Design of the Women's Health Initiative clinical trial and observational study
TL;DR: The rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component is described, including a brief description of the scientific and logistic complexity of the WHI.
About: This article is published in Controlled Clinical Trials.The article was published on 1998-01-01. It has received 2310 citations till now. The article focuses on the topics: Women's Health Initiative & Clinical trial.
Citations
More filters
TL;DR: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
Abstract: Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD
14,646 citations
TL;DR: Treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease and the treatment did increase the rate of thromboembolic events and gallbladder disease.
Abstract: Context.—Observational studies have found lower rates of coronary heart disease
(CHD) in postmenopausal women who take estrogen than in women who do not,
but this potential benefit has not been confirmed in clinical trials.Objective.—To determine if estrogen plus progestin therapy alters the risk for
CHD events in postmenopausal women with established coronary disease.Design.—Randomized, blinded, placebo-controlled secondary prevention trial.Setting.—Outpatient and community settings at 20 US clinical centers.Participants.—A total of 2763 women with coronary disease, younger than 80 years,
and postmenopausal with an intact uterus. Mean age was 66.7 years.Intervention.—Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone
acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383).
Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were
taking it at the end of 1 year, and 75% at the end of 3 years.Main Outcome Measures.—The primary outcome was the occurrence of nonfatal myocardial infarction
(MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization,
unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke
or transient ischemic attack, and peripheral arterial disease. All-cause mortality
was also considered.Results.—Overall, there were no significant differences between groups in the
primary outcome or in any of the secondary cardiovascular outcomes: 172 women
in the hormone group and 176 women in the placebo group had MI or CHD death
(relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The
lack of an overall effect occurred despite a net 11% lower low-density lipoprotein
cholesterol level and 10% higher high-density lipoprotein cholesterol level
in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically
significant time trend, with more CHD events in the hormone group than in
the placebo group in year 1 and fewer in years 4 and 5. More women in the
hormone group than in the placebo group experienced venous thromboembolic
events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84
vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences
in several other end points for which power was limited, including fracture,
cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).Conclusions.—During an average follow-up of 4.1 years, treatment with oral conjugated
equine estrogen plus medroxyprogesterone acetate did not reduce the overall
rate of CHD events in postmenopausal women with established coronary disease.
The treatment did increase the rate of thromboembolic events and gallbladder
disease. Based on the finding of no overall cardiovascular benefit and a pattern
of early increase in risk of CHD events, we do not recommend starting this
treatment for the purpose of secondary prevention of CHD. However, given the
favorable pattern of CHD events after several years of therapy, it could be
appropriate for women already receiving this treatment to continue.
5,991 citations
TL;DR: The use of conjugated equine estrogen (CEE) increases the risk of stroke, decreases therisk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years, indicating no overall benefit.
Abstract: Author(s): Anderson, Garnet L; Limacher, Marian; Assaf, Annlouise R; Bassford, Tamsen; Beresford, Shirley AA; Black, Henry; Bonds, Denise; Brunner, Robert; Brzyski, Robert; Caan, Bette; Chlebowski, Rowan; Curb, David; Gass, Margery; Hays, Jennifer; Heiss, Gerardo; Hendrix, Susan; Howard, Barbara V; Hsia, Judith; Hubbell, Allan; Jackson, Rebecca; Johnson, Karen C; Judd, Howard; Kotchen, Jane Morley; Kuller, Lewis; LaCroix, Andrea Z; Lane, Dorothy; Langer, Robert D; Lasser, Norman; Lewis, Cora E; Manson, JoAnn; Margolis, Karen; Ockene, Judith; O'Sullivan, Mary Jo; Phillips, Lawrence; Prentice, Ross L; Ritenbaugh, Cheryl; Robbins, John; Rossouw, Jacques E; Sarto, Gloria; Stefanick, Marcia L; Van Horn, Linda; Wactawski-Wende, Jean; Wallace, Robert; Wassertheil-Smoller, Sylvia; Women's Health Initiative Steering Committee | Abstract: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain.To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States.A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity.Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo.The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects.In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years.The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.
4,298 citations
TL;DR: Information on discriminatory attitudes and behaviors against obese individuals is reviewed, integrating this to show whether systematic discrimination occurs and why, and needed work in the field is discussed.
Abstract: This article reviews information on discriminatory attitudes and behaviors against obese individuals, integrates this to show whether systematic discrimination occurs and why, and discusses needed work in the field. Clear and consistent stigmatization, and in some cases discrimination, can be documented in three important areas of living: employment, education, and health care. Among the findings are that 28% of teachers in one study said that becoming obese is the worst thing that can happen to a person; 24% of nurses said that they are "repulsed" by obese persons; and, controlling for income and grades, parents provide less college support for their overweight than for their thin children. There are also suggestions but not yet documentation of discrimination occurring in adoption proceedings, jury selection, housing, and other areas. Given the vast numbers of people potentially affected, it is important to consider the research-related, educational, and social policy implications of these findings.
2,069 citations
Cites background from "Design of the Women's Health Initia..."
...Although tens of thousands of women are participating in this longitudinal study, and despite overweight women having increased vulnerability for some of the diseases being investigated, the study excluded obese women (5,127)....
[...]
Harvard University1, George Washington University2, University of Tennessee Health Science Center3, National Institutes of Health4, Brown University5, Rutgers University6, University at Buffalo7, Rush University Medical Center8, University of Washington9, University of California, Los Angeles10, Emory University11, University of California, Irvine12, Wake Forest University13, University of Vermont14
TL;DR: Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use.
Abstract: Background Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI). Methods The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD). Results After a mean follow-up of 5.2 years (planned duration, 8.5 years), the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (nominal 95 percent confidence interval, 1.00 to 1.54; 95 percent confidence interval after adjustment for sequential monitoring, 0.97 to 1.60). The elevation in risk was most apparent at one year (hazard ratio, 1.81 [95 percent confidence interval, 1.09 to 3.01]). Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD. Conclusions Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease.
1,980 citations
References
More filters
Journal Article•
8,920 citations
Journal Article•
TL;DR: What do you do to start reading statistical methods in cancer research vol ii the design and analysis of cohort studies?
Abstract: What do you do to start reading statistical methods in cancer research vol ii the design and analysis of cohort studies? Searching the book that you love to read first or find an interesting book that will make you want to read? Everybody has difference with their reason of reading a book. Actuary, reading habit must be from earlier. Many people may be love to read, but not a book. It's not fault. Someone will be bored to open the thick book with small words to read. In more, this is the real condition. So do happen probably with this statistical methods in cancer research vol ii the design and analysis of cohort studies.
4,226 citations
TL;DR: Data indicate that a simple self-administered dietary questionnaire can provide useful information about individual nutrient intakes over a one-year period.
Abstract: The aim of this study was to evaluate the reproducibility and validity of a 61-item semiquantitative food frequency questionnaire used in a large prospective study among women. This form was administered twice to 173 participants at an interval of approximately one year (1980-1981), and four one-week diet records for each subject were collected during that period. Intraclass correlation coefficients for nutrient intakes estimated by the one-week diet records (range = 0.41 for total vitamin A without supplements to 0.79 for vitamin B6 with supplements) were similar to those computed from the questionnaire (range = 0.49 for total vitamin A without supplements to 0.71 for sucrose), indicating that these methods were generally comparable with respect to reproducibility. With the exception of sucrose and total carbohydrate, nutrient intakes from the diet records tended to correlate more strongly with those computed from the questionnaire after adjustment for total caloric intake. Correlation coefficients between the mean calorie-adjusted intakes from the four one-week diet records and those from the questionnaire completed after the diet records ranged from 0.36 for vitamin A without supplements to 0.75 for vitamin C with supplements. Overall, 48% of subjects in the lowest quintile of calorie-adjusted intake computed from the diet records were also in the lowest questionnaire quintile, and 74% were in the lowest one of two questionnaire quintiles. Similarly, 49% of those in the highest diet record quintile were also in the highest questionnaire quintile, and 77% were in the highest one or two questionnaire quintiles. These data indicate that a simple self-administered dietary questionnaire can provide useful information about individual nutrient intakes over a one-year period.
4,012 citations
TL;DR: Results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia.
Abstract: In a randomized, double-blind five-year trial, we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein (HDL) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men (40 to 55 years of age) with primary dyslipidemia (non-HDL cholesterol greater than or equal to 200 mg per deciliter [5.2 mmol per liter] in two consecutive pretreatment measurements). One group (2051 men) received 600 mg of gemfibrozil twice daily, and the other (2030 men) received placebo. Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total, low-density lipoprotein (LDL), and non-HDL cholesterol and triglycerides. There were minimal changes in serum lipid levels in the placebo group. The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group--a reduction of 34.0 percent in the incidence of coronary heart disease (95 percent confidence interval, 8.2 to 52.6; P less than 0.02; two-tailed test). The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study. There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates. The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia.
3,697 citations