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P T. 2019;44(12): 738-744; 746-747

Direct-Acting Oral Anticoagulant Use In Special Populations

Daniel E. Hilleman PharmD
Mark A. Malesker PharmD
Daniel Hannig PharmD

ABSTRACT

Direct-acting oral anticoagulants (DOACs) are being used with increasing frequency, primarily for a reduction in stroke risk in atrial fibrillation (AF) and in the treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE). The outcome studies comparing the efficacy and safety of DOACs with warfarin excluded patients with severe renal or hepatic dysfunction. In addition, elderly (age 75 years or older) patients, underweight and overweight patients, and patients receiving drugs known to interact with the DOACs were underrepresented in these trials compared to the estimated numbers of patients who are expected to be treated with DOACs in real-world settings. The purpose of this review is to identify the best available evidence concerning the appropriate use and dosing of DOACs among these populations. Subgroup analyses of the outcomes trials suggest that the relative benefit of DOACs compared to warfarin persists among elderly (75 years or older) patients. In underweight (less than 60 kg) or overweight (more than 120 kg) patients, there are insufficient data to support recommendations concerning initial selection of a DOAC or warfarin or for DOAC dosage adjustment. Limited observational data suggest DOACs are as safe and effective as warfarin in overweight and obese patients using standard dosage regimens. The outcomes trials excluded patients with severe renal dysfunction, defined as a creatinine clearance (CrCl) less than 30 mL/min, including patients with end-stage renal disease (ESRD) or patients on dialysis. Subgroup analyses of the outcomes trials indicate that the relative benefit of DOACs persists compared to warfarin in patients with moderate renal dysfunction (CrCl 30–50 mL/min). Among patients with severe renal dysfunction, evidence-based recommendations concerning selection of DOACs and warfarin are tenuous. The AF guidelines suggest that the use of apixaban or warfarin is reasonable in ESRD or dialysis patients. Whether this recommendation can be extrapolated to DVT/PE patients is unknown. There are no outcomes data with the use of DOACs in patients with moderate or severe (Child-Pugh class B or C) hepatic dysfunction. Due to its limited hepatic clearance, the prescribing information for dabigatran indicates it does not require dose adjustment in patients with mild-to-moderate hepatic dysfunction. There are few data concerning dosage adjustment or selection of specific DOACs in patients taking drugs known to cause interactions other than those described in their respective prescribing information. Recommendations concerning dosage adjustment or avoidance of DOACs with specific interacting drugs can only be based on the respective prescribing information for each drug. Ongoing clinical investigations in these patient populations should provide further clarity concerning appropriate selection and use of specific anticoagulants.

INTRODUCTION

The direct-acting oral anticoagulants (DOACs) are being used with increasing frequency to reduce the risk of ischemic stroke associated with atrial fibrillation (AF), for the treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and for a variety of other thromboembolic indications. Compared to warfarin, DOACs have a rapid onset and offset of anticoagulant activity, a more consistent pharmacokinetic and pharmacodynamic profile, do not require monitoring of their anticoagulant effect, and are generally associated with a lower risk of major bleeding, life-threatening bleeding, and intracranial hemorrhage.1 

As DOAC use expands, a greater number of patients either underrepresented or not included in the outcomes trials for AF or acute DVT/PE are being treated with this class of drugs. Subgroup analyses of the phase 3 outcomes studies allow for an estimate of the relative efficacy and safety of DOACs in some underrepresented patients (i.e., elderly, renal dysfunction, etc). For patients excluded from the outcomes trials, the efficacy and safety of DOACs can be based only on studies in healthy subjects or on analyses of real-world experience. While retrospective insurance claims database analyses and reviews of electronic health records, patient registries, and observational case series lack the validity of randomized controlled trials, the Food and Drug Administration (FDA) recently issued a guidance document outlining certain principles on which real-world evidence can be used to assist with clinical decision-making.

The objective of this review is to summarize the best available evidence concerning the use of DOACs in special populations excluded from or underrepresented in the outcomes trials with DOACs. Recommendations concerning the use and dosing of DOACs in these patients are based on subgroup analyses of the outcomes trials and analyses of real-world experience in these patients. 

OUTCOMES TRIALS WITH DOACs 

Each DOAC has been compared to warfarin in large outcomes studies of patients for the treatment of acute DVT/PE and for reducing the risk of stroke in patients with AF (Table 1).3–11 In the AF studies, all of the DOACs were at least as effective as warfarin in reducing the risk of stroke. Dabigatran and apixaban were associated with a statistically significant reduction in the risk of stroke compared to warfarin, while edoxaban and rivaroxaban were noninferior to warfarin.4,7,8,11 In the AF trials, apixaban and edoxaban were associated with a statistically significant lower rate of major bleeding compared to warfarin, while major bleeding rates were not statistically significantly different between dabigatran and warfarin or between rivaroxaban and warfarin. 

Table 1 Efficacy and Safety of Direct-Acting Oral Anticoagulant (DOAC) Therapy Versus Warfarin in Outcomes Trials in Acute DVT/PE and AF
DVT/PE Trial Recurrent DVT/PE (% Per Year) Major Bleeding Plus CRNMB (% Per Year)
  DOAC Warfarin HR (95% CI) DOAC Warfarin HR (95% CI)
RECOVER I/II10 Dabigatran 2.4 2.2 1.08 (0.64–1.80)
P = 0.64
4.4 7.7 0.57 (0.47–0.73)
P < 0.001
EINSTEIN DVT/PE5,6 Rivaroxaban 1.8 2.3 0.90 (0.68–1.20)
P = 0.48
9.4 10.0 0.94 (0.76–1.22)
P = 0.69
AMPLIFY3
Apixaban
2.3 2.7 0.84 (0.60–1.18)
P = 0.31
4.3 9.7 0.44 (0.36–0.55)
P < 0.001
HOKUSAI-VTE9 Edoxaban 3.2 3.5 0.89 (0.70–1.13)
P = 0.33
8.5 10.3 0.81 (0.71–0.94)
P = 0.004
AF Trial Stroke/Systemic Embolism (% Per Year) Major Bleeding (% Per Year)
  DOAC Warfarin HR (95% CI) DOAC Warfarin HR (95% CI)
RE-LY11
Dabigatran*
1.11 1.69 0.66 (0.53–0.82)
P < 0.001
3.11 3.36 0.93 (0.81–1.07)
P = 0.31
ROCKET-AF7 Rivaroxaban 2.10 2.40 0.88 (0.75–1.03)
P = 0.12
5.60 5.40 1.04 (0.90–1.20)
P = 0.58
ARISTOTLE4 Apixaban 1.27 1.60 0.79 (0.66–0.95)
P = 0.01
2.13 3.09 0.69 (0.60–0.80)
P < 0.001
ENGAGE AF-TIMI 488 Edoxaban† 1.57 1.80 0.87 (0.73–1.04)
P = 0.08
2.75 3.43 0.80 (0.71–0.91)
P < 0.001
AF = atrial fibrillation; CI = confidence interval; CRNMB = clinically relevant nonmajor bleeding; DVT = deep vein thrombosis; HR = hazard ratio; PE = pulmonary embolism
*150 mg twice daily; †60 mg daily

All DOACs were as effective as warfarin in reducing recurrent DVT/PE, but none was statistically significantly more effective than warfarin.3,5,6,9,10 In the DVT/PE studies, apixaban and edoxaban were associated with statistically significantly less major bleeding plus clinically relevant nonmajor bleeding (CRNMB) compared to warfarin.3,9 Bleeding rates were not statistically significantly different between dabigatran and warfarin or between rivaroxaban and warfarin.5,6,10 Because the durations of follow-up averaged about six months in the DVT/PE trials, the composite of major bleeding combined with CRNMB was chosen as the primary safety endpoint due to the relatively low incidence of major bleeding alone. It should be noted that the specific criteria used in the clinical trials to define major bleeding and CRNMB were different. An in-depth discussion of the clinical validity of the components that defined each type of bleeding used in these trials is outside the scope of this review. The important point is that the frequency of bleeding as defined in each study was applied consistently to each treatment group. 

Elderly Patients 

The prevalence of DVT/PE and AF increases with advancing age. The prevalence of DVT/PE in the U.S. among individuals younger than 65 years is approximately 500 per 100,000 patients. DVT/PE prevalence increases to 1,000, 1,500, and 2,000 per 100,000 patients among those ages 65 to 74 years, 75 to 84 years, and 85 years or older, respectively.12 Among individuals living in the community who develop acute DVT/PE, approximately 50% are 75 or older.13 Age is the strongest independent risk factor for the development of AF. Compared to individuals ages 50 to 59 years, increasing age of 60 to 69 years, 70 to 79 years, and 80 to 89 years was associated with a 4.98-, 7.35-, and 9.33-fold increased risk of AF, respectively.14 It is estimated that among patients with AF, one-half are 75 or older and one in three is 80 or older.

In the outcomes studies comparing DOACs to warfarin in acute DVT/PE, the mean age of participants was 56 years; less than 15% of randomized participants were 75 years of age or older.3,5,6,9,10 In the outcomes studies in AF, the average age of participants was 72 years, with about 40% being 75 or older.4,7,8,11 The proportion of elderly patients enrolled in the DOAC outcomes trials underrepresents the numbers of patients ages 75 or older who are likely to be treated with anticoagulants for these indications in a real-world setting. 

Subgroup analyses of the outcomes studies stratifying patients into those younger than 75 years and 75 years or older have been published (Table 2).15,16 There also are data for patients 80 years of age or older from subgroup analyses of the AF outcomes trials with dabigatran and edoxaban.17,18 These subgroup analyses demonstrated that the results in both the DVT/PE and AF trials were consistent among elderly patients compared to younger patients. The relative efficacy and safety of DOACs compared to warfarin in patients ages 75 years and older or 80 years and older were not statistically significantly different compared to patients younger than 75 years of age. 

Table 2 Relative Risk of DOACs Versus Warfarin on Efficacy and Safety Based on Subgroup Analysis of Elderly Patients in the Outcomes Trials in Acute DVT/PE and AF
DVT/PE Trial Recurrent DVT/PE
(RR and 95% CI)
P interaction Major Bleeding Plus CRNMB
(RR and 95% CI)
P interaction
RECOVER I/II15 Dabigatran ≤ 75 years
> 75 years
1.13 (0.78–1.64)
0.65 (0.17–2.45)
0.70 ≤ 75 years
> 75 years
0.55 (0.42–0.71)
0.76 (0.47–1.25)
0.51
EINSTEIN DVT/PE15 Rivaroxaban < 75 years
≥ 75 years
0.98 (0.71–1.37)
0.62 (0.33–1.17)
0.47 < 75 years
≥ 75 years
0.96 (0.83–1.12)
0.84 (0.63–1.12)
0.69
AMPLIFY15
Apixaban
≥ 75 years
≥ 75 years
0.92 (0.63–1.32)
0.50 (0.21–1.20)
0.41 < 75 years
≥ 75 years
0.64 (0.47–0.87)
0.63 (0.43–0.85)
0.40
HOKUSAI-VTE15 Edoxaban < 75 years
≥ 75 years
0.98 (0.76–1.26)
0.50 (0.27–0.94)
0.18 < 75 years
≥ 75 years
0.82 (0.70–0.96)
0.82 (0.62–1.12)
0.97
AF Trial Stroke/Systemic Embolism
(RR and 95% CI)
  Major Bleeding
(RR and 95% CI)
 
RE-LY17
Dabigatran*
< 75 years
75–79 years
80–84 years
≥ 85 years
0.63 (0.46–0.86)
0.65 (0.42–1.01)
0.67 (0.41–1.10)
0.70 (0.31–1.57)
0.99 < 75 years
75–79 years
80–84 years
≥ 85 years
0.70 (0.57–0.86)
1.18 (0.98–1.42)
1.41 (1.02–1.94)
0.70 (0.31–1.25)
0.001
ROCKET-AF16 Rivaroxaban < 75 years
≥ 75 years
0.95 (0.76–1.19)
0.80 (0.63–1.02)
0.31 < 75 years
≥ 75 years
0.93 (0.84–1.04)
1.13 (1.02–1.25)
0.34
ARISTOTLE16 Apixaban < 65 years
65–75 years
≥ 75 years
1.16 (0.77–1.73)
0.72 (0.54–0.96)
0.71 (0.53–0.95)
0.11 < 65 years
65–75 years
≥ 75 years
0.78 (0.55–1.11)
0.71 (0.56–0.89)
0.64 (0.52–0.79)
0.63
ENGAGE AF-TIMI 4818 Edoxaban† < 65 years
65–74 years
≥ 75 years
≥ 80 years
0.94 (0.65–1.37)
0.89 (0.68–1.16)
0.83 (0.66–1.04)
0.88 (0.64–1.20)
0.84 < 65 years
65–74 years.
≥ 75 years
≥ 80 years
0.81 (0.58–1.12)
0.75 (0.60–0.94)
0.83 (0.70–0.99)
0.75 (0.58–0.98)
0.31
AF = atrial fibrillation; CI = confidence interval; CRNMB = clinically relevant nonmajor bleeding; DOAC = direct-acting oral anticoagulant; DVT = deep vein thrombosis; PE = pulmonary embolism; RR = relative risk
*150 mg twice daily; †60 mg daily

Additional analyses evaluated oral anticoagulant use in AF patients 85 years of age or older and 90 years of age or older. Data in these advanced age groups are not available for DOAC use in acute DVT/PE. The AVERROES trial compared apixaban to aspirin in 5,599 patients with AF who were not suitable candidates for warfarin or who were unwilling to take warfarin.19 The overall study results found that apixaban was associated with a statistically significant reduction in the risk of stroke compared to aspirin (1.6%/year versus 3.7%/year; hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.32–0.62) with no statistically significant increase in major hemorrhage (1.4%/year versus 1.2%/year) or intracranial bleeding (0.4%/year for both treatment groups). Hazard ratios for the risk of stroke in the subgroups of patients ages 75 years or older (n = 1,897) and 85 years or older (n = 366) for apixaban versus aspirin were 0.33 (95% CI, 0.20–0.54) and 0.14 (95% CI, 0.02–0.48), respectively.20 Hazard ratios for the risk of major bleeding in the subgroups of patients ages 75 years or older and 85 years or older for apixaban versus aspirin were 1.14 (95% CI, 0.74–1.75) and 0.96 (95% CI, 0.38–2.39), respectively. The absolute reductions in stroke were greater in patients ages 75 years or older and 85 years or older compared to younger patients, while the risk of major bleeding and intracranial hemorrhage remained similar between apixaban and aspirin in the older subgroups. 

In an observational study of the Taiwan National Health Insurance Research database, 15,756 AF patients 90 years of age or older treated with no antithrombotic therapy, antiplatelet agents alone, warfarin, or a DOAC were evaluated.21 In a comparison of warfarin against either antiplatelet therapy alone or no antithrombotic therapy, warfarin reduced the risk of ischemic stroke without an increase in the risk of intracranial hemorrhage. In a comparison of warfarin and DOACs, the risks of ischemic stroke and major bleeding were not different between the treatment groups. However, the risk of intracranial hemorrhage was statistically significantly less with DOACs than with warfarin. This study indicates that oral anticoagulant therapy should be considered for the very elderly AF patient, with DOACs being the more favorable choice. 

The most common question concerning the use of anticoagulant therapy in the elderly patient relates to the risk of bleeding. Elderly patients have higher risks of bleeding as well as ground-level falls. In these patients, aspirin is often used as a potentially safer alternative to anticoagulant therapy. The data from the AVERROES study and Taiwan National Health Insurance Research database indicate that anticoagulant therapy is superior to aspirin for prevention of stroke without a statistically significant increase in the risk of intracranial hemorrhage in the elderly, including patients 85 to 90 years of age.20,21 Although elderly patients taking either antiplatelet or anticoagulant therapy following ground-level falls have a higher mortality rate, the incidence of intracranial hemorrhage is low with both antiplatelet and anticoagulant use.22,23 There is also no statistically significant difference in the risk of intracranial hemorrhage based on the use of anticoagulants compared to antiplatelet therapy in this elderly population who suffer ground-level falls.23 The use of aspirin rather than anticoagulants in elderly patients at risk of falls, based on the assumption that aspirin is less likely to be associated with intracranial hemorrhage, is not supported by evidence.22,23 

Weight

One advantage of DOACs compared to warfarin is the ability to use a fixed dose without coagulation assay monitoring. This advantage stems from the more consistent pharmacokinetic and pharmacodynamic profile of DOACs. Dose adjustments with DOACs are primarily based on changes in renal function.24–27 Limited data are available for DOAC use in underweight patients. There are recommended dose adjustments for underweight patients in the prescribing information for apixaban and edoxaban. The apixaban dose should be reduced in AF patients from 5 mg twice daily to 2.5 mg twice daily if they meet at least two of the three following characteristics: age 80 years or older, body weight 60 kg or less, or serum creatinine 1.5 mg/dL or more.25 This dosage adjustment was not used with apixaban in the acute DVT/PE trial.3 The recommended dose of edoxaban is 30 mg once daily for patients 60 kg or less when used for acute DVT/PE.27 Observational data concerning the use of DOACs in patients with a low body weight were evaluated in patients in the Korean National Health Insurance Service database.28 Outcomes with DOACs (n = 14,103) or warfarin (n = 7,576) were compared in AF patients with a body weight of 60 kg or less. DOACs were associated with lower risks of ischemic stroke, intracranial hemorrhage, hospitalization for major bleeding, and all-cause death compared to warfarin. Given the inherent study design limitations, conclusions from this analysis are tenuous. Extrapolation of these results in a Korean population may not be applicable to low-weight patients in the Western world.29

Recommendations for dosage adjustments in overweight/obese patients are not included in the prescribing information of any DOAC.24–27 Patients weighing more than 100 kg accounted for less than 20% of patients in the DOAC outcomes trials. Considering the large numbers of patients requiring anticoagulant therapy who are overweight or obese, data on the relative efficacy and safety of DOACs in this population are important. The International Society on Thrombosis and Hemostasis (ISTH) issued a guidance recommendation against the use of DOACs in patients with a body mass index (BMI) greater than 40 kg/m2 or a weight greater than 120 kg unless drug-specific peak or trough levels fall within the usual on-therapy range.30 There are few data concerning the use of serum/plasma drug concentrations to make dosage adjustments with DOACs in patients who are overweight or obese.31,32 It would seem logical that plasma concentrations would be lower with standard DOAC doses in obese patients. The largest analysis of plasma concentrations in obese patients indicates there are no substantial differences in DOAC plasma concentrations or changes in coagulation assay results when patients weighing more than 120 kg are compared to patients weighing 50 kg to 120 kg.32

A systematic review of 11 phase 3 clinical trials comparing DOACs and warfarin in AF and acute DVT/PE evaluated the association of body weight and clinical outcomes.33 This systematic review stratified patients into low body weight (less than 60 kg), normal body weight (60 kg to 100 kg), and high body weight (more than 100 kg). Low body weight was associated with a paradoxical increase in the risk of thromboembolism with both warfarin and DOACs compared to normal-weight patients. High-body-weight AF patients receiving DOACs or warfarin had a reduced risk of thromboembolism compared to normal-body-weight patients. Bleeding outcomes were similar across all body-weight comparisons. The effect of DOACs and warfarin on thrombotic risk was most likely due to differences in baseline thrombotic risk in each weight category rather than an effect of the type of or dose of anticoagulant used. The authors concluded that dose adjustment with DOACs outside of those included in their respective prescribing information is unlikely to improve efficacy or safety. 

A retrospective analysis of U.S. veterans compared DVT/PE recurrence in 133 patients 120 kg or more and 1,063 patients less than 120 kg during treatment with a DOAC.34 There was no difference in DVT/PE recurrence between the groups over a five-year follow-up period. A low rate of DVT/PE occurrence in both weight groups limited the study’s ability to detect a difference between the groups. In an analysis of the Dresden prospective registry, clinical outcomes among patients with AF or acute DVT/PE treated with DOACs for at least three months were evaluated based on BMI.35 Among 3,432 patients, 1,446 were overweight (BMI 25–29.9) and 1,077 were obese (BMI 30 or greater). Overweight and obese patients had lower rates of major adverse cardiovascular effects compared to patients with BMIs less than 25. These data found no indication that a high BMI is associated with suboptimal DOAC efficacy or safety. A retrospective cohort analysis of 3,458 patients receiving a DOAC for AF or acute DVT/PE at a community health system hospital evaluated clinical outcomes based on BMI.36 Patients were stratified into three BMI categories: less than 30, 30–40, and greater than 40. No statistically significant difference in the rates of thromboembolic or bleeding events was found between the BMI groups. 

Outcomes in 761 AF patients undergoing electrical cardioversion without prior transesophageal echocardiography (TEE) who were taking a DOAC or warfarin for at least three weeks were evaluated in a single-center observational analysis.37 Patients were stratified by BMI class. There were 159 patients with a BMI less than 25, 254 with a BMI of 25 to less than 30, 197 with a BMI of 30 to less than 35, 78 with a BMI of 35 to less than 40, and 73 with a BMI of 40 or more. The overall rate of stroke was exceptionally low, with only two strokes occurring at the end of the 30-day follow-up period. One occurred in a patient with a BMI of 35 to less than 40 and the other in a patient with a BMI less than 25. Both occurred in patients receiving apixaban. No bleeding events were reported. This study suggests that both warfarin and DOAC use are comparable in obese patients undergoing electrical cardioversion in the absence of a TEE. 

A retrospective, single-center analysis compared the efficacy and safety of DOACs (n = 64) and warfarin (n = 64) in AF patients with a BMI greater than 40 or a weight greater than 120 kg.38 Major bleeding occurred in five patients in the DOAC group and in 12 warfarin patients. Stroke occurred in four patients in the DOAC group and in three warfarin patients. This analysis lacked power to demonstrate a statistically significant difference in either outcome between DOACs and warfarin. In an analysis of the Truven MarketScan insurance database, 3,563 matched pairs of morbidly obese AF patients treated with rivaroxaban or warfarin were identified.39 The risks of ischemic stroke and major bleeding were not statistically different between the two treatment groups. 

There are no randomized trial data to support the selection of a specific anticoagulant or to make an adjustment in DOAC dosing in patients weighing less than 60 kg or more than 120 kg other than that included in the prescribing information of apixaban and edoxaban for low-body-weight patients. In a subgroup analysis of the outcomes trials, high-body-weight (more than 100 kg) AF patients receiving DOACs or warfarin had a reduced risk of thromboembolism compared to normal-body-weight patients. Bleeding outcomes were similar regardless of weight. Limited observational data also suggest that DOACs are as safe and effective as warfarin in overweight and obese patients using standard dosage regimens. Outcomes studies designed to evaluate the efficacy and safety of DOACs in overweight/obese patients are needed. 

Renal Dysfunction

An estimated 37 million adults in the U.S. have chronic kidney disease (CKD).40 The risk of both bleeding and thromboembolic events is increased in patients with CKD. Patients with CKD are also at a higher risk of developing AF.41 As previously discussed, DOACs vary in the extent of unchanged drug cleared by the kidney (dabigatran, 80%; edoxaban, 50%; rivaroxaban, 33%; and apixaban, 25%).24–27 Dabigatran is the only DOAC that is substantially removed by hemodialysis.41 There are no outcomes data concerning the relative efficacy and safety of DOAC use in patients with severe renal dysfunction, including patients with end-stage renal disease (ESRD) or those receiving dialysis.

The outcome trials comparing DOACs with warfarin in patients with renal dysfunction used the Cockcroft-Gault equation to estimate creatinine clearance (CrCl).3–11 These trials did not include patients with CrCl less than 30 mL/min with the exception of the apixaban DVT/PE and AF trials that excluded patients with a serum creatinine greater than 2.5 mg/dL
 or a CrCl less than 25 mL/min.3,11 As a result, only about 10% of the patients included in the DVT/PE studies and 20% of the patients included in the AF trials had moderate renal dysfunction (defined as a CrCl of 25–30 mL/min to 50 mL/min). 

Subgroup analyses of the phase 3 DVT/PE and AF outcomes trials compared the risks of thromboembolic and major bleeding in patients with and without moderate renal dysfunction (Table 3).15,42,43 In the subgroup analyses of the individual trials, the relative risk (RR) of recurrent DVT/PE was not statistically significantly different based on the presence of moderate renal dysfunction with the exception of dabigatran. Rates of venous thromboembolism (VTE) recurrence were less with dabigatran in patients with moderate renal dysfunction compared to patients without moderate renal dysfunction.15 The relative risk of major bleeding in the DVT/PE trials was not statistically significantly different based on the presence of moderate renal dysfunction with the exception of rivaroxaban.15 Rates of major bleeding were less with rivaroxaban in patients with moderate renal dysfunction compared to patients without moderate renal dysfunction. In the meta-analysis of the DVT/PE trials, pooled rates of recurrent VTE or major bleeding were not statistically significantly different in patients with CrCl of less than 50 mL/min compared to CrCl of 50 mL/min or greater in DOAC-treated patients.42 

Table 3 Relative Risk of DOACs Versus Warfarin on Efficacy and Safety Based on Subgroup Analysis of Creatinine Clearance (CrCl) in the Outcomes Trials in Acute DVT/PE and AF
DVT/PE Trial Recurrent DVT/PE
(RR and 95% CI)
P interaction Major Bleeding
(RR and 95% CI)
P interaction
RECOVER I/II15 CrCl ≥ 50
CrCl < 50
1.18 (0.82–1.71)
0.10 (0.01–1.74)
0.05 CrCl ≥ 50
CrCl < 50
0.52 (0.29–0.90)
1.29 (0.43–3.89)
0.66
EINSTEIN DVT/PE15 CrCl ≥ 50
CrCl < 50
0.89 (0.65–1.22)
0.96 (0.43–2.21)
0.94 CrCl ≥ 50
CrCl < 50
0.63 (0.42–0.94)
0.22 (0.06–0.73)
0.04
AMPLIFY15 CrCl ≥ 50
CrCl < 50
0.98 (0.67–1.43)
0.93 (0.34–2.50)
0.97 CrCl ≥ 50
CrCl < 50
0.25 (0.12–0.51)
0.51 (0.18–1.44)
0.36
HOKUSAI-VTE15 CrCl ≥ 50
CrCl < 50
0.93 (0.74–1.20)
0.51 (0.22–1.14)
0.33 CrCl ≥ 50
CrCl < 50
0.83 (0.73–0.96)*
0.73 (0.46–1.15)*
0.76
AF Trial Stroke/Systemic Embolism
(RR and 95% CI)
  Major Bleeding
(RR and 95% CI)
 
RE-LY17,† CrCl > 80
CrCl 50–80
CrCl < 50
0.67 (0.42–1.09)
0.68 (0.50–0.92)
0.56 (0.37–0.85)
0.75 CrCl > 80
CrCl 50–80
CrCl < 50
0.84 (0.62–1.13)
0.91 (0.75–1.11)
1.01 (0.79–1.30)
0.64
ROCKET-AF43 CrCl ≥ 50
CrCl < 50
0.78 (0.63–0.98)
0.84 (0.75–1.23)
0.76 CrCl ≥ 50
CrCl < 50
1.07 (0.91–1.26)
0.95 (0.72–1.26)
0.48
ARISTOTLE43 CrCl >80
CrCl 50–80
CrCl < 50
0.88 (0.64–1.22)
0.74 (0.56–0.97)
0.79 (0.55–1.14)
0.70 CrCl > 80
CrCl 50–80
CrCl < 50
0.80 (0.61–1.04)
0.77 (0.62–0.94)
0.50 (0.38–0.66)
0.03
ENGAGE AF-TIMI 4843,‡ CrCl ≥ 50
CrCl < 50
0.87 (0.65–1.18)
0.87 (0.72–1.04)
0.94 CrCl ≥ 50
CrCl < 50
0.82 (0.71–0.95)
0.76 (0.58–0.98)
0.62
AF = atrial fibrillation; CI = confidence interval; DOAC = direct-acting oral anticoagulant; DVT = deep vein thrombosis; PE = pulmonary embolism; RR = relative risk
*Included major bleeding and clinically relevant non-major bleeding; †150 mg twice daily; ‡60 mg daily

In a subgroup analysis of the individual AF outcomes trials, the risk of stroke was not statistically significantly different in patients with moderate renal dysfunction compared to patients without moderate renal function for any of the DOACs.15 An exploratory analysis found a numerically higher risk of stroke with high-dose edoxaban in patients with a CrCl of 95 mL/min or greater, but this difference was not statistically significant (P = 0.08).44 However, the FDA recommends that edoxaban not be used in AF patients with a CrCl of 95 mL/min or greater.26 The risk of major bleeding in the subgroup analysis of individual AF trials in patients with and without moderate renal dysfunction was not statistically significantly different with dabigatran, rivaroxaban, or edoxaban. The risk of major bleeding was, however, statistically significantly less with apixaban in patients with moderate renal dysfunction (P = 0.03).15 A pooled analysis of the outcomes studies found the risk of stroke to be statistically significantly lower for DOACs than for warfarin among patients with moderate renal impairment compared to normal renal function (RR, 0.80; 95% CI, 0.69–0.92).45 DOACs were also associated with fewer major bleeds in patients with moderate renal dysfunction (RR, 0.73; 95% CI, 0.65–0.82).45 The results of this meta-analysis suggest DOACs are a better choice than warfarin for AF patients with moderate renal dysfunction. 

Data concerning the selection of anticoagulant therapy in patients with severe renal disease, with ESRD, or on dialysis are sparse. Two observational studies designed to evaluate the use of DOACs in patients with severe renal disease, ESRD, and dialysis have been published.46,47 A retrospective analysis of the U.S. Renal Data System included AF patients with ESRD on dialysis. Because of low numbers of patients on DOACs other than apixaban, the study compared outcomes among dialysis patients receiving either warfarin (n = 23,172) or apixaban (n = 2,351). There was no difference in the risk of stroke between apixaban and warfarin (HR, 0.88; 95% CI, 0.69–1.12; P = 0.29), but apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59–0.87; P < 0.001). A sensitivity analysis of the data showed that apixaban 5 mg twice a day was superior to both apixaban 2.5 mg twice daily and warfarin for the risk of stroke and death in patients with CKD.46 Another study analyzed AF patients undergoing dialysis identified from the Fresenius Medical Care North America ESRD database who were treated with warfarin (n = 8,064), dabigatran (n = 281), or rivaroxaban (n = 244).47 Poisson regression analysis was used to compare the rate of stroke and major bleeding with dabigatran, rivaroxaban, or warfarin. Compared to warfarin, dabigatran (rate ratio, 1.48; 95% CI, 1.21–1.81; P < 0.001) and rivaroxaban (rate ratio, 1.38; 95% CI, 1.03–1.83; P = 0.04) were associated with a higher risk of hospitalization or death from bleeding. The risk of hemorrhagic death alone was also greater with dabigatran (rate ratio, 1.78; 95% CI, 1.18–2.68; P = 0.006) and rivaroxaban (rate ratio, 1.71; 95% CI, 0.94–3.12; P = 0.07) relative to warfarin.

The selection of a specific DOAC or warfarin in patients with severe renal dysfunction including patients on dialysis is difficult. There is a lack of data with DOACs in patients on dialysis being treated with a DOAC for acute DVT/PE. Data with DOACs in AF patients on dialysis are conflicting. The U.S. Renal Data System analysis suggests apixaban to be a better option than warfarin. The Fresenius ESRD database suggests that dabigatran and rivaroxaban were associated with worse outcomes compared to warfarin. For AF patients with ESRD and those receiving dialysis, the 2019 American Heart Association/American College of Cardiology/Heart Rhythm Society Focused Update on Management of AF does not recommend the use of dabigatran, edoxaban, or rivaroxaban (Class III C-EO, indicating a consensus of expert opinion based on clinical experience).48 These guidelines indicate it is reasonable to use warfarin or apixaban in patients with ESRD or receiving dialysis (IIb B-NR, indicating less well-established efficacy and data derived from nonrandomized trials or meta-analyses).48 Whether this recommendation can be extrapolated to DVT/PE patients with ESRD or on dialysis is unknown. On-going randomized outcomes trials comparing DOACs with warfarin will provide greater clarity concerning the optimal anticoagulant strategy in patients with ESRD and those on dialysis. 

Drug Interactions

The potential for bleeding resulting from pharmacodynamic interactions between oral anticoagulants and other drugs associated with bleeding is relevant for both DOACs and warfarin. The shorter duration of anticoagulant effect of DOACs compared to warfarin may impact the duration and severity of bleeding resulting from pharmacodynamic interactions.49 The consistently lower rates of life-threatening bleeding and intracranial hemorrhage with DOACs may result from the difference in their duration of action. A similar degree of caution is advised when using either a DOAC or warfarin with other drugs associated with an increased risk of bleeding, such as other anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatory agents. 

Pharmacokinetic interactions should occur less frequently with DOACs compared to warfarin due to less interindividual variation with DOACs. Many of the pharmacokinetic interactions with DOACs listed in their prescribing information are based on pharmacokinetic studies in healthy volunteers.24–27 Because DOAC dose adjustment is not based on changes in coagulation assays, it is more difficult to predict the potential magnitude of changes in therapeutic effect when these drugs are prescribed with interacting drugs. Changes in the prothrombin time and international normalized ratio with warfarin are helpful in the identification of clinically relevant drug interactions. 

All DOACs are substrates for the p-glycoprotein (P-gp) efflux transporter in the intestine.24–27 Drugs that inhibit P-gp will reduce efflux from the gut and increase bioavailability of DOACs, leading to higher plasma concentrations and a potential increased risk of bleeding. P-gp inducers increase efflux of DOACs from the gut, reducing bioavailability and leading to a potential increase in the risk of thromboembolism. The DOACs differ substantially regarding renal clearance and cytochrome P450 (CYP) enzyme metabolism. The proportion of drug cleared unchanged by renal elimination is 80% for dabigatran, 50% for edoxaban, 36% for rivaroxaban, and 27% for apixaban.24–27 Dabigatran and edoxaban are not metabolized by CYP enzymes to any extent. Approximately 25% of apixaban and 18% of rivaroxaban undergo metabolism primarily by CYP3A4. 

The concomitant administration of P-gp inducers is discouraged with all DOACs (Table 4).24–27 A substantial reduction in plasma concentrations of any of the DOACs would increase the risk of a thromboembolic event. The specific recommendations about the concomitant use of P-gp inducers in the prescribing information are somewhat different for each DOAC. The prohibited P-gp–inducing drugs also induce the CYP3A4 enzymes, which are responsible for partial metabolism of apixaban and rivaroxaban.24,27 The prescribing information for apixaban and rivaroxaban state that combined P-gp and strong CYP3A4 inducers should be avoided. The P-gp inducers that interact with dabigatran and edoxaban are also known to induce CYP3A4. Drugs that are both P-gp and CYP3A4 inducers include rifampin, the first-generation anticonvulsant agents (phenytoin, phenobarbital, and carbamazepine), conivaptan, and St. John’s wort. 

Table 4 FDA Prescribing Information Concerning Drug Interactions With DOACs
  Apixaban24 Dabigatran25 Edoxaban26 Rivaroxaban27
P-gp inducers Not mentioned Generally avoid (i.e., rifampin) Avoid (i.e., rifampin) Not mentioned
P-gp inducers and strong CYP3A4 inducers Avoid Not mentioned Not mentioned Avoid
P-gp inhibitors Not mentioned AF: CrCl 30–50 mL/min, dose reduction to 75 mg BID
AF: avoid if CrCl < 30 mL/min
DVT/PE: avoid if CrCl < 50 mL/min
Dose reduction to 30 mg/day with use of verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole Not mentioned
P-gp inhibitors and strong CYP3A4 inhibitors 50% dose reduction from 5 or 10 mg BID; avoid if 2.5 mg BID Not mentioned Not mentioned Avoid (e.g., azole antifungals, ritonavir)
P-gp inhibitors and moderate CYP3A4 inhibitors Not mentioned Not mentioned Not mentioned Avoid in CrCl < 80 mL/min unless benefit justifies risk (e.g., diltiazem, verapamil, dronedarone, erythromycin)
AF = atrial fibrillation; BID = twice daily; CrCl = creatinine clearance; DOAC = direct-acting oral anticoagulant; DVT = deep vein thrombosis; PE = pulmonary embolism

The magnitude of the interaction between P-gp inhibitors and DOACs differs with the specific drug. As P-gp inhibition and renal dysfunction both result in increased levels of dabigatran, restrictions on the concomitant use of P-gp inhibitors with dabigatran is impacted by the presence of renal dysfunction.25 A reduction in the dose of dabigatran to 75 mg twice daily is recommended with the concomitant use of P-gp inhibitors in AF patients with moderate renal impairment (CrCl 30–50 mL/min). It is recommended that P-gp inhibitors be avoided with dabigatran in DVT/PE patients with moderate renal impairment (CrCl 30–50 mL/min) and in AF patients with severe renal impairment (CrCl 15–30 mL/min). With edoxaban, concomitant administration of a P-gp inhibitor does not require a dose adjustment in patients with AF. For acute DVT/PE, the edoxaban dose should be reduced from 60 mg a day to 30 mg a day when administered with a P-gp inhibitor.26

The recommendations in the prescribing information of apixaban and rivaroxaban for drugs that are both P-gp and CYP3A4 inhibitors are different for each drug. Dose adjustment from 5 mg twice daily to 2.5 mg twice daily is recommended for apixaban when used with a P-gp inhibitor that is also a strong CYP3A4 inhibitor.24 Patients taking apixaban 2.5 mg twice daily should avoid P-gp inhibitors with strong CYP3A4 inhibition (e.g., azole antifungals, ritonavir). In the label for rivaroxaban, recommendations are stratified on the basis of whether the interacting drug is a strong or moderate CYP3A4 inhibitor.27 Examples of strong CYP3A4 inhibitors include ketoconazole and ritonavir, while moderate CYP3A4 inhibitors include diltiazem, verapamil, dronedarone, and erythromycin. Rivaroxaban should be avoided with concomitant use of a P-gp inhibitor and a strong CYP3A4 inhibitor. Rivaroxaban should not be used with a P-gp inhibitor and a moderate CYP3A4 inhibitor if the CrCl is less than 80 mL/min. Amiodarone is considered a weak CYP3A4 inhibitor in the rivaroxaban prescribing information.27 Concomitant use of amiodarone with either apixaban or rivaroxaban is not mentioned in either drug’s label.24,27

Two reports evaluated clinical outcomes with amiodarone and apixaban and with edoxaban in their respective AF trials. In the ARISTOTLE trial, apixaban was superior to warfarin in reducing thromboemoblic events, death, and major bleeding in amiodarone-treated patients as well as in patients not receiving amiodarone.50 Although a formal comparison of outcomes with apixaban with and without amiodarone was not performed, the observed rates of stroke were not different among patients receiving apixaban with or without amiodarone. However, the rates of all-cause death and cardiovascular death were greater with apixaban and amiodarone compared to apixaban without amiodarone. Major bleeding, major bleeding plus CRNMB, and intracranial bleeding were numerically less with apixaban and amiodarone compared to apixaban alone. In the edoxaban outcomes trial, low-dose edoxaban with amiodarone reduced stroke to a statistically significantly greater extent when compared to warfarin with amiodarone.51 This result differed from the overall trial outcome, which demonstrated noninferiority between low-dose edoxaban and warfarin for prevention of stroke. Amiodarone use did not affect the risk of stroke with high-dose edoxaban or bleeding risk with either dose of edoxaban. The results of these post hoc analyses are difficult to evaluate. These studies were unable to determine the mechanism of the resulting differences in outcomes. It would appear that amiodarone had little relative impact on apixaban compared to warfarin, while amiodarone was associated with a favorable effect on efficacy of low-dose edoxaban. 

The bulk of the evidence concerning DOAC use with interacting drugs is primarily based on extrapolation from pharmacokinetic studies in healthy volunteers. Differences in the prescribing information concerning drug interactions for each of the DOACs are somewhat arbitrary and are not based on clinical evidence. Following the recommendations in the prescribing information as closely as is feasible with careful clinical monitoring will be required to provide the best clinical outcomes. 

Hepatic Dysfunction

Hepatic dysfunction occurs secondary to a wide variety of causes.52 The most common causes of chronic liver disease include nonalcoholic fatty liver disease (NAFLD), hepatitis B or C viral infections, and alcohol-related liver disease. Patients with chronic liver disease are at increased risk for both AF and DVT/PE.53 Risk factors for the development of NAFLD include obesity, diabetes mellitus, metabolic syndrome, and dyslipidemia. These risk factors are also associated with an increased risk of AF.14 Alcohol consumption is also a well-defined risk factor for AF. Chronic liver disease is also associated with systemic inflammation, elevated estrogen levels, and decreased synthesis of endogenous anticoagulants leading to an increased risk of DVT/PE.53 Chronic liver disease is also associated with an increased risk of portal vein thrombosis resulting from impaired blood flow in the splanchnic vascular system, intra-abdominal infections, inflammation, and portal vein compression secondary to ascites.54

Managing thromboembolic risk in patients with chronic liver disease is complicated. Elevations in the prothrombin time and/or partial thromboplastin time in chronic liver disease (referred to as auto-anticoagulation) were once thought to reduce the risk of thromboembolic events. Current evidence indicates that patients with chronic liver disease continue to have a high risk of thromboembolic events despite these elevations in coagulation assay test results.55 This is complicated by the finding that despite the increased risk of thromboembolism, chronic liver disease is also associated with an increased risk of bleeding.55 

Patients with chronic liver disease were largely excluded from the outcomes studies with DOACs.24–27 Patients with abnormal biochemical markers (transaminases, bilirubin) associated with liver disease, a history of hepatitis B or C, active liver disease, or cirrhosis were excluded from these trials. In the AF outcomes study with edoxaban, 1,083 patients with a history of mild liver disease were enrolled.56 In a post hoc analysis, the adjusted risk of stroke was not different between patients with and without liver disease (1.45%/year versus 1.71%/year; HR, 0.89; 95% CI, 0.65–1.22; P = 0.48). However, the adjusted risk of major bleeding was increased in patients with liver disease compared to those without (3.32%/year versus 2.55%/year; HR, 1.38; 95% CI, 1.10–1.74; P = 0.006). Outcomes with edoxaban and warfarin in patients with mild liver disease were similar to patients without liver disease. The primary composite efficacy endpoint was not significantly different between edoxaban and warfarin in patients with and without liver disease, while edoxaban was associated with a significantly lower risk of major hemorrhage compared to warfarin in patients with and without liver disease. Mild liver disease did not affect peak and trough factor Xa inhibition with edoxaban. 

The largest systematic review of DOAC use in patients with chronic liver disease included 19,798 patients included in seven retrospective cohort studies of AF.57 Anticoagulant use in the seven cohorts ranged from about 8% to 54%. Anticoagulation was associated with a significant reduction in the risk of stroke compared to no anticoagulant use (pooled HR, 0.58; 95% CI, 0.35–0.96). Anticoagulation was associated with a numerically higher risk of bleeding compared to no treatment, but the difference was not statistically significant (pooled HR, 1.45; 95% CI, 0.96–2.17). Compared to warfarin, DOACs were associated with a lower risk of bleeding and a similar risk of stroke. 

Due to the lack of outcomes data with DOACs in patients with chronic liver disease, prescribing information concerning their use in patients with hepatic dysfunction is primarily based on pharmacokinetic data.24–27 None of the DOACs is recommended for use in patients with Child-Pugh class C (severe) hepatic disease. No dose adjustment is required for dabigatran in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Dabigatran has the lowest hepatic clearance (20%) of any of the DOACs. About 50% of edoxaban is cleared hepatically. No dose adjustment is recommended in Child-Pugh class A hepatic disease, but the drug is not recommended in Child-Pugh class B patients. No dose adjustment is recommended for apixaban in Child-Pugh class A patients. No recommendations concerning the use of apixaban in Child-Pugh class B patients is provided in its label. Rivaroxaban can be used without dose adjustment in Child-Pugh class A patients, but is not recommended in Child-Pugh class B patients. 

No anticoagulant strategy has clearly been shown to be superior to others in patients with severe chronic liver injury. Patients with chronic liver disease and an indication for anticoagulation should be treated. The risk of thromboembolism typically outweighs the risk of bleeding in these patients. Until additional data comparing outcomes with different anticoagulation strategies in chronic liver disease become available, the selection of an anticoagulant should be individualized based on a comprehensive assessment of a patient’s clinical characteristics. 

CONCLUSION

Recommendations concerning the selection of the type of oral anticoagulant to be used in patients excluded from or underrepresented in the outcomes trials comparing DOACs to warfarin are tenuous. The relative benefits of DOACs compared to warfarin appear to be similar in elderly patients (age 75 years or older) compared to their younger counterparts. In patients with severe renal dysfunction, the ACC/AHA/HRS AF guidelines indicate that either apixaban or warfarin is the most reasonable treatment option. Whether this recommendation can be extrapolated to the treatment of acute DVT/PE in patients with severe renal dysfunction is uncertain. The relative benefits of DOACs compared to warfarin in underweight or overweight/obese patients have not been adequately defined. Limited observational data suggest that DOACs are as safe and effective as warfarin in overweight and obese patients using standard dosage regimens. However, the ISTH indicates that DOACs cannot be recommended in patients with weights greater than 120 kg or a BMI greater than 40 kg/m2. A recommendation for the selection of an anticoagulant in patients with severe hepatic disease cannot be made due to a lack of data. Dabigatran appears to be the most reasonable option in patients with moderate hepatic dysfunction based on prescribing information. Recommendations concerning dosage adjustment or avoidance of DOACs with specific interacting drugs can only be based on the respective prescribing information for each drug due to a lack of clinical data. Ongoing studies in these patient populations should provide further clarity concerning appropriate selection of specific anticoagulants and dosage adjustments based on the clinical characteristics of patients.

Disclosure: The authors report no financial or commercial interest in regard to this article.

Author bio: 

Dr. Hilleman and Dr. Malesker are Professors in the School of Pharmacy and Health Professions at Creighton University in Omaha, Nebraska, where Dr. Hilleman is also Director of Continuing Education. Dr. Hannig is affiliated with CHI Health Creighton University Medical Center–Bergan Mercy Hospital in Omaha. Dr. Hilleman (hilleman@creighton.edu) is the corresponding author.

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