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

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

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.

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 (S4.1.1-11, S4.1.1-24-S4.1.1-28). 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 (S4.1.1-26, S4.1.1-29, S4.1.1-30). 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.

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 2019. d. Eliquis® PI 2018.

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;39:1330-1393.

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.

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, 2888-99, 2016, with permission from Elsevier

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

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

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;383:955-962.

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;383:955-962.

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;131:972-979.

NOAC Use in Patients With ESKD and AF on Dialysis Trends in NOAC Prescriptions in Patients With ESKD and AF on Dialysis (United States, 2010-2015) Timepoint: 11:05 ESKD = end-stage kidney disease Siontis KC, et al. Circulation. 2018;138:1519-1529.

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;138:1519-1529.

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]

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, 2621-32, 2017, with permission from Elsevier Yao X, et al. J Am Coll Cardiol. 2017;70:2621-2632.

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;70:2621-2632.

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

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. 2019. [Epub ahead of print].

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

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