This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers—patients and clinicians, health system leaders, and policymakers—make more informed decisions and improve the quality of health care services. ii Systematic Evidence Review Number 13 Hormone Replacement Therapy and Cognition Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 2101 East Jefferson Street Rockviille, MD 20852 www.ahrq.gov Contract No. 290-97-0018 Task Order No. 2 Technical Support for the U.S. Preventive Services Task Force Prepared by: Oregon Health & Science University Evidence-based Practice Center, Portland, Oregon Erin Leblanc M.D., M.P.H. Benjamin Chan, M.S. Heidi D. Nelson, M.D., M.P.H. August 2002 iii Preface The Agency for Healthcare Research and Quality (AHRQ) sponsors the development of Systematic Evidence Reviews (SERs) through its Evidence-based Practice Program. With ∗ guidance from the third U.S. Preventive Services Task Force (USPSTF) and input from Federal partners and primary care specialty societies, two Evidence-based Practice Centers—one at the Oregon Health Sciences University and the other at Research Triangle Institute-University of North Carolina—systematically review the evidence of the effectiveness of a wide range of clinical preventive services, including screening, counseling, immunizations, and chemoprevention, in the primary care setting. The SERs—comprehensive reviews of the scientific evidence on the effectiveness of particular clinical preventive services—serve as the foundation for the recommendations of the third USPSTF, which provide age- and risk-factor- specific recommendations for the delivery of these services in the primary care setting. Details of the process of identifying and evaluating relevant scientific evidence are described in the “Methods” section of each SER. The SERs document the evidence regarding the benefits, limitations, and cost-effectiveness of a broad range of clinical preventive services and will help to further awareness, delivery, and coverage of preventive care as an integral part of quality primary health care. AHRQ also disseminates the SERs on the AHRQ Web site (http://www.ahrq.gov/uspstfix.htm) and disseminates summaries of the evidence (summaries of the SERs) and recommendations of the third USPSTF in print and on the Web. These are available through the AHRQ Web site (http://www.ahrgq.gov/uspstfix.htm), through the National Guideline Clearinghouse (http://www.ncg.gov), and in print through the AHRQ Publications Clearinghouse (1-800-358-9295). We welcome written comments on this SER. Comments may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852. Carolyn M. Clancy, M.D. Acting Director Agency for Healthcare Research and Quality Robert Graham, M.D. Director, Center for Practice and Technology Assessment Agency for Healthcare Research and Quality ∗ The USPSTF is an independent panel of experts in primary care and prevention first convened by the U.S. Public Health Service in 1984. The USPSTF systematically reviews the evidence on the effectiveness of providing clinical preventive services--including screening, counseling, immunization, and chemoprevention--in the primary care setting. AHRQ convened the third USPSTF in November 1998 to update existing Task Force recommendations and to address new topics. iv The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service. v STRUCTURED ABSTRACT Context: Although postmenopausal hormone replacement (HRT) therapy is widely used, its risks and benefits are not well understood. Some observational data suggest that HRT may reduce the risk of cognitive decline and dementia but results have been conflicting. Objective: To review and evaluate studies of HRT for preventing cognitive decline and dementia in healthy postmenopausal women. Data Sources: Studies with English-language abstracts identified in MEDLINE (1966- December 2000), HealthSTAR (1975-December 2000), PsychINFO (1984-December 2000); Cochrane Library databases; and articles listed in reference lists of key articles. Study Selection: Randomized controlled trials and cohort studies were reviewed for the effects of HRT on cognitive decline; cohort and case-control studies were reviewed for dementia risk. No randomized controlled trials regarding dementia risk were identified. Data Extraction: Twenty-nine studies met inclusion criteria and were rated. Two reviewers rated study quality independently and 100% agreement was reached on Jadad scores and 80% agreement was reached on U.S. Preventive Services Task Force quality scores. A final score was reached through consensus if reviewers disagreed. Data Synthesis: Studies of cognition were not combined quantitatively because of heterogeneous study design. Women symptomatic from menopause had improvements in verbal memory, vigilance, reasoning, and motor speed, but no enhancement of other cognitive functions. Generally, no benefits were observed in asymptomatic women. A Bayesian meta- analysis of 12 observational studies suggested that HRT was associated with a decreased risk of dementia (summary odds ratio, 0.66; 95% confidence interval, 0.53-0.82). However, possible biases and lack of control for potential confounders limit interpretation of these studies. vi Eight studies received a poor quality rating, 3 fair, and 1 good. Studies did not contain enough information to assess adequately the effects of progestin use, various estrogen preparations or doses, or duration of therapy. Conclusions: In women with menopausal symptoms, HRT may have specific cognitive effects, and future studies should target these effects. The meta-analysis found a decreased risk of dementia in HRT users but most studies had important methodological limitations. vii Table Of Contents Chapter 1. Introduction Burden of Suffering 1 Prior Recommendations 2 Analytic Frameworks and Key Questions 2 Chapter 2. Methods Literature Search Strategy 3 Inclusion/Exclusion Criteria 3 Size of Literature Reviewed 4 Data Extraction and Synthesis 5 Chapter 3. Results Effects on Cognition 1. Does HRT improve or stabilize cognition? 9 Memory 10 Attention 13 Concept formation and reasoning 15 Motor speed 15 Dementia screening measures 16 Verbal function 16 Influence of symptoms 16 Effects of progestins 17 2. What is the optimal dose and duration of use? 18 Summary 19 Effects on Dementia 1. Does HRT lower the risk for dementia? 20 2. What is the optimal dose and duration of use? 24 Summary 25 Chapter 4. Discussion Conclusions 26 Limitations of the Literature 27 Future Research 27 References 29 viii Figures 1. Benefits of Hormone Replacement Therapy--Analytic Framework 36 2. Adverse Effects of Hormone Replacement Therapy– Analytic Framework 37 3. Results of Meta-analysis of Dementia Studies 38 Tables 1. Summary of Cognitive Test Results 39 2. Influence on Symptoms on Results of Randomized Controlled Trials 41 3. Summary of Meta-analysis Results of HRT and Dementia 42 4. Summary of Evidence 43 Appendices 1. Search Strategy 44 2. Search Results 45 3. Inclusion/Exclusion Criteria 46 4. a. Criteria for Grading Quality of Randomized Controlled Trials: The Jadad Score 47 4. b. Criteria for Grading the Internal Validity of Individual Studies 48 5. Evidence Tables • Table 1. HRT and Cognition–Randomized Controlled Trials 50 • Table 2. HRT and Cognition–Cohort Studies 56 • Table 3. HRT and Dementia–Case Control Studies 65 • Table 4. HRT and Dementia–Cohort Studies 75 6. Cognitive Measures Used in Studies 77 7. Abbreviation and Acronym List 80 8. Acknowledgements 82 ix Chapter 1. Introduction In this systematic evidence review, we evaluate data on the use of hormone replacement therapy (HRT) to prevent cognitive decline and dementia in healthy postmenopausal women. Specifically, we reviewed the literature reporting effects of HRT on cognitive function in women without dementia. In addition, we conducted a review and meta-analysis of studies of HRT and dementia, focusing on Alzheimer disease. Results of this review have been recently published.1 This report is part of a larger project on the risks and benefits of HRT prepared for the U.S. Preventive Services Task Force to assist them in making recommendations. Burden of Suffering Between 3 and 8 million people in the United States have dementia.2 The most common type of dementia is Alzheimer disease, which affects 3 to 4 million people and is the fourth leading cause of death in the United States.3, 4 The incidence of dementia is 1 percent per year in older individuals, although in the most elderly populations