From the Editorial Team Lead of the Geriatric Cardiology Section:

In their Expert Analysis for the Geriatric Cardiology Clinical Topic Collection ("Geriatric Cardiology: Patient-Centered Care for Contemporary Health Care Challenges"), Andrea M. Elliott, MD and Daniel E. Forman, MD, FACC, wrote eloquently about the "fascination of geriatric cardiology due to the breadth of the disease process." They also brought to attention the lack of "evidence-based care for a fragile elderly patient." To expand on these points, Gautam R. Shroff, MBBS, FACC; Sarah E. Thordsen, MD; and Charles A. Herzog, MD, FACC have written a series that will be posted over the next two months that we hope will be useful to both the geriatric cardiology community as well as to the overall ACC.org community. This series focuses on the complex intersections between advancing age, deteriorating renal function, and the benefits to risk ratio of recently introduced novel oral anticoagulants. The authors also point to the specific gaps of knowledge in this area. We have divided the clinical content material over the following two months based on the stage of renal disease. We hope you find this information useful to your clinical practice.

Ashok Krishnaswami, MD, MAS, FACC

I. Understanding the Scope of the Problem

There is an increase in incident atrial fibrillation (AF) in patients with chronic kidney disease (CKD),¹ and this relationship has been proven to increase in magnitude in the setting of progressively worsening estimated glomerular filtration rate (eGFR). Moreover, in patients with CKD, AF portends an increased risk of stroke or systemic embolization.² Multiple new oral anticoagulants (NOACs) have been compared to warfarin for thromboembolic prophylaxis in the setting of non-valvular AF. There have not been any randomized controlled trials that have specifically evaluated the risks versus benefits of therapeutic anticoagulation among CKD patients; fortunately, trials involving the newer oral anticoagulants did include patients with moderate/stage 3 CKD. These randomized trials for NOACs had wide representation of patients with CKD stage 2, in whom no modification of dose is generally recommended. Since most of the NOACs have high renal clearance, several nuances related to the doses/inclusions among various major randomized controlled trials (RCTs) that are applicable to CKD stages 3-5 need to be carefully studied. It is important to remember that CKD stages are dynamic, and any patient with CKD stage 2 should be monitored carefully while on NOACs for any dose modification that may be necessary with deteriorating renal function.

II. Understanding the Evidence

CKD Stage 3

There is considerable evidence available to guide management regarding risks and benefits of warfarin in patients with stage 3 CKD.³ In the Stroke Prevention in Atrial Fibrillation (SPAF) III trial, adjusted-dose warfarin reduced the risk of systemic embolism by 76% compared to the aspirin/low-dose warfarin arm in CKD stage 3.⁴ Data from large registries have similarly demonstrated the association of warfarin use with reduction in clinically meaningful outcomes.^5,6 Patients with CKD stage 3 constituted 15-30% of the study population in the major NOAC trials (non-inferiority designs) allowing for reasonable extrapolation from predefined post hoc analyses. Although patients with estimated creatinine clearance (eCrCl) <25-30 ml/min (CKD stage 4) were excluded from these trials, there are currently data available for more than 15,000 patients with CKD stage 3 from the various RCTs (Table 1).

Table 1: Randomized Trials That Have Evaluated Patients With Atrial Fibrillation and CKD Stage 3

Study (n of CKD stage 3 patients, % of total study population)	Agents/doses	Exclusions based on renal function	Range of CKD severity	Age of participants (years)	FDA recommended dose for CKD stage 3
SPAF III (n = 516; 42%)	Adjusted dose Warfarin vs. aspirin + low dose warfarin	Serum creatinine > 3mg/dl	eGFR 30-59 ml/min*	73 (mean)	Adjusted dose warfarin
RE-LY (n = 3,505; 19%)	Dabigatran 150 mg or 110 mg twice daily vs. warfarin	eCrCl <30 ml/min	eCrCl 30-49 ml/min‡	71 (mean)	Dabigatran 150 mg twice daily. (Dabigatran 75 mg twice daily for CKD stage 4)
AVERROES (n = 1,697; 30%)	Apixaban 5 mg twice daily vs. aspirin	Serum creatinine >221 µmol/L or eCrCl <25 ml/min	eGFR 30-59 ml/min*	70 (median)	Apixaban 5 mg twice daily. Dose reduced to 2.5 mg twice daily if age >80 years or weight < 60 kg
ARISTOTLE (n = 3,017; 15%)	Apixaban 5 mg twice daily vs. warfarin	Serum creatinine >221 µmol/l or eCrCl <25 ml/min	eCrCl 25-50 ml/min‡	70 (median)
ROCKET AF (n = 2,950; 21%)	Rivaroxaban 20 mg per day vs. warfarin	eCrCl <30 ml/min	eCrCl 30-49 ml/min‡	73 (median)	Rivaroxaban 15 mg daily
ENGAGE AF – TIMI 48 (n=4,074; 19%)	Edoxaban 60 mg or 30 mg vs. warfarin	eCrCl<30 ml/min	eCrCl 30-50 ml/min‡	72 (median)	Edoxaban 30 mg daily

Modified from Hart RG, Eikelboom JW, Ingram AJ, Herzog CA. Anticoagulants in atrial fibrillation patients with chronic kidney disease. Nat Rev Nephrol 2012;8:569-78.
Legend: CKD = chronic kidney disease; eCrCl = estimated creatinine clearance; eGFR = estimated glomerular filtration rate.
*Based on the CKD-EPI equation
‡eCrCl using the Cockcroft-Gault formula.

Dabigatran is an oral direct thrombin inhibitor (80% renal clearance) that was studied in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY study).⁷ In the main trial, it was reported that among patients with CKD stage 3, there was a significant reduction in ischemic stroke/embolism with dabigatran 150 mg twice daily, with equivalent rates of bleeding. A recent subanalysis⁸ specifically evaluated outcomes in relation to renal function among 3,374 patients with eGFR <50 mL/min (CKD-EPI equation). The rates of stroke/embolism, all-cause mortality and major bleeding were significantly higher relative to the group with eGFR>80 mL/min across both the study doses (150 mg and 110 mg twice daily) and warfarin groups. However, the authors concluded that the net efficacy of both doses of dabigatran were consistent across all the eGFR categories (including CKD stage 3).

Rivaroxaban is an oral factor Xa inhibitor (35% renal clearance), studied in the 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) study.⁹ A lower dose of rivaroxaban 15 mg daily was studied among the 2,950 (21%) patients with CKD stage 3 (i.e., eGFR between 30-49 mL/min/1.73 m² [Cockcroft-Gault formula]). In a post hoc analysis of patients with CKD stage 3, the rates of ischemic stroke/embolism as well as the safety endpoint were similar between the rivaroxaban and warfarin groups, but fatal bleeding occurred less often in the rivaroxaban group.¹⁰

Apixaban is an oral factor Xa inhibitor (25% renal clearance) that has been studied in two RCTs viz. Apixaban Versus Acetylsalicylic Acid to Prevent Strokes (AVERRHOES) (apixaban vs. aspirin in patients deemed too high-risk for anticoagulation)¹¹ and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) (apixaban vs. warfarin in patients with non-valvular AF).¹² A sub-analysis of the ARISTOTLE trial examined outcomes of apixaban in comparison to warfarin in 3,017 (15%) patients with eGFR 25-50 mL/min/1.73 m² (Cockcroft-Gault formula).¹³ Of note, 733 (24.3%) patients in this cohort met criteria for reduced apixaban dosing of 2.5 mg twice daily. The authors reported that the effectiveness of apixaban (i.e., reduction in stroke/systemic embolism) was similar across all the eGFR categories. However, among patients with an eGFR <50 ml/min, apixaban was associated with greatest relative decrease in major bleeding compared to patients with higher eGFR values (regardless of the method used to estimate eGFR). Of interest, in a subgroup analysis of the AVERRHOES study, the rates of major bleeding of apixaban were comparable to aspirin among patients with CKD stage 3.¹⁴

Edoxaban is the latest NOAC to be approved by the U.S. Food and Drug Administration (FDA); a direct oral factor Xa inhibitor (50% renal excretion) based on the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study.¹⁵ About 19% of patients in each group (edoxaban 60 mg, 30 mg and warfarin) had an eCrCl<50 ml/min. Based on subgroup analysis reported by the FDA advisory panel,¹⁶ the event rate of stroke/systemic embolism was significantly lower with high-dose edoxaban compared to warfarin among patients with mild/moderate renal impairment; with significantly lower risk of bleeding. Among patients with moderate CKD (eCrCL 15 to 50 mL/min), it is recommended that the dose of Edoxaban be reduced to 30 mg daily.

There have been several meta-analyses that have been performed in the past few years to address the efficacy of NOACs in relation to vitamin K antagonists in this population.^17,18,19 Although the conclusions of the meta-analyses are not entirely consistent, it is apparent that in patients with advanced CKD, there appears to be no significant differences in the risks of stroke/thromboembolism between the other NOACs versus vitamin K antagonists (VKAs). Moreover, some meta-analyses indicate a lower risk of bleeding with NOACs compared to VKA,^17,19 whereas others demonstrate equivalent bleeding risks.¹⁸

CKD Stage 4

Among patients with CKD stage 4, evidence pertaining to both warfarin and NOACs is unfortunately far less robust. Only a few hundred patients have been enrolled among all the major NOAC trials put together; not enough to draw any meaningful conclusions to guide clinical practice. By extrapolation of pharmacokinetic data, the FDA has approved dabigatran 75 mg PO twice daily for patients with CKD stage 4; although it bears emphasis that there is lack of clinical evidence to support this dose.^20,21 Again, by extrapolation, a lower dose of rivaroxaban (15 mg daily) and apixaban (2.5 mg twice daily) has been recommended in certain patient populations with advanced CKD (Table 2). It is certainly worth noting that in general, the risks of major bleeding are significantly higher among these patients relative to patients with higher eGFR.²²

Table 2: Anticoagulation Options Based on CKD Stage

Age	Normal renal function or CKD stages 1-2	CKD stage 3	CKD stage 4	CKD stage 5D
<75 years	(Extensive RCT data available) Warfarin—adjusted dose Dabigatran 150 mg PO BID Rivaroxaban 20 mg PO daily Apixaban 5 mg PO BID* Edoxaban 60 mg PO daily (Edoxaban is not recommended if CrCl >95 ml/min.)	(Reasonable representation in RCTs) Warfarin—adjusted dose Dabigatran 150 mg PO BID Rivaroxaban 15 mg PO daily Apixaban 5 mg or 2.5 mg PO BID* Edoxaban 30 mg PO daily	(No RCT data) Dabigatran 75 mg twice daily approved by FDA.	(No RCT data) Warfarin—adjusted dose Apixaban 5 mg or 2.5 mg twice daily*
>75 years	Based on meta-analysis of 10 RCTs ** involving 25,031 patients >75 years, newer anticoagulants (dabigatran/rivaroxaban/apixaban) equivalent to conventional therapy in efficacy and bleeding risk. In ENGAGE AF-TIMI 48 for Edoxaban, 40% patients were >75 yrs and 17% >80 years of age.		(No RCT data)	(No RCT data) Warfarin-adjusted dose Apixaban 2.5 mg daily*

Legend: RCT = randomized controlled trial; CrCl = creatinine clearance; BID = twice daily.
*Based on the ARISTOTLE trial, FDA label recommends dose of apixaban to be reduced to 2.5 mg twice daily if any two of the following criteria are met: age >80 years, creatinine >1.5 mg/dl or weight <60 kg.
** Sardar P, Chatterjee S, Chaudhari S, Lip GY. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014;62:857-64.

References

1. Nelson SE, Shroff GR, Li S, Herzog CA. Impact of chronic kidney disease on risk of incident atrial fibrillation and subsequent survival in Medicare patients. J Am Heart Assoc 2012;1:e002097.
2. U.S. Renal Data System. USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2006.
3. Hart RG, Eikelboom JW, Ingram AJ, Herzog CA. Anticoagulants in atrial fibrillation patients with chronic kidney disease. Nat Rev Nephrol 2012;8:569-78.
4. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol 2011;6:2599-604.
5. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014;311:919-28.
6. Bonde AN, Lip GY, Kamper AL, et al. Net linical 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.
7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
8. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014;129:961-70.
9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
10. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011;32:2387-94.
11. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
12. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
13. Hohnloser SH, Hijazi Z, Thomas L et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012;33:2821-30.
14. Eikelboom JW, Connolly SJ, 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.
15. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
16. U.S. Food and Drug Administration. FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) (FDA website). Available at: fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
    Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM420704.pdf. Accessed 10/30/2014.   
17. Lega JC, Bertoletti L, Gremillet C, Boissier C, Mismetti P, Laporte S. Consistency of safety profile of new oral anticoagulants in patients with renal failure. J Thromb Haemost 2014;12:337-43.
18. Harel Z, Sholzberg M, Shah PS, et al. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol 2014;25:431-42.
19. Providência 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. Am J Cardiol 2014;114:646-53.
20. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49:259-68.
21. U.S. Food and Drug Administration. Safety: Pradaxa (dabigatran etexilate mesylate) capsules (FDA website). 2014. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm250657.htm. Accessed October 30, 2014.
22. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study. J Am Coll Cardiol 2011;58:395-401.

Keywords: Adult, Aged, Animals, Anticoagulants, Arm, Aspirin, Atrial Fibrillation, Attention, Benzimidazoles, Creatinine, Embolism, Factor Xa, Factor Xa Inhibitors, Glomerular Filtration Rate, Humans, Lip, Morpholines, Myocardial Infarction, Odds Ratio, Patient-Centered Care, Pyrazoles, Pyridines, Pyridones, Registries, Renal Insufficiency, Chronic, Risk Assessment, Stroke, Thiazoles, Thiophenes, Thromboembolism, United States, United States Food and Drug Administration, Ursidae, Vitamin K, Warfarin, beta-Alanine

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