The correct answer is: A. Warfarin, titrated for an international normalized ratio (INR) of 2.0-3.0.

Case Discussion

The correct answer is to use warfarin with a target INR of 2.0-3.0 for stroke prevention, due to his elevated risk score (CHA₂DS₂-VASc = 4). The 2014 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) Guideline for the Management of Patients With Atrial Fibrillation recommends against the use of dabigatran and rivaroxaban in patients with end-stage renal disease (ESRD) (estimated creatinine clearance [CrCl] less than 15 mL/min) as these medications have a relatively high renal clearance, and these patients were excluded from the landmark trials (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY] and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF]). Apixaban, on the other hand, has a lower renal clearance (approximately 27%) and has been approved by the FDA to be used in patients with ESRD at the standard dose of 5 mg twice-daily, or a reduced dose of 2.5 mg twice-daily if patients are ≥80-years-old or weigh less than 60 kg. Our patient did not meet either of these criteria; hence, apixaban 2.5 mg twice-daily would not be the FDA-approved dose (apixaban 5 mg twice-daily would be the appropriate dose for this patient). Lastly, the use of warfarin has been associated in a large cohort study with lower overall mortality in dialysis patients.¹⁵

Role of DOACs in Renal Impairment

All four direct oral anticoagulants (DOACs) undergo dosing adjustments based on a patient's CrCl and level of renal impairment.¹ Dabigatran should be used at a dose of 75 mg twice-daily for CrCl 15-30 mL/min, rivaroxaban at 15 mg once-daily for CrCl 15-50 mL/min, edoxaban at 30 mg once-daily for CrCl 15-50 mL/min, and apixaban at 2.5 mg twice-daily for patients with two of the following three criteria: serum creatinine greater than 1.5 mg/dL, age 80 years or older, or a weight less than 60 kg. In a recent meta-analysis by Ruff et al., appropriately dosed DOACs as compared to warfarin did not demonstrate increased risks of major bleeding or ischemic stroke in patients with various levels of renal dysfunction, including CrCl <50 mL/min.² Of note, dabigatran 75 mg twice-daily and patients on dialysis were never studied in a randomized trial and, therefore, were not included in this meta-analysis.

The appropriate dosing of edoxaban in patients with renal impairment has generated interest.³ The landmark trial that examined edoxaban for prevention of stroke in non-valvular AF (Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) and Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48]), compared two dosing strategies of edoxaban. In patients with moderate-to-severe renal impairment (CrCl 30-50 mL/min), the doses were reduced to edoxaban 30 mg once-daily (higher-dose arm) and edoxaban 15 mg once-daily (lower-dose arm).⁴ At this level of renal impairment, edoxaban 30 mg was non-inferior to warfarin for the prevention of stroke or embolic phenomenon. Meanwhile, in these patients, edoxaban 30 mg reduced bleeding events to an even greater degree relative to warfarin than was observed in patients who do not require dose reduction (interaction p-value 0.02). Interestingly, post-hoc analysis of the overall trial revealed that in patients with normal renal function (CrCl >95 mL/min), the rate of ischemic stroke was higher with edoxaban 60 mg once-daily relative to warfarin (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.17-3.97).⁵ This is the first case in which normal renal function is a contraindication for an anticoagulant.

The AHA/ACC/HRS joint guidelines recommend evaluating renal function prior to starting a direct thrombin inhibitor (e.g., dabigatran) or factor Xa inhibitors (e.g., rivaroxaban, apixaban, or edoxaban), with a minimum of once-yearly re-evaluation. Patients with ESRD (CrCl <15 mL/min) and not on renal replacement therapy were systematically excluded from all pivotal DOAC trials. For these patients, the joint guidelines recommend dose-adjusted warfarin with a target INR of 2.0-3.0. As stated above, edoxaban 30 mg is approved for patients with severe renal function defined as CrCl 15-50 mL/min. Reduced dosing of dabigatran at 75 mg is approved for patients with CrCl of 15-30 mL/min; however, this dose was approved based on pharmacokinetic modeling data and has not been verified in a real-world cohort. Practice guidelines and clinical statements from the European Society of Cardiology (ESC) also recommend avoiding DOACs in patients with severe renal impairment, though at a slightly high level of creatinine clearance (CrCl <30 mL/min).⁶

Role of DOACS in Dialysis Patients

The only DOAC approved for patients on hemodialysis is apixaban. In 2014, the FDA released an advisory statement approving use in these patients (apixaban 5 mg twice-daily or reduced dose 2.5 mg twice-daily for patients either older than 80 years of age or with a body weight of less than 60 kg).⁷ This reduced-dosing scheme is derived from pharmacokinetic data and has not been validated in a prospective manner; European agencies have not approved these agents for use in dialysis patients. Winkelmayer et al. analyzed Medicare claims data from 2010-2011 to examine the usage of DOACs among patients on dialysis.⁸ Although they found that use of dabigatran and rivaroxaban in patients on hemodialysis was relatively uncommon, they cautioned that the use of these agents without evidence-based dosing constituted a risky practice and urged more prospective data before widespread use. Chan et al. used a large database of AF patients on hemodialysis to study the DOACs' prescription patterns in this population and its effects. Despite being contraindicated in ESRD, dabigatran and rivaroxaban were prescribed in 3.1% and 2.8% of cases, respectively. The use of DOACs was strongly associated with a higher rate of major bleeding when compared to warfarin (HR 1.7, CI 1.44-2.15 for dabigatran; HR 1.45, CI 1.09- 1.93 for rivaroxaban).¹⁶

Systemic Thromboembolism, CKD, and AF

Impaired renal function is a strong predictor of stroke or systemic embolism in patients with non-valvular AF. In a sub-analysis of the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial, chronic kidney disease (CKD) stage III was found to be an independent predictor of the primary endpoint of stroke and non-central nervous system embolism.⁹ Moreover, Piccini et al. found in the large international ROCKET-AF trial that a model that includes creatinine clearance (R₂CHADS₂), improves the re-stratification of patients with AF by 6.2% compared to CHA₂DS₂-VASc (C statistics = 0.578), by 8.2% compared to CHADS₂ (C statistics = 0.575), and reclassified almost 20% of patients to a more appropriate risk category.¹⁰ A score that comprises age, diabetes, previous stroke, female gender, proteinuria, and a CrCl less than 45 mL/min has been recently derived showing better C-statistics than CHADS₂ and CHA₂DS₂-VASc.¹¹ This information is further supported by a large meta-analysis showing strong association between renal disease and stroke or systemic embolism in patients with AF. This association was true for both non-dialysis CKD patients and those undergoing dialysis.¹²

Risk of Bleeding and CKD in AF Patients

Renal disease not only increases the risk of systemic embolism but also increases the chances of bleeding, making the decision of whether to use anticoagulation in this situation very challenging. In a community-based study using province-wide laboratory and administrative data in Canada, Jun et al. looked to determine the rate of major bleeding in patients >66 years old with chronic renal disease and AF starting warfarin. During the first 30 days of warfarin treatment, rates of major bleeding were more than ten times higher in patients with lower versus higher CrCl (incidence rate ratio [IRR] 10.33, CI 2.34- 45.54, p = 0.002 for CrCl >15 mL/min). Increases in major bleeding rates were largely due to gastrointestinal bleeding, but intracranial bleeding was not increased with worsening kidney function.¹³ Similar findings were observed in a large Danish registry cohort, in which the risk of bleeding in patients with non-valvular AF and renal disease was found to be higher when compared to the risk in those patients without renal disease. This risk remained higher regardless of the medication used to decrease systemic thromboembolism (warfarin HR 1.33, 95% CI 1.16- 1.53, P <0.001; aspirin HR 1.17, 95% CI 1.02- 1.34, P = 0.03; both aspirin and warfarin HR 1.61, 95% CI 1.32- 1.96, P <0.001).¹⁴ These two studies showed conflicting evidence in demonstrating a correlation with increased risked of stroke and the degree of renal dysfunction.

The overall effect of renal function on bleeding and stroke risk with warfarin was assessed by Bonde et al. in a Danish registry.¹⁵ They observed that in patients receiving renal replacement therapy with a CHA₂DS₂-VASc score of 2 or greater, warfarin was associated with a lower risk of all-cause mortality, a non-significant trend toward lower risk of cardiovascular death, and a composite outcome of death/hospitalization from stroke/systemic thromboembolism/bleeding as compared to no anticoagulant therapy. In patients with non-ESRD, treatment with warfarin was associated with significantly lower risks of the composite outcome of fatal stroke/fatal bleeding, cardiovascular death, and all-cause mortality, respectively. In patients at low-to-intermediate risk of stroke, warfarin did not improve outcomes in patients receiving renal replacement therapy. In contrast, low-intermediate risk patients with non-ESRD did experience a significant reduction in all-cause mortality with warfarin therapy.

Summary

Deciding on the use of anticoagulation in patients with advanced renal disease and AF represents a difficult clinical dilemma. The authors of this Patient Case Quiz believe that the first approach to this situation should be to include the patient in the decision-making process by explaining the benefits of anticoagulation, the potential harms, and the different treatment options. We adhere to the recommendation of the ACC/AHA/HRS and ESC guidelines to use risk scores (CHA₂DS₂-VASc, HAS-BLED) when considering the use of anticoagulants. As discussed above, renal function is associated with an increased risk of stroke or systemic thromboembolism, but this variable is not included in the most popular risk scores. It is reasonable to use renal function in patients with intermediate risk score (CHA₂DS₂-VASc = 1) to further assess the risk of thromboembolism and guide therapy.

Choosing the right anticoagulant can also be cumbersome. Warfarin has been studied in both end-stage and non-end-stage CKD, and the dose should be adjusted to a target INR of 2.0-3.0 in non-valvular AF patients. In patients requiring dialysis, the only DOAC approved is apixaban at a dose of 5 mg twice-daily, or 2.5 mg twice-daily if the patient is ≥80 years old and/or weighs less than 60 kg. Dabigatran, rivaroxaban, and edoxaban have not been approved for use in patients receiving dialysis. In patients with CKD, it is important to notice that each DOAC has different CrCl cut offs that must be taken into consideration. Dabigatran should be prescribed at a dose of 150 mg twice-daily for a CrCl >30 mL/min, and 75 mg twice-daily for a CrCl 15-30 mL/min. Rivaroxaban can be used at a full dose of 20 mg once-daily for CrCl >50 mL/min, and at a reduced-dose of 15 mg once-daily for CrCl 15-50 mL/min. Apixaban is prescribed at a dose of 5 mg twice-daily, and 2.5 mg twice-daily if any two patient characteristics are present: creatinine is >1.5 mg/dL, age is ≥80 years old, weight is less than 60 kg. Edoxaban is dosed at 60 mg once-daily for a CrCl 50-95 mL/min, 30 mg once-daily for a CrCl 15-50 mL/min, and is not advised in patients with a CrCl >95 mL/min.

Ultimately, the decision of starting an anticoagulant and which medication to use comes down to a joint decision between the patient and his or her physician, taking into account risk of embolism, bleeding, and the patient's own cultural, social, and personal experiences.

References

1. January C, Wann L, Alpert J, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:2246-80.
2. Ruff CT, Giugliano R, 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 randomized trials. Lancet 2014;383:955-62.
3. Hart RG, Eikelbook J, Ingram A, et al. Anticoagulants in atrial fibrillation patients with chronic kidney disease. Nat Rev Nephrol 2012;8:569–78.
4. Giugliano R, Ruff C, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
5. Daiichi Sankyo, Inc. Edoxaban: Highlights of Prescribing Information. 2015 Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. Accessed 5/27/2015.
6. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with on-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094-106.
7. U.S. Department of Health and Human Services. Supplement Approval NDA 202155/S-002 (FDA website). 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/202155Orig1s002ltr.pdf. Accessed 5/27/2015.
8. Winkelmayer W, Herzog C, Montez-Rath M, et al. Use of novel oral anticoagulants in patients with end-stage renal disease. Hemodial Int 2015;19:150-3.
9. Eikelboom J, Connolly S, Gao P, et al. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovasc Dis 2012;21:429-35.
10. Piccini J, Stevens S, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the 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) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation 2013;127:224-32.
11. Singer D, Chang Y, Borowsky L, et al. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J Am Heart Assoc 2013;2:e000250.
12. Providencia R, Marijon E, Boveda S, et al. Meta-analysis of the influence of chronic kidney disease on the risk of thromboembolism among patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2014;114:646-53.
13. Jun M, James M, Manns B, et al. The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study. BMJ 2015;350:h246.
14. Olesen J, Lip G, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625-35.
15. Bonde A, Lip G, Kamper A, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014;64:2471-82.
16. Chan K, Edelman E, Wenger J, et al. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 2015;131:972-9.