NOACs and renally impaired patients: Green or red light?Lena RivardMD, MSc, FRCPC

1

Conflict of Interest Disclosures

• Grants/research support: Heart and Stroke Foundation, Fonds de Santé en

recherche du Québec, Canadian Stroke Prevention Network, MHI Foundation, Bayer Inc.

• Consulting fees: Biosense Webster

• Speaker fees: Biosense Webster, St. Jude Medical, Bristol-Myers-Squibb, Bayer Inc

• Other: None

• I will discuss off-label uses for apixaban for CrCl <25 mL/min and

dabigatran/edoxaban/xarelto for CrCl <30 mL/min

Introduction

• Atrial fibrillation and chronic kidney disease (CKD) frequently coexist1

• AF is present in 16 to 21% of non-dialysis patients and from 15 to 40% in ESRD

• On the other hand, prevalence of CKD is high in AF patients (up

to 30%)

1- Barber et al.Association of chronic kidney disease with atrial fibrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circulation

Arrhythmia and electrophysiology 2011

2-Boriani et al.Glomerular filtration rate in patients with atrial fibrillation and 1-year outcomes. Scientific reports 2016; 6: 302713

Introduction• Risks of both thromboembolic and hemorrhagic complications

are higher in patients with CKD1

• 1.5-fold increase in stroke

• 2-fold increase in bleeding

• Incident of AF in CKD is independently associated with risk to progression to severe CKD2

• Reduced eGFR and high albuminuria rates are associated with a greater risk of incidence of AF3

1- Barber et al.Association of chronic kidney disease with atrial fibrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circulation

Arrhythmia and electrophysiology 2011

2-Boriani et al.Glomerular filtration rate in patients with atrial fibrillation and 1-year outcomes. Scientific reports 2016; 6: 30271

3-Bansal et al. A meta-analysis of the Jackson heart study. Clin J Am Soc Nephrol 20174

Renal elimination of NOACs

• All NOACs are dependent on renal clearance to varying degrees

• Hemodialysis is effective in removing dabigatran from circulation but has little effect on rivaroxaban, edoxaban or apixaban exposure

5Wison et al. An evaluation of oral dabigatran etexilate pharmacokinetics and pharmacodynamics in hemodialysis. J Clin Pharmacol 2014;54(8):901-909

Apixaban Dabigatran Edoxaban Rivaroxaban

Excretion Intestinal excretion

Renal

Renal Renal

Biliary/intestinal

excretion

Renal

Biliary/intestinal

routes

Renal excretion 27% 80% 50% 33%

KDIGO Clinical practice Guideline for the evaluation and management of chronic kidney disease. Kidney In Suppl. 2013;3:1-150

Assessment of Kidney Function

• In clinical practice, the estimated glomerular filtration rate (eGRF) is used (calculated using MDRD study or CKD- EPI Epidemiology Collaboration equations)

• A recent analysis showed that eGRF (calculated with MDRD and CKD-EPI formulae) better estimate renal function and eGRF is used to define CKD stages

• But, landmark RCT and dosing recommendations used on creatinine clearance equation (eCLr) using the Cockcroft-Gault equation with the actual body weight

Overestimation in obese patients since ideal body weight was used in the original equation

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Q 1: Do you systematically use eGRF before NOAC initiation?

1- Yes

2- No

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Soliman et al. Chronic kidney disease and prevalent AF: the chronic renal insufficiency cohort (CRIC). Am Heart J 2010;159(6):1102-1107

Camm et al. XANTHUS: a real world prospective, observational study of patients treated with rivaroxaban for stroke prevention in AF. Eur Heart J 2016;37(14):1145-1153

Assessment of Kidney Function

• Clinicians are intuitively drawn towards using eGFR leading to inappropriate dosing of NOACs

• Registry from the UK shows that 5.3% of patients <80 y and 15% of those >80 y received an inappropriate dose of dabigatran (using eGRF instead of eCLr)

• In the XANTUS study, 36% of patients with moderate to severe CKD received a dose of 20 mg rather than a dose of 15 mg

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Canadian Journal of Cardiology 2018

The authors recommend calculating eCrCl using the Cockcroft-Gault formula for all patients with an eGRF <70 mL/min

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eCRF using CKD-EPIeCRF using MDRD

eC

rCL

eC

rCL

NOACs in moderate CKD (≥30 mL/min)• Pivotal RCTs for NOACs have adequate representation of patients with mild

to moderate CKD

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RE-LY ROCKET AF ARISTOTLE ENGAGE AF-

TIMI 48

Drugs Dabigatran Rivaroxaban

5 mg DIE for eCCL

30-49

Apixaban Edoxaban

30 mg DIE for a

CL ≤50

Cutoff for CKD 31-49 mL/min 30-49 mL/min 25-50 mL/min 30-50 mL/min

Patients with CKD

(warfarin and NOAC

groups)

3,554 2,950 3,017 2,740

Primary Outcome

(stroke and SE)

110 mg: 0.85 (0.59-1.24)

150 mg: 0.56 (0.37-0.85)

0.84 (0.57-1.23) 0.79 (0.55-1.14) 0.87 (0.64-1.19)

Safety Outcome

(Major bleeding)

110 mg: 0.99 (0.77-1.28)

150 mg: 1.02 (0.79-1.30)

0.95 (0.72-1.26) 0.50 (0.38-0.66) 0.76 (0.58-0.98)

NOACs in moderate CKD (≥30 mL/min)

• All NOACS are noninferior to warfarin in terms of reduction of SSE, with the except for dabigatran (150 mg twice daily), which was superior

• Apixaban and edoxaban had less major bleeding compared to warfarin

• No head-to-head comparison between NOACs

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• 269 pts with AF and CrCl 25 to 30 mL/min enrolled in the ARISTOTLE trial apixaban 5 mg twice daily (N=88) or 2.5 mg twice daily (N=48) for those with ≥ 2 criteria

• Similar rates of stroke or SE : 2.81 in the apixaban group and 5.06 in the warfarin group for HR 0.55 (0.20-1.51)

• Lower major and CRNM bleeding in the apixaban group (HR 0.35; 95% CI 0.17-0.72)

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Stanifer et al. Circulation 2020

1- Piccini Circulation 2015

2- Tan et al

OAC in severe CKD (<25-30 ml/min)

• Use of OACs (NOACs and warfarin) is controversial and debated due to conflicting data and the absence of RCT

• Data from Danish and Sweden registries demonstrated a benefit towards warfarin but TTR in those trials was >80%1

• However, several recent large meta-analyses showed that the use of warfarin was associated with an increased risk of bleeding compared to non-warfarin use2

• Available non-randomized studies on NOACs have warfarin as a comparator arm

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NOACs in severe CKD (<25-30 ml/min)

• No available data from RCT on the use of NOACs in patients with severe CKD

• Real world data are conflicting and usually include both hemodialysis and non-hemodialysis patients

• Current recommendations are based on limited pharmacokinetic and pharmacodynamic analyses

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Q 2: Do you prescribe NOAC in severe CKD?

1- Yes, sometimes

2- Yes, frequently

3- No, never

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• ESC AF guidelines recommend a dose reduction of NOACs for patients with CrCl 15-30 mL/min

• FDA approved the use of apixaban for dialysis patients and according to 2019 AHA/ACC/HRS

guidelines, it is reasonable to use apixaban for dialysis patients

1- Siontis et al. Circulation 2018; Coleman et al. Am J Med 2019

2- Nielsen 2019; De Catarina 2019

3-Chan et al. Circulation 2015; Chang et al 2019

Data on real world are conflicting

• In large databases, apixaban and rivaroxaban were associated with lower risks of major bleeding but similar rates of SSE compared to warfarin1

• In several cohorts, edoxaban 30 mg has shown identical rates of SSE as those in ENGAGE-AF TIMI 48 and low major bleeding2

• However, other large databases of hemodialysis and non-hemodialysis patients showed that NOACs were associated with an increased risk of major bleeding3

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No significant difference in SSE in patients taking NOACs or no OACs

Increase risk of bleeding in both NOACs and warfarin groups

Am J Cardiol 2019•Real-world multicenter study

•N= 3,894 (NOACs=280, warfarin=520, No OACs=2,791)

•CKD 4 or 5 (25% on dialysis)

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CJASN 2020 in press

• Retrospective cohort study using US renal dataSystem

• 514 patients treated with apixaban and 1,561 patients without any OAC

• Compared with no anticoagulation, apixaban was associated with:

• Identical primary outcome (ischemic and hemorrhagic strokes/TIA or SE) HR 1.24; 95% CI 0.69 to 2.23

• Higher rates of intracranial bleeding (HR 2.74; 95% CI 1.37 to 5.47)

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CJASN 2020 in press

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Higher incidence of any stroke/TIA/SE in the apixaban group 5 mg

Gaps in knowledge

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Ongoing RCT in Haemodialysis patients

• AVKDIAL (NCT02886962)

VKA vs. no OAC

N = 855

Estimated date of completion = 2023

• AXADIA (NCT02933697)

Apixaban vs. VKA

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Conclusion

• In patients with AF and moderate CKD (30-50 mL/min; 25-50 mL/min for apixaban), NOACs showed comparable efficacy to warfarin (lower risk of SSE with dabigatran 150 mg) with a better safety profile

• Renal function should be assessed before initiation and during treatment with NOACs (at least once a year) using the Cockcroft-Gault formula

• Further clinical safety/efficacy data are needed before routine use of NOACs can be recommended in patients with eCrCl <25 to 30 mL/min

• In hemodialysis patients, given the relative absence of net-clinical benefit of warfarin, it is critical to have RCTs with no-treatment comparator arm

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Questions

• Retrospective cohort of Medicare beneficiaries with AF and undergoing dialysis

• Total of 25,523 patients (2,351 on apixaban and 23,172 on warfarin)

• In matched cohorts, there was no difference in the risk of SSE but apixaban was associated with a significant lower risk of major bleeding

• In a sensitivity analysis, a standard dose of apixaban (5 mg) was associated with a lower risk of SSE compared to warfarin (HR 0.63; 95% CI 0.46-0.85)

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Siontis et al Circulation 2018