Technology Assessment Low Density Lipoprotein Subfractions: Systematic Review of Measurement Methods and Association with Cardiovascular Outcomes Technology Assessment Program June 16, 2008 Agency for Healthcare Research and Quality 540 Gaither Road Rockville, Maryland 20850 1 Low Density Lipoprotein Subfractions: Systematic Review of Measurement Methods and Association with Cardiovascular Outcomes Technology Assessment Report Project ID: LIPS0707 June 16, 2008 Tufts Evidence­based Practice Center Ethan Balk, MD MPH Stanley Ip, MD Mei Chung, MPH Joseph Lau, MD Alice H. Lichtenstein, DSc This report is based on research conducted by the Tufts Evidence­based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290­02­0022). The findings and conclusions in this document are those of the authors who are responsible for its contents. The findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of the Agency for Healthcare Research and Quality 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, make well­informed 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. 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, ie, in the context of available resources and circumstances presented by individual patients. 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 as 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. None of the investigators has any affiliations or financial involvement related to the material presented in this report. 2 Table of contents Abbreviations......................................................................................................................................................... 5 CHAPTER 1. INTRODUCTION........................................................................................................................... 7 Key questions to be addressed.......................................................................................................................... 8 CHapter 2. methods............................................................................................................................................. 10 Search strategy .............................................................................................................................................. 10 Classification of LDL Subfraction Methods (Tests)........................................................................................ 10 Study Selection.............................................................................................................................................. 11 Data Extraction.............................................................................................................................................. 13 Quality Assessment ....................................................................................................................................... 14 Applicability assessment................................................................................................................................ 14 Summary Tables............................................................................................................................................ 15 CHapter 3. Results............................................................................................................................................... 17 Literature Search ........................................................................................................................................... 17 Question 1 .................................................................................................................................................... 17 Question 2 .................................................................................................................................................... 21 Question 3 .................................................................................................................................................... 25 Question 3.1 ........................................................................................................................................... 25 Question 3.2 ........................................................................................................................................... 25 Question 4 .................................................................................................................................................... 32 Question 4.1 ........................................................................................................................................... 32 Question 4.2 ........................................................................................................................................... 63 Question 4.3 ........................................................................................................................................... 63 Question 4.4 ........................................................................................................................................... 73 CHapter 4. discussion .......................................................................................................................................... 80 LDL subfraction methodology ................................................................................................................ 80 Association between LDL subfractions and CVD.................................................................................... 81 Limitations ............................................................................................................................................. 83 Future research ....................................................................................................................................... 84 Summary................................................................................................................................................ 86 References ........................................................................................................................................................... 87 Appendix A. Search strategy................................................................................................................................ 94 Appendix B. Rejected articles.............................................................................................................................. 95 Appendix C. Potential treatment studies ............................................................................................................ 104 3 Tables and Figures Table 1. Comparison of different methods for measuring LDL subfractions ......................................................... 23 Table 2. Test Variability (or Imprecision) ........................................................................................................... 30 Table 3a. Characteristics of the nested case­control studies of incident CVD and NMR­measured LDL subfractions .............................................................................................................................. 36 Table 3b. Nested case­control studies of incident CVD and NMR­measured LDL subfractions ............................ 37 Table 4. Longitudinal study of NMR­measured LDL subfractions and progression of CVD ................................. 39 Table 5a. Characteristics of patients in the cross­sectional studies of prevalent CVD and NMR­measured LDL subfractions .............................................................................................................................. 40 Table 5b. Cross­sectional studies of NMR­measured LDL subfractions and prevalent CVD outcomes 41 Table 6a. Characteristics of case­control studies of prevalent CVD and LipoPrint GE­measured LDL subfractions 42 Table 6b. Case­control studies of LipoPrint GE­measured LDL subfractions and prevalent CVD .......................... 42 Table 7a. Characteristics of patients in the cross­sectional studies of prevalent CVD and LipoPrint GE­measured LDL subfractions ............................................................................................................................... 43 Table 7b. Cross­sectional studies of LipoPrint GE­measured LDL subfractions and prevalent CVD ...................... 44 Table 8. Longitudinal study of time­averaged Berkeley HeartLab GE­measured LDL subfractions and progression of CVD..................................................................................................................................... 45 Table 9. Association between LDL Subfraction and incident CVD events (not full extraction).............................. 49 Table 10. Association between LDL Subfraction