Improving the promise of embedded pragmatic trials: Surmountable barriers encountered in an evaluation of home-based HPV self-sampling to increase cervical cancer screening in overdue women.

Despite increased attention on how to conduct pragmatic trials and their importance, there remains an under-appreciation for the reality of what they take to design, compete and secure funding and execute. Many barriers are surmountable through increased exposure to experiences from completed trials. This report summarizes our experience in designing, securing funding and implementing the Home-Based Options to Make screening Easier (HOME) pragmatic trial, which was designed to evaluate home human papillomavirus testing for cervical cancer screening in underscreened women (women who had not received a cervical cancer screening test in ≥3.5 years). This report highlights factors at the level of research teams, organizations seeking to conduct embedded research, reviewers and funding agencies that challenge pragmatic trial design and execution. There is an urgent need to train on peer-reviewers how to evaluate embedded trial grant proposals, for agencies to pursue more rapid and innovative funding strategies, and to consider strategies for reviewers and funders to evaluate stakeholder buy-in (beyond letters of support). These factors together are needed to realize the promise of pragmatic trials to more efficiently and effectively generate critical data that inform changes in health care delivery and benefit patients.

Preoperative breast MRI and mortality in older women with breast cancer.

PURPOSE: The survival benefit from detecting additional breast cancers by preoperative magnetic resonance imaging (MRI) continues to be controversial. METHODS: We followed a cohort of 4454 women diagnosed with non-metastatic breast cancer (stage I-III) from 2/2005-6/2010 in five registries of the breast cancer surveillance consortium (BCSC). BCSC clinical and registry data were linked to Medicare claims and enrollment data. We estimated the cumulative probability of breast cancer-specific and all-cause mortality. We tested the association of preoperative MRI with all-cause mortality using a Cox proportional hazards model. RESULTS: 917 (20.6%) women underwent preoperative MRI. No significant difference in the cumulative probability of breast cancer-specific mortality was found. We observed no significant difference in the hazard of all-cause mortality during the follow-up period after adjusting for sociodemographic and clinical factors among women with MRI (HR 0.90; 95% CI 0.72-1.12) compared to those without MRI. CONCLUSION: Our findings of no breast cancer-specific or all-cause mortality benefit supplement prior results that indicate a lack of improvement in surgical outcomes associated with use of preoperative MRI. In combination with other reports, the results of this analysis highlight the importance of exploring the benefit of preoperative MRI in patient-reported outcomes such as women's decision quality and confidence levels with decisions involving treatment choices.

Factors associated with non-compliance with hormone therapy cessation before screening mammography.

OBJECTIVES: To evaluate factors associated with non-compliance with discontinuation of hormone therapy (HT) within a study on the effect of HT cessation on mammography performance. METHODS: This randomized, controlled trial was conducted at Group Health, a health plan in Washington State, USA. Eligibility included: age 45-80 years; due for screening ('study') mammogram; and prior screening mammogram while using HT. We randomized 1704 women to no cessation (n = 567), 1-month (n = 570), or 2-month cessation (n = 567), and called participants before cessation to review instructions. We collected self-reported data at randomization (baseline) and before the study mammogram, including symptoms and compliance. This analysis includes women randomized to 1-month or 2-month cessation with complete baseline and follow-up questionnaires (n = 883). RESULTS: Most participants were using unopposed estrogen (63.3%) and intended to continue HT (90%); 9.6% were non-compliant with HT cessation. Comparing 2-month vs. 1-month cessation, the age and body mass index (BMI)-adjusted relative risk (RR) for non-compliance was 1.72 (95% confidence interval (CI) 1.12-2.60). Baseline variables associated with non-compliance included: age ≤55 vs. >55 years (RR 2.34; 95% CI 1.34-4.41); BMI < 25 vs. BMI ≥30 kg/m 2 (RR 1.63; 95% CI 1.01-2.63); unopposed estrogen vs. estrogen plus progestin (RR 1.59; 95% CI 1.01-2.51); using HT to manage sleep (RR 1.80; 95% CI 1.20-2.71); severe vs. no night sweats (RR 1.68; 95% CI 1.03-2.74); and night sweats that interfered with sleep (RR 1.78; 95% CI 1.02-3.11). CONCLUSIONS: Non-compliance with HT cessation before screening mammogram was associated with younger age, lower BMI, symptom severity and use of unopposed estrogen. Alternatives for menopause symptom management are needed to assist women with HT cessation.

Effect of previous benign breast biopsy on the interpretive performance of subsequent screening mammography.

BACKGROUND: Most breast biopsies will be negative for cancer. Benign breast biopsy can cause changes in the breast tissue, but whether such changes affect the interpretive performance of future screening mammography is not known. METHODS: We prospectively evaluated whether self-reported benign breast biopsy was associated with reduced subsequent screening mammography performance using examination data from the mammography registries of the Breast Cancer Surveillance Consortium from January 2, 1996, through December 31, 2005. A positive interpretation was defined as a recommendation for any additional evaluation. Cancer was defined as any invasive breast cancer or ductal carcinoma in situ diagnosed within 1 year of mammography screening. Measures of mammography performance (sensitivity, specificity, and positive predictive value 1 [PPV1]) were compared both at woman level and breast level in the presence and absence of self-reported benign biopsy history. Referral to biopsy was considered a positive interpretation to calculate positive predictive value 2 (PPV2). Multivariable analysis of a correct interpretation on each performance measure was conducted after adjusting for registry, year of examination, patient characteristics, months since last mammogram, and availability of comparison film. Accuracy of the mammogram interpretation was measured using area under the receiver operating characteristic curve (AUC). All statistical tests were two-sided. RESULTS: A total of 2,007,381 screening mammograms were identified among 799,613 women, of which 14.6% mammograms were associated with self-reported previous breast biopsy. Multivariable adjusted models for mammography performance showed reduced specificity (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.73 to 0.75, P < .001), PPV2 (OR = 0.85, 95% CI = 0.79 to 0.92, P < .001), and AUC (AUC 0.892 vs 0.925, P < .001) among women with self-reported benign biopsy. There was no difference in sensitivity or PPV1 in the same adjusted models, although unadjusted differences in both were found. Specificity was lowest among women with documented fine needle aspiration-the least invasive biopsy technique (OR = 0.58, 95% CI = 0.55 to 0.61, P < .001). Repeating the analysis among women with documented biopsy history, unilateral biopsy history, or restricted to invasive cancers did not change the results. CONCLUSIONS: Self-reported benign breast biopsy history was associated with statistically significantly reduced mammography performance. The difference in performance was likely because of tissue characteristics rather than the biopsy itself.

Lone mothers are at higher risk for cardiovascular disease compared with partnered mothers. Data from the National Health and Nutrition Examination Survey III (NHANES III).

Lone mothers are a disadvantaged population, with research in several countries indicating that they experience low levels of physical and mental health. While research has demonstrated a socioeconomic gradient for cardiovascular disease (CVD), little research has explored lifestyle and clinical risk for CVD and prevalence of CVD events in lone mothers. The purpose of this study is (1) to compare select CVD lifestyle risks (smoking, obesity, physical activity), health, and relevant sociodemographic variables in partnered versus lone mothers; (2) to examine the relationship between partner status and having experienced a CVD event (myocardial infarction [MI], congestive heart failure [CHF], stroke). Data from the U.S. National Health and Nutrition Examination Survey III (NHANES III) included 1,446 women over 60 years with one or more children less than 17 years old. Lone mothers included women who were widowed, divorced, separated, never married, or married without the spouse living in the household (n = 623; weighted sample represents n = 3,904,450). Partnered mothers included women who reported living as married or married with the spouse in the household (n = 832; weighted sample represents n = 8,614,362). Weighted logistic regression was used to compare the prevalence of CVD risk factors in lone (43%) ver sus partnered (57%) mothers. Multivariate modeling was used to examine the relationship between partner status, CVD risks, and Coronary Heart Disease (CHD) events. Compared with partnered mothers, lone mothers were less educated and reported lower levels of income, health, and social support; and they were more likely to report non-White ethnicity. Lone mothers were more likely to be current smokers, overweight or obese, and physically active than partnered mothers. Those with clinical risks for CVD, including diabetes, elevated C-reactive protein, hypercholesterolemia, or hypertension, or all of these were more likely to be lone mothers. After adjusting for age, we found that mothers who had experienced a CVD event (MI, CHF, or stroke) were 3.3 times more likely to be a lone mother than a partnered mother (95% confidence interval (CI) 3.24, 3.31). Lone mothers are at increased risk for CVD. Health professionals and lone mothers should collaborate in the development of programs and policies not only to reduce lone mothers' risk for CVD, but also improve their conditions of living.

Women's responses to a mailed hormone replacement therapy workbook.

OBJECTIVE: Effectively communicating information about the complex decisions that face women at midlife, including whether to use hormone replacement therapy (HRT), is an ongoing challenge. Although numerous decision-making tools exist, few have been evaluated. The objective of this study was to examine women's use of a workbook designed to promote informed HRT decision-making. DESIGN: We developed a workbook to prepare women to discuss HRT, osteoporosis, heart disease, and breast cancer with their providers. To evaluate the workbook, women aged 45-65 years were randomly assigned to one of three groups: (1) workbook plus baseline and 6-month surveys, (2) workbook and 6-month survey, or (3) no workbook with both surveys. Results are based on the responses of 580 women in groups 1 and 2 (response rate, 84.2%). RESULTS: At 6 months, 79% of women recalled receiving the workbook, of whom 51% read all or most of it, 35% skimmed or read part of it, and 14% did not read it. The percentages of women completing self-assessments were 55% osteoporosis; 56% heart disease; 58% breast cancer; 57% advantages and disadvantages of HRT; and 52% personal preferences about HRT. As a result of the workbook, 10% made an appointment with their providers, and 12% had a discussion about HRT with their providers. Use of the workbook was not associated with menopause symptoms, attitudes about or use of HRT, hysterectomy, or provider discussions about menopause and HRT. CONCLUSION: This simple approach of using a mailed workbook holds promise as a successful mechanism to prepare women to discuss HRT and other related health issues with their providers.

What factors account for hormone replacement therapy prescribing frequency?

OBJECTIVES: The purpose of this study was to compare hormone replacement therapy (HRT) prescribing frequency to provider characteristics, attitudes and beliefs about menopause and HRT. METHODS: There was a mailed survey of providers at a large staff-model HMO in Washington state. Participants included 250 family practice physicians, 22 gynecologists, and 13 women's health care specialists and nurse midwives (83% response rate). The primary outcome, "HRT prescribing frequency" (derived from automated pharmacy and visit data) was defined as: the total number of estrogen prescriptions written by the provider and filled by women aged 50-80 years during the 12 months prior to the survey, divided by the number of visits made to the provider by women aged 50-80 years during that same 12-month period. Covariates included provider characteristics and beliefs about menopause and HRT. Logistic regression was used to distinguish providers in the upper 40% versus the lower 60% of HRT prescribing frequency. RESULTS: Controlling for age and practice type, HRT prescribing frequency was lower among men than women providers (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.21-0.65), higher among providers who agreed (vs. disagreed or neutral) that a convincing scientific case has been made that HRT prevents heart disease (OR 2.66, 95% CI 1.53-4.61), and higher among those in the upper tertile vs. lower tertiles of an HRT encouragement scale (OR 2.50, 95% CI 1.29-4.85). CONCLUSIONS: Female providers and providers with positive attitudes toward HRT are the most likely to prescribe it.

Bone mineral density and endogenous hormones and risk of breast cancer in postmenopausal women (United States).

OBJECTIVE: This case-cohort study was designed to examine whether total hip bone mineral density (BMD) is independently associated with breast cancer over and above its association with other determinants, including levels of total and bioavailable estradiol and testosterone and sex-hormone binding globulin. METHODS: Our study population was selected from a cohort of 8,203 postmenopausal women who were screened for the Fracture Intervention Trial in 1992, at which time BMD was assessed, and blood samples were obtained. A total of 109 women developed breast cancer during four years of follow-up; 173 other randomly selected women from the larger cohort were also selected. Cox proportional hazards with robust variance adjustment was used for these analyses. RESULTS: Relative to women in the lower fourth of the BMD distribution, the risk associated with being in the upper fourth was 2.6 (95% confidence interval (CI) 1.1-5.8). After adjusting for serum hormone levels, the corresponding relative risk was 2.5 (95% CI 0.9-5.2). With body mass index and number of years since menopause added to the multivariate analysis, the relative risk decreased to 1.4 (95% CI 0.5-4.0). CONCLUSIONS: BMD may not influence breast cancer risk independent of its relationship with endogenous hormones and measured covariates.

Bone mineral density and breast cancer risk in postmenopausal women.

Two recent studies have shown a woman's bone mineral density (BMD) (a composite measure of exposure to many different factors throughout one's lifetime) predicts breast cancer. In a prospective cohort study, we examined whether hip BMD was associated with breast cancer risk among 8203 postmenopausal women. During an average follow-up of 3.7 years, 131 incident breast cancer cases (102 invasive) were identified. Cox proportional hazards models were used to obtain estimates of the relative risk of breast cancer. Our results demonstrate an increase in breast cancer risk among women with higher BMD. Independent of age, geographic area, and body mass index, relative to the lowest BMD quartile the risk of breast cancer (95% confidence interval) by increasing quartile was 1.9 (1.1, 3.2), 1.5 (0.8, 2.6), and 1.5 (0.8, 2.7), respectively. An examination of other factors important in determining BMD may help explain the positive association between BMD and breast cancer.

Cost comparison of mastectomy versus breast-conserving therapy for early-stage breast cancer.

BACKGROUND: Choice of treatment for early-stage breast cancer depends on many factors, including the size and stage of the cancer, the woman's age, comorbid conditions, and perhaps the costs of treatment. We compared the costs of all medical care for women with early-stage breast cancer cases treated by breast-conserving therapy (BCT) or mastectomy. METHODS: A total of 1675 women 35 years old or older with incident early-stage breast cancer were identified in a large regional nonprofit health maintenance organization in the period 1990 through 1997. The women were treated with mastectomy only (n = 183), mastectomy with adjuvant hormonal therapy or chemotherapy (n = 417), BCT with radiation therapy (n = 405), or BCT with radiation therapy and adjuvant hormonal therapy or chemotherapy (n = 670). The costs of all medical care for the period 1990 through 1998 were computed for each woman, and monthly costs were analyzed by treatment, adjusting for age and cancer stage. All statistical tests were two-sided. RESULTS: At 6 months after diagnosis, the mean total medical care costs for the four groups differed statistically significantly (P:<.001), with BCT being more expensive than mastectomy. The adjusted mean costs were $12 987, $14 309, $14 963, and $15 779 for mastectomy alone, mastectomy with adjuvant therapy, BCT plus radiation therapy, and BCT plus radiation therapy with adjuvant therapy, respectively. At 1 year, the difference in costs was still statistically significant (P:<.001), but costs were influenced more by the use of adjuvant therapy than by type of surgery. The 1-year adjusted mean costs were $16 704, $18 856, $17 344, and $19 081, respectively, for the four groups. By 5 years, BCT was less expensive than mastectomy (P:<.001), with 5-year adjusted mean costs of $41 930, $45 670, $35 787, and $39 926, respectively. Costs also varied by age, with women under 65 years having higher treatment costs than older women. CONCLUSIONS: BCT may have higher short-term costs but lower long-term costs than mastectomy.

Understanding attitudes of older women toward hormone replacement therapy.

BACKGROUND: Counseling women facing the decision to initiate, continue, or discontinue hormone replacement therapy represents a major challenge for providers. Women's attitudes deserve careful consideration in this context, because attitudes may influence hormone replacement therapy use and patients' satisfaction with decision-making. Little is known about factors that may explain different attitudes. METHODS: To evaluate the association between char acteristics of peri- and postmenopausal women and their attitudes toward hormone replacement therapy, we conducted a population-based, computer-assisted telephone survey of 1,076 randomly selected women, ages 50-80, at a staff-model health maintenance organization. Women with a positive or neutral attitude were compared to those with a negative attitude. We exam ined associations between attitudes and demographic and clinical characteristics, self-rated health status, physical function, personal and family history of condi tions affected by hormone replacement therapy, gyne cologic visits, provider characteristics, interactions with provider, and sources of information about hor mone replacement therapy. RESULTS: The perception of being adequately informed about the benefits of hormone replacement therapy by one's provider was associated with a tripling of the likelihood of having a positive attitude toward hormone replacement therapy. Additional fac tors associated with positive attitudes included past hormone replacement therapy use, younger age, a higher level of physical functioning, and personal history of heart disease. Relationships between these vari ables and attitudes varied among current hormone replacement therapy users and nonusers. CONCLUSIONS: The study findings reinforce the critical role of provider counseling in shaping women's atti tudes about hormone replacement therapy.

Inclusion of older women in randomized clinical trials: factors associated with taking study medication in the fracture intervention trial.

OBJECTIVES: The purpose of this study is to describe the early study medication discontinuation (SMD) experience during the first year of follow-up in a randomized clinical trial in older women and to determine the associations between various baseline characteristics and risk of SMD. DESIGH, SETTING, AND PARTICIPANTS: The authors studied 6,459 postmenopausal women aged 55 to 80 from 11 clinical settings during their first year of participation in the Fracture Intervention Trial (FIT). This trial was designed to test the efficacy of alendronate (Fosamax) on fracture prevention among women with low bone mass. RESULTS: Study medication discontinuation was greatest in the first month post-randomization (2.2%) and declined thereafter. Cumulative rates of study medication discontinuation were 4.8% (n = 311) at 3 months and 11.1% (n = 717) at 12 months. SMD was not associated with age, marital status, alcohol consumption, regular exercise, past estrogen replacement therapy use, bone mineral density, or personal or maternal fracture history. After adjusting for covariates and markers of comorbidity, the strongest predictor of SMD was fair-to-poor self-rated health (relative risk (RR) 2.10; 95% confidence interval (CI) 1.47, 2.99). Having four or more depressive symptoms was also a significant predictor and had a risk associated with SMD (RR vs none 1.34; 95% CI 1.05, 1.71) similar to that seen for individuals with good self-rated health (RR 1.49; 95% CI 1.16, 1.91). CONCLUSIONS: Results from this cohort emphasize that clinical trials in older women with multiple concomitant conditions can achieve high levels of adherence. Thought should be given to measuring self-rated health and depressive symptoms before randomization to help identify individuals to be targeted for special assistance programs that focus on encouraging adherence.

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women.

BACKGROUND: Inhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women. METHODS: We investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis. FINDINGS: There were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs. INTERPRETATION: Statins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

Perceived barriers and recommendations concerning hormone replacement therapy counseling among primary care providers.

OBJECTIVE: To increase our understanding of the factors that impede or promote counseling about hormone replacement therapy, we asked clinicians to provide information concerning barriers and strategies to promote counseling. DESIGN: We asked clinicians to consider two different scenarios: (1) what they do in they current practice and (2) what they would do if their health care systems implemented the United States Preventive Services Task Force recommendation regarding hormone replacement therapy counseling. A total of 49 of 50 invited clinicians participated in one of six focus group interviews (three women's groups and three men's groups). Our analysis consisted of four steps: (1) identifying segments and classifying them into themes, (2) categorizing themes into topic areas, (3) establishing a final consensus of themes and topics, and (4) ascertaining similarities and contrasts among groups. Transcripts of sessions were analyzed across groups for themes using a text-based analysis system. Conceptualization of themes was derived using a system model of preventive care. Interrater agreement before consensus was good: Kappa (kappa) ranged from 0.70 to 1.00. RESULTS: For current practice, identified barriers included lack of information about risks and benefits, unique challenges of counseling, and lack of resources to conduct counseling. The major strategies suggested were to develop and distribute patient education materials. Discussions about barriers to implementing the United States Task Force recommendation focused on lack of information and resources. CONCLUSIONS: Suggested strategies were multiple, involving individual-, relationship-, and system-level interventions. We expect the strategies identified to be supportive of future efforts to promote counseling for hormone replacement therapy.

Are long-term hormone replacement therapy users different from short-term and never users?

The characteristics that differentiate long-term (> or = 10 years) hormone replacement therapy (HRT) users from short-term (<10 years) users and nonusers are not well documented. The epidemiology of long-term HRT use was investigated within a random sample survey of 703 women aged 50-80 years who were members of Group Health Cooperative (GHC) of Puget Sound. Women who had been menopausal for > or = 10 years comprised the study population. Long-term HRT users (29.4 percent) were compared with short-term (28.1 percent) and never users (42.5 percent). The authors examined the association between duration of HRT use and demographic characteristics, personal and family medical history, menopausal symptoms, information used in decision making, attitudes toward HRT, provider encouragement to use HRT, and GHC utilization. Compared with never users, the strongest correlates of long-term HRT use were having a hysterectomy before or after menopause, positive attitudes espousing the benefits of HRTs, and perceived provider encouragement to use HRT. Long-term HRT use was not associated with educational attainment, ethnicity, body mass index, health status, physical activity, or family medical history. Correlates commonly associated with HRT use, such as higher education, greater physical activity and functioning, and lower chronic disease comorbidity, did not significantly distinguish long-term from short-term users.