Association of Factor V Leiden With Subsequent Atherothrombotic Events
Authors: 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. , Wilson Tang 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. 
Published: July 2020

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.