Comparative Effectiveness Review Number 96 Primary Care Management of Abnormal Uterine Bleeding Comparative Effectiveness Review Number 96 Primary Care Management of Abnormal Uterine Bleeding Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-2007-10065-I Prepared by: Vanderbilt Evidence-based Practice Center Nashville, TN Investigators: Katherine E. Hartmann, M.D., Ph.D. Rebecca N. Jerome, M.L.I.S., M.P.H. Mary Louise Lindegren, M.D. Shannon A. Potter, M.L.I.S. Tracy C. Shields, M.S.I.S. Tanya S. Surawicz, M.P.H. Jeffrey C. Andrews, M.D. AHRQ Publication No. 13-EHC025-EF March 2013 This report is based on research conducted by the Vanderbilt Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10065 I). The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report may be used, in whole or in part, to inform the development of clinical practice guidelines, other quality enhancement tools, methodologic guidance for systematic review, or to inform 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. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials that are clearly noted in the document. Further reproduction of those copyrighted materials is prohibited without the specific permission of copyright holders. Persons using assistive technology may not be able to fully access information in this report. For assistance contact [email protected]. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. Suggested citation: Hartmann KE, Jerome RN, Lindegren ML, Potter SA, Shields TC, Surawicz TS, Andrews JC. Primary Care Management of Abnormal Uterine Bleeding. Comparative Effectiveness Review No. 96. (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No. 290-2007-10065 I.) AHRQ Publication No. 13-EHC025-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2013. www.effectivehealthcare.ahrq.gov/reports/final.cfm. ii Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. These reviews provide comprehensive, science-based information on common, costly medical conditions, and new health care technologies and strategies. Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews can help clarify whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about AHRQ EPC systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm. AHRQ expects that these systematic reviews will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an e- mail list to learn about new program products and opportunities for input. We welcome comments on this systematic review. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by email to [email protected]. Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. Director Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Stephanie Chang, M.D., M.P.H. Shilpa Amin, M.D., M.Bsc., FAAFP Director Task Order Officer Evidence-based Practice Program Center for Outcomes and Evidence Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality iii Acknowledgments We are indebted to an exceptional group of colleagues who made this report possible. Each step of a systematic review draws on the skills and attention of an entire team. The authors gratefully acknowledge the following individuals for their contributions to this project: Dr. Mamata Raj was instrumental in extracting data and completing tables. Dedicated staff members Ms. Kathy Lee, Ms. Sanura Latham, and Mr. Ross Brown assisted with formatting, data entry, and article retrieval. Ms. J. Nikki McKoy and Ms. Nila Sathe provided guidance on logistics of the review process and organization of the report. Dr. Melissa McPheeters offered key input and feedback on the protocol, conceptual framework for the report, and methodological issues. Key Informants Janet R. Albers, M.D. Kristen A. Matteson, M.D., M.P.H. SIU Center for Family Medicine Women and Infants’ Hospital Springfield, IL Providence, RI Barbara S. Apgar, M.D. Malcolm G. Munro, M.D. University of Michigan University of California, Los Angeles Ann Arbor, MI Los Angeles, CA Marc A. Fritz, M.D. UNC Fertility Preservation Program Chapel Hill, NC Technical Expert Panel In designing the study questions and methodology at the outset of this report, the EPC consulted several technical and content experts. Broad expertise and perspectives are sought. Divergent and conflicted opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design and/or methodologic approaches do not necessarily represent the views of individual technical and content experts. Andrea S. Lukes, M.D. Malcolm G. Munro, M.D. Duke University University of California, Los Angeles Durham, NC Los Angeles, CA Kristen A. Matteson, M.D., M.P.H. Anita L. Nelson, M.D. Women and Infants’ Hospital University of California, Los Angeles Providence, RI Los Angeles, CA iv Peer Reviewers Peer reviewer comments on a preliminary draft of this report were considered by the EPC in preparation of this final report. Synthesis of the scientific literature presented here does not necessarily represent the views of individual reviewers. Jeffrey Jensen, M.D., M.P.H. Anita Nelson, M.D. Oregon Health & Science University University of California, Los Angeles Portland, OR Los Angeles, CA Annekathryn Goodman, M.D. Lee A. Learman, M.D., Ph.D. Gillette Center for Women’s Cancer Indiana University Boston, MA Indianapolis, IN Jonathan Klein, M.D., M.P.H. Malcolm Munro, M.D. University of Rochester University of California, Los Angeles Rochester, NY Los Angeles, CA Patricia Langenberg, M.A., Ph.D. University of Maryland, Baltimore Baltimore, MD v Primary Care Management of Abnormal Uterine Bleeding Structured Abstract Objective. The Vanderbilt Evidence-based practice Center systematically reviewed evidence about interventions for symptomatic abnormal uterine bleeding (AUB), both irregular and cyclic. We focused on interventions that are suitable for use in primary care practice including medical, behavioral, and complementary and alternative medicine approaches. Data sources. We searched MEDLINE®, CINAHL®, and Embase for randomized controlled trials (RCTs) published in English from January 1980 to June 2012 in women with symptomatic AUB. We also searched regulatory data and scientific publications for data about harms. Review methods. Using dual review with a priori criteria, we excluded 1,734 publications because they did not address a Key Question, were not an eligible study design, or did not apply to the primary care treatment of AUB. Results. Thirty-nine RCTs (6 good quality, 10 fair quality, and 23 poor quality) evaluated 12 distinct interventions. These included 7 studies of the levonorgestrel-releasing intrauterine system (LNG-IUS), 13 of nonsteroidal anti-inflammatory drugs (NSAIDs), 6 of tranexamic acid (TXA), and 5 of combined oral contraceptive pills (COCs). The majority of studies made direct comparisons to other drugs. Ten studies enrolled women with irregular uterine bleeding; the remainder focused on women with heavy cyclic bleeding. Among women with irregular menses, metformin, metformin with exenatide, and a tricyclic oral contraceptive improved menstrual regularity. Among women with heavy, cyclic menstrual bleeding all seven studies of LNG-IUS favored the intrauterine system in comparisons that included NSAIDs, COCs, progestogens and usual care. Reduction in menstrual blood loss ranged from 70 to 87 percent less bleeding than baseline. NSAIDs reduced bleeding in six of six studies when compared with placebo or progestogens. The degree of improvement was highly variable for individual women. TXA was more effective than progestogens and NSAIDs in three of four studies, and COCs provided benefit compared with placebo in two studies. Harms were rare and trials underpowered to assess harms for all interventions. For most interventions, surveillance studies of longer-term risks were not done in comparable populations. Conclusions. Two interventions for irregular bleeding (metformin, COCs) and four for heavy cyclic bleeding (LNG-IUS, NSAIDs, TXA) have low or moderate strength of evidence for effectiveness, while COCs have high strength of evidence. Several common interventions (including diet and exercise and acupuncture) lack sufficient evidence. Across interventions, data are sparse to evaluate long-term improvements and risk of harms. Limitations include a predominance of small, short trials lacking standard terminology and diagnostic criteria for identifying and including women with AUB. Tools for collecting outcome data are crude (e.g., collection of sanitary products to measure blood loss) and may contribute to a high rate of attrition. Emphasis on biologic outcomes may neglect the importance of patient- reported outcomes that assess whether symptoms are considered resolved by women themselves. vi Contents Executive Summary ........................................................................................................ ES-1 Introduction ........................................................................................................................... 1 Background ....................................................................................................................... 1 Condition..................................................................................................................... 1 Terminology ................................................................................................................ 1 Therapies ........................................................................................................................... 2 Primary Care Treatment Options ................................................................................ 3 Scope and Key Questions ................................................................................................. 5 Scope of the Review ................................................................................................... 5 Key Questions ............................................................................................................. 6 Analytic Framework ......................................................................................................... 6 Organization of This Report ............................................................................................. 7 Methods .................................................................................................................................. 9 Topic Refinement and Review Protocol ........................................................................... 9 Literature Search Strategy................................................................................................. 9 Search Strategy ........................................................................................................... 9 Supplementary Information for KQ2 ........................................................................ 10 Inclusion and Exclusion Criteria ..................................................................................... 10 Study Selection ............................................................................................................... 11 Quality (Risk of Bias) Assessment of Individual Studies ............................................... 11 Data Extraction ............................................................................................................... 12 Data Synthesis ................................................................................................................. 12 Strength of the Body of Evidence ................................................................................... 12 Applicability ................................................................................................................... 13 Peer Review and Public Commentary ............................................................................ 14 Results .................................................................................................................................. 15 Introduction ..................................................................................................................... 15 Results of Literature Searches ........................................................................................ 15 Description of Included Studies ...................................................................................... 18 KQ1A. Management of Irregular Uterine Bleeding ....................................................... 19 Description of Included Studies ................................................................................ 19 Key Points ................................................................................................................. 20 Detailed Synthesis ..................................................................................................... 21 KQ1B. Management of Abnormal Cyclic Bleeding ....................................................... 26 Description of Included Studies ................................................................................ 26 Levonorgestrel-Releasing Intrauterine System (Mirena®)........................................ 26 Contraceptive Vaginal Ring ...................................................................................... 33 Nonsteroidal Anti-Inflammatory Drugs .................................................................... 34 Tranexamic Acid ....................................................................................................... 45 Combined Oral Contraceptives ................................................................................. 51 Use of Decision Aids in Treatment of Menorrhagia ................................................. 54 KQ2. Harms of Interventions for Management of Abnormal Bleeding ......................... 56 Description of Included Studies and Sources of Information ................................... 56 Key Points for Harms of Reviewed Treatments ....................................................... 57 vii Detailed Synthesis ..................................................................................................... 58 Summary ................................................................................................................... 75 Discussion............................................................................................................................. 76 Key Findings ................................................................................................................... 76 State of the Literature................................................................................................ 76 Effectiveness of Interventions for Abnormal Bleeding ............................................ 76 Applicability ............................................................................................................. 79 Summary of Strength of Evidence and Findings ............................................................ 85 Implications for Clinical and Policy Decisionmaking .................................................... 88 Limitations of This CER ................................................................................................. 89 Limitations of the Evidence Base ................................................................................... 89 Methodologic Limitations ......................................................................................... 90 Ongoing Research ........................................................................................................... 90 Future Research Needs ................................................................................................... 91 Irregular Uterine Bleeding ........................................................................................ 91 Abnormal Cyclic Uterine Bleeding .......................................................................... 91 Conclusions ..................................................................................................................... 92 References ............................................................................................................................ 94 Abbreviations and Acronyms .......................................................................................... 104 Tables Table A. PICOTS .............................................................................................................. ES-3 Table B. Strength of evidence for improving menstrual regularity (KQ1A) .................. ES-13 Table C. Strength of evidence for improving heavy menstrual bleeding (KQ1B) ......... ES-15 Table 1. PICOTS ..................................................................................................................... 5 Table 2. Definitions of eligible patient populations.............................................................. 11 Table 3. Strength of evidence grades and definitions ........................................................... 13 Table 4. Medications from studies included in the CER ...................................................... 19 Table 5. Primary outcomes of medical interventions for irregular uterine bleeding ............ 21 Table 6. Primary outcomes of medical interventions for irregular uterine bleeding in women with PCOS...................................................................................................... 23 Table 7. Primary outcomes of behavioral interventions for irregular uterine bleeding in women with PCOS...................................................................................................... 24 Table 8. Primary outcomes of acupuncture for irregular uterine bleeding ........................... 25 Table 9. Primary outcomes of LNG-IUS for abnormal cyclic uterine bleeding ................... 28 Table 10. Percent change in blood loss from baseline in studies of LNG-IUS .................... 30 Table 11. Change in blood loss volume from baseline in studies of LNG-IUS ................... 30 Table 12. Primary outcomes of contraceptive vaginal ring for abnormal cyclic uterine bleeding ............................................................................................................... 34 Table 13. Primary Outcomes of NSAIDs for Abnormal Cyclic Uterine Bleeding .............. 36 Table 14. Percent change in blood loss from baseline in studies of NSAIDs ...................... 40 Table 15. Change in blood loss volume from baseline in studies of NSAIDs...................... 42 Table 16. Primary outcomes of TXA for abnormal cyclic uterine bleeding ........................ 47 Table 17. Percent change in blood loss from baseline in studies of TXA ............................ 48 Table 18. Change in blood loss volume from baseline in studies of TXA ........................... 49 Table 19. Primary outcomes of COCs for abnormal cyclic uterine bleeding ....................... 52 viii Table 20. Primary outcomes of decision aids for abnormal cyclic uterine bleeding ............ 56 Table 21. Side effects reported in Cabergoline trials ............................................................ 67 Table 22. Strength of evidence for improving menstrual regularity (KQ1A) ...................... 86 Table 23. Strength of evidence for improving heavy menstrual bleeding (KQ1B) .............. 87 Figures Figure 1. Analytic Framework ................................................................................................ 7 Figure 2. Flow diagram of literature search and screening (KQ1) ....................................... 16 Figure 3. Flow diagram of literature search and screening (KQ2) ....................................... 17 Appendixes Appendix A. Literature Search Strategies Appendix B. Abstract Review Form (KQ1) Appendix C. Abstract Review Form (KQ2) Appendix D. Full-Text Review Form (KQ1) Appendix E. Full-Text Review Form (KQ2) Appendix F. Cochrane Risk of Bias Tool Appendix G. Cochrane Risk of Bias Criteria Appendix H. Thresholds for Quality Assessment Appendix I. Risk of Bias and Quality Score for Individual Studies Appendix J. Evidence Table Appendix K. Reasons for Exclusion (KQ1) Appendix L. Reasons for Exclusion (KQ2) Appendix M. Labeled Indications for Drugs Included in Review Appendix N. Harms from Package Inserts for Drugs Included in Review Appendix O. Systematic Reviews Appendix P. Ongoing Studies ix