title: Plasma homocysteine and the risk of venous thromboembolism: insights from the FIELD study.
abstract: BACKGROUND
  The lipid-lowering effect of fenofibrate is accompanied by a rise in plasma homocysteine (HCY), a potential risk factor for venous thromboembolism (VTE).This study investigated the relationship between HCY and the risk of VTE in patients treated with fenofibrate.
  
  
  METHODS
  The relationship between HCY and deep-vein thrombosis or pulmonary embolism was investigated in 9522 participants of the 5-year Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All subjects received fenofibrate during a 6-week active run-in phase before randomization.A Cox proportional-hazards model was used to assess the effect of HCY on risk of venous thromboembolic events.
  
  
  RESULTS
  During active-drug run-in, HCY rose on average by 6.5 μ mol/L, accompanied by a substantial rise in plasma creatinine ( + 12 % ). Fenofibrate-induced changes in HCY and creatinine were fully reversible in the placebo group but persisted in the treatment group until reversing at the end of therapy. During follow-up, 1.8 % had at least one episode of deep-vein thrombosis or pulmonary embolism: 103 on fenofibrate and 68 on placebo (log-rank p = 0.006). In multivariate analysis, every 5 μ mol/L higher baseline HCY was associated with 19 % higher risk of VTE. Fenofibrate treatment was associated with 52 % higher risk, but the change in HCY with fenofibrate was not significantly associated with VTE after adjustment for baseline HCY.
  
  
  CONCLUSIONS
  Hyperhomocysteinemia is prospectively associated with VTE. Fenofibrate may predispose individuals with high pretreatment HCY towards VTE. The fenofibrate induced increase in HCY did not, however, explain the risk associated with fenofibrate therapy.
authors.affiliation: Department of Clinical Biochemistry , Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Markus
authors.initials: M
authors.lastname: Herrmann
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Whiting
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Veillard
authors.forename: Christian
authors.initials: C
authors.lastname: Ehnholm
authors.forename: David R
authors.initials: DR
authors.lastname: Sullivan
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Keech
mesh_terms: D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D011345:Fenofibrate / Q000009:adverse effects*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects*; D008297:Male; D010919:Placebos; D016016:Proportional Hazards Models; D054556:Venous Thromboembolism / Q000097:blood / Q000453:epidemiology*
chemical_list: D015415:Biomarkers; D000960:Hypolipidemic Agents; D010919:Placebos; D006710:Homocysteine; D011345:Fenofibrate