1. NOACs and Renal Impairment
Addressing Common Concerns
Moderator
Christian T. Ruff, MD, MPH
Assistant Professor of Medicine Harvard Medical School Director of General Cardiology Cardiovascular Division TIMI Study Group Brigham and Women's Hospital Boston, Massachusetts, United States
NOAC = non-vitamin K antagonist oral anticoagulant
Timecode: 00:00
Chapter title: Introduction

2. Jeffrey I. Weitz, MD, FRCPC
Panelists
Craig I. Coleman, PharmD
Professor of Pharmacy Practice
University of Connecticut School of Pharmacy
Director of UCONN/Hartford Hospital
Evidence Based Practice Center
Hartford, Connecticut, United States
Jeffrey I. Weitz, MD, FRCPC
Professor of Medicine and Biochemistry
McMaster University
Hamilton, Ontario, Canada
Timecode: 00:22

3. Introduction
Importance of considering renal status when selecting and initiating a NOAC
Practice guidelines specifically address importance of assessing renal function
Baseline
Regular intervals
Timecode: 00:42
January CT, et al. Circulation. 2019;139:1-49.

4. 2019 US Recommendations: AF Baseline and Reevaluation of Renal Function
2019 AHA/ACC/HRS Focused Update on Atrial Fibrillation I
B-NR
7. Renal function and hepatic function should be evaluated before initiation of a NOAC and should be reevaluated at least annually (S , S S ). Modified: Evaluation of hepatic function was added. LOE was updated from B to B-NR. New evidence was added. (Section 4.1 in the 2014 AF Guideline)
IIb
13. For patients with AF who have a CHA2DS2-VASc score of 2 or greater in men or 3 or greater in women and who have end-stage chronic kidney disease (CKD; creatinine clearance [CrCI] <15mL/min) or are on dialysis, it might be reasonable to prescribe warfarin (INR 2.0 to 3.0) or apixaban for oral anticoagulation (S , S , S ). Modified: New evidence has been added. LOE was updated from B to B-NR. (Section 4.1 in the 2014 AF Guideline)
Timecode: 00:56
ACC = American College of Cardiology
AF = atrial fibrillation
AHA = American Heart Association
CKD = chronic kidney disease
CrCl = creatinine clearance
HRS = Heart Rhythm Society
LOE = level of evidence
January CT, et al. Circulation.2019;139:1-49.

5. NOAC Selection Considering Renal Clearance
Apixaban[d]
27% renal clearance
Dabigatran etexilate[a]
80% renal clearance
Edoxaban[b]
50% renal clearance
Rivaroxaban[c]
36% renal clearance
Timecode: 01:06
a. Pradaxa® PI 2018; b. Savaysa® PI 2017; c. Xarelto® PI d. Eliquis® PI 2018.

6. 2018 European Recommendations Frequency of Renal Assessment
If CrCl ≤ 60 mL/min, more frequent evaluation is recommended
Additional risk factors need to be considered when determining frequency
Age
Comorbidities
2018 EHRA Recommendation for monitoring of hemoglobin, renal and liver function
Yearly Patients other than those specified below
6 monthly ≥ 75 years (especially if on dabigatran) or frail
X-monthly If renal function CrCl ≤ 60 mL/min: recheck interval (calculate CrCl/10)
If needed If concomitant condition that may impact renal or hepatic function
EHRA = European Heart Rhythm Association 
Timecode: 02:01
Table 2
Steffel J, et al. Eur Heart J. 2018;39:

7. Dose Adjustment in Renal Impairment US Prescribing Information
NOAC
Standard dose for Reduction of risk of Stroke and Embolism and NVAF
Reduced Dosage Recommendations
Dabigatran[a]
150 mg orally, twice daily
(CrCl >30 mL/min)
CrCl 15 to 30 mL/min: 75 mg twice daily
CrCl < 15 mL/min or on dialysis: dosing recommendations cannot be provided _____________________________________________________________________
CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole
CrCl < 30 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration
Rivaroxaban[b]
20 mg daily with evening meal (CrCI >50 mL/min)
15 mg daily with evening meal (CrCI 15 to 50 mL/min) Avoid use with P-gp +CYP 3A4 inducer/inhibitor
Apixaban[c]
5 mg BID (Most patients)
Note: dosing recommendations for apixaban are according to serum creatinine
2.5 mg BID (≥ 2 of the following: age ≥ 80 years; weight ≤ 60 kg; SCr ≥ 1.5 mg/dL OR strong dual inhibitors P-gp and CYP 3A4) Avoid use with strong dual inducers of P-gp and CYP 3A4
Edoxaban[d]
60 mg daily (CrCI 51 to 95 mL/min)
30 mg daily (CrCI 15 to 50 mL/min)
Avoid use with rifampin; do not use if CrCI ≥ 95 mL/min
Timecode: 03:01
SCr = serum creatinine
a. Pradaxa® PI 2018; b. Xarelto® PI 2019; c. Eliquis® PI 2018; d. Savaysa® PI 2017.

8. NOAC Pharmacokinetics
Timepoint: 5:50
Reprinted from J Am Coll Cardiol, 67(24), Chan KE, et al, Nonvitamin K Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF, , 2016, with permission from Elsevier

9. Factors Affecting Total Drug Exposure
Patient and Product Specific Considerations
Total drug exposure
Patient's age, body weight and concomitant medications
Patient status:
renal impairment or hepatic impairment?
PK/PD profile of agent in renal impairment
Metabolic profile, potential for drug-drug interactions
PD = pharmacodynamics
PK = pharmacokinetics
Timepoint: 6:40

10. NOAC Prescribing Information Awareness
Assessing Bleeding Risk: Clinical Considerations
Individual NOAC labels
Drug-drug interaction profile of NOAC
Effect of P-gp inhibitor or inducer on total exposure of NOAC
Metabolic features and profile
Patient's concomitant medications
Timepoint: 7:40

11. NOACs vs Warfarin: Stroke or Systemic Embolic Events
Meta-Analysis According to Renal Status and Function Stroke or Systemic Embolic Events
NOACs vs Warfarin: Stroke or Systemic Embolic Events
Timecode: 9:20
Figure 4A
RR=risk ratio
TIA=transient ischemic attack
VKA=vitamin K antagonist
TTR=time in therapeutic range
When you look across the trials and meta-analysis of approximately 72,000 patients
Patients with at least mild to moderate renal dysfunction did quite well on the NOACs
For warfarin, harder to maintain a therapeutic INR in patients who have progressive renal impairment
Ruff CT, et al. Lancet. 2014;383:

12. Meta-Analysis According to Renal Status and Function Major Bleeding
NOACs vs Warfarin: Major Bleeding
Timecode: 9:20
Figure 4A
RR=risk ratio
TIA=transient ischemic attack
VKA=vitamin K antagonist
TTR=time in therapeutic range
When you look across the trials and meta-analysis of approximately 72,000 patients
Patients with at least mild to moderate renal dysfunction did quite well on the NOACs
For warfarin, harder to maintain a therapeutic INR in patients who have progressive renal impairment
Ruff CT, et al. Lancet. 2014;383:

13. NOAC Use in End-Stage Renal Disease According to Dose
Fresenius Medical Care North America (FMCNA) ESRD Database*
Timepoint: 10:41
ESRD = end-stage renal disease
*Point prevalence of dabigatran and rivaroxaban among anticoagulated chronic hemodialysis patients with atrial fibrillation, by drug dose.
Chan KE, et al. Circulation. 2015;131:

14. NOAC Use in Patients With ESKD and AF on Dialysis
Trends in NOAC Prescriptions in Patients With ESKD and AF on Dialysis (United States, )
Timepoint: 11:05
ESKD = end-stage kidney disease
Siontis KC, et al. Circulation. 2018;138:

15. Outcomes Analysis: Apixaban vs Warfarin AF and End-Stage Kidney Disease
Retrospective Analysis: US Renal Data System October 2010 to December 2015 in Patients With ESKD and AF*
Timepoint 11:29
Table 2
*Event rates and association estimates from cox regression analyses in prognostic score‒matched cohorts of apixaban and warfarin.
Siontis KC, et al. Circulation. 2018;138:

16. US Truven MarketScan* Data January 2012 to December 2017
Analysis of Major Bleeding: Rivaroxaban vs Warfarin NVAF With CKD or Undergoing Dialysis
Retrospective Claims Analysis: NVAF with Stage 4 or 5 CKD or Undergoing Dialysis
US Truven MarketScan* Data January 2012 to December 2017 †
Timepoint 11:50
Figure 1
*Truven MarketScan combines 2 separate databases: commercial database and Medicare supplemental database. †Event rates and hazard ratios with 95% confidence intervals in inverse probability-of-treatment weighted cohorts of rivaroxaban and warfarin.
Coleman CI, et al. Am J Med. 2019; May 2. [Epub ahead of print]

17. Renal Outcomes: Oral Anticoagulant Agents Possible Mechanisms and Outcomes
Vitamin K antagonists (VKAs) decrease the carboxylation of MGP
Vitamin K is required for full activity of MGP, an important inhibitor of vascular calcification
Renal calcification due to VKA
VKA nephropathy
Timepoint: 14:30
MGP = matrix Gla protein
VKA = vitamin K antagonist
Figure: Central Illustration, not numbered
Reprinted from J Am Coll Cardiol., Vol 70, Yao X, et al., Renal Outcomes in Anticoagulated Patients With Atrial Fibrillation, , 2017, with permission from Elsevier
Yao X, et al. J Am Coll Cardiol. 2017;70:

18. NOACs vs Warfarin: Risk of Adverse Renal Outcomes
NOACs Associated with Lower Risks of Adverse Renal Outcomes Compared with Warfarin (Particularly Dabigatran and Rivaroxaban)*
Timepoint: 15:27
AKI = acute kidney injury
NVAF = nonvalvular atrial fibrillation
*Analysis of NVAF patients (apixaban n = 1883, dabigatran n = 1216, rivaroxaban n = 2485, warfarin n = 4185) in the US Optum Labs Data Warehouse (administrative database) with linked laboratory results.
Yao X, et al. J Am Coll Cardiol. 2017;70:

19. Tailoring NOAC Therapy in Patients With Renal Impairment
First step is to determine renal function
Choice of warfarin or NOAC
If choosing NOAC
Be informed of the dose adjustments needed according to the prescribing information
Clinical thresholds and opinions for specific NOACs
Concerns about calcification, vascular calcification and accelerating kidney decline
Randomized trial data not available in dialysis users
Timepoint: 17:17

20. NOACs and Renal/Hepatic Function 2019 Guideline Update
2019 AHA/ACC/HRS Focused Update on Atrial Fibrillation
All 4 NOACs with FDA approval for use in patients with AF have dosing defined by renal function (creatinine or CrCl using the Cockcroft-Gault equation)
Apixaban adds additional dosing considerations of age ≥ 80 years or weight ≤ 60 kg
Edoxaban is not approved for use in patients with poor renal function (CrCl < 30 mL/min) or upper-range renal function (CrCl > 95 mL/min)
Renal function should be regularly monitored and CrCl calculated at an interval that depends on the individual degree of renal dysfunction and likelihood of fluctuation, and dose adjustments should be made according to FDA dosing guidelines
In addition, for the factor Xa inhibitors, hepatic function should occasionally be monitored. NOACs are not recommended for use in patients with severe hepatic dysfunction
Timecode: 19:47
January CT, et al. Circulation [Epub ahead of print].

21. Concluding Remarks Assessment of renal status prior to initiating NOAC
Continue to reassess renal function
At least annually and much more frequent with renal impairment
Renal status and NOAC selection
Awareness of different NOAC PK profiles, metabolism and renal clearance
Be sure patients are on the right dose
Different dose adjustment guidance for each NOAC
Consult prescribing information
Minimal data available in patients with ESRD
Real-world data provide some insight
Timepoint: 22:05

22. Abbreviations
ACC = American College of Cardiology AF = atrial fibrillation AHA = American Heart Association AKI = acute kidney injury CKD = chronic kidney disease CrCl = creatinine clearance eGFR = estimated glomerular filtration rate EHRA = European Heart Rhythm Association ESKD = end-stage kidney disease ESRD = end-stage renal disease HRS = Heart Rhythm Society INR = international normalized ratio LOE = level of evidence MGP = matrix Gla protein NOAC = non-vitamin K antagonist oral anticoagulant NVAF = nonvalvular atrial fibrillation PD = pharmacodynamics PK = pharmacokinetics SCr = serum creatinine VKA = vitamin K antagonist