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 S. Patel

doi:https://doi.org/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 S. Patel

Research output: Contribution to journal › Article › Academic › peer-review

9 Citations (Scopus)

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
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.119.045526
Publication status	Published - 11 Aug 2020

Keywords

Atherosclerosis
Clinical Trials as Topic
Coronary Disease/diagnosis
Factor V/genetics
Genetic Predisposition to Disease
Genotype
Humans
Polymorphism, Single Nucleotide
Precision Medicine
Prognosis
Risk
Thrombosis/genetics

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https://doi.org/10.1161/CIRCULATIONAHA.119.045526

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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. S. (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{9a847ec8212144ea889a0871aa318716,

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 = "Atherosclerosis, Clinical Trials as Topic, Coronary Disease/diagnosis, Factor V/genetics, Genetic Predisposition to Disease, Genotype, Humans, Polymorphism, Single Nucleotide, Precision Medicine, Prognosis, Risk, Thrombosis/genetics",

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 {Wilson Tang}, {W. H.} 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 Patel, {Riyaz S.}",

year = "2020",

month = aug,

day = "11",

doi = "https://doi.org/10.1161/CIRCULATIONAHA.119.045526",

language = "English",

volume = "142",

pages = "546--555",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins Ltd.",

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, Wilson Tang, WH, 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, RS 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 - Wilson Tang, W. H.

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 S.

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 - Atherosclerosis

KW - Clinical Trials as Topic

KW - Coronary Disease/diagnosis

KW - Factor V/genetics

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Precision Medicine

KW - Prognosis

KW - Risk

KW - Thrombosis/genetics

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

U2 - https://doi.org/10.1161/CIRCULATIONAHA.119.045526

DO - https://doi.org/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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