Association of Factor V Leiden with Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

Bakhtawar K. Mahmoodi; Vinicius Tragante; Marcus E. Kleber; Michael V. Holmes; Amand F. Schmidt; Raymond O. McCubrey; Laurence J. Howe; Kenan Direk; Hooman Allayee; Ekaterina V. Baranova; Peter S. Braund; Graciela E. Delgado; Niclas Eriksson; Crystel M. Gijsberts; Yan Gong; Jaana Hartiala; Mahyar Heydarpour; Gerard Pasterkamp; Salma Kotti; Pekka Kuukasjärvi; Petra A. Lenzini; Daniel Levin; Leo-Pekka Lyytikäinen; Jochen D. Muehlschlegel; Christopher P. Nelson; Kjell Nikus; Anna P. Pilbrow; W. H. Wilson Tang; Sander W. van der Laan; Jessica van Setten; Ragnar O. Vilmundarson; John Deanfield; Panos Deloukas; Frank Dudbridge; Stefan James; Ify R. Mordi; Andrej Teren; Thomas O. Bergmeijer; Simon C. Body; Michiel Bots; Ralph Burkhardt; Rhonda M. Cooper-DeHoff; Sharon Cresci; Nicolas Danchin; Robert N. Doughty; Diederick E. Grobbee; Emil Hagström; Stanley L. Hazen; Claes Held; Imo E. Hoefer; G. Kees Hovingh; Julie A. Johnson; Marcin P. Kaczor; Mika Kähönen; Olaf H. Klungel; Jari O. Laurikka; Terho Lehtimäki; Anke H. Maitland-van der Zee; Ruth McPherson; Colin N. Palmer; Adriaan O. Kraaijeveld; Carl J. Pepine; Marek Sanak; Naveed Sattar; Markus Scholz; Tabassome Simon; John A. Spertus; Alexandre F. R. Stewart; Wojciech Szczeklik; Joachim Thiery; Frank L. J. Visseren; Johannes Waltenberger; A. Mark Richards; Chim C. Lang; Vicky A. Cameron; Axel Åkerblom; Guillaume Pare; Winfried März; Nilesh J. Samani; Aroon D. Hingorani; Jurriën M. Ten Berg; Lars Wallentin; Folkert W. Asselbergs; Riyaz Patel

doi:10.1161/CIRCULATIONAHA.119.045526

Association of Factor V Leiden with Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

Bakhtawar K. Mahmoodi, Vinicius Tragante, Marcus E. Kleber, Michael V. Holmes, Amand F. Schmidt, Raymond O. McCubrey, Laurence J. Howe, Kenan Direk, Hooman Allayee, Ekaterina V. Baranova, Peter S. Braund, Graciela E. Delgado, Niclas Eriksson, Crystel M. Gijsberts, Yan Gong, Jaana Hartiala, Mahyar Heydarpour, Gerard Pasterkamp, Salma Kotti, Pekka KuukasjärviPetra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Jochen D. Muehlschlegel, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, W. H. Wilson Tang, Sander W. van der Laan, Jessica van Setten, Ragnar O. Vilmundarson, John Deanfield, Panos Deloukas, Frank Dudbridge, Stefan James, Ify R. Mordi, Andrej Teren, Thomas O. Bergmeijer, Simon C. Body, Michiel Bots, Ralph Burkhardt, Rhonda M. Cooper-DeHoff, Sharon Cresci, Nicolas Danchin, Robert N. Doughty, Diederick E. Grobbee, Emil Hagström, Stanley L. Hazen, Claes Held, Imo E. Hoefer, G. Kees Hovingh, Julie A. Johnson, Marcin P. Kaczor, Mika Kähönen, Olaf H. Klungel, Jari O. Laurikka, Terho Lehtimäki, Anke H. Maitland-van der Zee, Ruth McPherson, Colin N. Palmer, Adriaan O. Kraaijeveld, Carl J. Pepine, Marek Sanak, Naveed Sattar, Markus Scholz, Tabassome Simon, John A. Spertus, Alexandre F. R. Stewart, Wojciech Szczeklik, Joachim Thiery, Frank L. J. Visseren, Johannes Waltenberger, A. Mark Richards, Chim C. Lang, Vicky A. Cameron, Axel Åkerblom, Guillaume Pare, Winfried März, Nilesh J. Samani, Aroon D. Hingorani, Jurriën M. Ten Berg, Lars Wallentin, Folkert W. Asselbergs, Riyaz Patel (Lead / Corresponding author)

Population Health and Genomics

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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.

Original language	English
Pages (from-to)	546-555
Number of pages	10
Journal	Circulation
Volume	142
Issue number	6
Early online date	13 Jul 2020
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.119.045526
Publication status	Published - 11 Aug 2020

Keywords

coronary artery disease
genetic association studies
myocardial infarction
prognosis
secondary prevention
single nucleotide polymorphism
thrombosis

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.119.045526

Author Accepted ManuscriptAccepted author manuscript, 423 KB

Cite this

Mahmoodi, B. K., Tragante, V., Kleber, M. E., Holmes, M. V., Schmidt, A. F., McCubrey, R. O., Howe, L. J., Direk, K., Allayee, H., Baranova, E. V., Braund, P. S., Delgado, G. E., Eriksson, N., Gijsberts, C. M., Gong, Y., Hartiala, J., Heydarpour, M., Pasterkamp, G., Kotti, S., ... Patel, R. (2020). Association of Factor V Leiden with Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data. Circulation, 142(6), 546-555. https://doi.org/10.1161/CIRCULATIONAHA.119.045526

@article{c61d1aca90b94537bf9b63811cfe9165,

title = "Association of Factor V Leiden with Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data",

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.",

keywords = "coronary artery disease, genetic association studies, myocardial infarction, prognosis, secondary prevention, single nucleotide polymorphism, thrombosis",

author = "Mahmoodi, {Bakhtawar K.} and Vinicius Tragante and Kleber, {Marcus E.} and Holmes, {Michael V.} and Schmidt, {Amand F.} and McCubrey, {Raymond O.} and Howe, {Laurence J.} and Kenan Direk and Hooman Allayee and Baranova, {Ekaterina V.} and Braund, {Peter S.} and Delgado, {Graciela E.} and Niclas Eriksson and Gijsberts, {Crystel M.} and Yan Gong and Jaana Hartiala and Mahyar Heydarpour and Gerard Pasterkamp and Salma Kotti and Pekka Kuukasj{\"a}rvi and Lenzini, {Petra A.} and Daniel Levin and Leo-Pekka Lyytik{\"a}inen and Muehlschlegel, {Jochen D.} and Nelson, {Christopher P.} and Kjell Nikus and Pilbrow, {Anna P.} and Tang, {W. H. Wilson} and {van der Laan}, {Sander W.} and {van Setten}, Jessica and Vilmundarson, {Ragnar O.} and John Deanfield and Panos Deloukas and Frank Dudbridge and Stefan James and Mordi, {Ify R.} and Andrej Teren and Bergmeijer, {Thomas O.} and Body, {Simon C.} and Michiel Bots and Ralph Burkhardt and Cooper-DeHoff, {Rhonda M.} and Sharon Cresci and Nicolas Danchin and Doughty, {Robert N.} and Grobbee, {Diederick E.} and Emil Hagstr{\"o}m and Hazen, {Stanley L.} and Claes Held and Hoefer, {Imo E.} and Hovingh, {G. Kees} and Johnson, {Julie A.} and Kaczor, {Marcin P.} and Mika K{\"a}h{\"o}nen and Klungel, {Olaf H.} and Laurikka, {Jari O.} and Terho Lehtim{\"a}ki and {Maitland-van der Zee}, {Anke H.} and Ruth McPherson and Palmer, {Colin N.} and Kraaijeveld, {Adriaan O.} and Pepine, {Carl J.} and Marek Sanak and Naveed Sattar and Markus Scholz and Tabassome Simon and Spertus, {John A.} and Stewart, {Alexandre F. R.} and Wojciech Szczeklik and Joachim Thiery and Visseren, {Frank L. J.} and Johannes Waltenberger and Richards, {A. Mark} and Lang, {Chim C.} and Cameron, {Vicky A.} and Axel {\AA}kerblom and Guillaume Pare and Winfried M{\"a}rz and Samani, {Nilesh J.} and Hingorani, {Aroon D.} and {Ten Berg}, {Jurri{\"e}n M.} and Lars Wallentin and Asselbergs, {Folkert W.} and Riyaz Patel",

note = "Funding Information: VT, FS, RM, KD, and MH helped develop the analysis scripts, curate and manage the data at the coordinating sites. BKM performed the meta-analysis of the collected estimates and drafted the article. RSP and FWA coordinated analyses and development of the GENIUS-CHD Consortium. All authors took part in the interpretation of the data, and all authors provided critical revisions of the article for important intellectual content. The GENIUS-CHD collaborators would like to express their immense gratitude to all patients who participated in each of the individual studies as well as the many personnel who helped with recruitment, collection, curation, management, and processing of the samples and data. Sponsors of the individual studies are listed here and study acronyms are listed in the supplemental material: The Cleveland Clinic Genebank Study was supported in part by NIH grants R0133169, R01ES021801, R01MD010358, and R01ES025786, R01HL103866, R01DK106000, R01HL126827, P20HL113452.P01HL098055, P01HL076491, and R01HL103931. The LURIC study was supported by the 7th Framework Program (AtheroRemo, grant agreement number 201668 and Risky-CAD, grant agreement number 305739) of the European Union. INVEST-GENES was supported by the National Institute of Health Pharmacogenomics Research Network grant U01-GM074492, NIH R01 HL074730, University of Florida Opportunity Fund, BASF Pharma and Abbott Laboratories. FAST-MI (French Registry of Acute ST-Elevation or non-ST-elevation Myocardial Infarction) 2005 is a registry of the French Society of Cardiology, supported by unrestricted grants from Pfizer and Servier. Additional support was obtained from a research grant from the French Caisse Nationale d{\textquoteright}Assurance Maladie. The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. FINCAVAS (Finnish Cardiovascular Study) has been financially supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, the Tampere Tuberculosis Foundation, EU Horizon 2020 (grant 755320 for TAXINOMISIS), and the Academy of Finland grant 322098. CABGenomics was supported by Stanton Shernan, C. David Collard, Amanda A. Fox/R01 HL 098601 NHLBI. The CDCS and PMI studies were funded by the Health Research Council and Heart Foundation of New Zealand. The TRIUMPH study was sponsored by the National Institutes of Health: Washington University School of Medicine SCCOR Grant P50 HL077113. The KRAKOW GENIUS Study was supported by a grant from the Polish Ministry of Science and Higher Education, no. NN402083939 and the National Science Center, no. 2013/09/B/ NZ5/00770. The ANGES has been financially supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, the Tampere Tuberculosis Foundation, EU Horizon 2020 (grant 755320 for TAXINOMISIS), and the Academy of Finland grant 322098. The UCP studies were funded by the Netherlands Heart Foundation and the Dutch Top Institute Pharma Mondriaan Project. LIFE-Heart was funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund and by funds of the Free State of Saxony within the framework of the excellence initiative. OHGS was funded in part by a Heart and Stroke Foundation grant. Funding Information: The funder(s) of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Funding and sponsors of all participating investigators not linked to this analysis are listed in the disclosures section and funding for the individual studies is acknowledged in the acknowledgments section. Dr Mahmoodi received a VENI grant from the Dutch Research Council for investigating the role of factor V Leiden in the pathogenesis of myocardial infarction. Dr Patel is funded by a British Heart Foundation Intermediate Fellowship (FS/14/76/30933). The GENIUS-CHD project was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Center. Funding Information: Dr Holmes has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of The Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. He works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Center. Dr Schmidt is funded by BHF grant PG/18/5033837. Dr Allayee was supported, in part, by NIH grants R01HL133169 and R01HL148110. Dr Eriksson reports Institutional research grants from AstraZeneca and GlaxoS-mithKline. Dr Nelson is funded by the British Heart Foundation. Dr Vilmundarson is supported by a graduate fellowship of the University of Ottawa Heart Institute. Dr James has received grants from AstraZeneca, The Medicines Company, Swedish heart and lung foundation, Swedish research council, Janssen; personal fees from Bayer. Dr Mordi is supported by an NHS Education of Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship (PCL 17/07). Dr Cresci is supported, in part, by the National Institutes of Health (Cresci R01 NR013396). Dr Hagstrom declares being an expert committee member, lecture fees, and institutional research grant from Sanofi, and Amgen; institutional research grants from AstraZeneca, and GlaxoSmithKline; expert committee member and lecture fees NovoNordisk and Behringer. Dr Held declares institutional research grant, advisory board member and speaker{\textquoteright}s bureau from AstraZeneca; institutional research grants from Bristol-Myers Squibb Merck and Co, GlaxoSmithKline, Roche Diagnostics. Advisory board for Bayer and Boehringer Ingelheim. Dr Palmer has received grant funding from the Wellcome Trust to develop the GoDARTS cohort. Dr Akerblom has received institutional research grant and speakers fee from AstraZeneca, institutional research grant from Roche Diagnostics. Prof. Samani is funded by the British Heart Foundation and is a NIHR Senior Investigator. Dr ten Berg reports receiving fees for board membership from AstraZeneca,consulting fees from AstraZeneca, Eli Lilly, and Merck, and lecture fees from Daiichi San-kyo and Eli Lilly, AstraZeneca, Sanofi and Accumetrics. Prof Wallentin reports institutional research grants, consultancy fees, lecture fees, and travel support from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, Boehringer In-gelheim; institutional research grants from Merck and Co, Roche Diagnostics; consultancy fees from Abbott; and holds a patent EP2047275B1 licensed to Roche Diagnostics, and a patent US8951742B2 licensed to Roche Diagnostics. Prof Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. The other authors report no conflicts. Publisher Copyright: {\textcopyright} 2020 Lippincott Williams and Wilkins. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = aug,

day = "11",

doi = "10.1161/CIRCULATIONAHA.119.045526",

language = "English",

volume = "142",

pages = "546--555",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "6",

}

Mahmoodi, BK, Tragante, V, Kleber, ME, Holmes, MV, Schmidt, AF, McCubrey, RO, Howe, LJ, Direk, K, Allayee, H, Baranova, EV, Braund, PS, Delgado, GE, Eriksson, N, Gijsberts, CM, Gong, Y, Hartiala, J, Heydarpour, M, Pasterkamp, G, Kotti, S, Kuukasjärvi, P, Lenzini, PA, Levin, D, Lyytikäinen, L-P, Muehlschlegel, JD, Nelson, CP, Nikus, K, Pilbrow, AP, Tang, WHW, van der Laan, SW, van Setten, J, Vilmundarson, RO, Deanfield, J, Deloukas, P, Dudbridge, F, James, S, Mordi, IR, Teren, A, Bergmeijer, TO, Body, SC, Bots, M, Burkhardt, R, Cooper-DeHoff, RM, Cresci, S, Danchin, N, Doughty, RN, Grobbee, DE, Hagström, E, Hazen, SL, Held, C, Hoefer, IE, Hovingh, GK, Johnson, JA, Kaczor, MP, Kähönen, M, Klungel, OH, Laurikka, JO, Lehtimäki, T, Maitland-van der Zee, AH, McPherson, R, Palmer, CN, Kraaijeveld, AO, Pepine, CJ, Sanak, M, Sattar, N, Scholz, M, Simon, T, Spertus, JA, Stewart, AFR, Szczeklik, W, Thiery, J, Visseren, FLJ, Waltenberger, J, Richards, AM, Lang, CC, Cameron, VA, Åkerblom, A, Pare, G, März, W, Samani, NJ, Hingorani, AD, Ten Berg, JM, Wallentin, L, Asselbergs, FW & Patel, R 2020, 'Association of Factor V Leiden with Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data', Circulation, vol. 142, no. 6, pp. 546-555. https://doi.org/10.1161/CIRCULATIONAHA.119.045526

TY - JOUR

T1 - Association of Factor V Leiden with Subsequent Atherothrombotic Events

T2 - A GENIUS-CHD Study of Individual Participant Data

AU - Mahmoodi, Bakhtawar K.

AU - Tragante, Vinicius

AU - Kleber, Marcus E.

AU - Holmes, Michael V.

AU - Schmidt, Amand F.

AU - McCubrey, Raymond O.

AU - Howe, Laurence J.

AU - Direk, Kenan

AU - Allayee, Hooman

AU - Baranova, Ekaterina V.

AU - Braund, Peter S.

AU - Delgado, Graciela E.

AU - Eriksson, Niclas

AU - Gijsberts, Crystel M.

AU - Gong, Yan

AU - Hartiala, Jaana

AU - Heydarpour, Mahyar

AU - Pasterkamp, Gerard

AU - Kotti, Salma

AU - Kuukasjärvi, Pekka

AU - Lenzini, Petra A.

AU - Levin, Daniel

AU - Lyytikäinen, Leo-Pekka

AU - Muehlschlegel, Jochen D.

AU - Nelson, Christopher P.

AU - Nikus, Kjell

AU - Pilbrow, Anna P.

AU - Tang, W. H. Wilson

AU - van der Laan, Sander W.

AU - van Setten, Jessica

AU - Vilmundarson, Ragnar O.

AU - Deanfield, John

AU - Deloukas, Panos

AU - Dudbridge, Frank

AU - James, Stefan

AU - Mordi, Ify R.

AU - Teren, Andrej

AU - Bergmeijer, Thomas O.

AU - Body, Simon C.

AU - Bots, Michiel

AU - Burkhardt, Ralph

AU - Cooper-DeHoff, Rhonda M.

AU - Cresci, Sharon

AU - Danchin, Nicolas

AU - Doughty, Robert N.

AU - Grobbee, Diederick E.

AU - Hagström, Emil

AU - Hazen, Stanley L.

AU - Held, Claes

AU - Hoefer, Imo E.

AU - Hovingh, G. Kees

AU - Johnson, Julie A.

AU - Kaczor, Marcin P.

AU - Kähönen, Mika

AU - Klungel, Olaf H.

AU - Laurikka, Jari O.

AU - Lehtimäki, Terho

AU - Maitland-van der Zee, Anke H.

AU - McPherson, Ruth

AU - Palmer, Colin N.

AU - Kraaijeveld, Adriaan O.

AU - Pepine, Carl J.

AU - Sanak, Marek

AU - Sattar, Naveed

AU - Scholz, Markus

AU - Simon, Tabassome

AU - Spertus, John A.

AU - Stewart, Alexandre F. R.

AU - Szczeklik, Wojciech

AU - Thiery, Joachim

AU - Visseren, Frank L. J.

AU - Waltenberger, Johannes

AU - Richards, A. Mark

AU - Lang, Chim C.

AU - Cameron, Vicky A.

AU - Åkerblom, Axel

AU - Pare, Guillaume

AU - März, Winfried

AU - Samani, Nilesh J.

AU - Hingorani, Aroon D.

AU - Ten Berg, Jurriën M.

AU - Wallentin, Lars

AU - Asselbergs, Folkert W.

AU - Patel, Riyaz

N1 - Funding Information: VT, FS, RM, KD, and MH helped develop the analysis scripts, curate and manage the data at the coordinating sites. BKM performed the meta-analysis of the collected estimates and drafted the article. RSP and FWA coordinated analyses and development of the GENIUS-CHD Consortium. All authors took part in the interpretation of the data, and all authors provided critical revisions of the article for important intellectual content. The GENIUS-CHD collaborators would like to express their immense gratitude to all patients who participated in each of the individual studies as well as the many personnel who helped with recruitment, collection, curation, management, and processing of the samples and data. Sponsors of the individual studies are listed here and study acronyms are listed in the supplemental material: The Cleveland Clinic Genebank Study was supported in part by NIH grants R0133169, R01ES021801, R01MD010358, and R01ES025786, R01HL103866, R01DK106000, R01HL126827, P20HL113452.P01HL098055, P01HL076491, and R01HL103931. The LURIC study was supported by the 7th Framework Program (AtheroRemo, grant agreement number 201668 and Risky-CAD, grant agreement number 305739) of the European Union. INVEST-GENES was supported by the National Institute of Health Pharmacogenomics Research Network grant U01-GM074492, NIH R01 HL074730, University of Florida Opportunity Fund, BASF Pharma and Abbott Laboratories. FAST-MI (French Registry of Acute ST-Elevation or non-ST-elevation Myocardial Infarction) 2005 is a registry of the French Society of Cardiology, supported by unrestricted grants from Pfizer and Servier. Additional support was obtained from a research grant from the French Caisse Nationale d’Assurance Maladie. The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. FINCAVAS (Finnish Cardiovascular Study) has been financially supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, the Tampere Tuberculosis Foundation, EU Horizon 2020 (grant 755320 for TAXINOMISIS), and the Academy of Finland grant 322098. CABGenomics was supported by Stanton Shernan, C. David Collard, Amanda A. Fox/R01 HL 098601 NHLBI. The CDCS and PMI studies were funded by the Health Research Council and Heart Foundation of New Zealand. The TRIUMPH study was sponsored by the National Institutes of Health: Washington University School of Medicine SCCOR Grant P50 HL077113. The KRAKOW GENIUS Study was supported by a grant from the Polish Ministry of Science and Higher Education, no. NN402083939 and the National Science Center, no. 2013/09/B/ NZ5/00770. The ANGES has been financially supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, the Tampere Tuberculosis Foundation, EU Horizon 2020 (grant 755320 for TAXINOMISIS), and the Academy of Finland grant 322098. The UCP studies were funded by the Netherlands Heart Foundation and the Dutch Top Institute Pharma Mondriaan Project. LIFE-Heart was funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund and by funds of the Free State of Saxony within the framework of the excellence initiative. OHGS was funded in part by a Heart and Stroke Foundation grant. Funding Information: The funder(s) of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Funding and sponsors of all participating investigators not linked to this analysis are listed in the disclosures section and funding for the individual studies is acknowledged in the acknowledgments section. Dr Mahmoodi received a VENI grant from the Dutch Research Council for investigating the role of factor V Leiden in the pathogenesis of myocardial infarction. Dr Patel is funded by a British Heart Foundation Intermediate Fellowship (FS/14/76/30933). The GENIUS-CHD project was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Center. Funding Information: Dr Holmes has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of The Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. He works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Center. Dr Schmidt is funded by BHF grant PG/18/5033837. Dr Allayee was supported, in part, by NIH grants R01HL133169 and R01HL148110. Dr Eriksson reports Institutional research grants from AstraZeneca and GlaxoS-mithKline. Dr Nelson is funded by the British Heart Foundation. Dr Vilmundarson is supported by a graduate fellowship of the University of Ottawa Heart Institute. Dr James has received grants from AstraZeneca, The Medicines Company, Swedish heart and lung foundation, Swedish research council, Janssen; personal fees from Bayer. Dr Mordi is supported by an NHS Education of Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship (PCL 17/07). Dr Cresci is supported, in part, by the National Institutes of Health (Cresci R01 NR013396). Dr Hagstrom declares being an expert committee member, lecture fees, and institutional research grant from Sanofi, and Amgen; institutional research grants from AstraZeneca, and GlaxoSmithKline; expert committee member and lecture fees NovoNordisk and Behringer. Dr Held declares institutional research grant, advisory board member and speaker’s bureau from AstraZeneca; institutional research grants from Bristol-Myers Squibb Merck and Co, GlaxoSmithKline, Roche Diagnostics. Advisory board for Bayer and Boehringer Ingelheim. Dr Palmer has received grant funding from the Wellcome Trust to develop the GoDARTS cohort. Dr Akerblom has received institutional research grant and speakers fee from AstraZeneca, institutional research grant from Roche Diagnostics. Prof. Samani is funded by the British Heart Foundation and is a NIHR Senior Investigator. Dr ten Berg reports receiving fees for board membership from AstraZeneca,consulting fees from AstraZeneca, Eli Lilly, and Merck, and lecture fees from Daiichi San-kyo and Eli Lilly, AstraZeneca, Sanofi and Accumetrics. Prof Wallentin reports institutional research grants, consultancy fees, lecture fees, and travel support from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, Boehringer In-gelheim; institutional research grants from Merck and Co, Roche Diagnostics; consultancy fees from Abbott; and holds a patent EP2047275B1 licensed to Roche Diagnostics, and a patent US8951742B2 licensed to Roche Diagnostics. Prof Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. The other authors report no conflicts. Publisher Copyright: © 2020 Lippincott Williams and Wilkins. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/8/11

Y1 - 2020/8/11

N2 - 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.

AB - 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.

KW - coronary artery disease

KW - genetic association studies

KW - myocardial infarction

KW - prognosis

KW - secondary prevention

KW - single nucleotide polymorphism

KW - thrombosis

UR - http://www.scopus.com/inward/record.url?scp=85089358992&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.119.045526

DO - 10.1161/CIRCULATIONAHA.119.045526

M3 - Article

C2 - 32654539

SN - 0009-7322

VL - 142

SP - 546

EP - 555

JO - Circulation

JF - Circulation

IS - 6

ER -

Association of Factor V Leiden with Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

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