Net Benefit of Antithrombotic Therapy in AF and CKD
Net Benefit of Antithrombotic Therapy in AF and CKD
Background The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial.
Objectives This study assessed the risk associated with CKD in individual CHA2DS2-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort.
Methods By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death.
Results From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA2DS2-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA2DS2-VASc score = 0 to a 1.6-fold higher risk in patients with CHA2DS2-VASc score ≥2. In patients receiving RRT with CHA2DS2-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA2DS2-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69).
Conclusions CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA2DS2-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention.
The optimal management of thromboprophylaxis in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is complex. Whereas CKD patients are at high risk of stroke and thromboembolism (TE), these patients are also at high risk of death and major bleeding. This is particularly true of patients with end-stage CKD treated with renal replacement therapy (RRT), whether as dialysis or renal transplantation. Thromboprophylaxis in this high-risk group is therefore complex, and clinical decision making requires interpretation of the balance between the risks of these important endpoints in individual patients.
The published evidence for oral anticoagulation in patients with AF shows that the use of adjusted dose warfarin, compared with placebo, results in a 64% reduction in stroke and, compared with placebo or aspirin, a 26% reduction in all-cause mortality. However, patients with a creatinine clearance of <30 ml/min have been excluded from clinical trials. Thus, antithrombotic treatment in patients with CKD stages 4 to 5 and AF has hitherto been on the basis of a number of small observational studies and a few registry-based cohorts.
We have previously shown that in AF patients with CKD, warfarin treatment was associated with a decreased risk of stroke/TE, as well as an increased risk of bleeding. The present study investigated the net clinical benefit of antithrombotic therapy in patients with both AF and CKD (e.g., balancing efficacy and safety of the treatment). During recent years, there has been growing attention to the question whether CKD should be included in stroke risk stratification models, and validation of stroke stratification models should ideally be performed in non-anti-coagulated real-world cohorts. For this reason, the risk of stroke/TE associated with CKD was determined in patients not receiving warfarin, and the net clinical benefit of warfarin was determined in individual stroke risk strata, as determined by the CHA2DS2-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) score. First, we hypothesized that CKD would be independently associated with a higher risk of stroke/TE in all stroke risk strata of non-anti-coagulated patients with AF. Second, we tested the hypothesis that the benefits of warfarin would outweigh its risks in AF patients with CKD and a high risk of stroke/TE.
Abstract and Introduction
Abstract
Background The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial.
Objectives This study assessed the risk associated with CKD in individual CHA2DS2-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort.
Methods By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death.
Results From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA2DS2-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA2DS2-VASc score = 0 to a 1.6-fold higher risk in patients with CHA2DS2-VASc score ≥2. In patients receiving RRT with CHA2DS2-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA2DS2-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69).
Conclusions CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA2DS2-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention.
Introduction
The optimal management of thromboprophylaxis in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is complex. Whereas CKD patients are at high risk of stroke and thromboembolism (TE), these patients are also at high risk of death and major bleeding. This is particularly true of patients with end-stage CKD treated with renal replacement therapy (RRT), whether as dialysis or renal transplantation. Thromboprophylaxis in this high-risk group is therefore complex, and clinical decision making requires interpretation of the balance between the risks of these important endpoints in individual patients.
The published evidence for oral anticoagulation in patients with AF shows that the use of adjusted dose warfarin, compared with placebo, results in a 64% reduction in stroke and, compared with placebo or aspirin, a 26% reduction in all-cause mortality. However, patients with a creatinine clearance of <30 ml/min have been excluded from clinical trials. Thus, antithrombotic treatment in patients with CKD stages 4 to 5 and AF has hitherto been on the basis of a number of small observational studies and a few registry-based cohorts.
We have previously shown that in AF patients with CKD, warfarin treatment was associated with a decreased risk of stroke/TE, as well as an increased risk of bleeding. The present study investigated the net clinical benefit of antithrombotic therapy in patients with both AF and CKD (e.g., balancing efficacy and safety of the treatment). During recent years, there has been growing attention to the question whether CKD should be included in stroke risk stratification models, and validation of stroke stratification models should ideally be performed in non-anti-coagulated real-world cohorts. For this reason, the risk of stroke/TE associated with CKD was determined in patients not receiving warfarin, and the net clinical benefit of warfarin was determined in individual stroke risk strata, as determined by the CHA2DS2-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) score. First, we hypothesized that CKD would be independently associated with a higher risk of stroke/TE in all stroke risk strata of non-anti-coagulated patients with AF. Second, we tested the hypothesis that the benefits of warfarin would outweigh its risks in AF patients with CKD and a high risk of stroke/TE.
