title: The impact of warfarin on the rate of progression of aortic stiffness in hemodialysis patients: a longitudinal study.
abstract: BACKGROUND
  Accelerated progression of aortic stiffness in patients with advanced chronic kidney disease is not well explained by the traditional cardiovascular risk factors. We hypothesized that vitamin K deficiency may result in an accelerated progression of aortic stiffness in the pro-calcifying uremic milieu.
  
  
  METHODS
  Eighteen hemodialysis (HD) patients on warfarin were matched to 54 HD patients without warfarin (control). Aortic stiffness was determined by carotid-femoral pulse wave velocity (cf-PWV) at baseline and after a mean follow-up of 1.2 years. In the control group, spontaneous vitamin K deficiency was defined as proteins induced by vitamin K deficiency/absence-II >median.
  
  
  RESULTS
  At baseline, clinical characteristics and cf-PWV were similar. Adjusted cf-PWV increased by 0.86 ± 1.87 m/s in control and by 2.24 ± 2.68 m/s in warfarin group (P = 0.024). After adjustments for confounders, warfarin therapy was independently associated with progression of aortic stiffness (P = 0.016). The rate of progression of aortic stiffness showed a linear trend in response to vitamin K status and warfarin therapy, suggesting that at least part of the effects are mediated through reduced availability of vitamin K. The unadjusted and adjusted hazard ratio (HR) of warfarin therapy on mortality were, respectively, 2.40 (P = 0.006) and 2.53 (P = 0.006). In a forward conditional Cox regression analysis, age, albumin, augmentation index (AIx) and a cf-PWV > 13.8 m/s at the time of follow-up (HR: 2.11, P = 0.05) were independent determinants of mortality, whereas warfarin use was not retained as an independent factor. Finally, control patients with poor vitamin K status had an intermediate survival as compared with controls with better vitamin K status and patients with warfarin (P = 0.01).
  
  
  CONCLUSIONS
  This is the first study to show a temporal association between warfarin, functional vitamin K deficiency and progression of aortic stiffness in HD patients. These findings suggest that the net cardiovascular benefit of long-term warfarin therapy may need to be reevaluated in this population.
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Mac-Way
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Poulin
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Mihai Silviu
authors.initials: MS
authors.lastname: Utescu
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Sacha A
authors.initials: SA
authors.lastname: De Serres
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Marquis
authors.affiliation: Département de biologie moléculaire, de biochimie médicale et de pathologie, Faculty of Medicine, Université Laval, Québec, QC, Canada Département de biologie médicale, L'Hôtel-Dieu de Québec Hospital, CHU de Québec, Québec, QC, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Douville
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Desmeules
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Larivière
authors.affiliation: Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Marcel
authors.initials: M
authors.lastname: Lebel
authors.affiliation: CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Agharazii
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology*; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology / Q000517:prevention & control; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000150:complications / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D063177:Pulse Wave Analysis; D011792:Quebec / Q000453:epidemiology; D006435:Renal Dialysis; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D059289:Vascular Stiffness / Q000187:drug effects*; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: aortic stiffness; chronic kidney disease; mortality; vitamin K; warfarin