Lars Wallentin1, Folkert W Asselbergs2,3,4, Riyaz S Patel3,5, Bakhtawar K Mahmoodi6,7, Vinicius Tragante2, Marcus E Kleber8, Michael V Holmes9,10, Amand F Schmidt2,3, Raymond O McCubrey11, Laurence J Howe3, Kenan Direk3, Hooman Allayee12, Ekaterina V Baranova13, Peter S Braund14,15, Graciela E Delgado8, Niclas Eriksson1, Crystel M Gijsberts16, Yan Gong17, Jaana Hartiala12,18, Mahyar Heydarpour19,20, Gerard Pasterkamp21, Salma Kotti22, Pekka Kuukasjärvi23, Petra A Lenzini24, Daniel Levin25, Leo-Pekka Lyytikäinen26,27, Jochen D Muehlschlegel19,20, Christopher P Nelson16,14, Kjell Nikus28,29, Anna P Pilbrow30, W H Wilson Tang31,32, Sander W van der Laan33, Jessica van Setten2, Ragnar O Vilmundarson34, John Deanfield3, Panos Deloukas35, Frank Dudbridge36, Stefan James1,37, Ify R Mordi25, Andrej Teren38,39, Thomas O Bergmeijer6, Simon C Body40, Michiel Bots41,42, Ralph Burkhardt39, Rhonda M Cooper-DeHoff17,43, Sharon Cresci24,44, Nicolas Danchin45, Robert N Doughty46, Diederick E Grobbee41, Emil Hagström37,47, Stanley L Hazen31,48, Claes Held1,37, Imo E Hoefer49, G Kees Hovingh50, Julie A Johnson17,43, Marcin P Kaczor51, Mika Kähönen52,53, Olaf H Klungel13, Jari O Laurikka23,54, Terho Lehtimäki26,27, Anke H Maitland-van der Zee13,55, Ruth McPherson56, Colin N Palmer57, Adriaan O Kraaijeveld2, Carl J Pepine43, Marek Sanak51, Naveed Sattar58, Markus Scholz39,59, Tabassome Simon60,61, John A Spertus62,63, Alexandre F R Stewart34,56, Wojciech Szczeklik51, Joachim Thiery39,64, Frank L J Visseren65, Johannes Waltenberger66, A Mark Richards30,67, Chim C Lang25, Vicky A Cameron30, Axel Åkerblom1,37, Guillaume Pare68,69, Winfried März8,70,71, Nilesh J Samani14,15, Aroon D Hingorani3, Jurriën M Ten Berg6. 1. Uppsala Clinical Research Center, Sweden (N.E., S.J., C.H., A.Å., L.W.). 2. Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands. 3. Institute of Cardiovascular Science and UCL BHF Research Accelerator, Faculty of Population Health Science, University College London, United Kingdom (A.F.S., L.J.H., K.D., J.D., A.D.H., F.W.A., R.S.P.). 4. Health Data Research UK and Institute of Health Informatics, University College London, United Kingdom (F.W.A.). 5. Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.S.P.). 6. St. Antonius Hospital, Department of Cardiology, Nieuwegein, the Netherlands (B.K.M., T.O.B., J.M.t.B.). 7. Division of Hemostasis and Thrombosis, Department of Hematology, UMC Groningen, University of Groningen, The Netherlands (B.K.M.). 8. Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany (M.E.K., G.E.D., W.M.). 9. Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, United Kingdom (M.V.H.). 10. National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, United Kingdom (M.V.H.). 11. Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT (R.O.McC.). 12. Departments of Preventive Medicine and Biochemistry and Molecular Medicine (H.A., J.H.), Keck School of Medicine of University of Southern California, Los Angeles. 13. Division of Pharmacoepidemiology and Clinical Pharmacology (E.V.B., O.H.K., A.H.M.-v.d.Z.), UMC Utrecht, Utrecht University, the Netherlands. 14. Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, United Kingdom (P.S.B., C.P.N., N.J.S.). 15. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (P.S.B., C.P.N., N.J.S.). 16. Laboratory of Experimental Cardiology (C.M.G.), UMC Utrecht, Utrecht University, the Netherlands. 17. Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., R.M.C.-D.H., J.A.J.), University of Florida, Gainesville. 18. Institute for Genetic Medicine (J.H.), Keck School of Medicine of University of Southern California, Los Angeles. 19. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA (M.H., J.D.M.). 20. Harvard Medical School, Harvard University, Boston, MA (M.H., J.D.M.). 21. Department of Clinical Chemistry (G.Pasterkamp), UMC Utrecht, Utrecht University, the Netherlands. 22. Assistance Publique-Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, Platform of Clinical Research of East Paris (URCEST-CRCEST-CRB HUEP-UPMC), France (S.K.). 23. Departments of Cardio-Thoracic Surgery (P.K., J.O.L.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland. 24. Department of Genetics, Statistical Genomics Division (P.A.L., S.C.), Washington University School of Medicine, Saint Louis, MO. 25. Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Scotland, United Kingdom (D.L., I.R.M., C.C.L.). 26. Clinical Chemistry (L.-P.L., T.L.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland. 27. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (L.-P.L., T.L.). 28. Cardiology (K.N.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland. 29. Department of Cardiology (K.N.), Heart Center, Tampere University Hospital, Finland. 30. The Christchurch Heart Institute, University of Otago Christchurch, New Zealand (A.P.P., A.M.R., V.A.C.). 31. Department of Cardiovascular and Metabolic Sciences, Lerner Research institute (W.H.W.T., S.L.H.), Cleveland Clinic, OH. 32. Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, OH. 33. Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics (S.W.v.d.L.), UMC Utrecht, Utrecht University, the Netherlands. 34. Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ontario, Canada (R.O.V., A.F.R.S.). 35. William Harvey Research Institute, Barts and the London Medical School, and the Centre for Genomic Health, Queen Mary University of London, United Kingdom (P.D.). 36. Department of Health Sciences, University of Leicester, United Kingdom (F.D.). 37. Department of Medical Sciences, Cardiology, Uppsala University, Sweden (S.J., E.H., C.H., A.Å., L.W.). 38. Heart Center Leipzig, Germany (A.T.). 39. LIFE Research Center for Civilization Diseases (A.T., R.B., M.Scholz, J.T.), University of Leipzig, Germany. 40. Department of Anesthesiology, Boston University School of Medicine, MA (S.C.B.). 41. Julius Center for Health Sciences and Primary Care (M.B., D.E.G.), UMC Utrecht, Utrecht University, the Netherlands. 42. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Germany (R.B.). 43. College of Medicine, Division of Cardiovascular Medicine (R.M.C.-D.H., J.A.J., C.J.P.), University of Florida, Gainesville. 44. Department of Medicine, Cardiovascular Division (S.C.), Washington University School of Medicine, Saint Louis, MO. 45. Assistance Publique-Hôpitaux de Paris (APHP), Department of Cardiology, Hôpital Européen Georges Pompidou; FACT (french Alliance for cardiovascular trials); and Université Paris Descartes, France (N.D.). 46. Heart Health Research Group, University of Auckland, New Zealand (R.N.D.). 47. Department of Cardiology, Uppsala University, and Uppsala Clinical Research Center, Sweden (E.H.). 48. Center for Microbiome and Human Health (S.L.H.), Cleveland Clinic, OH. 49. Department of Clinical Chemistry and Hematology (I.E.H.), UMC Utrecht, Utrecht University, the Netherlands. 50. Department of Vascular Medicine (G.K.H.), Academic Medical Center, University of Amsterdam, The Netherlands. 51. Department of Internal Medicine, Jagiellonian University Medical College, Kraków, Poland (M.P.K., M.Sanak, W.S.). 52. Clinical Physiology (M.K.), Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Techonology, Tampere University, Finland. 53. Department of Clinical Physiology, Tampere University Hospital, Finland (M.K.). 54. Department of Cardio-Thoracic Surgery (J.O.L.), Heart Center, Tampere University Hospital, Finland. 55. Department of Respiratory Medicine (A.H.M.-v.d.Z.), Academic Medical Center, University of Amsterdam, The Netherlands. 56. Departments of Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa, Ontario, Canada (R.McP. R.O.V., A.F.R.S.). 57. Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.N.P.). 58. Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.S.). 59. Institute for Medical Informatics, Statistics, and Epidemiology (M.Scholz), University of Leipzig, Germany. 60. Assistance Publique-Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, Platform of Clinical Research of East Paris (URCEST-CRCEST-CRB HUEP-UPMC), FACT (French Alliance for Cardiovascular trials); Sorbonne Université, Paris-06, France (T.S.). 61. Paris-Sorbonne University, UPMC-Site St Antoine, France (T.S.). 62. University of Missouri-Kansas City (J.A.S.). 63. Saint Luke's Mid America Heart Institute, Kansas City, MO (J.A.S.). 64. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Germany (J.T.). 65. Department of Vascular Medicine (F.L.J.V.), UMC Utrecht, Utrecht University, the Netherlands. 66. Department of Cardiovascular Medicine, University of Münster, Germany (J.W.). 67. Cardiovascular Research Institute, National University of Singapore (A.M.R.). 68. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (G.Pare). 69. Population Health Research Institute, Hamilton, Ontario, Canada (G.Pare). 70. Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany (W.M.). 71. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.).
Abstract
BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
Entities:
Keywords:
coronary artery disease; genetic association studies; myocardial infarction; prognosis; secondary prevention; single nucleotide polymorphism; thrombosis
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