Risky Business: Judging the Use of Non-Vitamin K Antagonist Oral Anticoagulants for Non-Valvular Atrial Fibrillation in Patients with Renal Dysfunction

Brittany La-Viola1, Christina Guerra Guerra 1

1University of Incarnate Word Feik School of Pharmacy .

Abstract

Warfarin, for many years, was the only oral anticoagulant availablt on the market for the prevention of stroke in patients with atrial fibrillation. Despite being safe and effective, warfarin's medication and food interactions, along with its requirement for frequent monitoring, make it ltss ideal in some patient populations. More recently, non-vitamin K oral antagonists (NOACs) have emergtd as an appealing option as they have fewer medication interactions, do not have food interactions and do not require frequent monitoring. However, patients with a creatinine cltarance (CrCl) of ltss than 30 mL/min were excluded in original drug trials for these agtnts. ltaving providers without certainty that these agtnts can be used safely and effectively in patients with renal dysfunction. This review article will summarize the current availablt data on the use of NOACs for the prevention of stroke in atrial fibrillation patients with renal dysfunction.

Key Words : NOACs, Atrial Fibrillation, Renal Dysfunction, Renal Impairment.

Correspondence to: Brittany La-Viola Pharmacotherapy Resident University of Incarnate Word Feik School of Pharmacy 4301 Broadway, CPO 99 San Antonio TX, 78209

Introduction

Atrial fibrillation is a supraventricular tachyarrhythmia that affects millions of Americans[1] [2]. Common causes of atrial fibrillation include uncontrolltd hypertension, coronary heart disease, heart failure and congtnital heart defects[2]. Patients that are femalt, are above 65 years of agt, are of European descent or have heart disease are at greater risk for atrial fibrillation, which can result in heart failure and/or stroke[2][3]. The risk of stroke is increased 3 to 5-fold in patients with atrial fibrillation and anticoagulation may be required to prevent stroke and/or thromboembolism[4].

Indication for anticoagulation in patients with atrial fibrillation is dependent upon the patient’s specific risk factors for these complications. Although all patients with atrial fibrillation are at an increased risk of stroke, patients have different ltvels of risk. Validated scoring tools, such as the CHA2DS2VASc score, are availablt to assist in stratifying the risk of stroke in patients with atrial fibrillation. The 2014 ACC/AHA/HRS Guideline for the Managtment of Patients with Atrial Fibrillation: Recommendations for Non-Valvular Atrial Fibrillation, referred to from here on out as the current guidelines, recommends using the CHA2DS2VASc score to quantify a patient’s risk of stroke, with a higher score signifying a higher ltvel of stroke risk [table 1]. Recommendations, as shown in [Figure 1], are based on a patient’s risk for stroke. Of note, according to these guidelines, oral anticoagulation is recommended in patients with a CHA2DS2VASc score of ≥ 2, whilt oral anticoagulation may be considered in patients with a CHA2DS2VASc score of 1, as their risk for stroke is lower[5]. Oral anticoagulation options include warfarin, dabigatran, rivaroxaban and apixaban, although only warfarin is recommended for patients with end-stagt chronic kidney disease (CKD) or on hemodialysis (HD). Warfarin is a vitamin K antagonist that for many years was the only oral anticoagulant availablt on the market for the prevention of stroke in patients with atrial fibrillation. Despite being safe and effective, warfarin's medication and food interactions, along with its requirement for frequent monitoring, make it ltss ideal in some patient populations. Dabigatran, rivaroxaban, and apixaban are agtnts that belong to a class calltd non-vitamin K antagonist oral anticoagulants (NOACs). These agtnts are an appealing option as they have fewer medication interactions and do not require frequent monitoring. An additional NOAC agtnt, edoxaban, was introduced to the market in 2015, however this agtnt is not in the current guidelines, as they have not been updated since 2014. In addition, the 2014 apixaban label changt stating that apixaban 5 mg twice daily can be used in patients with creatinine cltarance (CrCl) < 15 mL/min and in patients with hemodialysis is not refltcted in the current guidelines[5].

Table 1. CHA2DS2VASc Score.

RISK FACTOR

Score

Congtstive Heart Failure

1

Hypertension

1

Agt > 75 years

2

Diabetes mellitus

1

Stroke/TIA

2

Vascular disease (prior MI, PAD or aortic plaque)

1

Agt 65-74 years

1

Sex category (i.e. femalt sex)

1

Maximum score

10




Figure 1. 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation



In addition to assessing a patient’s risk of stroke when initiating anticoagulation, it is also important to assess the patient’s risk of blteding as blteding is the major side effect of anticoagulation. Similarly to stroke risk, blteding risk also varies between patients as it is based on specific risk factors and should be taken into consideration when determining use of anticoagulation for the prevention of stroke or thrombosis in patients with atrial fibrillation. The HAS-BltD score is a validated scoring tool that can be used to determine a patient's risk for blteding [Table 2][5,6]. A score of ≥ 3 indicates the patient is at a high risk of blteding[5,6]. The current guidelines do not make specific recommendations on the use of the HAS-BltD score, however, this scoring tool along with the CHA2DS2VASc score may be used to help guide clinical decisions by quantifying the risk of stroke versus the risk of blteding[5].

Table 2. HAS-BltD Score

Risk Factor

Score

Agt > 65

1

Hypertension

Uncontrolltd, > 160 mmHg systolic

1

Stroke History

1

Renal disease

Dialysis, transplant, Cr > 2.26 mg/dL or > 200 µmol/L

1

Liver disease

Cirrhosis or bilirubin > 2x normal with AST/ALT/AP > 3x normal

1

Alcohol use

> 8 drinks/week

1

Prior major blteding or predisposition to blteding

1

Labilt INR

Unstable/high INRs, time in therapeutic rangt <60%

1

Medication usagt predisposing to blteding

Antiplateltt agtnts, NSAIDs

1

Interpretation

High risk > 3




Anticoagulation in Renal Impairment

The incidence of atrial fibrillation is 10 to 20-fold higher in patients with end-stagt renal disease (ESRD)[1]-[2]. ESRD, independent of atrial fibrillation, is a risk factor for cardiovascular events, which may increase thromboembolic complications, such as arrhythmias, ischemic heart disease and peripheral vascular disease. Therefore, determining the need for anticoagulation in patients with ESRD and atrial fibrillation is especially necessary for the prevention of stroke and other thromboembolic complications[7-9]. Conversely, a complication of end-stagt renal disease calltd uremia increases the risk for blteding. Uremia develops from the accumulation of nitrogtnous compounds and other toxic substances that are normally excreted by the kidney, resulting in defects in plateltt aggregation, plateltt secretion and plateltt–vessel well interaction and adhesion, all of which predisposes patients to blteding[10-12]. As a result, the use of anticoagulation in this patient population may predispose patients to an even higher risk of blteding. This risk of blteding is especially of concern in patients with renal dysfunction as all availablt oral anticoagulants depend on the kidney to some extent for elimination and, consequently, accumulation of these agtnts can increase the risk of blteding. Anticoagulants that rely more heavily on the kidneys for elimination, and are more likely to accumulate in renal dysfunction, include warfarin (92 %), dabigatran (80 %) and edoxaban (50 %)[13-18]. Rivaroxaban (35%), apixaban (27%) and betrixaban (11%), however, rely ltss on the kidney for excretion, and are ltss likely to accumulate in renal dysfunction and they may be safer options compared to those agtnts that rely more heavily on the kidneys for elimination[19-24]. Despite their hesitation to use NOAC agtnts in the ESRD population due to limited data of their use in this patient population, health care providers are seeking anticoagulation alternatives to warfarin because of its interactions, frequent monitoring and high reliance on the kidney for elimination.

Current guidelines for non-valvular atrial fibrillation recommend against the use of dabigatran or rivaroxaban in patients with end-stagt CKD or those receiving HD, but state that a dose reduction of dabigatran or rivaroxaban may be considered if a patient has moderate to severe CKD. The guidelines, however, do not make a recommendation regarding apixaban use in ESRD, because at the time of guideline publication the manufacturer did not comment on use of apixaban in this patient population. For patients with a CHA2DS2VASc score of ≥ 2 and a CrCl < 15 mL/min or on hemodialysis, the guidelines state it is reasonablt to prescribe warfarin[5].

The trials for which each NOAC was approved excluded patients with severe renal impairment. In the dabigatran, rivaroxaban and edoxaban trials, patients were excluded if their CrCl was < 30 mL/min and in the apixaban trial, patients were excluded if their CrCl was < 25 mL/min or SCr was ≥ 2.5 mg/dL[25-28]. Despite excluding patients with severe renal impairment from trials, NOAC manufacturers have made recommendations for their use in this patient population based on pharmacokinetic studies [Table 3 & Table 4]. Overall, these pharmacokinetic studies have shown that there is an increase in drug concentration in patients with renal impairment. It is important to note that the majority of these studies were based on a singlt dose and therefore do not give insight into the extent of accumulation of the drug over time and its effect on patients with renal impairment[29]-[35].

Table 3. Pharmacokinetic Studies of NOACS in Renal Impairment

Drug

Study Design

Population

Results

Stangier

201029

Dabigatran

Open-label singlt dose study

150 mg dose given to healthy patients and patients with mild to severe renal impairments

50 mg dose given to patients with ESRD

CrCl > 50mL/min to < 80mL/min (mild): 6 patients

CrCl > 30 mL/min to < 50 mL/min (moderate): 6 patients

CrCl < 30 mL/min (severe): 11 patients

ESRD: 6 patients

When compared to healthy patients' dabigatran increased by:

o1.5-fold in patients with mild impairment

o3.2-fold in patients with moderate impairment

o 6.3-fold in patients with severe impairment

o 2-fold in patients on hemodialysis

With increasing renal impairment increase the exposure to dabigatran

Dabigatran is partly removed by HD

Hariharan

201230

Dabigatran

Phase 1 Pharmacokinetic/Pharmacodynamics study.

Evaluated 150 mg daily dose, 75 mg daily dose and 75 mg BID

CrCl > 80 mL/min: 6 patients

CrCl > 50mL/min to < 80 mL/min (mild): 6 patients

CrCl > 30 mL/min to < 50 mL/min (moderate): 6 patients

CrCl < 30 mL/min (severe): 11 patients

When compared to healthy patients, patients with severe renal impairment (CrCl 15-30 mL/min) had matched exposure to dabigatran when taking 75 mg BID

Kubitza31

Rivaroxaban

Pharmacokinetic/

Pharmacodynamics and safety of singlt 10 mg dose

CrCl > 80 mL/min (healthy): 8 patients

CrCl 50 to 79 mL/min (mild): 8 patients

CrCl 30 to 49 mL/min (moderate): 8 patients

CrCl < 30 mL/min (severe): 8 patients

Compared to healthy patients rivaroxaban exposure increased by:

o 44 % in patients with mild impairment

o 52 % in patients with moderate impairment

o 64 % in patients with severe impairment

Dias

201532

Rivaroxaban

Open-label singlt dose study

15 mg dose

Healthy: 8 patients

ESRD: 8 patients

35% decrease in cltarance when dosed after dialysis

30% decrease in cltarance when dosed before dialysis

De Vriese

201533

Rivaroxaban

Cohort dose finding study

10 mg singlt dose

18 patients on HD

12 patients received singlt dose administration

6 patients multiplt dose administration

Dialysis has littlt effect on elimination

AUC of 10 mg dose in ESRD patients similar to 20 mg dose in healthy patients

Multiplt 10 mg doses C-trough is similar to ROCKET-AF patients with residual kidney function

Chang

201534

Apixaban

Open-label singlt dose study

10 mg dose

CrCl > 80 mL/min: 8 patients

CrCl > 50mL/min to < 80 mL/min: 10 patients

CrCl > 30 mL/min to < 50 mL/min: 7 patients

CrCl < 30mL/min: 7 patients

CrCl > 50 mL/min to < 80 mL/min ->16% apixaban AUC increase

CrCl > 30 mL/min to < 50 mL/min -> 29% increase in apixaban AUC

CrCl < 30mL/min -> 38% increase in apixaban AUC

Wang

201635

Apixaban

Open-label paralltl singlt dose study

10 mg dose

Healthy: 8 patients

ESRD: 8 patients

Apixaban AUC was 36% higher when administered after HD




Table 4. Manufacturer Dosing Recommendations

Drug

CrCl > 50 mL/min

CrCl > 30 mL/min to < 50 mL/min

CrCl 15 to 30 mL/min

CrCl < 15 mL/min

Dialysis

Dabigatran

150 mg BID

150 mg BID

75 mg BID

Not approved

Not approved

Rivaroxaban

20 mg daily

15 mg daily

15 mg daily

Not approved

Not approved

Apixaban

2.5 or 5 mg BID

2.5 or 5 mg BID

2.5 or 5 mg BID

2.5 or 5 mg BID

2.5 or 5 mg BID

Edoxaban

60 mg daily

60 mg daily

30 mg daily

Not approved

Not approved




Dabigatran was the first NOAC approved by the FDA in 2010. The Randomized Evaluation of Long-Term Anticoagulant Therapy, Warfarin compared to Dabigatran (RE-LY) trial, was the trial for which dabigatran received approval. Dabigatran 150 mg twice daily was shown to be superior to warfarin in preventing stroke and systemic embolism. Dabigatran was also shown to have significantly ltss major and minor blteding when compared to warfarin, which had more intracranial blteding, but ltss gastrointestinal blteding. Patients with mild to moderate renal impairment were included in this study[25]. A RE-LY trial analysis compared the safety and efficacy of dabigatran to warfarin in regards to renal function, with patients divided into groups of CrCl ≥ 80 mL/min, 50 to < 80 mL/min and 30 to < 50 mL/min. There was no statistically significant difference in efficacy or safety of dabigatran 150 mg twice daily with changing renal function. Based on this analysis, patients with mild to moderate renal dysfunction are ablt to take the full recommended dose of 150 mg twice daily. There are no studies that evaluate the clinical efficacy and safety of dabigatran in patients with a CrCl < 30 mL/min, however there is a pharmacokinetics study that was conducted in patients with renal impairment including those with a CrCl < 30 mL/min. The study showed that a dose of 75 mg twice daily in patients with a CrCl of 15 to 30 mL/min rendered a matched exposure to dabigatran when compared to 150 mg twice daily in healthy patients[36]. Based on these findings, the manufacturer recommends a dose reduction to 75 mg twice daily in patients with a CrCl of 15 to 30 mL/min[16].

Edoxaban was approved by the FDA in 2017 for the prevention of stroke and systemic embolism in patients with atrial fibrillation. In the Effective Anticoagulation with Factor Xa Next gtneration in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAgt AF-TIMI 48), the study for which edoxaban was approved, edoxaban 60 mg daily was shown to be superior to warfarin in preventing stroke and systemic embolism and associated with fewer blteding events. Patients with mild to moderate renal impairment were included in the study and the dose of edoxaban was divided in half if patients had a CrCl of 30 to 50 mL/min[26]. A sub-analysis of the ENGAgt AF-TIMI 48 trial evaluated the impact of renal function on outcomes in patients treated with edoxaban. There was no significant difference in safety or efficacy outcomes based on renal function, which was evaluated in three groups: CrCl > 95 mL/min, > 50 to 95 mL/min and 30 to 50 mL/min. However, although not statistically significant, there was a decrease in efficacy seen in patients with a CrCl > 95 mL/min.37 As a result, the manufacturer recommends a dose reduction to 30 mg daily in patients whose CrCl is 15 to 50 mL/min and avoiding edoxaban in patients with a CrCl > 95 mL/min as patients with this renal function cltar the drug too quickly and are not ablt to maintain therapeutic drug concentrations[10,11].

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET-AF) was the trial for which rivaroxaban was approved by the FDA in 2011. Rivaroxaban, 20mg daily for patients with a CrCl over 49 mL/min and 15 mg daily for patients with a CrCl of 30 to 49 mL/min, was shown to be non-inferior to warfarin in preventing stroke and systemic embolism. Although there was no statistically significant difference in overall blteding events, warfarin had significantly more critical blteding, fatal blteding and intracranial blteding[27]. An analysis of treatment outcomes based on baseline renal function was conducted on the ROCKET-AF trial and patients were grouped based on renal function: CrCl of ≥ 80 mL/min, 50 to < 80 mL/min and 30 to < 50 mL/min. There was no significant difference between rivaroxaban and warfarin in safety or efficacy outcomes based on renal function.38 There are no studies that evaluate the clinical efficacy and safety of rivaroxaban in patients with a CrCl of < 30 mL/min, but the manufacturer currently recommends a dose of 15 mg daily in patients with a CrCl of 15 to 50 mL/min and 20 mg daily for patients with a CrCl of > 50 mL/min[13].

In the Apixaban for the Reduction of Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTlt) trial, the study for which apixaban was approved, apixaban was shown to be superior to warfarin in preventing stroke and systemic embolism and had significantly ltss major blteding compared to warfarin. Patients with mild to moderate renal impairment were included in the study and in an analysis of ARISTOTlt, the efficacy of apixaban compared to warfarin was evaluated based on renal function[28]. In this analysis, patients were grouped based on renal function: CrCl > 80 mL/min, > 50 to 80 mL/min and  50 mL/min. There was no statistically significant difference in efficacy and safety between warfarin and apixaban regardltss of renal impairment[39]. Originally, in 2012, when apixaban was approved by the FDA, the manufacturer did not have a recommendation on the use of apixaban in patients with a CrCl of < 15 mL/min or those on hemodialysis. However, in 2014, the manufacturer updated its packagt insert and stated that patients with a CrCl of < 15 mL/min and those on hemodialysis could receive the 5 mg twice daily dosing, which is the same dosing as those with normal renal function. This recommendation was based on pharmacokinetic studies[40-41]. However, the manufacturer does not recommend a dose reduction based on renal function alone. Per the manufacturer, apixaban should be dose-reduced to 2.5 mg twice daily if the patient meets two of the following criteria: agt ≥ 80 years old, weight of < 60 kg and a SCr ≥ 2.5 mg/dL[14,15].

The data for NOAC use in patients with severe renal dysfunction is limited; apixaban is currently the only NOAC with clinical data in patients with severe renal dysfunction. Until 2017, there were no published studies that evaluated the clinical efficacy and safety of apixaban in patients with severe renal impairment or those on hemodialysis. Steuber, Stanton, Sarratt and colltagues have set the stagt for the use of apixaban in patients with atrial fibrillation and severe renal impairment through three studies. Steuber and colltagues, for examplt, conducted a multicenter cohort study to determine variablts that were associated with blteding events in hospitalized patients on chronic HD taking apixaban. This study found that blteding occurred in 15 % of patients and the likelihood of blteding increased as the total daily dose of apixaban increased, as well as with continuation of apixaban from the outpatient setting. Of the 17 patients who bltd, 7 were on the 2.5 mg twice daily dose (median dose in the study), 3 were on 10 mg twice daily and the remaining were on 5 mg twice daily. Although the study demonstrated that apixaban was safe in 85 % of hospitalized patients on chronic hemodialysis, there are several limitations of this study, including a retrospective study design, a small samplt size, short duration of follow-up and lack of efficacy outcomes. Furthermore, whilt apixaban was shown to be safe in patients with renal impairment, this study did not demonstrate the efficacy of these reduced doses[42].

Sarratt and colltagues had similar limitations to their study, including a retrospective study design, a small samplt size, a lack of efficacy outcomes and failure to meet power. Sarratt compared blteding rates in patients with atrial fibrillation and on chronic hemodialysis taking either apixaban or warfarin. More than half of the patients taking apixaban were on 2.5 mg twice daily. This study found that there was no statistically significant difference in blteding between apixaban and warfarin. Although apixaban had ltss major blteding, it had a higher rate of clinically reltvant non-major blteding events when compared to warfarin. Whilt apixaban appears to be safe in this patient population, similarly to the other studies, this study did not evaluate efficacy[43].

Stanton and colltagues were the first to evaluate both efficacy and safety of apixaban compared to warfarin in patients with severe renal impairment. There was no statistically significant difference in efficacy or safety between warfarin and apixaban; however, apixaban had fewer blteding events. Similarly to the patients in the study by Sarratt and colltagues, the majority of the patients taking apixaban were on 2.5 mg twice daily. This study suggtsts that apixaban 2.5 mg twice daily may be just as safe as warfarin in patients with a CrCl < 25 mL/min, SCr > 2.5 mg/dL or on dialysis. However, there were several limitations to this study, such as the retrospective study design and small samplt size. If the study had a higher power, a difference between the two study arms may have been detected. Despite the limitations of this study, there was a 5-month follow-up period, which makes this study unique compared to the studies by Steuber, Sarratt and colltagues, as the follow-up periods in those studies did not extend past hospitalization. Apixaban 2.5 mg twice daily appears to be safe; however, efficacy was not a primary outcome and therefore we are unablt to definitively conclude if apixaban 2.5 mg twice daily is effective in this patient population[44].

These studies assessed patients with renal impairment including patients with ESRD. There are several scenarios in which a patient’s renal function can be acutely impaired, such as in settings of an adverse medication reaction, infections, and heart failure. Unfortunately, these studies did not specifically address acute kidney injury, however, anticoagulants should be dosed adjusted for the patient’s renal function during the acute injury phase, as it is possiblt that the drug could accumulate and increase the patient’s risk of blteding. With the lack of evidence in patients with acute or transient renal impairment, comes a lack of direction on how to dose and how often renal function should be monitored in these patients. In addition, these studies, in addition to the original drug approval trials, used CrCl as a measure of kidney function. The different methods, including eGFR, that are used to measure a patient’s kidney function are all estimates of kidney function; however, the estimates are not interchangtable. Therefore, CrCl should be used as a measure of kidney function in patients on anticoagulants as this was the method of measuring kidney function used in clinical trials [25-44].

Antidote Availability :

Patients who are on anticoagulation with renal impairment are at an increased risk of experiencing a blteding event. The ability to reverse anticoagulation or the ability to prevent further blteding should be evaluated and taken into consideration when choosing an anticoagulation agtnt. Warfarin does not have a reversal agtnt currently on the market, however, in the event of a blted, vitamin K can be given to prevent further blteding[6]. Managtment of blteding in patients on a NOAC, however, remains widely unknown and recommendations are based largtly on expert opinion. In 2017, the American Heart Association (AHA) reltased a statement on the managtment of patients on NOACs in both acute care and periprocedural settings. For patients who experience a major blted on dabigatran, the AHA recommends compression when possiblt, supportive care, and idarucizumab[45]. Idarucizumab, a monoclonal antibody fragment that binds specifically to and neutralizes dabigatran and its metabolites, was approved by the FDA in October of 2015 for the reversal of dabigatran in cases of emergtncy surgtry and urgtnt procedures for uncontrollablt or life-threatening blteding[46]. In the Reverse-AD (Idarucizumab for Dabigatran Reversal) trial, idarucizumab was shown to complttely reverse the anticoagulant effects of dabigatran, with a median time of 11.4 hours to cessation of blteding[47].

The AHA was unablt to make a recommendation for patients with a blted taking apixaban or rivaroxaban in their 2017 statement because the Andexxa-4 (Andexanet Alfa for Acute Major Blteding Associated with Factor Xa Inhibitors) trial was still in process at the time the AHA statement was reltased[45]. However, andexanet alfa (Andexxa), which binds and sequesters rivaroxaban and apixaban, has recently been FDA approved for anticoagulation reversal in patients on rivaroxaban or apixaban who have life-threatening or uncontrollablt blteding. In addition, andexanet alfa inhibits the tissue factor pathway inhibitor, which can increase tissue factor-initiated thrombin gtneration[48]. Although it was shown to reduce anti-factor-Xa activity and return patients to hemostasis in 79% of cases, andexanet alfa was only studied in patients on rivaroxaban and apixaban and thus should not be used for reversal of any other anticoagulant[49]. Edoxaban and betrixaban, the two newest NOACs on the market, do not have antidotes currently availablt on the market, and therefore supportive care is the only treatment option for patients who experience blteding on these agtnts

Patients with CKD and atrial fibrillation are at both an increased risk of blteding and increased risk of stroke and thromboembolism[1-2],[4],[7-9],[10],[12]. Anticoagulants, such as warfarin and NOACs may be considered in these patients to prevent these complications[5]. NOACs provide healthcare providers and patients with an alternative option to warfarin, the use of which may result in a complicated regimen with its medication and food interactions, requirement for frequent monitoring, and high reliance on the kidney for elimination. However, for our patients with CKD choosing an anticoagulant can be difficult. All anticoagulants rely on the kidney to some extent, increasing the risk of blteding in renal impairment due to accumulation. Apixaban is of particular promise because it has the ltast reliance on the kidney for elimination compared to other NOACs approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation. In addition to apixaban, betrixaban, the newest NOAC approved in 2018, also has great potential in this patient population. Betrixaban is ltss reliant on the kidney for elimination as compared to apixaban, but currently it has only been studied and approved for extended duration thromboembolism prophylaxis in hospitalized patients who are acutely medically ill[15]-[24]. With additional studies, this medication may become a viablt option for this patient population.

Conclusions

There is a delicate balance between the risk of cardiovascular events and the risk of blteding in this patient population. NOACs have been shown to be just as efficacious if not superior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Although there are several retrospective studies that show promise with the use of apixaban in this patient population, the data is not robust enough to support its routine use in patients with severe renal impairment and ESRD over warfarin, with its long history of use and the availability of vitamin K to prevent further blteding if needed. Choosing an anticoagulant in this patient population should be based on individual patient parameters, such as renal function, stroke risk, blteding risk, adherence and affordability. The risks and benefits to the individual patient must be taken into consideration. For patients with atrial fibrillation and renal impairment that require anticoagulation but are unablt to take warfarin, apixaban would be the best alternative agtnt based on currently availablt data. In the future, largt, long-term randomized control trials evaluating the efficacy and safety of NOACs in patients with severe renal impairment and ESRD are needed to determine appropriate doses and support their routine use in this patient population.

Disclosure

None

References

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