to evaluate cognitive function (Modified Mini-Mental State Exam total score)

o Increased risks of strokes were also found for estrogen/ progestin combination.

o In terms of quality of life, HRT was found to have no significant effects on general health, vitality, mental health, depressive symptoms, or sexual satisfaction.

In conclusion, the associated risks of HRT outweighed the benefits in terms of prevention. The effects of estrogen alone should be published soon.

How can we reconcile the divergent results of observational studies and Randomized Controlled Trials?

• A A meta-analysis of observational studies adjusted for socioeconomic status or education and other CHD risks, found no benefit in the secondary or primary prevention of CVD events, consistent with the findings of recent RCTs

(Annals of Internal Medicine: Linda L. Humphrey, MD, MPH; Benjamin K.S. Chan, MS; and Harold C. Sox, MD, Editor, August 2002: )

• In an article in the New England Journal of Medicine, Francine Grodstein, Thomas B. Clarkson and Jo Ann E. Manson set out to explore the differences in results between RCTs and observational studies for HRT. (“Understanding the Divergent Data on Postmenopausal Hormone Therapy” February 2003)

o “In randomized clinical trials, subjects are randomly assigned to treatments, thereby minimizing possible differences between the groups in lifestyle or health-related factors. In observational studies, by contrast, subjects who choose to take a given agent may be very different from those who do not.”

o They found methodological differences:

- Confounding bias: “healthy user”

- Compliance bias

- Incomplete capture of early events

o And postulated biological differences:

- Hormone regimen (formulation and dose)

- Characteristics of study population: endogenous estrogen level, time since menopause, stage of atherosclerosis

What is the role of hormone therapy in postmenopausal women?

• The FDA issued New Labels for Estrogen and Estrogen with Progestin Therapy:

o

o Highlighting the increased risks for heart disease, heart attacks, strokes, and breast cancer

o Emphasizing that these products are not approved for heart disease prevention

o Requesting similar label changes for all other manufacturers of estrogen and estrogen with a progestin because all products are believed to have similar risks

• The FDA also modified its approved indications for HRT, now only to include:

o Treatment of moderate to severe vasomotor symptoms associated with menopause:

o

o

o

o - Prescribe at the lowest dose and for the shortest duration for the individual woman.

o Treatment of moderate to severe symptoms of vulvar and vaginal atrophy (dryness and irritation) associated with menopause.

o When prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, consider topical vaginal products.

o Prevention of postmenopausal osteoporosis

o When ET or EPT prescribed solely for prevention of osteoporosis, approved non-estrogen treatments should be carefully considered.

o

o ET and EPT products should only be considered for women with significant risk of osteoporosis that outweighs the risks of the drug.

• FDA’s recommendations:

o

In Summary:

o Consider lower dose hormone therapy for symptom relief at menopause in symptomatic women

o Women should be counseled about the small but real increased risk of CHD, stroke, VTE, and breast cancer

o The CEE arm of the WHI will help to answer questions about unopposed estrogen risks/benefits

o At least annually, reassess, and consider preventive strategies with safer risk profiles that target benefits to specific individual risks: SERMs, bisphosphonates, statins, etc.

o More research on different doses, modes of administration, and type of hormone therapy will be important in the future.

2) PRESENTATION: Mary Devereaux

What are the ethical considerations involved in hormone replacement therapy?

• For years doctors prescribed powerful drugs (HRT) to a large patient population in the belief that estrogen alone, or in combination, would protect against heart disease, osteoporosis and other diseases. Recent studies (e.g., The Women's Health Initiative) fail to support such claims. What aspects of medical practice led so many doctors to "get it wrong for so long"?

o Existing guidelines should have helped avoid this kind of episode. Why didn’t they?

▪ Ethical principles: ‘Do not harm’; Informed Consent.

▪ Scientific Principle: Evidence-based medicine.

▪ Medical Principle: ‘Only prescribe what works’

o Need prophylactic regimens be evaluated more conservatively than therapeutic ones, before being approved?

• What role did pharmaceutical interests play in encouraging the widespread use of HRT for menopausal and post-menopausal women?

o The FDA survives at the will of Congress, which gets lobbied by pharmaceutical companies.

o Who sponsors the studies?

▪ HERS study was sponsored by a pharmaceutical company: Wyeth-Ayerst Research, an affiliate of American Home Products Corp. SR

▪ WHI was NIH-sponsored.

▪ PEPI was sponsored by various national institutes (National Heart, Lung, and Blood Institute (NHLBI) National Institute on Aging (NIA) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Institute of Child Health and Human Development (NICHD))

• Were there clinical warning signs that should have gained greater attention earlier, but didn't?  And if so, what happened?

o Disregard of low compliance rate (large numbers of women would quit regimen within a year)

o Conventional wisdom, “the old story” versus “the new story”

• What role did cultural views about women, female reproduction and aging play in contributing to this outcome?

o Does medicine, as historically a “predominantly male field” tend to dismiss or under treat women’s health concerns? Studies focusing on female populations alone are rare, as is funding for such studies.

o The marketing of HRT drugs relies heavily on selling youth and beauty (better skin, delayed signs of aging) as well as purported health benefits. Aging itself treated as a disease.

o Assumption that women aren’t in a position to make medical decisions for themselves. “Physicians know best what’s good for me”

• Is menopause (male or female) in need of medical treatment?

o Female menopause has gone from being seen as a natural life event to “estrogen deficiency” and pathology.

o Developing market for symptoms of “male menopause” -- hormone therapies (testosterone) and sexual enhancement drugs (Viagra, etc) – support the view that male aging is also a disease in need of treatment.

• What lessons can we learn from the HRT “fiasco”? What conclusions might we draw from a public health/clinical standpoint?

o How, for example, ought new (and unexpected) medical results best be handled in the future? 

o Inflammatory press, prompting widespread nervousness and panic among patients immediately followed WHI findings on HRT. Patients assailing their doctors with questions, to which the doctors didn’t yet have answers.

o To the extent that public trust in researchers and clinicians was harmed by this episode, what, if anything, can be done to reestablish trust, post WHI?

3) DISCUSSION:

• Why is there a practice/ data disconnect about menopause? How do you feel that doctors in the general community are taking the WHI findings? Are they changing their clinical treatment? Are there any surveys on how clinicians are prescribing?

o Sales of HRT drugs have dropped and the main HRT drug companies’ stock market value significantly went down.

o However the clinician consensus remains: 60% pro estrogen. 40% against.

o There are a lot of vested economic and institutionalized interests in continuing to prescribe HRT despite WHI findings.

o Clinicians and researchers stand to have “reputation damage”

o Pharmaceutical industry interests/ Role of estrogen marketing:

- Best-seller, “Feminine Forever,” praising estrogen as the latest beauty secret later revealed to have been sponsored by several drug manufacturers.

o National Institutes rely on donors as well and are not necessarily protected from conflict of interests in their agendas.

• Symptomology of Menopause?

o We went from prescribing HRT for symptomatic causes to prescribing HRT for prevention reasons. It is this shift that got us into trouble.

o “Grandma didn’t care about hot flashes and didn’t feel bad through menopause”

o Yes, but earlier generations “had valiums, cocktails” and other ways of self-medicating.

o Are there cultural studies studying symptoms across different cultures?

o There is no word for “hot flash” in Japanese, for instance.

o Women suffering from menopausal symptoms in the US do not care whether or not other women in other cultures don’t. For an individual, “a hot flash is a hot flash” no matter why it happens.

o From a medical standpoint, is the physiological response to menopause affected by different diets, for example?

• The question asked by the title of this seminar is “What went wrong?” Members of the audience felt that it could also have been “What went right?” It is remarkable that a study like the WHI received funding from the NIH to test “what everybody thought was true.”

• Economic fallout: Birth control pills prices have risen because the drug companies selling HRT lost money.

• Public Health dimension of this episode:

o Many people feel that the release of the WHI findings was poorly handled. The data came out to the media before it reached the medical community. A media frenzy immediately ensued provoking high level of anxiety in the population. What can we learn from this case? How could we have best handled this clinically?

• Is it ethical to prescribe and ignore data?

o The commitment in the medical community to adhere to the “old way” is worrisome.

o Evidence-based medicine is new. Many old physicians do not operate according to this new model of evidence-based medicine. Prior to that, medical education emphasized “clinical judgment.” Such clinical judgment is dependent on the placebo effect. The very belief in estrogen can have a placebo effect.

o There are also culture differences within medical specialties. For instance, Cardiology specialists seem very excited to hear about new findings (many well attended meetings presenting new data) and are ready to change things accordingly and quickly. In other disciplines, like Obstetrics and Gynecology, things are slower to change.

o Prescribing patterns HAVE changed though, as sales for HRT have dropped by 30%.

• Intersection of Culture and Medicine:

o Helping patients “Feel Good” is a different objective from “Preventing long term disease.”

- The question becomes: Are you “miserable” enough during your menopause to be willing to accept the risks associated with HRT?

o A patient today can get medical information from the media or the Internet. Better-informed patients may feel more comfortable making demands on physicians. Physicians thus need to be clear about the data and the risks for a given patient.

:

o Aging, moods, menopause, sexual behavior has all recently been redefined by medicine (or marketing) as pathological rather than natural.

o Medicine is increasingly treating non-medical problems. For instance, initially plastic surgery was only used for gross deformities or potentially medically problematic issues and evolved to become “cosmetic surgery.”

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