Topical Reviews Stroke Prevention in Patients With Atrial Fibrillation and Renal Dysfunction Scott Kaatz, DO, MSc; Charles E. Mahan, PharmD, PhC
T
he overall prevalence of atrial fibrillation (AF) is 1% of the US population. However, diagnosis of AF is increasingly common with age, and prevalence rises to ≈10% in Americans aged >80 years. As the population ages, the estimated prevalence of AF may nearly triple from 2.3 million to 5.6 million US adults by 2050, with more than half of the patients aged ≥80 years.1 The prevalence of renal dysfunction also increases with age.2 More than 10% of the US population or >20 million people aged ≥20 years have chronic kidney disease (CKD).3 The definition of CKD is glomerular filtration rate (GFR) 70 years.8 AF, older age, and CKD are independent risk factors for stroke, which indicates an intensified need for stroke prophylaxis.8–10 Warfarin use is associated with a reduction in risk for stroke or thromboembolism in patients with AF with CKD (hazard ratio, 0.76), whereas acetylsalicylic acid is associated with increased risk (hazard ratio, 1.17).10 Current national and international guidelines for the care of patients with AF recommend stroke prophylaxis.11–15 Many patients with AF and coexisting CKD do not receive adequate anticoagulation; as many as 50% of eligible patients are not receiving anticoagulant therapy.16–21 However, the benefit of warfarin and the newer anticoagulants in patients receiving dialysis is undetermined.22 CKD is associated with an increased risk of bleeding, particularly in patients with end-stage renal disease, which may increase physicians’ apprehension of prescribing an anticoagulant.10,23–25 Many anticoagulants are eliminated renally and require dosage adjustment in patients with reduced renal function. The balance between preventing thrombosis and avoiding bleeding is particularly challenging in patients with renal impairment. This review will address the pharmacokinetics of new anticoagulants approved to reduce the risk of stroke in AF, clinical research in patients with AF and renal impairment, and considerations in dosing and practical aspects of management of patients with comorbid AF and renal impairment.
Pharmacokinetics and Renal Failure In addition to increasing the associated risk of thrombosis26 and bleeding,23 CKD can alter the pharmacokinetics of antithrombotic drugs (Table 1). Warfarin excretion is not affected by CKD; however, CKD may downregulate hepatic cytochrome P450 (CYP450) metabolism, resulting in lower warfarin dosage requirements in moderate to severe CKD.27 Table 1 allows comparison of the pharmacokinetics of the 3 new oral anticoagulants (NOACs) approved in the United States, Canada, and Europe.28–32 Apixaban is a direct factor Xa inhibitor that is approved to reduce the risk of stroke in AF in the United States, Canada, and Europe. The renal clearance of apixaban is ≈25%; ≈80% of the renally excreted fraction is excreted unchanged in the urine within 24 hours after dosing in patients with normal renal function. Apixaban has no active metabolites.33,34 An exposure response model suggests that apixaban clearance is 40% lower with moderate renal impairment (creatinine clearance [CrCl], 30–50 mL/min) than with normal renal function. This reduced clearance corresponds to a 70% increase in the area under the concentration curve.35 Another direct factor Xa inhibitor, rivaroxaban, is also approved to reduce the risk of stroke in AF in the United States, Canada, and Europe. Rivaroxaban is eliminated via 3 mechanisms. One third of the administered dose is excreted unchanged in the urine and two thirds degraded to inactive metabolites, with approximately equal excretion by the renal and hepatobiliary routes. Rivaroxaban has no active metabolites.36 Renal clearance of rivaroxaban decreases with increasing renal impairment, and factor Xa inhibition increases ≤2-fold in severe renal impairment.28,37 Dabigatran, a direct thrombin inhibitor, is approved to reduce the risk of stroke in AF in >100 countries, including the United States, Canada, and many European countries. Dabigatran etexilate, the prodrug, undergoes hydrolysis by ubiquitous esterases to its active form, dabigatran.38 Dabigatran is >80% eliminated by glomerular filtration, the primary excretion pathway, without net secretion or reabsorption.39 The area under the concentration curve increases 6-fold with severe renal impairment, and the half-life approximately doubles to 28 hours in comparison to patients without renal impairment.40
Received February 13, 2014; final revision received May 13, 2014; accepted May 20, 2014. From the Hurley Medical Center, Flint, MI (S.K.); and New Mexico Heart Institute, Albuquerque, NM (C.E.M.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 114.005117/-/DC1. Correspondence to Charles E. Mahan, PharmD, PhC, Presbyterian Healthcare Services, 1100 Central Ave SE, Albuquerque NM 87106. E-mail [email protected] (Stroke. 2014;45:2497-2505.) © 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.005117
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2015 2497
2498 Stroke August 2014 Table 1. Pharmacokinetics of New Anticoagulants28–32 Factor IIa (Thrombin) Inhibitor
Factor Xa Inhibitors
Dabigatran Bioavailability, %
Rivaroxaban
6 ≤30
Onset of action, min
50
≤30
Duration of action, h
24–36
Tmax, h
1.0–2.0
Renal excretion, %
Apixaban
80
Not stated
24 36*
>50 30
≥24
≤24
3.0
1.0–2.0
2.5–4.0
80
Edoxaban
27
35–39
Elimination half-life (h) by degree of renal dysfunction Normal (CrCl >80 mL/min)
13.8
8.3
7.6
NA
Mild (CrCl 50–79 mL/min)
16.6
8.7
7.3
8.6†
Moderate (CrCl 30–49 mL/min)
18.7
9.0
17.6
9.4‡
Severe (CrCl
T
he overall prevalence of atrial fibrillation (AF) is 1% of the US population. However, diagnosis of AF is increasingly common with age, and prevalence rises to ≈10% in Americans aged >80 years. As the population ages, the estimated prevalence of AF may nearly triple from 2.3 million to 5.6 million US adults by 2050, with more than half of the patients aged ≥80 years.1 The prevalence of renal dysfunction also increases with age.2 More than 10% of the US population or >20 million people aged ≥20 years have chronic kidney disease (CKD).3 The definition of CKD is glomerular filtration rate (GFR) 70 years.8 AF, older age, and CKD are independent risk factors for stroke, which indicates an intensified need for stroke prophylaxis.8–10 Warfarin use is associated with a reduction in risk for stroke or thromboembolism in patients with AF with CKD (hazard ratio, 0.76), whereas acetylsalicylic acid is associated with increased risk (hazard ratio, 1.17).10 Current national and international guidelines for the care of patients with AF recommend stroke prophylaxis.11–15 Many patients with AF and coexisting CKD do not receive adequate anticoagulation; as many as 50% of eligible patients are not receiving anticoagulant therapy.16–21 However, the benefit of warfarin and the newer anticoagulants in patients receiving dialysis is undetermined.22 CKD is associated with an increased risk of bleeding, particularly in patients with end-stage renal disease, which may increase physicians’ apprehension of prescribing an anticoagulant.10,23–25 Many anticoagulants are eliminated renally and require dosage adjustment in patients with reduced renal function. The balance between preventing thrombosis and avoiding bleeding is particularly challenging in patients with renal impairment. This review will address the pharmacokinetics of new anticoagulants approved to reduce the risk of stroke in AF, clinical research in patients with AF and renal impairment, and considerations in dosing and practical aspects of management of patients with comorbid AF and renal impairment.
Pharmacokinetics and Renal Failure In addition to increasing the associated risk of thrombosis26 and bleeding,23 CKD can alter the pharmacokinetics of antithrombotic drugs (Table 1). Warfarin excretion is not affected by CKD; however, CKD may downregulate hepatic cytochrome P450 (CYP450) metabolism, resulting in lower warfarin dosage requirements in moderate to severe CKD.27 Table 1 allows comparison of the pharmacokinetics of the 3 new oral anticoagulants (NOACs) approved in the United States, Canada, and Europe.28–32 Apixaban is a direct factor Xa inhibitor that is approved to reduce the risk of stroke in AF in the United States, Canada, and Europe. The renal clearance of apixaban is ≈25%; ≈80% of the renally excreted fraction is excreted unchanged in the urine within 24 hours after dosing in patients with normal renal function. Apixaban has no active metabolites.33,34 An exposure response model suggests that apixaban clearance is 40% lower with moderate renal impairment (creatinine clearance [CrCl], 30–50 mL/min) than with normal renal function. This reduced clearance corresponds to a 70% increase in the area under the concentration curve.35 Another direct factor Xa inhibitor, rivaroxaban, is also approved to reduce the risk of stroke in AF in the United States, Canada, and Europe. Rivaroxaban is eliminated via 3 mechanisms. One third of the administered dose is excreted unchanged in the urine and two thirds degraded to inactive metabolites, with approximately equal excretion by the renal and hepatobiliary routes. Rivaroxaban has no active metabolites.36 Renal clearance of rivaroxaban decreases with increasing renal impairment, and factor Xa inhibition increases ≤2-fold in severe renal impairment.28,37 Dabigatran, a direct thrombin inhibitor, is approved to reduce the risk of stroke in AF in >100 countries, including the United States, Canada, and many European countries. Dabigatran etexilate, the prodrug, undergoes hydrolysis by ubiquitous esterases to its active form, dabigatran.38 Dabigatran is >80% eliminated by glomerular filtration, the primary excretion pathway, without net secretion or reabsorption.39 The area under the concentration curve increases 6-fold with severe renal impairment, and the half-life approximately doubles to 28 hours in comparison to patients without renal impairment.40
Received February 13, 2014; final revision received May 13, 2014; accepted May 20, 2014. From the Hurley Medical Center, Flint, MI (S.K.); and New Mexico Heart Institute, Albuquerque, NM (C.E.M.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 114.005117/-/DC1. Correspondence to Charles E. Mahan, PharmD, PhC, Presbyterian Healthcare Services, 1100 Central Ave SE, Albuquerque NM 87106. E-mail [email protected] (Stroke. 2014;45:2497-2505.) © 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.005117
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2015 2497
2498 Stroke August 2014 Table 1. Pharmacokinetics of New Anticoagulants28–32 Factor IIa (Thrombin) Inhibitor
Factor Xa Inhibitors
Dabigatran Bioavailability, %
Rivaroxaban
6 ≤30
Onset of action, min
50
≤30
Duration of action, h
24–36
Tmax, h
1.0–2.0
Renal excretion, %
Apixaban
80
Not stated
24 36*
>50 30
≥24
≤24
3.0
1.0–2.0
2.5–4.0
80
Edoxaban
27
35–39
Elimination half-life (h) by degree of renal dysfunction Normal (CrCl >80 mL/min)
13.8
8.3
7.6
NA
Mild (CrCl 50–79 mL/min)
16.6
8.7
7.3
8.6†
Moderate (CrCl 30–49 mL/min)
18.7
9.0
17.6
9.4‡
Severe (CrCl
