Impact of serum albumin levels on supratherapeutic PT-INR control and bleeding risk in atrial fibrillation patients on warfarin: A prospective cohort study

Abstract

BackgroundSince warfarin is primarily bound to serum albumin, hypoalbuminemia is likely to increase the free fraction of warfarin and to increase the risk of bleeding. We prospectively evaluated the impact of serum albumin levels (ALB) on international normalized ratio of prothrombin time (PT-INR) control and hemorrhagic events in atrial fibrillation (AF) patients treated with warfarin.MethodsSeven hundred fifty-five non-valvular AF patients on warfarin were enrolled. PT-INR control and major bleeding events (MB, International Society on Thrombosis and Haemostasis) were prospectively followed and were related to ALB at enrollment.ResultsTwenty-seven patients developed MB during 1-year follow-up. In univariate/multivariate analyses, ALB (OR = 0.49, 95% CI 0.26–0.99, p = 0.04) and hemoglobin levels (OR = 0.78, 95% CI 0.65–0.92, p = < 0.01) were predictive for the annual risk of MB. In Spearman's rank correlation analysis, the baseline ALB was inversely correlated with the percentage of the time in PT-INR > 3.0 (ρ = −0.15, p < 0.0001), but neither 2.0 ≤ PT-INR ≤ 3.0 (ρ = 0.056, p = 0.13) nor PT-INR < 2.0 (ρ = −0.008, p = 0.82) during 1-year follow-up, suggesting that patients with low ALB had a directional tendency to be supratherapeutic control of PT-INR. The ROC curve showed that a cutoff of ALB was 3.6 g/dl to identify MB (AUC = 0.65). In Kaplan-Meier analysis, patients with ALB <3.6 g/dl (23/80, 29%) had more MB than those with ALB ≥3.6 g/dl (87/675, 13%, log-rank = 16.80, p < 0.0001) during long-term follow-up (3.8 ± 2.0 years).ConclusionsHypoalbuminemia increases the likelihood of supratherapeutic PT-INR control and the risk of MB. ALB can be a practical surrogate marker to prevent excessive warfarin control and warfarin-related MB.

Bound to bleed: How altered albumin binding may dictate warfarin treatment outcome

“…In this issue of the International Journal of Cardiology Heart & Vasculature , human serum albumin (HSA) is highlighted as a culprit modifier of warfarin kinetics [3]. Low HSA levels are shown to predict major bleeding in AF patients anticoagulated with warfarin.…”

“…Kawai and colleagues [3] show reduced HSA correlates inversely with time in INR > 3.0, and predicts the annual risk of major bleeds, with a cut-off value of 3.6 g/dl. Based on this, the authors suggest that close monitoring for hypoalbuminemia may help to prevent excessive warfarin levels and hence adverse bleeding.…”

Severe undernutrition increases bleeding risk on vitamin-K antagonists

“…Warfarin, a specific VKA, is primarily bound to serum albumin, meaning that hypoalbuminemia is likely to increase the free fraction of warfarin, thereby increasing the risk of major bleeding. [36] In patients under 75 years old, hypoalbuminemia was a significant predictor of all bleeding events (minor and major). [37] Hypoalbuminemia is similarly associated with age-related frailty and could thus reflect underlying conditions and diseases that in their turn facilitate bleeding.…”

Anticoagulation in difficult settings RELOADed: Evidence for applicability of direct oral anticoagulants in patients with atrial fibrillation, renal impairment and cancer

“…Kidney dysfunction per se increases the dual risk of thromboembolism and bleeding, and impacts detrimentally on DOAC pharmacokinetics, which are renally cleared to different extents [9]. Although the clearance of coumarins is not directly dependent on renal function, warfarin is subject to a multitude of drug interactions, which occur in part through its high degree of serum albumin binding [10,11] and which are more likely to occur with the polypharmacy that is common practice in patients with kidney disease. Accordingly, kidney disease remains a difficult scenario for anticoagulant management of patients with AF [7].…”

“…Further prospective evidence on how different approaches actually fare in the real-world setting are therefore invaluable to guide not only the individual clinician's decision-making but also to guide evolution. The new data provided by Bonnemeier et al [10] may help to manage AF patients with renal impairment and concomitant cancer.…”