Association of Factor V Leiden With Subsequent Atherothrombotic Events

Mahmoodi, Bakhtawar K. ; Tragante, Vinicius ; Kleber, Marcus E. ; Holmes, Michael V. ; Schmidt, Amand F.

; McCubrey, Raymond O. ; Howe, Laurence J. ; Direk, Kenan ; Allayee, Hooman ; Baranova, Ekaterina V. ; Braund, Peter S. ; Delgado, Graciela E. ; Eriksson, Niclas ; Gijsberts, Crystel M. ; Gong, Yan ; Hartiala, Jaana ; Heydarpour, Mahyar ; Pasterkamp, Gerard ; Kotti, Salma ; Kuukasjärvi, Pekka ; Lenzini, Petra A. ; Levin, Daniel ; Lyytikäinen, Leo-Pekka ; Muehlschlegel, Jochen D.

; Nelson, Christopher P. ; Nikus, Kjell ; Pilbrow, Anna P. ; Tang, Wilson W. H. ; van der Laan, Sander W. ; van Setten, Jessica ; Vilmundarson, Ragnar O. ; Deanfield, John ; Deloukas, Panos

; Dudbridge, Frank ; James, Stefan ; Mordi, Ify R. ; Teren, Andrej ; Bergmeijer, Thomas O. ; Body, Simon C. ; Bots, Michiel ; Burkhardt, Ralph

; Cooper-DeHoff, Rhonda M. ; Cresci, Sharon ; Danchin, Nicolas ; Doughty, Robert N. ; Grobbee, Diederick E. ; Hagström, Emil ; Hazen, Stanley L. ; Held, Claes

; Hoefer, Imo E. ; Hovingh, G. Kees ; Johnson, Julie A. ; Kaczor, Marcin P. ; Kähönen, Mika ; Klungel, Olaf H. ; Laurikka, Jari O. ; Lehtimäki, Terho ; Maitland-van der Zee, Anke H. ; McPherson, Ruth ; Palmer, Colin N.

; Kraaijeveld, Adriaan O. ; Pepine, Carl J. ; Sanak, Marek ; Sattar, Naveed ; Scholz, Markus ; Simon, Tabassome ; Spertus, John A. ; Stewart, Alexandre F. R.

; Szczeklik, Wojciech

; Thiery, Joachim ; Visseren, Frank L. J. ; Waltenberger, Johannes ; Richards, A. Mark ; Lang, Chim C. ; Cameron, Vicky A. ; Åkerblom, Axel ; Pare, Guillaume ; März, Winfried ; Samani, Nilesh J. ; Hingorani, Aroon D. ; ten Berg, Jurriën M. ; Wallentin, Lars ; Asselbergs, Folkert W.

; Patel, Riyaz S.

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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];I-2=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.

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