Novel Anticoagulants for Stroke Prevention in AF and CKD
Novel Anticoagulants for Stroke Prevention in AF and CKD
Atrial fibrillation (AF) is about three-times more prevalent in patients with chronic kidney disease and the prevalence of AF increases with the degree of renal impairment. Clinical studies have shown increased risk of stroke, bleeding and death in patients with chronic kidney disease and AF. Despite, this increased risk, anticoagulation is underutilized due to increased bleeding risk in this population. Recently direct thrombin inhibitors and factor Xa inhibitors have been shown to be more efficacious in stroke prevention with reduced bleeding than warfarin. As the usage of these novel anticoagulants increases it is important to understand the data available in regard to these high risk patients.
Atrial fibrillation (AF) is the most common dysrhythmias seen in clinical practice. AF is associated with other common vascular comorbidites which are also risk factors for chronic kidney disease (CKD). According to one study one in five patients with CKD had AF. AF is about three-times more prevalent in patients with CKD and the prevalence of AF increases with the degree of renal impairment. According to the United States Renal Data System (USRDS) the incidence of stroke was 15.1% in hemodialysis (HD) patients' versus 9.6% in CKD without HD versus 2.6% in patients without chronic renal impairment. Data from the USRDS has demonstrated that patients with CKD and AF had a 1.6-fold higher rate of stroke than those without AF. However, the type of dialysis (HD vs peritoneal dialysis) did not alter stroke risk in this subgroup. There was no reported difference in the rates of stroke between patients on HD or peritoneal dialysis. Several clinical trials have demonstrated that anticoagulation with either warfarin or one of the novel agents is highly efficacious for stroke prevention in AF when compared to aspirin. However, the current practice guidelines in managing antithrombotics in AF with CKD are not well defined. CKD patients are at increased risk of both gastrointestinal and intracranial bleeding due to platelet dysfunction from uremic toxins and coagulopathy from poor drug clearance. Studies have also demonstrated increased mortality in CKD patients with AF (5 vs 2%) in those without it. There are reports demonstrating the increase in 2-year mortality following a stroke or transient ischemic attack (TIA) in this patient population. Three new oral anticoagulants (dabigatran, rivaroxaban and apixaban) have been recently approved across the world for stroke prevention in AF. Despite their efficacy; their usage in CKD patients is not well defined. As the usage of these novel anticoagulants increases it is important to understand the data available in regard to CKD patients.
Anticoagulation for stroke prevention in AF has traditionally been performed by vitamin K antagonists (VKA) like warfarin. Though VKA are highly effective treatment option in reducing the risk of stroke, their use is limited by their narrow therapeutic range, drug and food interactions, need for close monitoring and high risk of severe bleeding. The risk of bleeding is even higher in patients with renal impairment. There have been some recent trials showing the efficacy of newer anticoagulants like direct thrombin inhibitors and factor Xa inhibitors in treatment of AF comparable or superior to warfarin with less risk of bleeding.
In the RE-LY trial, dagibatran (110 mg twice daily (b.i.d.) and 150 mg b.i.d.) was compared against warfain in blinded fashion in 18,113 patients who had AF for a mean duration of 2 years. RE-LY excluded patients with creatinine clearance (CrCl) <30 ml/min. The study consisted of 3505 subjects with moderate CKD (CrCl of 30–49 ml/min). The rate of stroke or systemic embolism was higher in warfarin (2.8%/year) versus dabigatran 150 mg (1.5%/year) versus 110 mg (2.2%/year); p < 0.01. Bleeding risk was about the same in all three groups (dabigatran 150 mg 5.44%/year vs dabigatran 110 mg 5.29%/year vs warfarin 5.41%/year) among the subgroup with moderate-severe kidney function (CrCl of 30–49 ml/min).
In the ROCKET-AF trial, rivaroxaban (20 mg daily and 15 mg daily in CKD) was compared against warfarin in a double blind fashion in 14,264 patients with AF. Like RE-LY, patients with CrCl <30 ml/min were excluded from the trial and 15 mg daily in patients with CrCl between 30–49 ml/min. The study consisted of 2950 subjects with a moderate CKD (CrCl of 30–49 ml/min). The rate of stroke or system embolism was higher in warfarin (2.77/100 patient years) vs rivaroxaban 15 mg (2.32/100 patient years; hazard ratio [HR]: 0.84; 95% CI: 0.57–1.23). Fatal bleeding was significantly higher in warfarin (0.74%/100 patient years) versus rivaroxaban (0.28%/100 patient years; p = 0.047) with no difference in intracranial bleeding between both the groups (0.71 vs 0.88/100 patient years; p = 0.54).
Apixaban was tested in the AVEROSS and ARISTOTLE trials. In the AVEROSS trial, apixaban (5 mg b.i.d. and 2.5 mg b.i.d. in CKD) was compared against aspirin. The study consisted of 1697 subjects with moderate CKD (CrCl of 30–49 ml/min). The rate of stroke or systemic embolism was higher in aspirin (5.6%/year) vs apixaban (1.8%/year; HR: 0.32; 95% CI: 0.18–0.55, p < 0.001). Bleeding risk was about the same in both groups (apixaban 2.5%/year vs aspirin 2.2%/year; HR: 1.2; 95% CI: 0.65–2.1) among those with moderate–severe renal impairment. The AVEROSS also included about 70 patients with CrCl between 15–29 ml/min but no results have been published.
In the ARISTOTLE trial, apixaban (5 mg daily and 2.5 mg daily in CKD) was compared against warfarin in a double blind fashion in 18,201 patients with AF. The study consisted of 3017 subjects with moderate-severe CKD (CrCl of 25–50 ml/min). The rate of stroke or systemic embolism was not higher in warfarin (2.7%/year) vs apixaban (2.1%/year; p = 0.72). Bleeding risk was significantly higher in warfarin compared to apixaban (apixaban 3.2%/year vs aspirin 6.4%/year; p = 0.03) among those with moderate–severe renal impairment. The ARISTOTLE trial included about 270 subjects with CrCl 15–29 ml/min but no results have been published.
Abstract and Introduction
Abstract
Atrial fibrillation (AF) is about three-times more prevalent in patients with chronic kidney disease and the prevalence of AF increases with the degree of renal impairment. Clinical studies have shown increased risk of stroke, bleeding and death in patients with chronic kidney disease and AF. Despite, this increased risk, anticoagulation is underutilized due to increased bleeding risk in this population. Recently direct thrombin inhibitors and factor Xa inhibitors have been shown to be more efficacious in stroke prevention with reduced bleeding than warfarin. As the usage of these novel anticoagulants increases it is important to understand the data available in regard to these high risk patients.
Introduction
Atrial fibrillation (AF) is the most common dysrhythmias seen in clinical practice. AF is associated with other common vascular comorbidites which are also risk factors for chronic kidney disease (CKD). According to one study one in five patients with CKD had AF. AF is about three-times more prevalent in patients with CKD and the prevalence of AF increases with the degree of renal impairment. According to the United States Renal Data System (USRDS) the incidence of stroke was 15.1% in hemodialysis (HD) patients' versus 9.6% in CKD without HD versus 2.6% in patients without chronic renal impairment. Data from the USRDS has demonstrated that patients with CKD and AF had a 1.6-fold higher rate of stroke than those without AF. However, the type of dialysis (HD vs peritoneal dialysis) did not alter stroke risk in this subgroup. There was no reported difference in the rates of stroke between patients on HD or peritoneal dialysis. Several clinical trials have demonstrated that anticoagulation with either warfarin or one of the novel agents is highly efficacious for stroke prevention in AF when compared to aspirin. However, the current practice guidelines in managing antithrombotics in AF with CKD are not well defined. CKD patients are at increased risk of both gastrointestinal and intracranial bleeding due to platelet dysfunction from uremic toxins and coagulopathy from poor drug clearance. Studies have also demonstrated increased mortality in CKD patients with AF (5 vs 2%) in those without it. There are reports demonstrating the increase in 2-year mortality following a stroke or transient ischemic attack (TIA) in this patient population. Three new oral anticoagulants (dabigatran, rivaroxaban and apixaban) have been recently approved across the world for stroke prevention in AF. Despite their efficacy; their usage in CKD patients is not well defined. As the usage of these novel anticoagulants increases it is important to understand the data available in regard to CKD patients.
Anticoagulation for stroke prevention in AF has traditionally been performed by vitamin K antagonists (VKA) like warfarin. Though VKA are highly effective treatment option in reducing the risk of stroke, their use is limited by their narrow therapeutic range, drug and food interactions, need for close monitoring and high risk of severe bleeding. The risk of bleeding is even higher in patients with renal impairment. There have been some recent trials showing the efficacy of newer anticoagulants like direct thrombin inhibitors and factor Xa inhibitors in treatment of AF comparable or superior to warfarin with less risk of bleeding.
In the RE-LY trial, dagibatran (110 mg twice daily (b.i.d.) and 150 mg b.i.d.) was compared against warfain in blinded fashion in 18,113 patients who had AF for a mean duration of 2 years. RE-LY excluded patients with creatinine clearance (CrCl) <30 ml/min. The study consisted of 3505 subjects with moderate CKD (CrCl of 30–49 ml/min). The rate of stroke or systemic embolism was higher in warfarin (2.8%/year) versus dabigatran 150 mg (1.5%/year) versus 110 mg (2.2%/year); p < 0.01. Bleeding risk was about the same in all three groups (dabigatran 150 mg 5.44%/year vs dabigatran 110 mg 5.29%/year vs warfarin 5.41%/year) among the subgroup with moderate-severe kidney function (CrCl of 30–49 ml/min).
In the ROCKET-AF trial, rivaroxaban (20 mg daily and 15 mg daily in CKD) was compared against warfarin in a double blind fashion in 14,264 patients with AF. Like RE-LY, patients with CrCl <30 ml/min were excluded from the trial and 15 mg daily in patients with CrCl between 30–49 ml/min. The study consisted of 2950 subjects with a moderate CKD (CrCl of 30–49 ml/min). The rate of stroke or system embolism was higher in warfarin (2.77/100 patient years) vs rivaroxaban 15 mg (2.32/100 patient years; hazard ratio [HR]: 0.84; 95% CI: 0.57–1.23). Fatal bleeding was significantly higher in warfarin (0.74%/100 patient years) versus rivaroxaban (0.28%/100 patient years; p = 0.047) with no difference in intracranial bleeding between both the groups (0.71 vs 0.88/100 patient years; p = 0.54).
Apixaban was tested in the AVEROSS and ARISTOTLE trials. In the AVEROSS trial, apixaban (5 mg b.i.d. and 2.5 mg b.i.d. in CKD) was compared against aspirin. The study consisted of 1697 subjects with moderate CKD (CrCl of 30–49 ml/min). The rate of stroke or systemic embolism was higher in aspirin (5.6%/year) vs apixaban (1.8%/year; HR: 0.32; 95% CI: 0.18–0.55, p < 0.001). Bleeding risk was about the same in both groups (apixaban 2.5%/year vs aspirin 2.2%/year; HR: 1.2; 95% CI: 0.65–2.1) among those with moderate–severe renal impairment. The AVEROSS also included about 70 patients with CrCl between 15–29 ml/min but no results have been published.
In the ARISTOTLE trial, apixaban (5 mg daily and 2.5 mg daily in CKD) was compared against warfarin in a double blind fashion in 18,201 patients with AF. The study consisted of 3017 subjects with moderate-severe CKD (CrCl of 25–50 ml/min). The rate of stroke or systemic embolism was not higher in warfarin (2.7%/year) vs apixaban (2.1%/year; p = 0.72). Bleeding risk was significantly higher in warfarin compared to apixaban (apixaban 3.2%/year vs aspirin 6.4%/year; p = 0.03) among those with moderate–severe renal impairment. The ARISTOTLE trial included about 270 subjects with CrCl 15–29 ml/min but no results have been published.