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      Cardiovascular Risk Factors Associated With Venous Thromboembolism

      research-article
      , PhD 1 , , PhD 2 , 3 , , MSc 2 , 3 , , PhD 2 , , MD 2 , 4 , , PhD 2 , 5 , , PhD 2 , 3 , , PhD 2 , , ScD 6 , , MD 7 , , MD 8 , , MD 9 , , MD 10 , , MD 11 , , MD 12 , , MD 1 , , MD 13 , , MD 14 , 15 , 16 , , PhD 17 , , MD 18 , , MD 19 , , PhD 13 , , MD 20 , , MD 21 , 22 , , MD 23 , 24 , 25 , , MD 26 , , MD 27 , , MBBS 28 , , PhD 29 , , MD 30 , , MD 31 , , MD 32 , , MD 33 , , MD 34 , , MD 35 , , MD 36 , , MD 37 , , PhD 18 , , MD 38 , , PhD 39 , , MD 27 , , MD 40 , , PhD 32 , , PhD 41 , 42 , , MD 43 , , FMedSci 44 , , MD 45 , , MD 46 , , MD 47 , , PhD 48 , , PhD 36 , , MD 8 , , PhD 21 , , MD 49 , , MD 11 , , MA 50 , , MBBS 51 , , PhD 52 , , MSc 52 , , MD 53 , , MSc 32 , 54 , , PhD 42 , , PhD 53 , , MD 55 , , MD 42 , 56 , , MD 57 , , PhD 58 , , MD 59 , , PhD 2 , , PhD 2 , 3 , , PhD 2 , , FMedSci 2 , 3 , , FRCP 2 , 3 , , , FRS 1
      JAMA Cardiology
      American Medical Association

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          Key Points

          Question

          To what extent are established cardiovascular risk factors associated with risk of venous thromboembolism (VTE)?

          Findings

          In this analysis of individual participant data from the Emerging Risk Factors Collaboration and the UK Biobank including 1.1 million participants, among a panel of several established cardiovascular risk factors, older age, smoking, and greater adiposity were consistently associated with higher VTE risk.

          Meaning

          There is overlap in at least some of the major population determinants of important venous and arterial thrombotic diseases.

          Abstract

          This analysis of data from the Emerging Risk Factors Collaboration and the UK Biobank estimates the associations of major cardiovascular risk factors with venous thromboembolism.

          Abstract

          Importance

          It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE).

          Objective

          To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism.

          Design, Setting, and Participants

          This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018.

          Exposures

          A panel of several established cardiovascular risk factors.

          Main Outcomes and Measures

          Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI).

          Results

          Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers.

          Conclusions and Relevance

          Older age, smoking, and adiposity were consistently associated with higher VTE risk.

          Related collections

          Most cited references56

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          UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

          Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
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            Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

            Summary Background Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. Findings In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively. Interpretation In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.
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              Deep vein thrombosis and pulmonary embolism

              Deep vein thrombosis and pulmonary embolism, collectively referred to as venous thromboembolism, constitute a major global burden of disease. The diagnostic work-up of suspected deep vein thrombosis or pulmonary embolism includes the sequential application of a clinical decision rule and D-dimer testing. Imaging and anticoagulation can be safely withheld in patients who are unlikely to have venous thromboembolism and have a normal D-dimer. All other patients should undergo ultrasonography in case of suspected deep vein thrombosis and CT in case of suspected pulmonary embolism. Direct oral anticoagulants are first-line treatment options for venous thromboembolism because they are associated with a lower risk of bleeding than vitamin K antagonists and are easier to use. Use of thrombolysis should be limited to pulmonary embolism associated with haemodynamic instability. Anticoagulant treatment should be continued for at least 3 months to prevent early recurrences. When venous thromboembolism is unprovoked or secondary to persistent risk factors, extended treatment beyond this period should be considered when the risk of recurrence outweighs the risk of major bleeding.
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                Author and article information

                Journal
                JAMA Cardiol
                JAMA Cardiol
                JAMA Cardiol
                JAMA Cardiology
                American Medical Association
                2380-6583
                2380-6591
                16 January 2019
                February 2019
                16 January 2019
                : 4
                : 2
                : 43-53
                Affiliations
                [1 ]London School of Hygiene and Tropical Medicine, London, United Kingdom
                [2 ]MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
                [3 ]National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
                [4 ]Medical University of Innsbruck, Innsbruck, Austria
                [5 ]MRC Biostatistics Unit, Cambridge University, Cambridge, United Kingdom
                [6 ]Harvard T. H. Chan School of Public Health, Boston, Massachusetts
                [7 ]Massachusetts General Hospital, Boston
                [8 ]Department of Clinical Sciences, Lund University, Malmö, Sweden
                [9 ]Assmann Foundation for Prevention, Münster, Germany
                [10 ]Icelandic Heart Association, Kópavogur, Iceland
                [11 ]University of Minnesota School of Public Health, Minneapolis
                [12 ]Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [13 ]University of Western Australia, Perth, Western Australia, Australia
                [14 ]Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
                [15 ]Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [16 ]Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
                [17 ]Osaka University, Osaka, Japan
                [18 ]University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [19 ]St George’s, University of London, London, United Kingdom
                [20 ]National Institute for Health and Welfare, Helsinki, Finland
                [21 ]Ludwig Maximilian University of Munich, Munich, Germany
                [22 ]Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [23 ]Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
                [24 ]German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
                [25 ]Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Ulm, Germany
                [26 ]Erasmus University Medical Center, Erasmus University, Rotterdam, the Netherlands
                [27 ]University of Greifswald, Greifswald, Germany
                [28 ]UCL Medical School, University College London, London, United Kingdom
                [29 ]Kyushu University, Fukuoka, Japan
                [30 ]University of Padova, Padua, Italy
                [31 ]University of Hawaii, Honolulu
                [32 ]Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom
                [33 ]Institute of Nutraceuticals and Functional Foods, Université Laval, Quebec, Quebec, Canada
                [34 ]The University of New South Wales, Sydney, New South Wales, Australia
                [35 ]University of California, San Diego
                [36 ]University of Gothenburg, Gothenburg, Sweden
                [37 ]Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy
                [38 ]University of Edinburgh, Edinburgh, United Kingdom
                [39 ]Medical University of South Carolina, Charleston
                [40 ]Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
                [41 ]VU University Medical Center Amsterdam, Amsterdam, the Netherlands
                [42 ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
                [43 ]Tel Aviv University, Tel Aviv, Israel
                [44 ]MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
                [45 ]National Institute of Health (ISS), Rome, Italy
                [46 ]Center of Health Equity, Diversity and Inclusion, University of Washington School of Medicine, Seattle
                [47 ]Clinical Research and Clinical Trials Unit, Plataforma de Innovación en Tecnologías Médicas y Sanitarias, Madrid, Spain
                [48 ]University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
                [49 ]Portland State University, Portland, Oregon
                [50 ]US Centers for Disease Control and Prevention, Atlanta, Georgia
                [51 ]Monash University, Melbourne, Victoria, Australia
                [52 ]Department of Epidemiology and Public Health, University College London, London, United Kingdom
                [53 ]Norwegian Institute of Public Health, Oslo, Norway
                [54 ]MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom
                [55 ]CUNY School of Medicine, City University of New York, New York
                [56 ]Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
                [57 ]Feinberg School of Medicine, Northwestern University, Chicago, Illinois
                [58 ]Albert Einstein College of Medicine, New York, New York
                [59 ]Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
                Author notes
                Article Information
                Group Information: Investigators of the Emerging Risk Factors Collaboration are listed at the end of this article.
                Accepted for Publication: November 15, 2018.
                Published Online: January 16, 2019. doi:10.1001/jamacardio.2018.4537
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Gregson J et al. JAMA Cardiology.
                Corresponding Author: Emanuele Di Angelantonio, FRCP, MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom ( erfc@ 123456phpc.cam.ac.uk ).
                Author Contributions: Drs Kaptoge and Di Angelantonio had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Gregson, Kaptoge, Danesh, Di Angelantonio, and Meade contributed equally.
                Study concept and design: Gregson, Pennells, Rodriguez, Kromhout, Deen, Svensson, Trevisan, Wood, Danesh, Di Angelantonio, Meade.
                Acquisition, analysis, or interpretation of data: Gregson, Kaptoge, Bolton, Pennells, Willeit, Burgess, Bell, Sweeting, Rimm, Kabrhel, Zöller, Assmann, Gudnason, Folsom, Arndt, Fletcher, Norman, Nordestgaard, Mahmoodi, Whincup, Knuiman, Salomaa, Meisinger, Koenig, Kavousi, Henry, J. Cooper, Ninomiya, Casiglia, Rodriguez, Ben-Shlomo, Després, Simons, Barrett-Connor, Björkelund, Notdurfter, Price, Sutherland, Sundstrom, Kauhanen, Gallacher, Beulens, Dankner, C. Cooper, Giampaoli, Gómez de la Cámara, Kuller, Rosengren, Nagel, Brenner, Albertorio-Diaz, Atkins, Shipley, Njølstad, Lawlor, van der Schouw, Selmer, Trevisan, Verschuren, Greenland, Wassertheil-Smoller, Lowe, Butterworth, Thompson, Danesh, Di Angelantonio.
                Drafting of the manuscript: Gregson, Bolton, Notdurfter, C. Cooper, Deen, Danesh, Di Angelantonio, Meade.
                Critical revision of the manuscript for important intellectual content: Kaptoge, Bolton, Pennells, Willeit, Burgess, Bell, Sweeting, Rimm, Kabrhel, Zöller, Assmann, Gudnason, Folsom, Arndt, Fletcher, Norman, Nordestgaard, Mahmoodi, Whincup, Knuiman, Salomaa, Meisinger, Koenig, Kavousi, Henry, J. Cooper, Ninomiya, Casiglia, Rodriguez, Ben-Shlomo, Després, Simons, Barrett-Connor, Björkelund, Kromhout, Price, Sutherland, Sundstrom, Kauhanen, Gallacher, Beulens, Dankner, C. Cooper, Giampaoli, Deen, Gómez de la Cámara, Kuller, Rosengren, Svensson, Nagel, Brenner, Albertorio-Diaz, Atkins, Shipley, Njølstad, Lawlor, van der Schouw, Selmer, Trevisan, Verschuren, Greenland, Wassertheil-Smoller, Lowe, Wood, Butterworth, Thompson, Danesh, Di Angelantonio, Meade.
                Statistical analysis: Gregson, Kaptoge, Bolton, Pennells, Burgess, Sweeting, Sutherland, C. Cooper, Albertorio-Diaz, Lawlor, Wood, Thompson.
                Obtained funding: Nordestgaard, Henry, Casiglia, Rodriguez, Simons, Kromhout, Sutherland, Gallacher, Rosengren, Lawlor, Wassertheil-Smoller, Danesh, Di Angelantonio.
                Administrative, technical, or material support: Bolton, Bell, Kabrhel, Zöller, Fletcher, Whincup, Salomaa, Casiglia, Rodriguez, Simons, Björkelund, Notdurfter, Kromhout, Sutherland, Kauhanen, Beulens, Dankner, Kuller, Svensson, Nagel, Atkins, Trevisan, Verschuren, Lowe, Danesh.
                Study supervision: Kaptoge, Willeit, Rimm, Kabrhel, Gudnason, Salomaa, Koenig, Kavousi, Casiglia, Rodriguez, Simons, Kromhout, Kauhanen, Svensson, Trevisan, Butterworth, Danesh, Meade.
                Conflict of Interest Disclosures: Dr Gregson has received grants from AstraZeneca and BioSensors as well as personal fees from BioSensors, Edwards Lifesciences, and MvRX. Dr Kaptoge has received grants from the British Heart Foundation and the UK Medical Research Council paid to the Department of Public Health and Primary Care of the University of Cambridge. Dr Kabrhel has received grant HL116854 from the National Heart, Lung, and Blood Institute as well as grants from Diagnostica Stago, Janssen Pharmaceuticals, and Siemens Healthcare Diagnostics. Dr Salomaa has received personal fees from Novo Nordisk. Dr Koenig has received grants and nonfinancial support from Abbott, Beckmann, Roche Diagnostics, and Singulex as well as personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, GlaxoSmithKline, DalCor, Kowa, and Amgen for consulting and from AstraZeneca, Sanofi, and Berlin-Chernie for lectures. Dr Lawlor has received grants from the UK Medical Research Council, UK Economic and Social Science Research Council, British Heart Foundation, Diabetes UK, European Research Council, and National Institute for Health as well as funds in kind from Medtronic and Roche Diagnostics paid to the University of Bristol. Dr Butterworth has received grants from AstraZeneca, Biogen, Merck, Novartis, and Pfizer. Dr Thompson has received grants from British Heart Foundation and the UK Medical Research Council. No other disclosures were reported.
                Funding/Support: This research has been conducted using the UK Biobank resource under Application Number 26865. This work was supported by underpinning grants from the UK Medical Research Council (grant G0800270), the British Heart Foundation (grant SP/09/002), the British Heart Foundation Cambridge Cardiovascular Centre of Excellence, UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (grant 268834), the European Commission Framework Programme 7 (grant HEALTH-F2-2012-279233), and Health Data Research UK. Dr Danesh holds a British Heart Foundation Personal Chair and a National Institute for Health Research Senior Investigator Award.
                Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Group Information: Investigators of the Emerging Risk Factors Collaboration include the following: Atherosclerosis Risk in Communities Study: Wayne Rosamond, PhD; Eric Whitsel, PhD; and Mary Cushman, BSc (University of North Carolina, Chapel Hill); Australian Diabetes Study: Elizabeth L. M. Barr, PhD; Jonathan E. Shaw, MD; and Paul Z. Zimmet, MD (Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia); Busselton Health Study: Matthew Knuiman, PhD (The University of Western Australia, Perth, Western Australia, Australia); British Regional Heart Study: Peter H. Whincup, PhD (St George’s, University of London, London, United Kingdom); Bruneck Study: Stefan Kiechl, MD; Siegfried Weger, MD; and Johann Willeit, MD (Department of Internal Medicine, Bruneck Hospital, Italy); British Women’s Heart and Health Study: Deborah A. Lawlor, PhD (University of Bristol, Bristol, United Kingdom); Antoinette Amuzu, MA; Caroline Dale, PhD; and Juan P. Casas, MD (University College London, London, United Kingdom); Caerphilly Prospective Study: John Gallacher, PhD (University of Oxford, Oxford, United Kingdom); Cardiovascular Study in the Elderly: Valérie Tikhonoff, MD (University of Padua, Padua, Italy); Chicago Heart Association Detection Project In Industry: Philip Greenland, MD (Northwestern University, Chicago, Illinois); Charleston Heart Study: Paul Nietert, PhD (Medical University of South Carolina, Charleston); Copenhagen City Heart Study: Anne Tybjærg-Hansen, MD; Ruth Frikke-Schmidt, MD; and Gorm B. Jensen, MD (University of Copenhagen, Copenhagen, Denmark); Diet and Risk of Cardiovascular Disease in Spain: David Lora Pablos, MD; and Pilar Cancelas Navia, MD (Hospital 12 de Octubre, Madrid, Spain); Dubbo Study of the Elderly: Leon Simons, MD (University of New South Wales, Sydney, New South Wales, Australia); Edinburgh Artery Study: Stela McLachlan, PhD (The University of Edinburgh, Edinburgh, United Kingdom); Epidemiologische Studie zu Chancen der Verhutung und optimierten Therapie chronischer Erkrankungen in der alteren Bevolkerung: Ben Schöttker, MD; Kai-Uwe Saum, PhD; and Bernd Holleczek, PhD (German Cancer Research Center, Heidelberg, Germany); Oslo Study, Cohort of Norway: Inger Ariansen, PhD; Haakon E. Meyer, MD; and Lise Lund Håheim, MD (Norwegian Institute of Public Health, Oslo, Norway); Finrisk Cohort 1992, Finrisk Cohort 1997: Erkki Vartiainen, MD; Pekka Jousilahti, MD; and Kennet Harald, MD (National Institute for Health and Welfare, Helsinki, Finland); The Glucose Intolerance, Obesity and Hypertension Study: Rachel Dankner, MD (Tel Aviv University, Tel Aviv, Israel); Goteborg Study 1933, MONICA Göteborg Study: Annika Rosengren, MD; and Lars Wilhelmsen, MD (University of Gothenburg, Gothenburg, Sweden); Population Study of Women in Göteborg, Sweden: Cecilia Björkelund, MD (University of Gothenburg, Gothenburg, Sweden); Göttingen Risk Incidence and Prevalence Study: Dorothea Nagel, MD (German Cancer Research Center, Heidelberg, Germany); Hertfordshire Cohort Study: Elaine Dennison, PhD; Holly Syddall, PhD; and Leo Westbury, MSc (University of Southampton, Southampton, United Kingdom); Health in Men Study: Leon Flicker, PhD; Graeme J. Hankey, MD (University of Western Australia, Perth, Western Australia, Australia); and Jonathan Golledge, MD (James Cook University, Townsville, Queensland, Australia); Hisayama Study: Toshiharu Ninomiya, PhD; Yasufumi Doi, PhD; and Yutaka Kiyohara, PhD (Kyushu University, Fukuoka, Japan); Honolulu Heart Program: Beatriz Rodriguez, MD (University of Hawaii, Honolulu); Hoorn Study: Petra Elders, MD; and Coen Stehouwer, MD (VU University Medical Center, Amsterdam, the Netherlands); Health Professionals Follow-up Study: Christopher Kabrhel, MD (Massachusetts General Hospital, Boston); and Majken Jensen, PhD (Harvard T. H. Chan School of Public Health, Boston, Massachusetts); Ikawa, Kyowa, and Noichi Study: Akihiko Kitamura, MD (Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan); Hiroyasu Iso, MD (Osaka University Graduate School of Medicine, Suita, Japan); and Kazumasa Yamagishi, MD (University of Tsukuba, Tsukuba, Japan); North Karelia Project: Veikko Salomaa, MD (National Institute for Health and Welfare, Helsinki, Finland); Kuopio Ischaemic Heart Disease Study: Kurl Sudhir, MD; Tomi-Pekka Tuomainen, PhD; and Jukka T. Salonen, MD (University of Eastern Finland, Keupio, Finland); Lower Extremity Arterial Disease Event Reduction Trial, Northwick Park Heart Study II: Jackie A. Cooper, MBBS, (UCL Medical School, University College London, London, United Kingdom); Monitoring of CVD Risk Factors Project, Dutch Monitoring Project on Risk Factors for Chronic Diseases: Jolanda M. A. Boer, PhD; and Anneke Blokstra, PhD (National Institute for Public Health and the Environment [RIVM], Bilthoven, the Netherlands); Malmö Diert and Cancer Cardiovascular Study, Malmö Preventive Project: Olle Melander, MD; Peter M. Nilsson, MD; and Gunnar Engström, PhD (Lund University, Lund, Sweden); Risk Factors and Life Expectancy Pooling Project, Risk Factors and Life Expectancy Pooling Project: Maurizio Trevisan, MD (The City College of New York, New York); Progetto CUORE: Luigi Palmieri, MD; Diego Vanuzzo, MD; and Simona Giampaoli, MD (National Health Institute of Health [ISS], Rome, Italy); MONICA/KORA Augsburg Survey S1, MONICA/KORA Augsburg Survey S2, MONICA/KORA Augsburg Survey S3: Annette Peters, MD; Barbara Thorand, PhD; and Margit Heier, PhD (German Research Center for Environmental Health, Neuherberg, Germany); MRC Study of Older People: Astrid Fletcher, MD (London School of Hygiene and Tropical Medicine, London, United Kingdom); Multiple Risk Factor Intervention Trial 1: Lewis H. Kuller, PhD (University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania); National Health and Nutrition Examination Survey I: Juan R. Albertorio-Diaz, MA (US Centers for Disease Control and Prevention, Atlanta, Georgia); Nurses’ Health Study: Eric B. Rimm, ScD; Frank B. Hu, MD; and JoAnn E. Manson, MD (Harvard T. H. Chan School of Public Health, Boston, Massachusetts); Prevention of Renal and Vascular End Stage Disease Study: Karina Meijer, MD; Ron T. Gansevoort, MD (University of Groningen, Groningen, the Netherlands); Puerto Rico Heart Health Program: Carlos J. Crespo, MD (Portland State University, Portland, Oregon); Prospective Cardiovascular Münster Study: Gerd Assmann, MD (Assmann Foundation for Prevention, Münster, Germany); and Helmut Schulte, PhD (University of Münster, Münster, Germany); Prospect EPIC Utrecht: Ivonne Sluijs, PhD (University Medical Center Utrecht, Utrecht, the Netherlands); Quebec Cardiovascular Study: Bernard Cantin, PhD; Benoît Lamarche, PhD; and Gilles R. Dagenais, MD (Université Laval, Quebec, Quebec, Canada); Rancho Bernardo Study: Linda McEvoy, PhD; Gail Laughlin, PhD; and Lori B. Daniels, MD (University of California, San Diego); Reykjavik Study: Thor Aspelund, PhD; Elías Freyr Gudmundsson, PhD; and Bolli Thorsson, PhD (University of Iceland, Reykjavík, Iceland); The Rotterdam Study: Maarten J. G. Leening, PhD; M. Arfan Ikram, MD; and Oscar H. Franco, MD (Erasmus Medical Centre, Rotterdam, the Netherlands); Scottish Heart Health Extended Cohort: Hugh Tunstall-Pedoe, MD (Dundee University, Dundee, United Kingdom); Study of Health in Pomerani: Henry Völzke, MD; and André Werner, MD (University of Greifswald, Greifswald, Germany); Strong Heart Study: Richard Devereux, MD (Weill Cornell Medicine, New York, New York); and Stacey Jolly, MD (Cleveland Clinic, Phoenix, Arizona); Speedwell Study: George Davey Smith, MD (Bristol University, Bristol, United Kingdom); Turkish Adult Risk Factor Study: Günay Can, MD (Trakya University, Edime, Turkey); Hüsniye Yüksel, MD (Ataşehir Florence Nightingale Hospital, Istanbul, Turkey); and Servet Altay, MD (Trakya University, Edime, Turkey); Tromsø Study: Inger Njølstad, MD (The Arctic University of Norway, Tromsø, Norway); Uppsala Longitudinal Study of Adult Men: Martin Ingelsson, MD; and Vilmantas Giedraitis, PhD (Uppsala University, Uppsala, Sweden); Wuertemberg Construction Workers Cohort: Hermann Brenner, MD (German Cancer Research Center, Heidelberg, Germany); Heiner Claessen, PhD (German Diabetes Center, Düsseldorf, Germany); and Dietrich Rothenbacher, MD (University of Ulm, Ulm, Germany); Women’s Health Initiative: Nisha I. Parikh, MD (University of California, San Francisco); and Charles Eaton, MD (Care New England, Pawtucket, Rhode Island); Whitehall I Study: Martin Shipley, MSc; and Mika Kivimaki, FMedSci (University College London, London, United Kingdom); Whitehall II Study: Eric J. Brunner, PhD; and Martin Shipley, MSc (University College London, London, United Kingdom); and Zutphen Elderly Study: Edith Feskens, MD; Johanna M. Geleijnse, MD; and Daan Kromhout, MD (Wageningen University, Wageningen, the Netherlands); Data Management Team: Thomas Bolton, MSc; Sarah Spackman, MMath; and Matthew Walker, PhD (MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom). Coordinating Centre: Thomas Bolton, MSc; Stephen Burgess, PhD; Adam S. Butterworth, PhD; Emanuele Di Angelantonio, FRCP; Stephen Kaptoge, PhD; Lisa Pennells, PhD; Sarah Spackman, MMath; Simon G. Thompson, PhD; Matthew Walker, PhD; Angela M. Wood, PhD; and John Danesh, FMedSci (principal investigator) (MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom).
                Article
                hoi180068
                10.1001/jamacardio.2018.4537
                6386140
                30649175
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                Copyright 2019 Gregson J et al. JAMA Cardiology.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 18 May 2018
                : 6 November 2018
                : 15 November 2018
                Funding
                Funded by: UK Medical Research Council
                Funded by: British Heart Foundation
                Funded by: British Heart Foundation Cambridge Cardiovascular Centre of Excellence
                Funded by: UK National Institute for Health Research Cambridge Biomedical Research Centre
                Funded by: European Research Council
                Funded by: European Commission Framework Programme 7
                Funded by: Health Data Research UK
                Categories
                Research
                Research
                Original Investigation
                Online First

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