Skip to main content
NCBI home page
Clinical Cardiology logoLink to Clinical Cardiology
. 2016 Oct 7;40(1):46–52. doi: 10.1002/clc.22591

Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age

Leo F Buckley 1,✉, Eva Rybak 2, Ahmed Aldemerdash 3, Judy WM Cheng 4, John Fanikos 2
PMCID: PMC6490382  PMID: 27716948

Abstract

A growing number of patients with an indication for stroke prevention in atrial fibrillation have kidney‐, age‐, or weight‐related alterations in pharmacokinetics that affect dosing of direct oral anticoagulants. Because these patients were excluded from or comprised a small number of patients in clinical trials, there is a lack of evidence to guide clinicians. As a consequence, many patients do not receive oral anticoagulation despite a high risk for atrial fibrillation–related stroke. Here, we present a review of direct oral anticoagulant pharmacokinetics and a review of the available clinical evidence in patients with weight‐, kidney‐, and age‐related disease.

Keywords: direct oral anticoagulants, stroke prevention, atrial fibrillation, chronic kidney disease, obesity, advanced age

1. Introduction

The search for an anticoagulant that maintains or improves the efficacy and safety of warfarin without the need for monitoring resulted in the development of the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban. Compared with warfarin, the DOACs have a wider therapeutic index, do not require routine laboratory monitoring, and lack dietary restrictions (see Supporting Information, Table 1, in the online version of this article).1, 2 Large randomized controlled trials of these agents have demonstrated their efficacy, safety, and ease of use for the prevention of stroke and systemic embolism (SSE) in patients with nonvalvular atrial fibrillation (AF; see Supporting Information, Figure 1, in the online version of this article).3, 4, 5, 6, 7

Table 1.

Key pharmacokinetic properties of direct oral anticoagulants in special populations 1

Population Half‐Life, h Total Body Clearance, L/h AUCss, ng*h/mL Vd, L
Dabigatran
CrCl, mL/min/m2 >80 13.8 164.4 901 3120
>50–80 16.6 124.8 1580 2570
>30–50 18.7 46 2470 1240
<30 27.5 31.7 6150 1220
Age, y <65 11.3 (M and F) 169.7 (M and F) 1116 (M and F) NR
≥65 12.1 (M), 13.4 (F) 69 (M), 58.9 (F) 1635 (M), 1920 (F)
Rivaroxaban
CrCl, mL/min/m2 ≥80 8.3 8.0 9.4 × 109 NR
50–79 8.7 5.4 14.8 × 109
30–49 9.0 4.8 15.4 × 109
<30 9.5 4.5 15.9 × 109
Age, y 18–45 11.7 (F), 6.9 (M) 8.26 (F), 6.77 (M) 8.2 × 109 (F), 11.7 × 109 (M) NR
>75 12 (F), 11.1 (M) 5.15 (F), 5.44 (M) 13.2 × 109 (F), 14.1 × 109 (M)
Weight, kg ≤50 9.6 NR 5665 2.44
70–80 7.2 7611 1.36
>120 7.3 15 230 0.69
Apixaban
Weight, kg ≤50 15.8 4.1 2424 52.7
65–85 12 4.9 2024 61
≥120 8.8 6.4 1561 75.6
Edoxaban
CrCl, mL/min/m2 >80 8.6 NR 100% NR
50–80 9.4 132%
30–50 16.9 174%
<30 NR 172%
Open in a new tab

Abbreviations: AUCss, area under the curve at steady state; CrCl, creatinine clearance; F, females; M, males; NR, not reported; Vd, volume of distribution.

1

There are no published pharmacokinetic studies of dabigatran in obesity, apixaban in renal impairment or advanced age, or edoxaban in renal impairment, obesity, or advanced age.

Figure 1.

Figure 1

Open in a new tab

US Food and Drug Administration analysis of stroke and systemic embolism in ENGAGE AF‐TIMI 48 according to renal function. Abbreviations: CrCl, creatinine clearance; ENGAGE AF‐TIMI 48, Global Study to Assess the Safety and Effectiveness of Edoxaban (DU‐176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation; HD, high dose; LD, low dose; QD, every day. Edoxaban HD = 60 mg QD (or 30 mg QD if CrCl 30–50 mL/min/m2, weight ≤60 kg, or concomitant use of verapamil or quinidine). Edoxaban LD = 30 mg QD (or 15 mg QD if CrCl 30–50 mL/min/m2, weight ≤60 kg, or concomitant use of verapamil or quinidine).

Despite the improvements in available anticoagulants, there remains considerable underuse of oral anticoagulation for stroke prevention in AF.8, 9, 10 A large part of the gap between indicated and prescribed anticoagulation may be attributed to clinician discomfort with extrapolating clinical trial results to real‐world populations. Clinical practice involves patients with renal impairment, advanced age, and obesity, who were excluded or underrepresented in clinical trials.10 Because of pharmacokinetic and pharmacodynamic differences between these subgroups and patients studied in clinical trials (see Supporting Information, Table 2, in the online version of this article), the clinical outcomes in the latter cannot be assumed for the former (see Supporting Information, Table 3, in the online version of this article). Here, we present a review of DOAC pharmacokinetics, and the clinical evidence on the safety and efficacy of DOACs with a focus on patients with renal impairment, advanced age, or obesity. We have focused on each drug individually (ie, avoided meta‐analyses) due to their markedly different profiles.

Table 2.

Summary overview of direct oral anticoagulants in special populations

Renal Impairment Extremes in Weight Advanced Age
Dabigatran Not preferred over other agents if CrCl <50 mL/min/m2; note that 75 mg BID dose approved for CrCl 15–30 mL/min/m2 but no outcomes data available Pharmacokinetic, pharmacodynamic, and clinical outcomes data are lacking Increased risk of bleeding if ≥75 years; similar anti‐ischemic benefit
Rivaroxaban Increased GI bleeding if CrCl <50 mL/min/m2; dose of 15 mg once daily approved for ESRD on hemodialysis but clinical outcomes not evaluated Reduced exposure in obesity, but clinical outcomes data lacking Lower risk of ICH in patients age <75 years but not >75 years
Apixaban Preferred option in renal impairment; note that dosing is based on age, weight, and serum Cr, not CrCl; dose of 5 mg twice daily approved for ESRD on hemodialysis but clinical outcomes not evaluated Reduced exposure in obesity, but clinical outcomes data lacking Appears to have similar efficacy and safety regardless of age
Edoxaban Efficacy appears greatest in lower GFR categories; not indicated for CrCl >95 mL/min/m2 or <15 mL/min/m2 Pharmacokinetic, pharmacodynamic, and clinical outcomes data are lacking Appears to have similar efficacy and safety regardless of age
Open in a new tab

Abbreviations: Cr, creatinine; CrCl, creatinine clearance; ESRD, end‐stage renal disease; GFR, glomerular filtration rate; GI, gastrointestinal; ICH, intracranial hemorrhage.

2. Pharmacokinetics of DOACs

2.1. Dabigatran

Dabigatran etexilate is an orally available prodrug that is hydrolyzed by gut and liver esterases to dabigatran, a direct inhibitor of free and clot‐bound thrombin.11 Dabigatran is eliminated primarily (80%) via renal filtration.12 Accordingly, dabigatran clearance is exquisitely sensitive to renal function. Renal impairment increases dabigatran's half‐life, slows its clearance, and increases total dabigatran exposure (Table 1).12

Age also affects dabigatran pharmacokinetics, albeit to a lesser degree than renal function. In patients age ≥65 years with normal renal function, the half‐life of dabigatran is increased by approximately 1 hour (13.8 hours for age >65 years vs 12.9 hours for age <65 years) and clearance reduced by 4 L/h, compared with younger patients (66 L/h for age >65 years vs 70–140 L/h for age <65 years).13 Total drug exposure is greater in elderly patients than in younger patients (1116 ng*h/mL for age <65 years compared with 1635 ng*h/mL for males age ≥65 years and 1920 ng*h/mL for females age ≥65 years).12

Based on pharmacokinetic modeling, the US Food and Drug Administration (FDA) approved the use of a 75‐mg dabigatran dose for stroke prevention in AF patients with creatinine clearance (CrCl) of 15 to 30 mL/min/m2.14 This dose has not been tested in a clinical trial, although a small pharmacokinetic study did not find evidence of significant accumulation with this dose in patients with CrCl of 15 to 30 mL/min/m2.14

2.2. Rivaroxaban

Rivaroxaban is an oral, direct inhibitor of activated factor X.15 Approximately two‐thirds of a rivaroxaban dose is hepatically metabolized to inactive metabolites prior to elimination through renal and hepatobiliary means. The kidney is responsible for the excretion of the remaining parent drug. Compared with dabigatran, rivaroxaban clearance is less reliant on renal function. Renal impairment slightly prolongs the half‐life of rivaroxaban (8.3 hours for CrCl ≥80 mL/min/m2 compared with 9.5 hours for CrCl <30 mL/min/m2) and increases total rivaroxaban exposure.16, 17 Rivaroxaban exposure as defined by area under the curve (AUC), peak concentration, and half‐life was measured in 18 maintenance hemodialysis patients.18 Based on nonhemodialysis patients from other studies, the authors noted that rivaroxaban exposure appears similar between hemodialysis and nonhemodialysis patients.

In patients age ≥75 years, the half‐life of rivaroxaban is increased (11.7 hours vs 12 hours for younger vs. older females; 6.9 hours vs 11.1 hours for younger vs. older males) and total body clearance is slower (8.26 L/h vs 5.15 L/h for younger vs. older females; 6.77 L/h vs 5.44 L/h for younger vs. older males) compared with younger patients.19 However, age does not appear to be a major determinant of rivaroxaban pharmacokinetics. In patients with obesity, overall rivaroxaban exposure is reduced despite a reduction in total body clearance.20 Rivaroxaban dosing recommendations are unavailable for patients with obesity.

2.3. Apixaban

After oral administration, apixaban directly and reversibly inhibits activated factor X.21 As body weight increases, total apixaban exposure decreases due to an obesity‐related increase in clearance.22 Among patients with body weight ≤50 kg, 65 to 85 kg, and ≥120 kg, the AUC for apixaban is 2424 ng*h/mL, 2024 ng*h/mL, and 1561 ng*h/mL, respectively. There are no published studies of apixaban pharmacokinetics in patients with renal impairment or advanced age.

Notably, in patients with end‐stage renal disease, apixaban exposure between hemodialysis sessions is only slightly increased due to its minimal reliance on renal clearance.23 The approved dose of apixaban in end‐stage renal disease patients on hemodialysis is 5 mg twice daily, although the clinical outcomes associated with this dosing regimen are unknown.

Several recommendations for apixaban dosing in renal insufficiency are available. An apixaban dose adjustment should be made only if a patient has 2 out of 3 risk factors (age ≥80 years, body weight ≤65 kg, or serum Cr ≥1.5 mg/dL). Apixaban should not be administered to patients with CrCl ≤25 mL/min/m2 who do not require dialysis.24

2.4. Edoxaban

Similar to rivaroxaban and apixaban, edoxaban directly inhibits activated factor X.25 Approximately 35% of edoxaban elimination occurs renally. In healthy volunteers, a single dose of edoxaban 60 mg or 30 mg had a half‐life of approximately 8.9 hours.25 The half‐life of edoxaban is mildly increased (9.4 hours) in patients with moderate renal impairment (CrCl 30– < 50 mL/min/m2) and severely increased (16.9 hours) in patients with severe renal impairment (CrCl <30 mL/min/m2), compared with healthy controls (8.6 hours).26 In addition, total edoxaban exposure was 32%, 74%, and 72% greater in patients with mild (CrCl 50– < 80 mL/min/m2), moderate (CrCl 30‐ < 50 mL/min/m2), and severe (CrCl < 30 mL/min/m2) renal impairment, respectively. Peak edoxaban concentrations were not affected by renal function. Edoxaban was not cleared by hemodialysis to a significant extent in an analysis of 10 patients27

Pharmacokinetic studies of edoxaban in patients with weight extremes or advanced age have not been published. According to the edoxaban package insert, age did not have a clinically significant effect on edoxaban pharmacokinetics, whereas low body weight (median, 55 kg) was associated with 13% less edoxaban exposure compared with high body weight (median, 84 kg).28

3. Outcomes of DOACs in Patients with Renal Impairment

3.1. Dabigatran

A post‐hoc analysis of the Randomized Evaluation of Long‐term Anticoagulation Therapy (RE‐LY) trial studied 3354 patients with CrCl 30 to 50 mL/min/m2 who received either dabigatran 110 mg (n = 1196), dabigatran 150 mg (n = 1232), or warfarin (n = 1126).29 The dabigatran 150‐mg dose was associated with a lower risk of SSE compared with warfarin among patients with CrCl <80 mL/min/m2 but was noninferior among patients with CrCl ≥80 mL/min/m2. Major bleeding was not different between dabigatran 150 mg and warfarin unless CrCl was ≥80 mL/min/m2, in which case dabigatran was associated with fewer major bleeds. Compared with warfarin patients, dabigatran 150 mg significantly reduced the risk of intracranial hemorrhage (ICH) in patients with CrCl <80 mL/min/m2, but not ≥80 mL/min/m2. In patients with moderate renal insufficiency, dabigatran 150 mg conferred additional ischemic protection without an increase in the risk of bleeding.

The dabigatran 110‐mg dose provides greater safety than the 150‐mg dose without an increase in ischemic risk compared to warfarin. Across all 3 CrCl subgroups (30– < 50 mL/min/m2, 50–80 mL/min/m2, and ≥80 mL/min/m2), the 110‐mg dose of dabigatran was similar to warfarin with respect to SSE and superior to warfarin with respect to ICH. The safety benefit of the 110‐mg dose was primarily due to the a reduction in the risk of major bleeding among patients with CrCl ≥50 mL/min/m2, as there was no difference between dabigatran 110 mg and warfarin among patients with CrCl <50 mL/min/m2.

In contrast with the RE‐LY trial subgroup analyses, a retrospective analysis of real‐world Medicare patients found that patients with chronic kidney disease had a significantly increased risk of major hemorrhage if they were taking dabigatran.30 The discordant results of these 2 analyses may be attributed to the small sample size in the RE‐LY trial subgroup, differences in bleeding definitions or patient characteristics, and the use of a 75‐mg dabigatran dose, which was not studied in RE‐LY.

In the presence of renal impairment, patients with a high ischemic risk (ie, CHA2DS2‐VASc score >3) and low bleeding risk may benefit from the ischemic protection of the dabigatran 150‐mg dose. However, extreme caution is required due to dabigatran's nearly exclusive reliance on the renal route of clearance. In a real‐world observational study of hemodialysis patients, dabigatran was associated with a significantly increased risk of bleeding and intracranial bleeding compared with warfarin.31

3.2. Rivaroxaban

A subanalysis of Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism (ROCKET AF) patients with moderate renal function (CrCl 30–49 mL/min/m2; n = 1474) who received an adjusted dose of 15 mg once daily demonstrated that the rates of SSE and major bleeding were not different between rivaroxaban and warfarin.32 The risk of gastrointestinal (GI) hemorrhage with rivaroxaban was increased compared with warfarin for patients with impaired clearance (CrCl 30–49 mL/min/m2). This effect was not seen for patients with CrCl ≥50 mL/min/m2.

Thus, in patients with CrCl ≥50 mL/min/m2, rivaroxaban is noninferior to warfarin for both ischemic and hemorrhagic risks. For CrCl below this threshold, rivaroxaban is associated with a significant risk of GI hemorrhage without a corresponding reduction in the risk of ischemic events. Renal insufficiency was found to be more common in rivaroxaban‐treated patients with a major bleeding event than those without a major bleeding event.33 In the hemodialysis population of a postmarketing cohort, an increased risk of bleeding was observed in rivaroxaban patients compared with warfarin patients.31 Patients at high risk for ischemic events may be best served with an alternative agent.

3.3. Apixaban

Hohnloser et al conducted a post‐hoc analysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with an analysis across subgroups of renal function.34 Apixaban was superior to warfarin with respect to SSE in the subgroup of patients with CrCl >50 to 80 mL/min/m2. However, in patients with either CrCl ≤50 mL/min/m2 or >80 mL/min/m2, apixaban was not different compared with warfarin for SSE. Apixaban was associated with a significantly lower risk of major bleeding among patients with CrCl ≤50 mL/min/m2 and >50 to 80 mL/min/m2, consistent with its low rate of renal clearance.

Among patients with severe renal impairment, apixaban confers meaningful hemorrhagic protection. Ischemic protection did not inversely correlate with renal impairment, reinforcing the limited role of the kidney in apixaban clearance.

3.4. Edoxaban

Edoxaban was presented to the FDA Cardiovascular and Renal Drugs Advisory Committee for consideration of approval for the prevention of SSE in October 2014.35 Post‐hoc analyses demonstrated that the rate of SSE in the edoxaban group increased as renal function improved. When the rate of SSE was analyzed according to quintile of CrCl (Figure 1), patients in the fourth (CrCl >77.9– ≤ 98.1 mL/min/m2) and fifth (>98.1 mL/min/m2) quintiles who received edoxaban had a higher risk of SSE compared with warfarin patients. In an analysis of SSE as a continuous function of CrCl, the hazard ratio (HR) crossed 1 at approximately 95 mL/min/m2, indicating superiority of warfarin over edoxaban for CrCl >95 mL/min/m2. As a result, edoxaban is not FDA‐approved for SPAF in patients with CrCl >95 mL/min/m2.

4. Outcomes of DOACs in Patients with Advanced Age

4.1. Dabigatran

Eikelboom et al conducted a post‐hoc analysis of safety outcomes from the RE‐LY trial with a focus on the differences between patients age ≥75 years and <75 years.36 Among patients age ≥75 years, dabigatran 150 mg reduced the risk of SSE, whereas dabigatran 110 mg was not different than warfarin—similar to overall trial results. Both doses of dabigatran reduced the risk of major bleeding for patients age <75 years, but this protection was lost among patients age ≥75 years. Dabigatran reduced the rate of ICH at the expense of an increase in GI bleeding across all ages.

Similar patterns were found in real‐world patients. A propensity score–weighted analysis of Medicare patients with AF was conducted by Hernandez et al.30 Age ≥75 years was associated with a higher risk of bleeding (HR: 1.48 compared with <65 years, 95% confidence interval [CI]: 1.12‐1.96), a reduced risk of ICH (HR: 0.10, 95% CI: 0.04‐0.24), and an increased risk of GI bleeding (HR: 1.85, 95% CI: 1.60‐2.14) in dabigatran patients compared with warfarin patients.

Graham et al conducted a propensity score–matched analysis of Medicare patients age ≥65 years who received either dabigatran (n = 67 207) or warfarin (n = 67 207) for AF.37 The incidence of ischemic stroke was significantly lower in the dabigatran group compared with the warfarin group (11.3% vs 13.9%, respectively; HR: 0.8, 95% CI: 0.67‐0.96, P = 0.02). Dabigatran patients had a lower risk of ICH (3.3% vs 9.6%; HR: 0.34, 95% CI: 0.26‐0.46, P < 0.001) but a higher risk of GI bleeding (34.2% vs 26.5%; HR: 1.28, 95% CI: 1.14‐1.44, P < 0.001). The higher risk of GI bleeding was primarily due to the subgroups of women age ≥75 years and men age ≥85 years.

Although there were no differences between dabigatran 75 mg (n = 10 522) and warfarin with respect to the incidence of ischemic stroke (HR: 0.88, 95% CI: 0.6‐1.27) or major GI bleeding (HR: 1.01, 95% CI: 0.78‐1.31), ICH was less common with dabigatran 75 mg (HR: 0.46, 95% CI: 0.26‐0.81).

Although advanced age is considered to be a risk factor for bleeding, several studies, strengthened by these post‐hoc findings, have demonstrated the benefits of cautious anticoagulation among the elderly.38, 39, 40

4.2. Rivaroxaban

In a post‐hoc analysis of the ROCKET AF trial, the rates of SSE and major bleeding were not different between rivaroxaban and warfarin regardless of age.41 However, rivaroxaban was associated with a reduced risk of ICH among the subgroup of patients age <75 years (n = 3082). This result was not found among patients age ≥75 years (n = 3999). The risk of GI bleeding was higher in both older and younger rivaroxaban patients. In a 27 467‐patient cohort, patients with major bleeding events on rivaroxaban were significantly older than were patients without major bleeding events.33

4.3. Apixaban

An analysis of apixaban in elderly patients was published by Halvorsen et al.42 Apixaban was superior for SSE, major bleeding, and ICH for patients either age ≥75 years or 65 to <75 years. Among patients age <65 years, there were no differences between apixaban and warfarin with respect to SSE, major bleeding, and ICH. Major bleeding occurred less often among apixaban patients age ≥75 years and CrCl ≤30 mL/min/m2 (4.64% vs 13.4%; HR: 0.35, 95% CI: 0.14‐0.86) or >30 to 50 mL/min/m2 (3.32% vs 6.27%; HR: 0.53, 95% CI: 0.37‐0.76). The risk of major bleeding increases continuously as a function of age, although bleeding was less common in apixaban‐treated patients compared with their warfarin counterparts across a wide range of ages.43

4.4. Edoxaban

In the subgroup of Global Study to Assess the Safety and Effectiveness of Edoxaban (DU‐176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGE AF‐TIMI 48) patients age ≥75 years, the rate of SSE was lower in the edoxaban high‐dose arm but higher in the edoxaban low‐dose arm compared with warfarin.6 A similar pattern occurred in the subgroup of patients age <75 years (1.35% vs 1.71% vs 1.48% for edoxaban high dose vs low dose vs warfarin, respectively). Both doses of edoxaban were associated with lower rates of major bleeding compared with warfarin for patients age ≥75 years and age <75 years.

5. Outcomes of DOACs in Patients With Obesity

5.1. Rivaroxaban

The FDA conducted an analysis (Figure 2) that compared the rates of SSE among rivaroxaban and warfarin patients from ROCKET AF across 5 weight categories (<50 kg, 50– ≤ 70 kg, 70– ≤ 90 kg, 90– ≤ 110 kg, and >100 kg).44 There was no statistical relationship between weight category and the rate of SSE.

Figure 2.

Figure 2

Open in a new tab

US Food and Drug Administration analysis of stroke and systemic embolism in ROCKET AF according to weight category. Abbreviations: ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

There are no published pharmacokinetic or clinical analyses of dabigatran in patients with weight extremes. In patients with body weight ≤60 kg (but age <80 years and serum Cr <1.5 mg/dL) who received apixaban 5 mg twice daily (n = 1426), major bleeding was significantly reduced compared with warfarin‐treated patients (HR: 0.6, 95% CI: 0.4‐0.9).43

6. Conclusion

There is considerable recognition of the underuse of oral anticoagulation for stroke prevention in AF. In the absence of randomized controlled trials that compare the use of these agents with warfarin in patients with renal impairment, advanced age, or obesity, post‐hoc analyses may be used to better inform clinicians and patients. The available data must be considered within the context of present limitations, and prospective studies are warranted (Table 2).

Supporting information

Table S1. Pharmacokinetic Properties of Oral Anticoagulants

Table S2. Summary of Key Demographics in Clinical Trials of Direct Oral Anticoagulants

Table S3. Efficacy and Safety Outcomes in Relevant Subgroups from Clinical Trials of Direct Oral Anticoagulants

Figure S1. Efficacy and Safety of Direct Oral Anticoagulants compared to Warfarin

Click here for additional data file. (151.6KB, docx)

Conflicts of interest

Dr. Rybak is currently an employee and shareholder of The Medicines Company. This project was not sponsored or initiated by The Medicines Company. The views expressed are those of the authors and do not necessarily represent those of The Medicines Company.

Buckley LF, Rybak E, Aldemerdash A, Cheng JWM and Fanikos J. Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age, Clin Cardiol, 2017;40(1):46–52.

References

  • 1. Bauer KA. Pros and cons of new oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2013;2013:464–470. [DOI] [PubMed] [Google Scholar]
  • 2. Schulman S. Advantages and limitations of the new anticoagulants. J Intern Med. 2014;275:1–11. [DOI] [PubMed] [Google Scholar]
  • 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010;363:1877]. N Engl J Med. 2009;361:1139–1151. [DOI] [PubMed] [Google Scholar]
  • 4. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators . Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891. [DOI] [PubMed] [Google Scholar]
  • 5. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators . Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992. [DOI] [PubMed] [Google Scholar]
  • 6. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF‐TIMI 48 Investigators . Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–2104. [DOI] [PubMed] [Google Scholar]
  • 7. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta‐analysis of randomised trials. Lancet. 2014;383:955–962. [DOI] [PubMed] [Google Scholar]
  • 8. Ogilvie IM, Newton N, Welner SA, et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123:638.e4–645.e4. [DOI] [PubMed] [Google Scholar]
  • 9. Piazza G, Karipineni N, Goldberg HS, et al. Underutilization of anticoagulation for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2016;67:2444–2446. [DOI] [PubMed] [Google Scholar]
  • 10. Alamneh EA, Chalmers L, Bereznicki LR. Suboptimal use of oral anticoagulants in atrial fibrillation: has the introduction of direct oral anticoagulants improved prescribing practices? Am J Cardiovasc Drugs. 2016;16:183–200. [DOI] [PubMed] [Google Scholar]
  • 11. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009;48:1–22. [DOI] [PubMed] [Google Scholar]
  • 12. Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. Clin Pharmacokinet. 2010;49:259–268. [DOI] [PubMed] [Google Scholar]
  • 13. Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47:47–59. [DOI] [PubMed] [Google Scholar]
  • 14. Kooiman J, van der Hulle T, Maas H, et al. Pharmacokinetics and pharmacodynamics of dabigatran 75 mg b.i.d. in patients with severe chronic kidney disease. J Am Coll Cardiol. 2016;67:2442–2444. [DOI] [PubMed] [Google Scholar]
  • 15. Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59‐7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78:412–421. [DOI] [PubMed] [Google Scholar]
  • 16. Graff J, Harder S. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet. 2013;52:243–254. [DOI] [PubMed] [Google Scholar]
  • 17. Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2010;70:703–712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. De Vriese AS, Caluwé R, Bailleul E, et al. Dose‐finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015;66:91–98. [DOI] [PubMed] [Google Scholar]
  • 19. Kubitza D, Becka M, Roth A, et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor. J Clin Pharmacol. 2013;53:249–255. [DOI] [PubMed] [Google Scholar]
  • 20. Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59‐7939) in healthy subjects [published correction appears in J Clin Pharmacol. 2008;48:1366–1367]. J Clin Pharmacol. 2007;47:218–226. [DOI] [PubMed] [Google Scholar]
  • 21. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37:74–81. [DOI] [PubMed] [Google Scholar]
  • 22. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013;76:908–916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end‐stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56:628–636. [DOI] [PubMed] [Google Scholar]
  • 24.Apixaban (Eliquis) [package insert]. New York, NY: Bristol‐Myers Squibb, 2015. [Google Scholar]
  • 25. Ogata K, Mendell‐Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743–753. [DOI] [PubMed] [Google Scholar]
  • 26. Ridout G, de la Motte S, Niemczyk S, et al. Effect of renal function on edoxaban pharmacokinetics (PK) and on population PK/PK‐PD model. J Clin Pharmacol. 2009;49(suppl):1124. Abstract 144. [Google Scholar]
  • 27. Parasrampuria DA, Marbury T, Matsushima N, et al. Safety, tolerability, and pharmacokinetics of edoxaban in end‐stage renal disease subjects undergoing hemodialysis. J Thromb Haemost. 2015;113:719–727. [DOI] [PubMed] [Google Scholar]
  • 28.Edoxaban [package insert]. Parsippany, NJ: Daiichi‐Sankyo Co., 2015.
  • 29. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE‐LY (Randomized Evaluation of Long‐term Anticoagulation Therapy) trial analysis. Circulation. 2014;129:961–970. [DOI] [PubMed] [Google Scholar]
  • 30. Hernandez I, Baik SH, Piñera A, et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2015;175:18–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Chan KE, Edelman ER, Wenger JB, et al. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation. 2015;131:972–979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32:2387–2394. [DOI] [PubMed] [Google Scholar]
  • 33. Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38:63–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33:2821–2830. [DOI] [PubMed] [Google Scholar]
  • 35. Food US and Administration Drug. FDA draft briefing document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), edoxaban (Savaysa) , 2014. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM420705.pdf.
  • 36. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long‐term Anticoagulant Therapy (RE‐LY) trial. Circulation. 2011;123:2363–2372. [DOI] [PubMed] [Google Scholar]
  • 37. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non‐valvular atrial fibrillation. Circulation. 2015;131:157–164. [DOI] [PubMed] [Google Scholar]
  • 38. Mant J, Hobbs FD, Fletcher K, et al; BAFTA Investigators . Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007;370:493–503. [DOI] [PubMed] [Google Scholar]
  • 39. Donzé J, Clair C, Hug B, et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med. 2012;125:773–778. [DOI] [PubMed] [Google Scholar]
  • 40. Hylek EM, Evans‐Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115:2689–2696. [DOI] [PubMed] [Google Scholar]
  • 41. Halperin JL, Hankey GJ, Wojdyla D, et al; ROCKET AF Steering Committee and Investigators . Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism (ROCKET AF). Circulation. 2014;130:138–146. [DOI] [PubMed] [Google Scholar]
  • 42. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014;35:1864–1872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Alexander JH, Andersson U, Lopes RD, et al. Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial. JAMA Cardiol. doi:10.1001/jamacardio.2016.1829. [DOI] [PubMed] [Google Scholar]
  • 44. Beasley N, Dunnmon P, Rose M; US Food and Drug Administration. Rivaroxaban clinical review: FDA draft briefing document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), rivaroxaban (Xarelto), 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm270796.pdf.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1. Pharmacokinetic Properties of Oral Anticoagulants

Table S2. Summary of Key Demographics in Clinical Trials of Direct Oral Anticoagulants

Table S3. Efficacy and Safety Outcomes in Relevant Subgroups from Clinical Trials of Direct Oral Anticoagulants

Figure S1. Efficacy and Safety of Direct Oral Anticoagulants compared to Warfarin

Click here for additional data file. (151.6KB, docx)

Articles from Clinical Cardiology are provided here courtesy of Wiley

RESOURCES