On July
9, 2002, the National Heart, Lung, and Blood Institute of the National
Institutes of Health announced premature termination of one component
of the Women's Health Initiative (WHI). This component was designed
to assess risks and benefits of hormone therapy (HT) combining estrogen
with progestin in healthy postmenopausal women. The WHI data and safety
monitoring board concluded that despite noteworthy benefits, the risks
of this combined HT outweighed the benefits in this study population.
The impact of the announcement was immediate and profound: These results
not only contradicted the medical community's previous understanding
of combined HT but also received much attention in the press. Millions
of women suddenly felt compelled to reassess their decision to continue
HT, and health care providers mobilized to address the flood of questions
and requests for counseling that continue to this day.
As recently
as 2002, overwhelming observational data and expert opinion led to the
conclusion that for most women, benefits of HT far outweighed its risks.
The clear benefits of HT included relief of vasomotor symptoms as well
as prevention of osteoporosis and heart disease. Potential benefits
of HT included improved quality of life (including, for example, improved
sexual function), prevention of colon cancer, and protection from Alzheimer's
disease. Consequently, the WHI results stunned the medical community,
and in the months after the July 2002 announcement, many major medical
organizations scrambled to prepare responses and to revise guidelines.
We health
care providers in the KP Northern California Region are fortunate: Within
hours after reading the press release, the KP Women's Health Care leadership
began preparing an educational response for prompt transmission to more
than 90,000 female Health Plan members aged 45 or older who were receiving
HT. Today, our regional Clinical Guidelines (revised in October 2002)
succinctly state: "The sole indication for hormone therapy (HT)
is for the treatment of menopausal symptoms. When HT is elected for
symptom relief, prescribe the lowest effective dose for the shortest
possible time (1-5 years)."1:p1
Women's Health Initiative
Results: Details to Date
Health
care practitioners must clearly understand this WHI study in detail
if they are to apply its results to individual perimenopausal patients.
Although absolute risk and calculated relative risk are difficult for
many patients to understand, clinicians must be able to explain these
risks as calculated for the treatment groups in the WHI study.
The estrogen-plus-progestin
(E+P) arm of the postmenopausal HT component of the WHI was designed
to end in 2005 after a mean follow-up of 8.5 years but was stopped in
May 2002 after a mean follow-up of 5.2 years.2 The 16,608
women eligible for the study had an intact uterus and were randomized
to treatment groups who received either a tablet containing 0.625 mg
conjugated equine estrogen combined with 2.5 mg medroxyprogesterone
acetate (PremPro) or a placebo tablet. Primary outcomes were coronary
heart disease (CHD) and breast cancer. Secondary outcomes were stroke,
pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture,
and death from other causes.2 Results of comparing health
benefits and risks were summarized by using a global index, defined
as the earliest occurrence of any study outcome (giving extra statistical
weight to the seven listed diseases). Randomized participants in both
groups had these baseline characteristics: mean age 63 years; race/ethnicity
84% white, 7% black, 5% Hispanic; 74% had never used HT; mean BMI 28.5;
mean blood pressure 128/76 mmHg; 50% had never smoked; 90% had at least
one term pregnancy; 87% had normal serum cholesterol levels; and few
had clinically significant chronic medical conditions.2
At the
tenth interim analysis of the study data, the data and safety monitoring
board recommended that the E+P arm of the trial be stopped because predetermined
limits for increased risk of breast cancer and for the global index
had been exceeded. The study found that use of E+P was associated with
increased risk of CHD, breast cancer, stroke, and pulmonary embolism
and with decreased risk of colorectal cancer and hip fracture. No difference
in mortality was seen between groups, but overall health risks exceeded
benefits for the group using E+P.2
Table
1 summarizes key study findings and may be useful for showing patients
alternative perspectives on the same data. This tabular summation can
facilitate patient counseling and can help us to tailor treatment to
the needs of individual patients.
For example,
annualized absolute risk of stroke (ie, the percentage of group participants
who had a stroke during each study year) was 0.21% for the placebo group
and was 0.29% for the E+P group. Thus, the projected ten-year risk of
stroke is 2.1% for the placebo group and is 2.9% for the E+P group;
in contrast, the projected 10-year risk of no stroke is 97.9% for the
placebo group and is 97.1% for the E+P group. An alternative perspective
would compare the 21 cases of stroke expected per 10,000 person-year
in the placebo group with the 29 cases expected per 10,000 person-year
in the E+P group; thus, a group of 10,000 women who take E+P for one
year might have eight more cases of stroke than if they took a placebo.
This comparison would show a 41% increased risk of stroke in the E+P
group, who would be 1.29 times more likely to have a stroke than the
placebo group (RR=1.29). Asymptomatic perimenopausal women balancing
the potential benefit and risk of HT might weigh "a 41% increased
risk of stroke after one year of using E+P" or "1.29 times
more likely to have a stroke" differently than "a 97.1% chance
(risk) of not having a stroke after 10 years of using E+P." Our
challenge as clinicians is to interpret findings for patients in an
unbiased, easily understood way so that our patients can be better informed
when making decisions about their health care.
The WHI
is more than a single study--it is a large, 15-year research program
based in the United States and designed to study major causes of death,
disability, and frailty in postmenopausal women. The goal of the WHI
is to use prevention and intervention strategies and risk factor identification
to reduce incidence of CHD, breast and colorectal cancer, and osteoporotic
fracture in women. Major components of the WHI include three clinical
trials evaluating promising-but-unproven approaches to prevention; an
observational study identifying predictors of disease; and a study evaluating
community-based approaches to adopting healthful behavior. Results of
major WHI studies on effects of E+P use on health-related quality of
life,3 global cognitive function,4 and dementia
and mild cognitive impairment were published in the first half of 2003.5
We can expect many more such publications in the future. Often, more
questions than answers will result from these studies; health care practitioners
will need not only to critically assess the clinical significance, scope,
and magnitude of study findings but also to develop tools that will
enable our patients to do the same.
Acknowledgment
Ruth
E Shaber, MD, reviewed the article.
References
- Permanente
Medical Group, Department of Quality and Utilization. Clinical practice
guidelines: mid-life women's health--the menopause transition. Rev.
Oakland (CA): Kaiser Permanente Northern California, TPMG Department
of Quality and Utilization; 2002. Available from: http://clinicallibrary.ca.kp.org/Search_Test/Search_Clinical_Guidelines.html;
search under "hormone therapy" (accessed July 31, 2003).
- Rossouw
JE, Anderson GL, Prentice RL, et al; Writing Group for the Women's
Health Initiative Investigators. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women: principal results from
the Women's Health Initiative randomized controlled trial. JAMA 2002
Jul 17;288(3):321-33.
- Hays
J, Ockene JK, Brunner RL, et al; Women's Health Initiative Investigators.
Effects of estrogen plus progestin on health-related quality of life.
N Engl J Med 2003 May 8;348(19):1839-54. Epub 2003 Mar 17.
- Rapp
SR, Espeland MA, Shumaker SA, et al; WHIMS Investigators. Effect of
estrogen plus progestin
on global cognitive function in postmenopausal women: the Women's
Health Initiative Memory Study: a randomized controlled trial. JAMA
2003 May 28;289(20):2663-72.
- Shumaker
SA, Legault C, Thal L, et al; WHIMS Investigators. Estrogen plus progestin
and the incidence of dementia and mild cognitive impairment in postmenopausal
women: the Women's Health Initiative Memory Study: a randomized controlled
trial. JAMA 2003 May 28;289(20):2651-62
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