title: Influence of kidney function on risk of supratherapeutic international normalized ratio-related hemorrhage in warfarin users: a prospective cohort study.
abstract: BACKGROUND
  Anticoagulation management is difficult in chronic kidney disease, with frequent supratherapeutic international normalized ratios (INRs ≥ 4) increasing hemorrhagic risk. We evaluated whether the interaction of INR and lower estimated glomerular filtration rate (eGFR) increases hemorrhage risk and whether patients with lower eGFRs experience slower anticoagulation reversal.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  Warfarin pharmacogenetics cohort (1,273 long-term warfarin users); warfarin reversal cohort (74 warfarin users admitted with INRs ≥ 4).
  
  
  METHODS
  eGFR, INR as time-dependent covariate, and their interaction in the pharmacogenetics cohort; eGFR in the reversal cohort.
  
  
  METHODS
  In the pharmacogenetics cohort, hemorrhagic (serious, life-threatening, and fatal bleeding) risk was assessed using proportional hazards regression. In the reversal cohort, anticoagulation reversal was assessed from changes in INR, warfarin and metabolite concentrations, clotting factors (II, VII, IX, and X), and PIVKA-II (protein induced by vitamin K absence or antagonist II) levels at presentation and after reversal, using linear regression and path analysis.
  
  
  RESULTS
  In the pharmacogenetics cohort, 454 (35.7%) had eGFRs < 60 mL/min/1.73 m(2). There were 137 hemorrhages in 119 patients over 1,802 person-years of follow-up (incidence rate, 7.6 [95% CI, 6.4-8.9]/100 person-years). Patients with lower eGFRs had a higher frequency of INR ≥ 4 (P<0.001). Risk of hemorrhage was affected significantly by eGFR-INR interaction. At INR<4, there was no difference in hemorrhage risk by eGFR (all P ≥ 0.4). At INR≥4, patients with eGFRs of 30 to 44 and < 30 mL/min/1.73 m(2) had 2.2-fold (95% CI, 0.8-6.1; P=0.1) and 5.8-fold (95% CI, 2.9-11.4; P<0.001) higher hemorrhage risks, respectively, versus those with eGFRs ≥ 60 mL/min/1.73 m(2). In the reversal cohort, 35 (47%) had eGFRs < 45 mL/min/1.73 m(2). Patients with eGFRs < 45 mL/min/1.73 m(2) experienced slower anticoagulation reversal as assessed by INR (P=0.04) and PIVKA-II level (P=0.008) than those with eGFRs ≥ 45 mL/min/1.73 m(2).
  
  
  CONCLUSIONS
  Limited sample size in the reversal cohort, unavailability of antibiotic use and urine albumin data.
  
  
  CONCLUSIONS
  Patients with lower eGFRs have differentially higher hemorrhage risk at INR ≥ 4. Moreover, because the INR reversal rate is slower, hemorrhage risk is prolonged.
authors.affiliation: Neurology, University of Alabama at Birmingham, Birmingham, AL. Electronic address: nlimdi@uab.edu.
authors.forename: Nita A
authors.initials: NA
authors.lastname: Limdi
authors.affiliation: Pharmacy and Therapeutics, Jean Mayer USDA Human Nutrition Research Center on Aging, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Nolin
authors.affiliation: Vitamin K Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Booth
authors.affiliation: Vitamin K Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Centi
authors.affiliation: Pathology, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Marisa B
authors.initials: MB
authors.lastname: Marques
authors.affiliation: Genetics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Crowley
authors.affiliation: Division of Nephrology, Medicine, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Michael
authors.initials: M
authors.lastname: Allon
authors.affiliation: Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: T Mark
authors.initials: TM
authors.lastname: Beasley
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D005260:Female; D005919:Glomerular Filtration Rate; D006470:Hemorrhage / Q000139:chemically induced* / Q000503:physiopathology*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: Kidney function; adverse event; chronic kidney disease (CKD); hemorrhage; pharmacokinetics; reversal of anticoagulation; supra-therapeutic international normalized ratio (INR); warfarin