|Limdi, Nita - UNIVERSITY OF ALABAMA|
|Nolin, Thomas - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY|
|Booth, Sarah - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY|
|Centi, Amanda - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY|
|Marques, Marisa - UNIVERSITY OF ALABAMA|
|Crowley, Michael - UNIVERSITY OF ALABAMA|
|Allon, Michael - UNIVERSITY OF ALABAMA|
|Beasley, T Mark - UNIVERSITY OF ALABAMA|
Submitted to: American Journal of Kidney Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2014
Publication Date: 11/25/2014
Citation: Limdi, N.A., Nolin, T.D., Booth, S.L., Centi, A., Marques, M.B., Crowley, M.R., Allon, M., Beasley, T.M. 2014. Influence of kidney function on risk of supratherapeutic international normalized ratio-related hemorrhage in warfarin users: a prospective cohort study. American Journal of Kidney Diseases. 65(5):701-709. https://doi.org/10.1053/j.ajkd.2014.11.004.
Interpretive Summary: Anticoagulation management with vitamin K antagonists is difficult in patients with chronic kidney disease. When not well managed, there is an increased risk of abnormal bleeding. We evaluated whether the interaction of blood clotting time and lower kidney function increases risk of abnormal bleeding and whether patients with lower kidney function experience slower reversal of the oral anticoagulant effect. To achieve these goals, we studied 1,347 patients on long-term vitamin K blockers who were participating in one of two studies on oral anticoagulants. In one study, serious, life-threatening, and fatal bleeding risk was assessed. In the second study, anticoagulation reversal was assessed by changes in blood clotting, drug dose, clotting factors, and circulating measures of vitamin K deficiency. In the first study, there were 137 bleeding events among 119 patients. Patients with lower kidney function had greater risk of abnormal clotting times, with those in the abnormal bleeding time category having almost a 6-fold greater risk for bleeding events. Patients with low kidney function experienced slower anticoagulation reversal as assessed by clotting times and vitamin K deficiency measures. The second study was limited in the number of patients participating and in the absence of antibiotic use and urine albumin data. In conclusion, patients with lower kidney function have higher risks of bleeding events when their clotting times are prolonged. Moreover, because the blood clotting reversal rate is slower, risk of bleeding events is prolonged.
Technical 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. Study Design: Prospective cohort study. Setting & Participants: Warfarin pharmacogenetics cohort (1,273 long-term warfarin users); warfarin reversal cohort (74 warfarin users admitted with INRs >/= 4). Predictor: eGFR, INR as time-dependent covariate, and their interaction in the pharmacogenetics cohort; eGFR in the reversal cohort. Outcomes & Measurements: 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 less than 60 mL/min/1.73 m2. There were 137 hemorrhages in 119 patients over 1,802 person-years of follow-up (incidence rate less than 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 less than 30 mL/min/1.73 m2 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 m2. In the reversal cohort, 35 (47%) had eGFRs < 45 mL/min/1.73 m2. Patients with eGFRs < 45 mL/min/1.73 m2 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 m2. Limitations: 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.