Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Analytic framework and key questions for full comparative effectiveness review.* Detailed descriptions are provided in the inclusion and exclusion criteria in Appendix Figure 2. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Inclusion and exclusion criteria for studies.RCT = randomized, controlled trial. * Benefit outcomes are defined by key question 1 and include invasive breast cancer; noninvasive breast cancer, including ductal carcinoma in situ; breast cancer mortality; all-cause mortality; and osteoporotic fractures. † Population subgroups are defined by key question 3 and include but are not limited to those based on age, menopausal status (pre-, peri-, postmenopausal), hysterectomy status, use of exogenous estrogen, level of risk for breast cancer (based on family history, body mass index, parity [number of pregnancies], age at first live birth, age at menarche, personal history of breast abnormalities, previous breast biopsy, estradiol levels, and breast density), ethnicity and race, metabolism status (CYP 2D6 mutation), and risk for thromboembolic events (obesity and other risk factors). ‡ Definitions of types of outcomes: primary outcome—the main outcome of a study that the study was designed and powered to demonstrate; secondary outcome—major outcome of a study that the study was designed and powered to demonstrate, but not the primary outcome of the study; health outcomes—signs, symptoms, conditions, or events that persons experience, such as myocardial infarction, death, or hot flashes; intermediate outcomes—health measures that persons do not personally experience, such as laboratory test results or bone mineral density. § Harms outcomes are defined by key question 2 and may include but are not limited to thromboembolic events (deep venous thrombosis, pulmonary embolism), cardiovascular events (coronary heart disease, stroke and transient ischemic attack, arrhythmias), metabolic disorders (diabetes), musculoskeletal symptoms (myalgia, leg cramps), mental health (depression, mood changes), genitourinary outcomes (vaginal dryness, uterine bleeding, hysterectomy, endometrial cancer, urinary symptoms), adverse breast outcomes (biopsies), other cancer (incidence, death), ophthalmologic disorders (cataracts), gastrointestinal/hepatobiliary disorders (abdominal pain, nausea), and other adverse events affecting quality of life (vasomotor symptoms, sexual function, sleep disturbances, headaches, cognitive changes, peripheral edema). Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Study flow diagram.RCT = randomized, controlled trial. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Meta-analysis of risk ratios for incidence of invasive breast cancer.Error bars represent 95% CIs. CORE = Continuing Outcomes Relevant to Evista; IBIS-I = International Breast Cancer Intervention Study; LIFT = Long- Term Intervention on Fractures with Tibolone; MORE = Multiple Outcomes of Raloxifene Evaluation; NR = not reported; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1; RUTH = Raloxifene Use for the Heart. * Per 1000 woman-years. † Italian Tamoxifen Prevention Trial and RUTH reported mean or median duration of actual treatment period. ‡ Analysis included data from both MORE and CORE. Participants from MORE had 4-year treatment, and those who continued in CORE had 4 additional years of treatment. Total follow-up time is averaged over both MORE and CORE for 7705 participants. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Meta-analysis of risk ratios for incidence of noninvasive breast cancer.Error bars represent 95% CIs. CORE = Continuing Outcomes Relevant to Evista; IBIS-I = International Breast Cancer Intervention Study; MORE = Multiple Outcomes of Raloxifene Evaluation; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1; RUTH = Raloxifene Use for the Heart. * Per 1000 woman-years. † Italian Tamoxifen Prevention Trial and RUTH reported mean or median duration of actual treatment period. ‡ Analysis included data from both MORE and CORE. Participants from MORE had 4-year treatment, and those who continued in CORE had 4 additional years of treatment. Total follow-up time is averaged over both MORE and CORE for 7705 participants. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Meta-analysis of risk ratios for incidence of venous thromboembolism.Error bars represent 95% CIs. IBIS-I = International Breast Cancer Intervention Study; LIFT = Long-Term Intervention on Fractures with Tibolone; MORE = Multiple Outcomes of Raloxifene Evaluation; NR = not reported; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1; RUTH = Raloxifene Use for the Heart. * Per 1000 woman-years. † For tamoxifen trials, venous thromboembolic events include deep venous thrombosis and pulmonary embolism only. For other trials, additional thromboembolic events may be included. ‡ Events were reported from at least 3 months after treatment was stopped until the end of follow-up. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Meta-analysis of risk ratios for incidence of stroke.Error bars represent 95% CIs. IBIS-I = International Breast Cancer Intervention Study; LIFT = Long-Term Intervention on Fractures with Tibolone; MORE = Multiple Outcomes of Raloxifene Evaluation; NR = not reported; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1; RUTH = Raloxifene Use for the Heart. * Per 1000 woman-years. † Events were reported from at least 3 months after treatment was stopped until the end of follow-up. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

Date of download: 6/27/2016 From: Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer Ann Intern Med. 2009;151(10): doi: / Meta-analysis of risk ratios for incidence of endometrial cancer and cataracts.Error bars represent 95% CIs. IBIS-I = International Breast Cancer Intervention Study; LIFT = Long-Term Intervention on Fractures with Tibolone; MORE = Multiple Outcomes of Raloxifene Evaluation; NR = not reported; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1. * Per 1000 woman-years. † Rates were based on number of women with an intact uterus. ‡ The rate and risk ratio were recalculated on the basis of the number of women at risk (having an intact uterus). The values reported by the study were based on all randomly assigned participants. § The number of women at risk (having an intact uterus) was not reported, and the risk ratio is calculated on the basis of the number of randomly assigned participants at baseline. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians