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Lipid Screening in Childhood and Adolescence for Detection of Familial Hypercholesterolemia: a Systematic Evidence Review for the U.S

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Lipid Screening in Childhood and Adolescence for Detection of Familial Hypercholesterolemia: a Systematic Evidence Review for the U.S Evidence Synthesis Number 141 Lipid Screening in Childhood and Adolescence for Detection of Familial Hypercholesterolemia: A Systematic Evidence Review for the U.S. Preventive Services Task Force Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov Contract No. HHSA-290-2012-00151-I, Task Order No. 2 Prepared by: Kaiser Permanente Evidence-based Practice Center Group Health Research Institute Seattle, WA Kaiser Permanente Center for Health Research Portland, OR Investigators: Paula Lozano, MD, MPH Nora B. Henrikson, PhD, MPH John Dunn, MD, MPH Caitlin C. Morrison, MPH Matt Nguyen, MPH Paula R. Blasi, MPH Melissa L. Anderson, MS Evelyn Whitlock, MD, MPH AHRQ Publication No. 14-05204-EF-2 August 2016 This report is based on research conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA-290-2012-00151-I, Task Order No. 2). The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. Therefore, 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, 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. 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. None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report. Acknowledgments The authors gratefully acknowledge the following individuals for their contributions to this project: Iris R. Mabry-Hernandez, MD, MPH, for project oversight on behalf of AHRQ; current and former members of the U.S. Preventive Services Task Force who contributed to topic deliberations; Stephen R. Daniels, MD, PhD, Patrick McBride, MD, MPH, and Alpo Vuorio, MD, PhD for expert review of the draft report; David Grossman, MD, MPH, for feedback on the research plan; Smyth Lai, MLS, for designing and conducting literature searches; Christel Kratohvil for research support and organization; So Man, PhD, for providing additional trial data; and Gabrielle Gundersen, BA, Brittany Burda, MPH, Caitlyn Senger, MPH, Tracy Beil, MS, and Aaron Scrol, MA. Suggested Citation Lozano P, Henrikson NB, Dunn J, Morrison CC, Nguyen M, Blasi PR, Anderson ML, Whitlock EP. Lipid Screening in Childhood and Adolescence for Detection of Familial Hypercholesterolemia: A Systematic Evidence Review for the U.S. Preventive Services Task Screening for Familial Hypercholesterolemia ii Kaiser Permanente Research Affiliates EPC Force. Evidence Synthesis No. 141. AHRQ Publication No. 14-05204-EF-2. Rockville, MD: Agency for Healthcare Research and Quality; 2016. Screening for Familial Hypercholesterolemia iii Kaiser Permanente Research Affiliates EPC Structured Abstract Background: Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism characterized by highly elevated total cholesterol (TC) concentrations early in life, independent of environmental influences. Around 1 in 200 to 1 in 500 persons in North America and Europe are estimated to have heterozygous FH. When untreated, FH is associated with a high incidence of premature clinical atherosclerotic cardiovascular disease. Purpose: We conducted a systematic evidence review of the benefits and harms of screening children and adolescents for heterozygous FH. The purpose of this review is to assist the U.S. Preventive Services Task Force (USPSTF) in updating its previous recommendations on such screening. Data Sources: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, and PubMed from 2006 through July 2014 to locate relevant trials for all key questions (KQs) published since the previous reviews in support of prior recommendations. We supplemented these searches with reference lists from relevant existing systematic reviews, cohort studies, suggestions from experts, and Clinicaltrials.gov to identify ongoing trials. Study Selection: Investigators independently reviewed 6,752 abstracts and 375 articles against a set of a priori inclusion criteria. Investigators also independently critically appraised each study using design-specific quality criteria based on USPSTF methods. We included fair- or good- quality studies that met the a priori criteria for each KQ. We resolved discrepancies by consensus. Data Extraction and Analysis: One investigator abstracted data from the 27 included articles into evidence tables and a second reviewer verified the accuracy of the abstracted data. We qualitatively summarized the evidence for screening and the effects of treatments on health outcomes. Lipid concentrations and measures of atherosclerosis were expressed as percent change from baseline or as differences from baseline. For KQ6, the number of included studies was sufficient to permit meta-analysis. For the randomized trials of statins that reported means and standard deviations for percent change (k=6), we summarized the results using forest plots. We did not combine data across studies, given the variability in drug, dose, and intended duration in the included studies. Results: We found no direct evidence for five KQs: the effectiveness of screening children and adolescents for FH in improving health outcomes (myocardial infarction [MI] or stroke) in adulthood (KQ1) or intermediate outcomes (lipid concentrations and atherosclerosis) in childhood (KQ2), the harms of screening for FH in children and adolescents (KQ4), the effectiveness of treating children and adolescents with FH on health outcomes (MI or stroke) in adulthood (KQ5), and the association between intermediate outcomes in childhood and adolescence and the future incidence or timing of MI and stroke in adulthood (KQ8). Studies met inclusion criteria for three KQs. KQ3. What is the diagnostic yield of appropriate screening tests for FH in children and adolescents? Screening for Familial Hypercholesterolemia iv Kaiser Permanente Research Affiliates EPC Two studies provided data allowing determination of the diagnostic yield of pediatric FH screening programs. A statewide universal screening program screened more than 80,000 10- to 11-year-olds in West Virginia schools and reported a diagnostic yield of about 1.3 cases per 1,000 screened. In this study, “probable FH” was defined as a low-density lipoprotein cholesterol (LDL-C) concentration greater than 155 mg/dL or TC concentration greater than 260 mg/dL plus DNA evidence of a low-density lipoprotein receptor (LDLR) mutation in a first- or second- degree relative. A Danish school-based study of more than 2,085 6- to 8-year-olds used the ApoB:ApoA-1 ratio and reported a diagnostic yield of 4.8 cases per 1,000 screened. We found no studies reporting diagnostic yield or effectiveness of selective screening for FH in youth (i.e., screening subjects with a family history or other targeting factor). KQ6. Does treatment of FH with lifestyle modifications and/or lipid-lowering medications in children and adolescents improve intermediate outcomes (i.e., reduce lipid concentrations or reverse or slow the progression of atherosclerosis) in childhood and adolescence? Eight good-quality randomized, controlled trials (RCTs) formed the evidence base for statin treatment of FH in youth. Studies of statins ranged from 6 weeks to 2 years long, with most shorter than 1 year. Treatment with statins lowered LDL-C and TC concentrations in the short term in children and adolescents with FH, with most studies reporting that statins lowered LDL- C by 20 to 40 percent compared to placebo. The greatest effect on LDL-C was in a trial of rosuvastatin. Participants who received the highest dose (20 mg/day) experienced a 50 percent decrease (least mean squares) in LDL-C from baseline compared to a 1 percent decrease among controls (p<0.001). Eight studies reported the effect of statins on TC, all showing decreases of about 20 to 30 percent from baseline (compared to no change with placebo). The effect on high-density lipoprotein cholesterol (HDL-C) was minimal or null. A single study assessed the effect on a measure of atherosclerosis and found that pravastatin reduced carotid intima-media thickness (CIMT) by 2.01 percent (compared to a 1.02% increase in the control group; p=0.02).
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