Use of non-steroidal anti-inflammatory drugs and pancreatic cancer risk in the Women's Health Initiative.

BACKGROUND: Pancreatic cancer is among the most fatal human cancers and the fourth leading cause of cancer death in the United States. Evidence suggests that chronic inflammation may play a role in pancreatic carcinogenesis, and its inhibition through non-steroidal anti-inflammatory drugs (NSAIDs) may reduce pancreatic cancer incidence. METHODS: We examined associations of total and individual NSAIDs with pancreatic cancer risk among postmenopausal women participating in the Women's Health Initiative observational study and clinical trials cohorts. Among 117,452 women, ages 55-79 years, 727 incident pancreatic cancer cases were reported over 18 years of follow-up. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs and pancreatic cancer risk. RESULTS: Relative to non-use, consistent use of any NSAID was inversely associated with pancreatic cancer risk (HR 0.71, 95% CI: 0.59-0.87), primarily driven by strong associations for aspirin use (HR 0.67, 95% CI: 0.52-0.86). Use of total or individual non-aspirin NSAIDs were not associated with pancreatic cancer. Upon stratified analysis, we observed stronger associations for NSAIDs among participants with prevalent diabetes (HR 0.28, 95% CI: 0.10-0.75) relative to those without (HR 0.75, 95% CI: 0.61-0.92; P-interaction=0.03). CONCLUSIONS: Additional large prospective studies with careful measurement of NSAID type, dose, and frequency are needed to further investigate the possibility of added benefit among individuals diagnosed with diabetes. IMPACT: This study adds to existing evidence from prospective studies and clinical trials suggesting that use of aspirin may provide moderate benefit for pancreatic cancer prevention.

Association Between CKD and Major Hemorrhage in Older Persons: Data From the Aspirin in Reducing Events in the Elderly Randomized Trial.

Introduction: Data on the association between chronic kidney disease (CKD) and major hemorrhage in older adults are lacking. Methods: We used data from a double-blind randomized controlled trial of aspirin in persons aged ≥ 70 years with prospective capture of bleeding events, including hemorrhagic stroke and clinically significant bleeding. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2 and/or urinary albumin-to-creatinine ratio (UACR) ≥ 3 mg/mmol (26.6 mg/g). We compared bleeding rates in those with and without CKD, undertook multivariable analyses, and explored effect modification with aspirin. Results: Of 19,114 participants, 17,976 (94.0%) had CKD status recorded, of whom 4952 (27.5%) had CKD. Participants with CKD had an increased rate of major bleeding events compared with those without CKD (10.4/1000 vs. 6.3/1000 person-years [py], respectively) and increased bleeding risk (risk ratio [RR] 1.60; 95% confidence interval [CI]: 1.40, 1.90 for eGFR < 60 ml/min per 1.73 m2) and RR (2.10; 95% CI: 1.70, 2.50) for albuminuria. In adjusted analyses, CKD was associated with a 35% increased risk of bleeding (hazard ratio [HR] 1.37; 95% CI: 1.15, 1.62; P < 0.001). Other risk factors were older age, hypertension, smoking, and aspirin use. There was no differential effect of aspirin on bleeding by CKD status (test of interaction P = 0.65). Conclusion: CKD is independently associated with an increased risk of major hemorrhage in older adults. Increased awareness of modifiable risk factors such as discontinuation of unnecessary aspirin, blood pressure control, and smoking cessation in this group is warranted.

Bolstering the Business Case for Adoption of Shared Decision-Making Systems in Primary Care: Randomized Controlled Trial.

BACKGROUND: Limited budgets may often constrain the ability of health care delivery systems to adopt shared decision-making (SDM) systems designed to improve clinical encounters with patients and quality of care. OBJECTIVE: This study aimed to assess the impact of an SDM system shown to improve diabetes and cardiovascular patient outcomes on factors affecting revenue generation in primary care clinics. METHODS: As part of a large multisite clinic randomized controlled trial (RCT), we explored the differences in 1 care system between clinics randomized to use an SDM intervention (n=8) versus control clinics (n=9) regarding the (1) likelihood of diagnostic coding for cardiometabolic conditions using the 10th Revision of the International Classification of Diseases (ICD-10) and (2) current procedural terminology (CPT) billing codes. RESULTS: At all 24,138 encounters with care gaps targeted by the SDM system, the proportion assigned high-complexity CPT codes for level of service 5 was significantly higher at the intervention clinics (6.1%) compared to that in the control clinics (2.9%), with P<.001 and adjusted odds ratio (OR) 1.64 (95% CI 1.02-2.61). This was consistently observed across the following specific care gaps: diabetes with glycated hemoglobin A1c (HbA1c)>8% (n=8463), 7.2% vs 3.4%, P<.001, and adjusted OR 1.93 (95% CI 1.01-3.67); blood pressure above goal (n=8515), 6.5% vs 3.7%, P<.001, and adjusted OR 1.42 (95% CI 0.72-2.79); suboptimal statin management (n=17,765), 5.8% vs 3%, P<.001, and adjusted OR 1.41 (95% CI 0.76-2.61); tobacco dependency (n=7449), 7.5% vs. 3.4%, P<.001, and adjusted OR 2.14 (95% CI 1.31-3.51); BMI >30 kg/m2 (n=19,838), 6.2% vs 2.9%, P<.001, and adjusted OR 1.45 (95% CI 0.75-2.8). Compared to control clinics, intervention clinics assigned ICD-10 diagnosis codes more often for observed cardiometabolic conditions with care gaps, although the difference did not reach statistical significance. CONCLUSIONS: In this randomized study, use of a clinically effective SDM system at encounters with care gaps significantly increased the proportion of encounters assigned high-complexity (level 5) CPT codes, and it was associated with a nonsignificant increase in assigning ICD-10 codes for observed cardiometabolic conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02451670; https://clinicaltrials.gov/ct2/show/NCT02451670.

Risk Patterns and Mortality in Postmenopausal Women Using Latent Class Analysis.

INTRODUCTION: Although risk factors often co-occur, previous studies examining lifestyle or psychosocial factors often treat these factors as individual predictors of health. This study aims to identify the underlying subgroups of women characterized by distinct lifestyle and psychosocial risk patterns and to investigate the prospective associations between risk patterns and mortality among postmenopausal women. METHODS: A total of 64,812 postmenopausal women aged 50-79 years without prevalent diabetes, cardiovascular disease, and cancer at baseline (1993-1998) were followed until 2019 with a mean follow-up duration of 14.6 (SD=6.4) years. Latent class analysis was used to identify the latent classes of women with homogeneous combinations of lifestyle and psychosocial variables and to test whether the classes were prospectively associated with mortality. Analyses were stratified by race/ethnicity and were performed in 2020. RESULTS: A total of 4 latent classes (Healthy Lifestyle and Psychosocial, Risky Psychosocial, Risky Lifestyle, and Risky Lifestyle and Risky Psychosocial) were identified for Hispanic, Black, and White women, and 2 classes (High Risk or Low Risk) were identified for American Indian and Asian women. Women in the Risky Lifestyle and Risky Psychosocial group had the highest hazard ratios for all outcomes studied for all race/ethnicity groups than those in the Healthy Lifestyle and Psychosocial group, followed by those in the Risky Lifestyle group. Risky Psychosocial class was significantly associated with an elevated risk of overall and cardiovascular disease mortality only in Black women. CONCLUSIONS: The class with concurrent risky lifestyle and psychosocial factors conveyed the greatest risk of all types of mortality than a low-risk ref group. Health promotion should address both behavioral and psychosocial risks concurrently.

Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial.

OBJECTIVE: There is a lack of robust data on significant gastrointestinal bleeding in older people using aspirin. We calculated the incidence, risk factors and absolute risk using data from a large randomised, controlled trial. DESIGN: Data were extracted from an aspirin versus placebo primary prevention trial conducted throughout 2010-2017 ('ASPirin in Reducing Events in the Elderly (ASPREE)', n=19 114) in community-dwelling persons aged ≥70 years. Clinical characteristics were collected at baseline and annually. The endpoint was major GI bleeding that resulted in transfusion, hospitalisation, surgery or death, adjudicated independently by two physicians blinded to trial arm. RESULTS: Over a median follow-up of 4.7 years (88 389 person years), there were 137 upper GI bleeds (89 in aspirin arm and 48 in placebo arm, HR 1.87, 95% CI 1.32 to 2.66, p<0.01) and 127 lower GI bleeds (73 in aspirin and 54 in placebo arm, HR 1.36, 95% CI 0.96 to 1.94, p=0.08) reflecting a 60% increase in bleeding overall. There were two fatal bleeds in the placebo arm. Multivariable analyses indicated age, smoking, hypertension, chronic kidney disease and obesity increased bleeding risk. The absolute 5-year risk of bleeding was 0.25% (95% CI 0.16% to 0.37%) for a 70 year old not on aspirin and up to 5.03% (2.56% to 8.73%) for an 80 year old taking aspirin with additional risk factors. CONCLUSION: Aspirin increases overall GI bleeding risk by 60%; however, the 5-year absolute risk of serious bleeding is modest in younger, well individuals. These data may assist patients and their clinicians to make informed decisions about prophylactic use of aspirin. TRIAL REGISTRATION NUMBER: ASPREE. NCT01038583.

Effect of Depression Screening After Acute Coronary Syndromes on Quality of Life: The CODIACS-QoL Randomized Clinical Trial.

Importance: Patients with acute coronary syndrome (ACS) and elevated depressive symptoms are at increased risk for recurrent cardiovascular events and mortality, worse quality of life, and higher health care costs. These observational findings prompted multiple scientific panels to advise universal depression screening in survivors of ACS prior to evidence from randomized screening trials. Objective: To determine whether systematically screening for depression in survivors of ACS improves quality of life and depression compared with usual care. Design, Setting, and Participants: A 3-group multisite randomized trial enrolled 1500 patients with ACS from 4 health care systems between November 1, 2013, and March 31, 2017, with follow-up ending July 31, 2018. Patients were eligible if they had been hospitalized for ACS in the previous 2 to 12 months and had no prior history of depression. All analyses were performed on an intention-to-treat basis. Interventions: Patients with ACS were randomly assigned 1:1:1 to receive (1) systematic depression screening using the 8-item Patient Health Questionnaire, with notification of primary care clinicians and provision of centralized, patient-preference, stepped depression care for those with positive screening results (8-item Patient Health Questionnaire score ≥10; screen, notify, and treat, n = 499); (2) systematic depression screening, with notification of primary care clinicians for those with positive screening results (screen and notify, n = 501); and (3) usual care (no screening, n = 500). Main Outcomes and Measures: The primary outcome was change in quality-adjusted life-years. The secondary outcome was depression-free days. Adverse effects and mortality were assessed by patient interview and hospital records. Results: A total of 1500 patients (424 women and 1076 men; mean [SD] age, 65.9 [11.5] years) were randomized in the 18-month trial. Only 71 of 1000 eligible survivors of ACS (7.1%) had elevated 8-item Patient Health Questionnaire scores indicating depressive symptoms at screening. There were no differences in mean (SD) change in quality-adjusted life-years (screen, notify and treat, -0.06 [0.20]; screen and notify, -0.06 [0.20]; no screen, -0.06 [0.18]; P = .98) or cumulative mean (SD) depression-free days (screen, notify and treat, 343.1 [179.0] days; screen and notify, 351.3 [175.0] days; no screen, 339.0 [176.6] days; P = .63). Harms including death, bleeding, or sleep difficulties did not differ among groups. Conclusions and Relevance: In patients with ACS without a history of depression, systematic depression screening with or without providing depression treatment did not alter quality-adjusted life-years, depression-free days, or harms. Trial Registration: ClinicalTrials.gov identifier: NCT01993017.

Rationale, design, and baseline data for a multicenter randomized clinical trial comparing depression screening strategies after acute coronary syndrome: The comparison of depression identification after acute Coronary Syndromes-Quality of Life and Cost Outcomes (CODIACS-QOL) trial.

BACKGROUND: Elevated depressive symptoms among survivors of acute coronary syndromes (ACS) confer recurrent cardiovascular events and mortality, worse quality of life, and higher healthcare costs. While multiple scientific groups advise routine depression screening for ACS survivors, no randomized trials exist to inform this screening recommendation. We aimed to assess the effect of screening for depression on change in quality of life over 18 months among ACS patients. METHODS: The Comparison of Depression Identification after Acute Coronary Syndrome on Quality of Life and Cost Outcomes (CODIACS-QoL) trial is a pragmatic, 3-arm trial that randomized ACS patients to 1) systematic depression screening using the 8-item Patient Health Questionnaire (PHQ-8) and if positive screen (PHQ-8 ≥ 10), notification of primary care providers (PCPs) and invitation to participate in centralized, patient-preference, stepped depression care (Screen, Notify, and Treat, N = 499); 2) systematic depression screening and PCP notification only (Screen and Notify, N = 501); and 3) usual care (No Screen, N = 500). Adults hospitalized for ACS in the previous 2-12 months without prior history of depression were eligible for participation. Key outcomes will be quality-adjusted life years (primary), cost of health care utilization, and depression-free days across 18 months. RESULTS: A total of 1500 patients were randomized in the CODIACS-QOL trial (28.3% women; 16.3% Hispanic; mean age 65.9 (11.5) years). Only 7% of ACS survivors had elevated depressive symptoms. CONCLUSIONS: Using a novel randomization schema and pragmatic design principles, the CODIACS-QoL trial achieved its enrollment target. Eventual results of this trial will inform future depression screening recommendations in cardiac patients. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01993017).

Priorities Wizard: Multisite Web-Based Primary Care Clinical Decision Support Improved Chronic Care Outcomes with High Use Rates and High Clinician Satisfaction Rates.

INTRODUCTION: Priorities Wizard is an electronic health record-linked, web-based clinical decision support (CDS) system designed and implemented at multiple Health Care Systems Research Network (HCSRN) sites to support high quality outpatient chronic disease and preventive care. The CDS system (a) identifies patients who could substantially benefit from evidence-based actions; (b) presents prioritized evidence-based treatment options to both patient and clinician at the point of care; and (c) facilitates efficient ordering of recommended medications, referrals or procedures. METHODS: The CDS system extracts relevant data from electronic health records (EHRs), processes the data using Web-based clinical decision support algorithms, and displays the CDS output seamlessly on the EHR screen for use by the clinician and patient. Through a series of National Institutes of Health-funded projects led by HealthPartners Institute and the HealthPartners Center for Chronic Care Innovation and HCSRN partners, Priorities Wizard has been evaluated in cluster-randomized trials and expanded to include over 20 clinical domains. RESULTS: Cluster-randomized trials show that this CDS system significantly improved glucose and blood pressure control in diabetes patients, reduced 10-year cardiovascular (CV) risk in high-CV risk adults without diabetes, improved management of smoking in dental patients, and improved high blood pressure identification and management in adolescents. CDS output was used at 71-77 percent of targeted visits, 85-98 percent of clinicians were satisfied with the CDS system, and 94 percent reported they would recommend it to colleagues. CONCLUSIONS: Recently developed EHR-linked, Web-based CDS systems have significantly improved chronic disease care outcomes and have high use rates and primary care clinician satisfaction.

Physical activity and weight gain after smoking cessation in postmenopausal women.

OBJECTIVE: Weight gain frequently occurs after smoking cessation. The objective of this study was to examine whether weight gain after smoking cessation was attenuated by physical activity (PA) in postmenopausal women. METHODS: A total of 4,717 baseline smokers from the Women's Health Initiative were followed for 3 years. One thousand two hundred eighty-two women quit smoking, and 3,435 continued smoking. Weight was measured at baseline and at the year 3 visit. PA was assessed at both times by self-report, summarized as metabolic equivalent task-hours per week. Multiple linear regression models were used to assess the association between PA and postcessation weight gain, adjusting for potential confounding factors. RESULTS: Compared with continuing smokers, quitters gained an average of 3.5 kg (SD = 5.6) between the baseline and year 3 visit. Quitters with decreased PA had the highest amount of weight gain (3.88 kg, 95% CI: 3.22-4.54); quitters with increased PA (≥15 metabolic equivalent task-hours /week) had the lowest weight gain (2.55 kg, 95% CI: 1.59-3.52). Increased PA had a stronger beneficial association for postcessation weight gain for women with obesity compared to normal weight women. Quitters who had low PA at baseline and high PA at year 3 and were also enrolled in a dietary modification intervention had nonsignificant weight gain (1.88 kg, 95% CI: -0.21-3.96) compared with continuing smokers. CONCLUSIONS: Our data demonstrate that even a modest increase in PA (equivalent to current recommendations) can attenuate weight gain after quitting smoking among postmenopausal women, especially in combination with improved diet.

Smoking cessation, weight gain, and risk of stroke among postmenopausal women.

The relationship between smoking cessation, concurrent weight gain, and stroke events is not yet understood. Thus, we examined the association between smoking cessation and subsequent stroke risk and whether the association was modified by concurrent weight gain. In 2017, we analyzed data from 109,498 postmenopausal US women enrolled in the Women's Health Initiative from 1993 to 1998. Women with a history of cancer or cardiovascular disease events were excluded. The median length of follow-up time was 14.01 years. Variables of primary focus were smoking cessation, weight change, and clinically confirmed incident cases of hemorrhagic and ischemic stroke. Hazard ratios were estimated for stroke incidences (all, ischemic, and hemorrhagic) associated with smoking cessation using Cox regression. The exposure-outcome relationship of smoking cessation and risk of stroke was evaluated for effect modification by weight change. Recent quitters between baseline and year 3 had a significantly lower risk for all stroke and ischemic stroke, but not hemorrhagic stroke, when compared to the reference group of continuing smokers. In the multivariable-adjusted model for ischemic stroke, the hazard ratio for recent quitters was 0.66 (95% CI: 0.46, 0.95). In the model for hemorrhagic stroke, the hazard ratio for recent quitters was 0.76 (95% CI: 0.36, 1.61). The association between recent quitting and stroke risk was not significantly modified by weight change. Smoking cessation was associated with a significant reduction in stroke risk. The benefit of smoking cessation on the risk of stroke was not attenuated by concurrent weight gain.

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly.

BACKGROUND: In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo. METHODS: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed. RESULTS: Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). CONCLUSIONS: Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Pooled Analysis of Nine Cohorts Reveals Breast Cancer Risk Factors by Tumor Molecular Subtype.

Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A-like (ER+ or PR+/HER2-), 1,368 luminal B-like (ER+ or PR+/HER2+), 521 HER2-enriched (ER-/PR-/HER2+), and 1,152 triple-negative (ER-/PR-/HER2-) disease. Ever parous compared with never was associated with lower risk of luminal A-like (HR, 0.78; 95% CI, 0.73-0.83) and luminal B-like (HR, 0.74; 95% CI, 0.64-0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02-1.50; P value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (P value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer (P value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies.Significance: These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. Cancer Res; 78(20); 6011-21. ©2018 AACR.

Development of a standardized definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial.

BACKGROUND: Bleeding is the major risk of aspirin treatment, especially in the elderly. A consensus definition for clinically significant bleeding (CSB) in aspirin primary prevention trials is lacking in the literature. METHODS: This paper details the development, modification, application, and quality control of a definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial, a primary prevention trial of aspirin in 19,114 community-dwelling elderly men and women. In ASPREE a confirmed bleeding event needed to meet criteria both for substantiated bleeding and clinical significance. Substantiated bleeding was defined as: 1) observed bleeding, 2) a reasonable report of symptoms of bleeding, 3) medical, nursing or paramedical report, or 4) imaging evidence. Bleeding was defined as clinically significant if it: 1) required transfusion of red blood cells, 2) required admission to the hospital for >24 h, or prolonged a hospitalization, with bleeding as the principal reason, 3) required surgery to stop the bleeding, or 4) resulted in death. Bleeding sites were subclassified as upper gastrointestinal, lower gastrointestinal, intracranial (hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, extradural hematoma, or other), or other sites. Potential events were retrieved from medical records, self-report or notification from treating doctors. Two reviewers adjudicated each event using electronic adjudication software, and discordant cases were reviewed by a third reviewer. Adjudication rules evolved to become more strictly defined as the trial progressed and decision rules were added to assist with frequent scenarios such as post-operative bleeding. CONCLUSIONS: This paper provides a detailed methodologic description of the development of a standardized definition for clinically significant bleeding and provides a benchmark for development of a consensus definition for future aspirin primary prevention trials. TRIAL REGISTRATION: ASPREE is registered on the International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and on clinicaltrials.gov (NCT01038583).

Clinical decision support directed to primary care patients and providers reduces cardiovascular risk: a randomized trial.

Objective: To test the hypothesis that use of a clinical decision support (CDS) system in a primary care setting can reduce cardiovascular (CV) risk in patients. Materials and Methods: Twenty primary care clinics were randomly assigned to usual care (UC) or CDS. For CDS clinic patients identified algorithmically with high CV risk, rooming staff were prompted by the electronic health record (EHR) to print CDS that identified evidence-based treatment options for lipid, blood pressure, weight, tobacco, or aspirin management and prioritized them based on potential benefit to the patient. The intention-to-treat analysis included 7914 adults who met high CV risk criteria at an index clinic visit and had at least one post-index visit, accounted for clustering, and assessed impact on predicted annual rate of change in 10-year CV risk over a 14-month period. Results: The CDS was printed at 75% of targeted visits, and providers reported 85% to 98% satisfaction with various aspects of the intervention. Predicted annual rate of change in absolute 10-year CV risk was significantly better in CDS clinics than in UC clinics (-0.59% vs. +1.66%, -2.24%; P < .001), with difference in 10-year CV risk at 12 months post-index favoring the CDS group (UC 24.4%, CDS 22.5%, P < .03). Discussion: Deploying to both patients and providers within primary care visit workflow and limiting CDS display and print burden to two mouse clicks by rooming staff contributed to high CDS use rates and high provider satisfaction. Conclusion: This EHR-integrated, web-based outpatient CDS system significantly improved 10-year CV risk trajectory in targeted adults.

Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials.

Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials. Design, Setting, and Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). Main Outcomes and Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Conclusions and Relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. Trial Registration: clinicaltrials.gov Identifier: NCT00000611.

Use of Calcium Channel Blockers and Breast Cancer Risk in the Women's Health Initiative.

Background: Use of calcium channel blockers (CCBs) has been associated with increased risk of breast cancer in some, but not all, studies. Differences in reported associations from prior studies may be due, in part, to inadequate control of confounding factors.Methods: Participants were 28,561 postmenopausal women from the Women's Health Initiative who reported use of either CCBs or other antihypertensive medications (AHMs) at baseline; 1,402 incident breast cancer cases were diagnosed during 12 years of follow-up. Adjusted Cox regression models were used to estimate HRs and 95% confidence intervals (CI) for the associations between CCB use relative to other AHM use and breast cancer risk.Results: Use of CCBs was not associated with breast cancer risk (HR, 1.06; 95% CI, 0.94-1.20) relative to use of other AHMs. Associations approximated the null value when CCBs were considered by duration of use, length of action, or drug class.Conclusions: We provide additional evidence that CCBs do not influence breast cancer risk in postmenopausal women.Impact: The results from this study, which includes strong control for potential confounding factors, cast doubt on increases in risk with CCBs. Cancer Epidemiol Biomarkers Prev; 26(8); 1345-8. ©2017 AACR.

Benign breast disease and risk of thyroid cancer.

BACKGROUND: It has been suggested that breast and thyroid diseases may be linked. The aim of this study was to investigate the association between benign breast disease and subsequent risk of thyroid cancer. METHODS: Postmenopausal women (n = 133,875) aged 50-79 years were followed up for a mean of 14 years. Benign breast disease was defined by history of biopsy. Incident thyroid cancer cases were confirmed by medical record review. Multivariable Cox proportional hazard modeling was used to estimate hazard ratios. RESULTS: There were 370 incident thyroid cancer cases during the follow-up period. Compared to women without BBD, women with BBD had a significant increased risk of thyroid cancer after adjusting for potential confounders (HR 1.38 95% CI 1.10-1.73), especially for women with more than two biopsies (HR 1.59 95% CI 1.10-2.26). There were no significant differences in thyroid tumor size, stage or histologic types between women with and without BBD. CONCLUSION: Our large prospective study observed that postmenopausal women with BBD had an increased risk for thyroid cancer compared with women without BBD. A more detailed investigation of thyroid cancer risk according to different subtypes of benign breast disease is needed to better understand the association observed between thyroid and benign breast diseases.

Effect of depression before breast cancer diagnosis on mortality among postmenopausal women.

BACKGROUND: Few previous studies investigating depression before the diagnosis of breast cancer and breast cancer-specific mortality have examined depression measured at more than 1 time point. This study investigated the effect of depression (combining depressive symptoms alone with antidepressant use) measured at 2 time points before the diagnosis of breast cancer on all-cause mortality and breast cancer-specific mortality among older postmenopausal women. METHODS: A large prospective cohort, the Women's Health Initiative, was used. The study included 3095 women with incident breast cancer who had measures of depressive symptoms and antidepressant use before their diagnosis at the baseline and at year 3. Multivariate Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) between depression at the baseline, depression at year 3, and combinations of depression at these time points and all-cause mortality and breast cancer-specific mortality. RESULTS: Depression at year 3 before a breast cancer diagnosis was associated with higher all-cause mortality after adjustments for multiple covariates (HR, 1.35; 95% confidence interval [CI], 1.02-1.78). There was no statistically significant association of baseline depression and all-cause mortality or breast cancer-specific mortality whether or not depression was also present at year 3. In women with late-stage (regional- or distant-stage) breast cancer, newly developed depression at year 3 was significantly associated with both all-cause mortality (HR, 2.00; 95% CI, 1.13-3.56) and breast cancer-specific mortality (HR, 2.42; 95% CI, 1.24-4.70). CONCLUSIONS: Women with newly developed depression before the diagnosis of breast cancer had a modestly but significantly increased risk for death from any cause and for death from breast cancer at a late stage. Cancer 2017;123:3107-15. © 2017 American Cancer Society.

Metabolic Phenotype and Risk of Colorectal Cancer in Normal-Weight Postmenopausal Women.

BACKGROUND: The prevalence of metabolically unhealthy phenotype in normal-weight adults is 30%, and few studies have explored the association between metabolic phenotype and colorectal cancer incidence in normal-weight individuals. Our aim was to compare the risk of colorectal cancer in normal-weight postmenopausal women who were characterized by either the metabolically healthy phenotype or the metabolically unhealthy phenotype. METHODS: A large prospective cohort, the Women's Health Initiative, was used. The analytic sample included 5,068 postmenopausal women with BMI 18.5 to <25 kg/m2 Metabolic phenotype was defined using the Adult Treatment Panel-III definition, excluding waist circumference; therefore, women with one or none of the four components (elevated triglycerides, low high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose) were classified as metabolically healthy. Multivariable Cox proportional hazards regression was used to estimate adjusted HRs for the association between metabolic phenotype and risk of colorectal cancer. RESULTS: Among normal-weight women, those who were metabolically unhealthy had higher risks of colorectal cancer (HR, 1.49; 95% CI, 1.02-2.18) compared with those who were metabolically healthy. CONCLUSIONS: A metabolically unhealthy phenotype was associated with higher risk of colorectal cancer among normal-weight women. IMPACT: Normal-weight women should still be evaluated for metabolic health and appropriate steps taken to reduce their risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 26(2); 155-61. ©2017 AACR.

Intentional Weight Loss and Endometrial Cancer Risk.

Purpose Although obesity is an established endometrial cancer risk factor, information about the influence of weight loss on endometrial cancer risk in postmenopausal women is limited. Therefore, we evaluated associations among weight change by intentionality with endometrial cancer in the Women's Health Initiative (WHI) observational study. Patients and Methods Postmenopausal women (N = 36,794) ages 50 to 79 years at WHI enrollment had their body weights measured and body mass indices calculated at baseline and at year 3. Weight change during that period was categorized as follows: stable (change within ± 5%), loss (change ≥ 5%), and gain (change ≥ 5%). Weight loss intentionality was assessed via self-report at year 3; change was characterized as intentional or unintentional. During the subsequent 11.4 years (mean) of follow-up, 566 incident endometrial cancer occurrences were confirmed by medical record review. Multivariable Cox proportional hazards regression models were used to evaluate relationships (hazard ratios [HRs] and 95% CIs) between weight change and endometrial cancer incidence. Results In multivariable analyses, compared with women who had stable weight (± 5%), women with weight loss had a significantly lower endometrial cancer risk (HR, 0.71; 95% CI, 0.54 to 0.95). The association was strongest among obese women with intentional weight loss (HR, 0.44; 95% CI, 0.25 to 0.78). Weight gain (≥ 10 pounds) was associated with a higher endometrial cancer risk than was stable weight, especially among women who had never used hormones. Conclusion Intentional weight loss in postmenopausal women is associated with a lower endometrial cancer risk, especially among women with obesity. These findings should motivate programs for weight loss in obese postmenopausal women.