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 ratio (INR ≥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 eGFR experience slower anticoagulation reversal. Study Design Prospective cohort study. Setting & Participants Warfarin pharmacogenetics cohort (WPC) (1273 long-term warfarin users). Warfarin reversal cohort (WRC) (74 warfarin users admitted with INR ≥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, 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 eGFR<60 mL/min/1.73 m2. There were 137 hemorrhages in 119 patients over 1802 person-years of follow-up (incidence rate, 7.6 [95% CI, 6.4–8.9]/100 person-years). Patients with lower eGFR had higher frequency of INR ≥4 (p<0.001). Risk of hemorrhage was significantly affected by INR-eGFR interaction. At INR<4 there was no difference in hemorrhage risk by eGFR (all p-values ≥0.4). At INR ≥4, patients with eGFR 30–44 and <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 risk, respectively, versus those with eGFR≥60 mL/min/1.73 m2. In the reversal cohort, 35 (47%) had eGFR<45 mL/min/1.73 m2. Patients with eGFR<45 mL/min/1.73 m2experienced slower anticoagulation reversal as assessed by INR (p=0.04) and PIVKA-II level (p=0.008) than those with eGFR≥45 mL/min/1.73 m2. Limitations Limited sample size in the reversal cohort, unavailability of antibiotic usage and urine albumin data. Conclusions Patients with lower eGFR have differentially higher hemorrhage risk at INR ≥4. Moreover as INR reversal rate is slower, hemorrhage risk is prolonged.

Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

“…baseline use not reflecting use at time of the VTE), underdosing in CKD patients (because of concerns about bleeding, and alterations in non‐renal clearance), or difficulties in achieving stable International Normalized Ratios in CKD patients. Whether warfarin would be practical in the primary prevention of VTE in CKD patients would require a randomized controlled trial to determine, and the bleeding risk, which might offset any protective effect, must be taken into account . Our finding related to statin use confirms the results of prior studies , and suggests further study of statins (which do not cause bleeding) for VTE prevention in CKD patients.…”

Renal Function and the Risk of Stroke and Bleeding in Patients With Atrial Fibrillation

“…Furthermore, observational studies have led to doubts about the use of warfarin in this population. 3,4 Only few observational studies have reported eGFR in AF cohorts, and these have generally focused on either the risk of stroke associated with reduced renal function without anticoagulation 5 or the risk of bleeding associated with reduced renal function while on anticoagulation. 3 Data on the risks associated with mildly reduced renal function are sparse.…”

Influence of Kidney Transplant Status on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage

“…Platelet dysfunction and alterations in the coagulation cascade can complicate the use of anticoagulants in patients with CKD . We have previously shown that patients with CKD have slower rates of INR reversal when presenting with overanticoagulation than do patients with normal renal function . This finding has led us to hypothesize that patients with CKD have a slower rate of carboxylation of clotting factors.…”

“…Warfarin is a commonly used oral anticoagulant for treatment of clotting disorders and prevention of AF‐related stroke. Recent evidence suggests that although warfarin is metabolized in the liver, renal function significantly affects warfarin dosing and toxicity . Patients with CKD have a higher frequency of supratherapeutic international normalized ratios (INRs), and the risk of warfarin‐associated hemorrhage is increased in patients with lower eGFRs .…”