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1.
J Am Pharm Assoc (2003) ; 53(5): 520-9, 2013.
Article in English | MEDLINE | ID: mdl-24030130

ABSTRACT

OBJECTIVE: To assess the effectiveness and sustainability of a 6-month Team Education and Adherence Monitoring (TEAM) intervention for black patients with hypertension in community chain pharmacies. DESIGN: Cluster randomized trial. SETTING: 28 chain pharmacies (14 TEAM and 14 control) in five Wisconsin cities from December 2006 to February 2009. PARTICIPANTS: 576 black patients with hypertension. INTERVENTION: Trained pharmacist-technician teams implemented a 6-month intervention using scheduled visits, Brief Medication Questionnaires (BMQs), and novel toolkits for facilitating medication adherence and pharmacist feedback to patients and physicians. Control participants received patient information only. MAIN OUTCOME MEASURES: Refill adherence (≥80% days covered) and changes in systolic blood pressure (SBP), diastolic blood pressure, and blood pressure control using blinded assessments at 6 and 12 months. RESULTS: At baseline, all patients had blood pressure of 140/90 mm Hg or more. Of those eligible, 79% activated the intervention (mean 4.25 visits). Compared with control participants at 6 months, TEAM participants achieved greater improvements in refill adherence (60% vs. 34%, P < 0.001), SBP (-12.62 vs. -5.31 mm Hg, P < 0.001), and blood pressure control (50% vs. 36%, P = 0.01). Six months after intervention discontinuation, TEAM participants showed sustained improvements in refill adherence ( P < 0.001) and SBP ( P = 0.004), though the difference in blood pressure control was not significant ( P < 0.05) compared with control participants. Analysis of intervention fidelity showed that patients who received the full intervention during months 1 through 6 achieved significantly greater 6- and 12-month improvements in refill adherence and blood pressure control compared with control participants. CONCLUSION: A team-based intervention involving community chain pharmacists, pharmacy technicians, and novel toolkits led to significant and sustained improvements in refill adherence and SBP in black patients with hypertension.


Subject(s)
Antihypertensive Agents/therapeutic use , Black or African American/statistics & numerical data , Community Pharmacy Services/organization & administration , Hypertension/drug therapy , Medication Adherence/ethnology , Pharmacists/organization & administration , Adult , Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Cluster Analysis , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Care Team/organization & administration , Patient Education as Topic/methods , Pharmacy Technicians/organization & administration , Professional Role , Time Factors , Wisconsin
2.
Circ Cardiovasc Qual Outcomes ; 5(6): 750-8, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23149426

ABSTRACT

BACKGROUND: Blacks have disproportionately high rates of cardiovascular disease. Psychosocial stress may contribute to this disparity. Previous trials on stress reduction with the Transcendental Meditation (TM) program have reported improvements in cardiovascular disease risk factors, surrogate end points, and mortality in blacks and other populations. METHODS AND RESULTS: This was a randomized, controlled trial of 201 black men and women with coronary heart disease who were randomized to the TM program or health education. The primary end point was the composite of all-cause mortality, myocardial infarction, or stroke. Secondary end points included the composite of cardiovascular mortality, revascularizations, and cardiovascular hospitalizations; blood pressure; psychosocial stress factors; and lifestyle behaviors. During an average follow-up of 5.4 years, there was a 48% risk reduction in the primary end point in the TM group (hazard ratio, 0.52; 95% confidence interval, 0.29-0.92; P=0.025). The TM group also showed a 24% risk reduction in the secondary end point (hazard ratio, 0.76; 95% confidence interval, 0.51-0.1.13; P=0.17). There were reductions of 4.9 mmHg in systolic blood pressure (95% confidence interval -8.3 to -1.5 mmHg; P=0.01) and anger expression (P<0.05 for all scales). Adherence was associated with survival. CONCLUSIONS: A selected mind-body intervention, the TM program, significantly reduced risk for mortality, myocardial infarction, and stroke in coronary heart disease patients. These changes were associated with lower blood pressure and psychosocial stress factors. Therefore, this practice may be clinically useful in the secondary prevention of cardiovascular disease. Clinical Trial Registration- URL: www.clinicaltrials.gov Unique identifier: NCT01299935.


Subject(s)
Black or African American/psychology , Coronary Disease/therapy , Health Knowledge, Attitudes, Practice/ethnology , Meditation , Myocardial Infarction/prevention & control , Patient Education as Topic , Secondary Prevention/methods , Stress, Psychological/therapy , Stroke/prevention & control , Aged , Coronary Disease/ethnology , Coronary Disease/mortality , Coronary Disease/psychology , Female , Hospitalization , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Myocardial Infarction/ethnology , Myocardial Infarction/mortality , Myocardial Infarction/psychology , Proportional Hazards Models , Risk Assessment , Risk Factors , Stress, Psychological/ethnology , Stress, Psychological/mortality , Stress, Psychological/psychology , Stroke/ethnology , Stroke/mortality , Stroke/psychology , Time Factors , Treatment Outcome , Wisconsin/epidemiology
3.
Clin J Pain ; 27(3): 268-74, 2011.
Article in English | MEDLINE | ID: mdl-21178593

ABSTRACT

OBJECTIVE: Temporomandibular joint and muscle disorders (TMJD) are ill-defined, painful debilitating disorders. This study was undertaken to identify the spectrum of clinical manifestations based on self-report from affected patients. METHODS: A total of 1511 TMJD-affected individuals were recruited through the web-based registry of patients maintained by The TMJ Association, Ltd, a patient advocacy organization, and participated in the survey as well as 57 of their nonaffected friends. Results were also compared with US population for questions in common with the National Health and Nutrition Examination Survey. RESULTS: The TMJD-affected individuals were on average 41 years of age and predominantly female (90%). Nearly 60% of both men and women reported recent pain of moderate-to-severe intensity with a quarter of them indicating interference or termination of work-related activities. In the case-control comparison, a higher frequency of headaches, allergies, depression, fatigue, degenerative arthritis, fibromyalgia, autoimmune disorders, sleep apnea, and gastrointestinal complaints were prevalent among those affected with TMJD. Many of the associated comorbid conditions were over 6 times more likely to occur after TMJD was diagnosed. Among a wide array of treatments used (46 listed), the most effective relief for most affected individuals (91%) was the use of thermal therapies--hot/cold packs to the jaw area or hot baths. Nearly 40% of individuals affected with TMJD patients reported one or more surgical procedures and nearly all were treated with one or many different medications. Results of these treatments were generally equivocal. Although potentially limited to the most severe TMJD affected individuals, the survey results provide a comprehensive dataset describing the clinical manifestations of TMJD. DISCUSSION: The data provide evidence that TMJD represent a spectrum of disorders with varying pathophysiologies, clinical manifestations, and associated comorbid conditions. The findings underscore the complex nature of TMJD, the need for more extensive interdisciplinary basic and clinical research, and the development of outcome-based strategies to more effectively diagnose, prevent, and treat these chronic, debilitating conditions.


Subject(s)
Pain/epidemiology , Registries , Temporomandibular Joint Disorders/epidemiology , Adult , Age Distribution , Comorbidity , Female , Humans , Male , Prevalence , Risk Assessment , Risk Factors , Sex Distribution , United States/epidemiology
4.
J Natl Cancer Inst ; 102(18): 1413-21, 2010 Sep 22.
Article in English | MEDLINE | ID: mdl-20709992

ABSTRACT

BACKGROUND: In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer. METHODS: The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50-79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided. RESULTS: After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79). CONCLUSION: Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.


Subject(s)
Estrogen Replacement Therapy/adverse effects , Estrogen Replacement Therapy/methods , Estrogens, Conjugated (USP)/administration & dosage , Estrogens, Conjugated (USP)/adverse effects , Lung Neoplasms/epidemiology , Postmenopause , Women's Health , Aged , Carcinoma, Non-Small-Cell Lung/epidemiology , Carcinoma, Small Cell/epidemiology , Double-Blind Method , Female , Humans , Incidence , Lung Neoplasms/chemically induced , Lung Neoplasms/mortality , Middle Aged , Progestins/administration & dosage , Progestins/adverse effects , United States/epidemiology
5.
J Am Geriatr Soc ; 58(8): 1427-32, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20646100

ABSTRACT

OBJECTIVES: To determine whether body mass index (BMI) is independently associated with cognitive function in postmenopausal women and the relationship between body fat distribution as estimated by waist-hip ratio (WHR). DESIGN: Cross-sectional data analysis. SETTING: Baseline data from the Women's Health Initiative (WHI) hormone trials. PARTICIPANTS: Eight thousand seven hundred forty-five postmenopausal women aged 65 to 79 free of clinical evidence of dementia who completed the baseline evaluation in the WHI hormone trials. MEASUREMENTS: Participants completed a Modified Mini-Mental State Examination (3MSE), health and lifestyle questionnaires, and standardized measurements of height, weight, body circumference, and blood pressure. Statistical analysis was performed of associations between 3MSE score, BMI, and WHR after controlling for known confounders. RESULTS: With the exception of smoking and exercise, vascular disease risk factors, including hypertension, waist measurement, heart disease, and diabetes mellitus, were significantly associated with 3MSE score and were included as covariables in subsequent analyses. BMI was inversely related to 3MSE score; for every 1-unit increase in BMI, 3MSE score decreased 0.988 points (P<.001) after adjusting for age, education, and vascular disease risk factors. BMI had the most pronounced association with poorer cognitive functioning scores in women with smaller waist measurements. In women with the highest WHR, cognitive scores increased with BMI. CONCLUSION: Higher BMI was associated with poorer cognitive function in women with smaller WHR. Higher WHR, estimating central fat mass, was associated with higher cognitive function in this cross-sectional study. Further research is needed to clarify the mechanism for this association.


Subject(s)
Body Mass Index , Cognition , Postmenopause , Waist-Hip Ratio , Aged , Cross-Sectional Studies , Female , Humans , Multivariate Analysis , Neuropsychological Tests , Obesity/epidemiology , Randomized Controlled Trials as Topic
6.
Circ Cardiovasc Qual Outcomes ; 2(3): 264-71, 2009 May.
Article in English | MEDLINE | ID: mdl-20031847

ABSTRACT

Recent studies suggest that involving pharmacists is an effective strategy for improving patient adherence and blood pressure (BP) control. To date, few controlled studies have tested the cost-effectiveness of specific models for improving patient adherence and BP control in community pharmacies, where most Americans obtain prescriptions. We hypothesized that a team model of adherence monitoring and intervention in corporately owned community pharmacies can improve patient adherence, prescribing, and BP control among hypertensive black patients. The Team Education and Adherence Monitoring (TEAM) Trial is a randomized controlled trial testing a multistep intervention for improving adherence monitoring and intervention in 28 corporately owned community pharmacies. Patients in the 14 control pharmacies received "usual care," and patients in the 14 intervention pharmacies received TEAM Care by trained pharmacists and pharmacy technicians working with patients and physicians. Data collectors screened 1250 patients and enrolled 597 hypertensive black patients. The primary end points were the proportion of patients achieving BP control and reductions in systolic and diastolic BP measured after 6 and 12 months. Secondary end points were changes in adherence monitoring and intervention, patient adherence and barriers to adherence, prescribing, and cost-effectiveness. Researchers also will examine potential covariates and barriers to change. Involving pharmacists is a potentially powerful means of improving BP control in blacks. Pharmacists are in an excellent position to monitor patients between clinic visits and to provide useful information to patients and physicians.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Medication Adherence , Pharmacies , Randomized Controlled Trials as Topic/methods , Black People , Humans , Hypertension/ethnology , Patient Care Team , Patient Education as Topic
7.
Lancet ; 374(9697): 1243-51, 2009 Oct 10.
Article in English | MEDLINE | ID: mdl-19767090

ABSTRACT

BACKGROUND: In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. METHODS: The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS: After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. INTERPRETATION: Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health.


Subject(s)
Estrogen Replacement Therapy/adverse effects , Lung Neoplasms , Postmenopause , Aged , Carcinoma, Non-Small-Cell Lung/chemically induced , Carcinoma, Non-Small-Cell Lung/epidemiology , Cause of Death , Double-Blind Method , Estrogen Replacement Therapy/methods , Female , Follow-Up Studies , Humans , Incidence , Kaplan-Meier Estimate , Lung Neoplasms/chemically induced , Lung Neoplasms/epidemiology , Middle Aged , Postmenopause/drug effects , Proportional Hazards Models , Risk Factors , Smoking/adverse effects , Smoking/epidemiology , United States/epidemiology , Women's Health
8.
J Addict Med ; 3(2): 83-8, 2009 Jun.
Article in English | MEDLINE | ID: mdl-21769003

ABSTRACT

OBJECTIVES: : To determine the prevalence of cocaine use and associated risk factors in African Americans volunteering as research subjects for a hypertension study. METHODS: : African Americans recruited from Milwaukee's inner city received $25 for completing a blood pressure screening protocol with the potential to participate in an additional protocol for $200, contingent on a negative drug test for cocaine. This study is based on the characteristics of the participants who completed the drug screen for cocaine. The significance of differences in the frequencies of categorical variables between users and nonusers was determined by χ analysis or Fisher exact test. RESULTS: : Of 389 drug-tested participants, 35% tested positive for cocaine. Cocaine positive volunteers were slightly older (P = 0.02), had a lower body mass index (P = 0.001), a smaller waist circumference (P = 0.005), and lower serum cholesterol levels (P = 0.04). Those testing positive were more likely to be tobacco smokers (P < 0.0001), unemployed (P = 0.001), and alcohol users (P < 0.0001), but less likely to use prescription medications (P = 0.01). Income and education did not differ between cocaine positive and negative subjects. Individuals employed full-time were less likely to test positive than the unemployed, whereas part-time employees were intermediate (P = 0.0003). Although those testing positive were slightly less likely to have a living mother (P = 0.07), there was no association with living fathers.Cigarette smokers were almost five times more likely to test positive for cocaine than nonsmokers (OR 4.88, 95% CI 2.73-8.71). Additional predictors of positive tests were alcohol consumption (OR 1.90, 95% CI 1.18-3.19), a reported history of substance abuse (OR 1.83, 95% CI 1.05-3.19), and a family history that included one or more deceased siblings (OR 1.82, 95% CI 1.03-3.21). CONCLUSIONS: : A high prevalence of substance use was detected among inner city African Americans offered financial incentives for participating in a general medical research protocol. This information may be relevant for designing future clinical trials and drug use intervention programs.

9.
Annu Rev Public Health ; 27: 465-90, 2006.
Article in English | MEDLINE | ID: mdl-16533126

ABSTRACT

Hypertension is the leading cause of cardiovascular disease worldwide. Prior to 1990, population data suggest that hypertension prevalence was decreasing; however, recent data suggest that it is again on the rise. In 1999-2002, 28.6% of the U.S. population had hypertension. Hypertension prevalence has also been increasing in other countries, and an estimated 972 million people in the world are suffering from this problem. Incidence rates of hypertension range between 3% and 18%, depending on the age, gender, ethnicity, and body size of the population studied. Despite advances in hypertension treatment, control rates continue to be suboptimal. Only about one third of all hypertensives are controlled in the United States. Programs that improve hypertension control rates and prevent hypertension are urgently needed.


Subject(s)
Hypertension/epidemiology , Hypertension/prevention & control , Health Services Needs and Demand , Health Surveys , Humans , Prevalence , Preventive Health Services , United States/epidemiology
10.
N Engl J Med ; 354(7): 669-83, 2006 Feb 16.
Article in English | MEDLINE | ID: mdl-16481635

ABSTRACT

BACKGROUND: The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal. METHODS: We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers. RESULTS: Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels. CONCLUSIONS: Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).


Subject(s)
Calcium Carbonate/therapeutic use , Fractures, Bone/prevention & control , Vitamin D/therapeutic use , Aged , Bone Density/drug effects , Calcium/therapeutic use , Calcium Carbonate/adverse effects , Calcium Carbonate/pharmacology , Double-Blind Method , Drug Combinations , Drug Interactions , Estrogen Replacement Therapy , Female , Follow-Up Studies , Fractures, Bone/epidemiology , Hip Fractures/prevention & control , Humans , Kidney Calculi/chemically induced , Middle Aged , Patient Compliance , Postmenopause , Proportional Hazards Models , Risk , Spinal Fractures/prevention & control , Vitamin D/adverse effects , Vitamin D/blood , Vitamin D/pharmacology
11.
N Engl J Med ; 354(7): 684-96, 2006 Feb 16.
Article in English | MEDLINE | ID: mdl-16481636

ABSTRACT

BACKGROUND: Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [corrected] twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study. RESULTS: The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P=0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics. CONCLUSIONS: Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.).


Subject(s)
Adenocarcinoma/prevention & control , Calcium Carbonate/therapeutic use , Colorectal Neoplasms/prevention & control , Vitamin D/therapeutic use , Adenocarcinoma/epidemiology , Aged , Calcium/therapeutic use , Calcium Carbonate/adverse effects , Calcium Carbonate/pharmacology , Colonic Polyps/epidemiology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/pathology , Double-Blind Method , Drug Combinations , Female , Follow-Up Studies , Humans , Incidence , Middle Aged , Postmenopause , Proportional Hazards Models , Vitamin D/adverse effects , Vitamin D/blood , Vitamin D/pharmacology
12.
JAMA ; 295(6): 629-42, 2006 Feb 08.
Article in English | MEDLINE | ID: mdl-16467232

ABSTRACT

CONTEXT: The hypothesis that a low-fat dietary pattern can reduce breast cancer risk has existed for decades but has never been tested in a controlled intervention trial. OBJECTIVE: To assess the effects of undertaking a low-fat dietary pattern on breast cancer incidence. DESIGN AND SETTING: A randomized, controlled, primary prevention trial conducted at 40 US clinical centers from 1993 to 2005. PARTICIPANTS: A total of 48,835 postmenopausal women, aged 50 to 79 years, without prior breast cancer, including 18.6% of minority race/ethnicity, were enrolled. INTERVENTIONS: Women were randomly assigned to the dietary modification intervention group (40% [n = 19,541]) or the comparison group (60% [n = 29,294]). The intervention was designed to promote dietary change with the goals of reducing intake of total fat to 20% of energy and increasing consumption of vegetables and fruit to at least 5 servings daily and grains to at least 6 servings daily. Comparison group participants were not asked to make dietary changes. MAIN OUTCOME MEASURE: Invasive breast cancer incidence. RESULTS: Dietary fat intake was significantly lower in the dietary modification intervention group compared with the comparison group. The difference between groups in change from baseline for percentage of energy from fat varied from 10.7% at year 1 to 8.1% at year 6. Vegetable and fruit consumption was higher in the intervention group by at least 1 serving per day and a smaller, more transient difference was found for grain consumption. The number of women who developed invasive breast cancer (annualized incidence rate) over the 8.1-year average follow-up period was 655 (0.42%) in the intervention group and 1072 (0.45%) in the comparison group (hazard ratio, 0.91; 95% confidence interval, 0.83-1.01 for the comparison between the 2 groups). Secondary analyses suggest a lower hazard ratio among adherent women, provide greater evidence of risk reduction among women having a high-fat diet at baseline, and suggest a dietary effect that varies by hormone receptor characteristics of the tumor. CONCLUSIONS: Among postmenopausal women, a low-fat dietary pattern did not result in a statistically significant reduction in invasive breast cancer risk over an 8.1-year average follow-up period. However, the nonsignificant trends observed suggesting reduced risk associated with a low-fat dietary pattern indicate that longer, planned, nonintervention follow-up may yield a more definitive comparison. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT00000611.


Subject(s)
Breast Neoplasms/prevention & control , Diet, Fat-Restricted , Aged , Biomarkers/blood , Body Weight , Breast Neoplasms/epidemiology , Cholesterol, LDL/blood , Diet Records , Female , Follow-Up Studies , Gonadal Steroid Hormones/blood , Humans , Incidence , Middle Aged , Postmenopause , Primary Prevention , Proportional Hazards Models , Risk , Sex Hormone-Binding Globulin/analysis
13.
JAMA ; 295(6): 643-54, 2006 Feb 08.
Article in English | MEDLINE | ID: mdl-16467233

ABSTRACT

CONTEXT: Observational studies and polyp recurrence trials are not conclusive regarding the effects of a low-fat dietary pattern on risk of colorectal cancer, necessitating a primary prevention trial. OBJECTIVE: To evaluate the effects of a low-fat eating pattern on risk of colorectal cancer in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: The Women's Health Initiative Dietary Modification Trial, a randomized controlled trial conducted in 48,835 postmenopausal women aged 50 to 79 years recruited between 1993 and 1998 from 40 clinical centers throughout the United States. INTERVENTIONS: Participants were randomly assigned to the dietary modification intervention (n = 19,541; 40%) or the comparison group (n = 29,294; 60%). The intensive behavioral modification program aimed to motivate and support reductions in dietary fat, to increase consumption of vegetables and fruits, and to increase grain servings by using group sessions, self-monitoring techniques, and other tailored and targeted strategies. Women in the comparison group continued their usual eating pattern. MAIN OUTCOME MEASURE: Invasive colorectal cancer incidence. RESULTS: A total of 480 incident cases of invasive colorectal cancer occurred during a mean follow-up of 8.1 (SD, 1.7) years. Intervention group participants significantly reduced their percentage of energy from fat by 10.7% more than did the comparison group at 1 year, and this difference between groups was mostly maintained (8.1% at year 6). Statistically significant increases in vegetable, fruit, and grain servings were also made. Despite these dietary changes, there was no evidence that the intervention reduced the risk of invasive colorectal cancer during the follow-up period. There were 201 women with invasive colorectal cancer (0.13% per year) in the intervention group and 279 (0.12% per year) in the comparison group (hazard ratio, 1.08; 95% confidence interval, 0.90-1.29). Secondary analyses suggested potential interactions with baseline aspirin use and combined estrogen-progestin use status (P = .01 for each). Colorectal examination rates, although not protocol defined, were comparable between the intervention and comparison groups. Similar results were seen in analyses adjusting for adherence to the intervention. CONCLUSION: In this study, a low-fat dietary pattern intervention did not reduce the risk of colorectal cancer in postmenopausal women during 8.1 years of follow-up. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT00000611.


Subject(s)
Colorectal Neoplasms/prevention & control , Diet, Fat-Restricted , Adenoma/epidemiology , Adenoma/prevention & control , Aged , Aspirin/therapeutic use , Colonic Polyps/epidemiology , Colonic Polyps/prevention & control , Colorectal Neoplasms/epidemiology , Estrogen Replacement Therapy , Female , Follow-Up Studies , Humans , Incidence , Likelihood Functions , Middle Aged , Postmenopause , Primary Prevention , Proportional Hazards Models , Risk , Risk Factors
14.
JAMA ; 295(6): 655-66, 2006 Feb 08.
Article in English | MEDLINE | ID: mdl-16467234

ABSTRACT

CONTEXT: Multiple epidemiologic studies and some trials have linked diet with cardiovascular disease (CVD) prevention, but long-term intervention data are needed. OBJECTIVE: To test the hypothesis that a dietary intervention, intended to be low in fat and high in vegetables, fruits, and grains to reduce cancer, would reduce CVD risk. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of 48,835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, who participated in the Women's Health Initiative Dietary Modification Trial. Women were randomly assigned to an intervention (19,541 [40%]) or comparison group (29,294 [60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years. INTERVENTION: Intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group received diet-related education materials. MAIN OUTCOME MEASURES: Fatal and nonfatal coronary heart disease (CHD), fatal and nonfatal stroke, and CVD (composite of CHD and stroke). RESULTS: By year 6, mean fat intake decreased by 8.2% of energy intake in the intervention vs the comparison group, with small decreases in saturated (2.9%), monounsaturated (3.3%), and polyunsaturated (1.5%) fat; increases occurred in intakes of vegetables/fruits (1.1 servings/d) and grains (0.5 serving/d). Low-density lipoprotein cholesterol levels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively; levels of high-density lipoprotein cholesterol, triglycerides, glucose, and insulin did not significantly differ in the intervention vs comparison groups. The numbers who developed CHD, stroke, and CVD (annualized incidence rates) were 1000 (0.63%), 434 (0.28%), and 1357 (0.86%) in the intervention and 1549 (0.65%), 642 (0.27%), and 2088 (0.88%) in the comparison group. The diet had no significant effects on incidence of CHD (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.90-1.06), stroke (HR, 1.02; 95% CI, 0.90-1.15), or CVD (HR, 0.98; 95% CI, 0.92-1.05). Excluding participants with baseline CVD (3.4%), the HRs (95% CIs) for CHD and stroke were 0.94 (0.86-1.02) and 1.02 (0.90-1.17), respectively. Trends toward greater reductions in CHD risk were observed in those with lower intakes of saturated fat or trans fat or higher intakes of vegetables/fruits. CONCLUSIONS: Over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVD risk. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT00000611.


Subject(s)
Coronary Disease/prevention & control , Diet, Fat-Restricted , Stroke/prevention & control , Aged , Cardiovascular Diseases/prevention & control , Coronary Disease/epidemiology , Coronary Disease/mortality , Energy Intake , Fatty Acids/administration & dosage , Female , Follow-Up Studies , Humans , Incidence , Middle Aged , Outcome Assessment, Health Care , Postmenopause , Primary Prevention , Proportional Hazards Models , Risk , Risk Factors , Stroke/epidemiology , Stroke/mortality
15.
Hypertension ; 45(4): 766-72, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15699471

ABSTRACT

The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations-blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P< or =0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.


Subject(s)
Black People , Hyperaldosteronism/complications , Hyperaldosteronism/ethnology , Hypertension/ethnology , Hypertension/etiology , White People , Adult , Aldosterone/blood , Atrial Natriuretic Factor/blood , Blood Pressure , Blood Pressure Monitoring, Ambulatory , Case-Control Studies , Female , Humans , Hypertension/blood , Hypertension/physiopathology , Male , Middle Aged , Renin/blood
16.
JAMA ; 291(14): 1701-12, 2004 Apr 14.
Article in English | MEDLINE | ID: mdl-15082697

ABSTRACT

CONTEXT: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
Estrogen Replacement Therapy , Estrogens, Conjugated (USP)/therapeutic use , Estrogens/therapeutic use , Hysterectomy , Aged , Breast Neoplasms/epidemiology , Cause of Death , Colorectal Neoplasms/epidemiology , Coronary Disease/epidemiology , Double-Blind Method , Female , Hip Fractures/epidemiology , Humans , Middle Aged , Postmenopause , Proportional Hazards Models , Pulmonary Embolism/epidemiology , Risk Assessment , Stroke/epidemiology
17.
JAMA ; 289(20): 2651-62, 2003 May 28.
Article in English | MEDLINE | ID: mdl-12771112

ABSTRACT

CONTEXT: Postmenopausal women have a greater risk than men of developing Alzheimer disease, but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin, in the Women's Health Initiative (WHI) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy. OBJECTIVE: To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo. DESIGN, SETTING, AND PARTICIPANTS: The Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women's Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS. INTERVENTION: Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or a matching placebo (n = 2303). MAIN OUTCOME MEASURES: Incidence of probable dementia (primary outcome) and mild cognitive impairment (secondary outcome) were identified through a structured clinical assessment. RESULTS: The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs 22 per 10 000 person-years; P =.01). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10 000 person-years; P =.72). CONCLUSIONS: Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older. In addition, estrogen plus progestin therapy did not prevent mild cognitive impairment in these women. These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.


Subject(s)
Cognition Disorders/epidemiology , Cognition/drug effects , Dementia/epidemiology , Estrogen Replacement Therapy , Estrogens, Conjugated (USP)/therapeutic use , Medroxyprogesterone Acetate/therapeutic use , Progesterone Congeners/therapeutic use , Aged , Cognition Disorders/chemically induced , Cognition Disorders/diagnosis , Dementia/chemically induced , Dementia/diagnosis , Double-Blind Method , Estrogen Replacement Therapy/adverse effects , Estrogens, Conjugated (USP)/adverse effects , Female , Humans , Medroxyprogesterone Acetate/adverse effects , Neuropsychological Tests , Postmenopause , Progesterone Congeners/adverse effects , Proportional Hazards Models , Risk
18.
Hypertension ; 40(5): 634-9, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12411455

ABSTRACT

To link hypertension-related phenotypes with chromosomal loci, genome scans were performed in 150 African American sib pairs concordant for essential hypertension. Phenotypes included blood pressure, anthropomorphic measurements, and estimates of body fluid compartments as determined by impedance plethysmography. These phenotypes were also measured in 335 normotensive African Americans. Phenotypes with LOD scores >3.3 were further evaluated for significance by use of permutation procedures. Significant linkage was detected for body mass index (BMI) on chromosomes 1 and 8 and for the ratio of extracellular water to total body water (ECF/TBW) on chromosomes 3, 5, 6, and 7. Both BMI and ECF/TBW were greater in hypertensive sibs than in normotensive subjects (P<0.001). In a subset of hypertensive sibs and normotensive subjects, average 24-hour blood pressures were correlated with ECF/TBW (P<0.01). A region linked to BMI in the hypertensive sibs corresponds to a region of conserved synteny containing blood pressure-related QTLs in an F2 cross of Brown NorwayxDahl salt-sensitive rats. Focusing on hypertension-related phenotypes is a promising approach for identifying the genetic determinants of hypertension.


Subject(s)
Black People/genetics , Black or African American , Hypertension/genetics , Quantitative Trait Loci/genetics , Siblings , Adolescent , Adult , Black or African American/statistics & numerical data , Blood Pressure/genetics , Body Fluid Compartments/physiology , Body Mass Index , Body Water/physiology , Chromosome Mapping , Chromosomes, Human/genetics , Electric Impedance , Female , Genetic Linkage/physiology , Humans , Hypertension/epidemiology , Hypertension/ethnology , Lod Score , Male , Middle Aged , Phenotype , Plethysmography, Whole Body/methods , Quantitative Trait Loci/ethics , Siblings/ethnology , Synteny/genetics , Wisconsin
19.
Am J Hypertens ; 15(11): 989-93, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12441220

ABSTRACT

Leptin may be a link in the relationship of obesity with hypertension. We evaluated associations of leptin with blood pressure (BP) in 54 normotensive and 114 hypertensive African American individuals. Plasma leptin was higher (P <.03) in hypertensive women than in normotensive women, although body mass index did not differ (30.5 +/- 0.5 v 30.2 +/- 0.8 kg/m(2)). After adjusting for obesity and insulin resistance, there were no significant relationships between leptin and BP; however, leptin independently predicted 28% of the variability of heart rate in hypertensive men (P <.01) and 18% of the variability of lithium clearance in hypertensive women (P <.01). Thus, in these obese hypertensive African American women, there is no direct or independent association of leptin with BP. However, leptin may contribute to hypertension in these women by increasing renal tubular sodium reabsorption.


Subject(s)
Hypertension/blood , Hypertension/ethnology , Leptin/blood , Obesity/ethnology , Adult , Black People , Body Mass Index , Female , Humans , Hypertension/physiopathology , Insulin/blood , Male , Obesity/blood , Obesity/physiopathology , Sex Factors
20.
JAMA ; 288(3): 321-33, 2002 Jul 17.
Article in English | MEDLINE | ID: mdl-12117397

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, 8.5 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, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 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 5.2 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, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) 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 5.2-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.


Subject(s)
Breast Neoplasms/epidemiology , Coronary Disease/epidemiology , Estrogen Replacement Therapy , Estrogens, Conjugated (USP)/therapeutic use , Medroxyprogesterone Acetate/therapeutic use , Progesterone Congeners/therapeutic use , Aged , Breast Neoplasms/prevention & control , Clinical Trials Data Monitoring Committees , Colorectal Neoplasms/epidemiology , Coronary Disease/prevention & control , Endometrial Neoplasms/epidemiology , Estrogen Replacement Therapy/adverse effects , Estrogens, Conjugated (USP)/adverse effects , Female , Fractures, Bone/epidemiology , Fractures, Bone/prevention & control , Humans , Medroxyprogesterone Acetate/adverse effects , Middle Aged , Myocardial Infarction/epidemiology , Postmenopause , Progesterone Congeners/adverse effects , Proportional Hazards Models , Pulmonary Embolism/epidemiology , Risk , Stroke/epidemiology , Survival Analysis , Thrombosis/epidemiology , Treatment Outcome
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