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Original Contribution
June 20, 2012

Lipid-Related Markers and Cardiovascular Disease Prediction

The Emerging Risk Factors Collaboration*
Author Affiliations

*Authors/Writing Group: Emanuele Di Angelantonio, MD, Pei Gao, PhD, Lisa Pennells, PhD, Stephen Kaptoge, PhD, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England; Muriel Caslake, PhD, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland; Alexander Thompson, PhD, Adam S. Butterworth, PhD, Nadeem Sarwar, PhD, David Wormser, PhD, and Danish Saleheen, MD, Department of Public Health and Primary Care, University of Cambridge; Christie M. Ballantyne, MD, Department of Medicine, Baylor College of Medicine, Houston, Texas; Bruce M. Psaty, MD, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle; Johan Sundström, MD, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Paul M Ridker, MD, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Dorothea Nagel, PhD, Klinikum der Universität München, LMU, München, Germany; Richard F. Gillum, MD, Center for Disease Control and Prevention, Washington, DC; Ian Ford, PhD, Robertson Centre for Biostatistics, University of Glasgow; Pierre Ducimetiere, PhD, INSERM, France; Stefan Kiechl, MD, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria; Wolfgang Koenig, MD, Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany; Robin P. F. Dullaart, MD, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands; Gerd Assmann, MD, Assmann-Stiftung fur Pravention, Germany; Ralph B. D'Agostino Sr, PhD, Department of Mathematics and Statistics, Boston University, Boston; Gilles R. Dagenais, MD, Départment de medicine, Institut universitaire de cardiologie et pneumologie de Québec, Québec, Canada; Jackie A. Cooper, MSc, Centre for Cardiovascular Genetics, University College London, England; Daan Kromhout, PhD, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands; Altan Onat, MD, Institute for Experimental Medical Research, Istanbul University, Istanbul, Turkey; Robert W. Tipping, MS, Merck Research Laboratories, Philadelphia, Pennsylvania; Agustín Gómez-de-la-Cámara, MD, Unidad de investigation, Hospital 12 de Octubre, Madrid, Spain; Annika Rosengren, MD, Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Susan E. Sutherland, PhD, Medical University of South Carolina; John Gallacher, PhD, Department of Epidemiology, Cardiff University, Cardiff, Wales; F. Gerry R. Fowkes, FRCPE, Wolfson Unit, Public Health Sciences, University of Edinburgh, Edinburgh; Edoardo Casiglia, MD, Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy; Albert Hofman, MD, Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Veikko Salomaa, MD, Department of Epidemiology, National Institute for Health and Welfare, Helsinki, Finland; Elizabeth Barrett-Connor, MD, Department of Family and Preventive Medicine, Division of Epidemiology, University of California, San Diego; Robert Clarke, MD, Clinical Trials Service Unit, University of Oxford, Oxford; Eric Brunner, PhD, Department of Epidemiology and Public Health, University College London; J. Wouter Jukema, MD, Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Leon A. Simons, MD, Lipid Research Department, University of New South Wales, Darlinghurst, Australia; Manjinder Sandhu, PhD, Department of Public Health and Primary Care; Nicholas J. Wareham, FRCP, MRC Epidemiology Unit, University of Cambridge; Kay-Tee Khaw, FMedSci, Department of Public Health and Primary Care, University of Cambridge; Jussi Kauhanen, MD, University of Eastern Finland, Kuopio, Finland; Jukka T. Salonen, MD, Metabolic Analytical Services Inc and University of Helsinki, Helsinki; William J. Howard, MD, MedStar Health Research Institute, Washington Hospital Center, Washington, DC; Børge G. Nordestgaard, MD, Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark; Angela M. Wood, PhD, and Simon G. Thompson, FMedSci, Department of Public Health and Primary Care, University of Cambridge; S. Matthijs Boekholdt, MD, Academic Medical Center, Amsterdam, the Netherlands; Naveed Sattar, FRCP, and Chris Packard, PhD, Institute of Cardiovascular and Medical Sciences, University of Glasgow; Vilmundur Gudnason, MD, Icelandic Heart Association and University of Iceland, Reykjavik, Iceland; and John Danesh, FRCP, Department of Public Health and Primary Care, University of Cambridge.

JAMA. 2012;307(23):2499-2506. doi:10.1001/jama.2012.6571
Abstract

Context The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.

Objective To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.

Design, Setting, and Participants Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).

Main Outcome Measures Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.

Results The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.

Conclusion In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

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