Practical Considerations for Using Oral Anticoagulants in Patients with Chronic Kidney Disease

Practical Considerations for Using Oral Anticoagulants in Patients with Chronic Kidney Disease Cyrille K. Cornelio, Pharm.D. PGY2 Cardiology Pharmacy Resident The University of Oklahoma College of Pharmacy Oklahoma Society for Health-System Pharmacists Fall Meeting September 14, 2018 Disclosures 2 I have no conflicts of interest to disclose. Off-label use of medications will be referenced. 1

Overview 3 1. Thrombosis and Bleeding Risk in Chronic Kidney Disease (CKD) 2. Review of Oral Anticoagulants in Non-Valvular Atrial Fibrillation (NVAF) and Venous Thromboembolism (VTE) 3. Dissecting Evidence of Direct Oral Anticoagulants (DOACs) in Chronic Kidney Disease Mild-Moderate Renal Impairment Moderate-Severe Renal Impairment Patients Receiving Dialysis 4. Patient Case Objectives 4 1. Explain the risks of thrombosis and bleeding in patients with CKD. 2. Compare and contrast the evidence associated with using DOACs and warfarin in patients with CKD. 3. Select appropriate oral anticoagulant therapy for a patient with CKD based on supporting evidence and clinical factors. 2

Thromboembolism in CKD 5 The risk for venous thromboembolism (VTE) starts to increase at egfr < 75 ml/min/1.73m2. Risk for VTE increases by more than 2-fold in patients with Stages 3 and 4 CKD. There is an associated 35% mortality rate in patients on dialysis who experienced a stroke. Curr Opin Pulm Med. 2009;15(5):408-12. J Am Soc Nephrol. 2008;19(1):135-40. Am J Kidney Dis. 2009;54(3):468-77. Hemostasis 3

Thrombosis Risk in CKD Antiphospholipid Antibodies Phosphatidylserine Bleeding Risk in CKD Alpha granule dysfunction 4

Oral Anticoagulation Options 9 Vitamin K Antagonist Warfarin Direct Thrombin Inhibitor Dabigatran Factor Xa Inhibitors Rivaroxaban Apixaban Edoxaban Betrixaban Renal Elimination of Oral Anticoagulants Agent Warfarin 10 Renal Clearance Elimination Half-Life Half-Life in Renal Impairment or HD Dialyzability 92 % 20-60 hours Not Reported Not Dialyzable (metabolites) Dabigatran 80 % 12-17 hours 15-34.1 hours 49-57 % Rivaroxaban 66 % 5-9 hours 8.7-9.5 hours Not Dialyzable Edoxaban 50 % 11.5 hours 10.6 hours 6.6 % Apixaban 27 % ~12 hours Half-life varies by weight and dose 4% Betrixaban 11 % 19-27 hours Not Reported Not Reported Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed August 20, 2018. IBM Micromedex (R). Greenwood Village (CO): Truven Analytics; Accessed August 20, 2018. 5

Outcomes Associated with Warfarin in Patients Receiving Dialysis 11 Patients with AF Outcome Adjusted HR (95% CI) Propensity Score Adjusted HR (95% CI) Non-dialysis n=1626 Stroke 0.87 (0.85-0.90) 0.89 (0.87-0.92) Bleeding 1.19 (1.16-1.22) 1.20 (1.17-1.23) Stroke 1.14 (0.78-1.67) 1.17 (0.79-1.75) Bleeding 1.44 (1.13-1.85) 1.41 (1.09-1.81) Dialysis n=204,210 AF = atrial fibrillation Circulation. 2014;129:1196-1203. Prescribing of DOACs 12 Dabigatran and rivaroxaban prescribing in hemodialysis increased to 3 per 100 patients each within the first 2 years of FDA-Approval. In 2015, over 26% of new anticoagulant prescriptions were for apixaban. DOACs accounted for 31% of 2015 Medicare Part D oral anticoagulant claims and $3.3 billion in payment costs. Circulation. 2015;131(11):972-9 Circulation. 2018; In Press PLoS ONE. 2018;13(6):e0198674 6

FDA-Approved Renal Dose Adjustments in NVAF Renal Function (ml/min) 13 Dabigatran Rivaroxaban Apixaban No Adjustment No Adjustment 2.5 mg twice daily if 2 of 3 criteria are met: No Adjustment 15 mg daily SCr > 1.5 mg/dl Age > 80 years Weight < 60 kg 30 mg daily No Recommendation No Recommendation Use not recommended > 95 Edoxaban Contraindicated 51-95 30-50 150 mg twice daily* 15-30 75 twice daily** < 15 or HD No Recommendation NVAF = non-valvular atrial fibrillation; HD = hemodialysis *75 mg twice daily if ketoconazole or dronedarone are used **Avoid co-administration with P-gp inhibitor Pradaxa(R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2018 Xarelto(R) [package insert]. Titusville,NJ: Janssen Pharmaceuticals, Inc.; 2016 Eliquis(R) [package insert]. Princeton, NJ: Bristol-Meyers Squibb, Inc.; 2016 Savaysa(R) [package insert]. Basking Ridge,NJ: Daiichi Sankyo, Inc.; 2017 FDA-Approved Renal Dose Adjustments in VTE Treatment Renal Function (ml/min) Dabigatran Rivaroxaban No Adjustment No Adjustment Apixaban 14 Edoxaban Betrixaban > 95 No Adjustment 51-94 No Adjustment 30-50 150 mg twice daily* No Adjustment 15-30 No Recommendation Avoid use < 15 or ESRD No Recommendation Avoid use No dose adjustment recommended. 30 mg daily Use not recommended 80 mg x 1 40 mg daily* No Recommendation VTE = venous thromboembolism; ESRD = end stage renal disease; *Avoid coadministration with P-gp inhibitor Pradaxa(R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2018 Xarelto(R) [package insert]. Titusville,NJ: Janssen Pharmaceuticals, Inc.; 2016 Eliquis(R) [package insert]. Princeton, NJ: Bristol-Meyers Squibb, Inc.; 2016 Savaysa(R) [package insert]. Basking Ridge,NJ: Daiichi Sankyo, Inc.; 2017 Bevyxxa(R) [package insert]. South San Francisco,CA: Portola Pharmaceuticals, Inc.; 2017 7

Guideline Recommendations 2014 ACC/AHA/HRS Atrial Fibrillation For patients with non-valvular AF and moderate-to-severe CKD with CHA2DS2-VASc score > 2 treatment with reduced doses of direct thrombin or factor Xa inhibitors may be considered but safety and efficacy have not been established. (Class IIb; Level C) For patients with non-valvular AF with a CHA2DS2-VASc score > 2 and who have end-stage chronic kidney disease (CKD) (creatinine clearance [CrCl] <15 ml/min) or are on hemodialysis, it is reasonable to prescribe warfarin (INR 2.0 to 3.0) for oral anticoagulation (Class IIa; Level B) 15 2016 CHEST VTE Treatment NOACs and LMWH are contraindicated with severe renal impairment. Dosing of NOACs with levels of renal impairment differ with the NOAC and among jurisdictions. Vitamin K Antagonist is preferred. J Am Coll Cardiol. 2014;64(21):e1-76. Chest. 2016;149(2):315-52. DOAC Landmark Trial Exclusion Criteria N Engl J Med. N Engl J Med. N Engl J Med. N Engl J Med. N Engl J Med. 16 Agent Clinical Trials Dabigatran RE-LY RE-COVER Rivaroxaban ROCKET AF EINSTEIN Edoxaban ENGAGE AF TIMI 48 Hokusai-VTE Betrixaban APEX CrCl < 15 ml/min Apixaban ARISTOTLE AMPLIFY SCr > 2.5 mg/dl OR CrCl < 25 ml/min 2009;361(12):1139-51. 2009;361(24):2342-52. 2011;365(10):883-91. 2010;363(26):2499-510. 2012;366(14):1287-97. Renal Function Cutoffs CrCl < 30 ml/min N Engl J Med. 2013;369(22):2093-104. N Engl J Med. 2013;369(15):1406-15. N Engl J Med. 2016;375(6):534-44. N Engl J Med. 2011;365(11):981-92. N Engl J Med. 2013;369(9):799-808. 8

DOAC Landmark Trial Baseline Characteristics Renal Function (ml/min) RE-LY > 80 48.4 % 50-79 32.2 % 30-49 19.4 % < 30 0 ROCKET AF Median: 67 ml/min IQR: 52-88 17 ARISTOTLE Renal Function (ml/min) ENGAGE-AF TIMI-48 41.3 % > 95 22 % 41.7 % 50-95 58.3 % 15.1 % 30-50 19.5 % 1.5 % < 30 0 N Engl J Med. 2009;361(12):1139-51. N Engl J Med. 2011;365(10):883-91. N Engl J Med. 2011;365(11):981-92. N Engl J Med. 2013;369(22):2093-104. Controversy of Oral Anticoagulants in CKD 18 1. The use of warfarin in CKD is controversial. 2. The use of DOACs have become more frequent, even in CKD and end-stage renal disease (ESRD). 3. All DOACs are renally eliminated. 4. Dosing recommendations for DOACs in severe renal impairment and ESRD are controversial. 9

Assessment Question 19 Which oral anticoagulant is significantly removed by dialysis? A. B. C. D. Rivaroxaban Dabigatran Warfarin Betrixaban Dissecting the Literature 20 10

Dabigatran Landmark Trials RE-LY 2009 21 RE-COVER 2009 RE-COVER II 2014 Endpoints Stroke/Systemic Embolism in NVAF Thromboembolism vs. warfarin Stroke/systemic embolism* = Recurrent VTE or Related Death = Recurrent VTE or Related Death Bleeding vs. warfarin = Major Bleeding Major GI Bleeding* = Major Bleeding Bleeding Recurrent VTE *Dabigatran 150 mg BID N Engl J Med. 2009;361(12):1139-51. N Engl J Med. 2009;361(24):2342-52. Circulation. 2014;129(7):764-72. Dabigatran Pharmacokinetics 22 Creatinine Clearance (ml/min) Increase in AUC > 80 1x 50-80 1.5x 30-50 3.2x < 30 6.3x Pradaxa(R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2018. 11

RE-LY Subgroup Analysis Subgroup Dabigatran 150 mg BID N=6,029 23 Warfarin N=5,965 HR (95% CI) 150 mg vs. Warfarin Yearly Event Rate for Stroke/Systemic Embolism > 80 ml/min 0.71 %/year 1.05 %/year 0.67 (0.42-1.09) 50-79 ml/min 1.25 %/year 1.83 %/year 0.68 (0.50-0.92) < 50 ml/min 1.53 %/year 2.70 %/year 0.56 (0.37-0.85) Yearly Event Rate for Major Bleeding > 80 ml/min 2.04 %/year 2.43 %/year 0.84 (0.62-1.13) 50-79 ml/min 3.35 %/year 3.70 %/year 0.91 (0.75-1.11) < 50 ml/min 5.50 %/year 5.49 %/year 1.01 (0.79-1.30) Circulation. 2014;129(9):961-70. Dabigatran Takeaways 24 Dabigatran accumulates with worsening renal impairment. Bleeding risk compared to warfarin increases as renal function declines. Overall, dabigatran is not an ideal anticoagulant for patients with a CrCl between 30 and 50 ml/min, and should not be used in patients with ESRD on dialysis. 12

Rivaroxaban Landmark Trials ROCKET AF 2011 25 EINSTEIN DVT 2010 EINSTEIN PE 2012 Endpoints Stroke/Systemic Embolism in NVAF Thromboembolism vs. warfarin = Stroke/systemic embolism = Recurrent VTE = Symptomatic recurrent VTE Bleeding vs. warfarin Critical/fatal bleeding Intracranial hemorrhage = Bleeding Bleeding Recurrent VTE N Engl J Med. 2011;365(10):883-91. N Engl J Med. 2010;363(26):2499-510. N Engl J Med. 2012;366(14):1287-97. ROCKET AF Subgroup Analysis CrCl 30-49 ml/min 26 CrCl > 50 ml/min Rivaroxaban 15mg* n=1474 Warfarin* n=1476 HR (95% CI) Rivaroxaban 20 mg* n=5637 Warfarin* n=5637 HR (95% CI) Stroke/ SE 2.32 2.77 0.84 (0.57-1.23) 1.57 2.00 0.78 (0.63-0.98) Major Bleeding 4.49 4.70 0.95 (0.72-1.26) 3.39 3.17 1.07 (1.03-1.52) ICH 0.71 0.88 0.81 (0.41-1.60) 0.44 0.71 0.62 (0.42-0.92) *Event rate per 100 patient-years SE= Systemic Embolism ICH=Intracranial Hemorrhage Eur Heart J 2011;32:2387 2394. 13

EINSTEIN Trials Pooled Analysis Subgroup Rivaroxaban 27 LMWH-Warfarin Incidence Recurrent VTE / VTE-Related Death Age >75 years 2.3% (15/656) 3.7% (23/627) CrCl <50 ml/min 3.3% (11/332) 3.4% (11/332) Weight <50 kg 7.1% (3/42) 3.0% (2/66) Age >75 years 1.2% (8/655) 4.5% (28/624) CrCl <50 ml/min 0.9% (3/329) 4.1% (13/320) Weight <50 kg 0.0 % (0/42) 4.6% (3/65) Major Bleeding Thrombosis Journal. 2013;11:21. Rivaroxaban Takeaways 28 In patients with CrCl > 50 ml/min, there was a statistically significant, but clinically insignificant increased risk of major bleeding versus warfarin in patients with NVAF. In patients with CrCl between 30 and 49 ml/min, rivaroxaban was similar to warfarin in preventing stroke in NVAF and associated with less intracranial hemorrhage. In patients with CrCl < 50 ml/min, rivaroxaban was similar to warfarin in treating VTE and significantly reduced major bleeding. Overall, rivaroxaban may be a reasonable alternative to warfarin in patients with a CrCl 30 and 49 ml/min. 14

Apixaban Landmark Trials 29 ARISTOTLE 2011 AMPLIFY 2013 Endpoint Stroke/systemic embolism in NVAF Recurrent VTE Thromboembolism vs. warfarin Stroke or systemic embolism = Recurrent symptomatic VTE or related death Bleeding vs. warfarin Bleeding Bleeding N Engl J Med. 2011;365(11):981-92. N Engl J Med. 2013;369(9):799-808. ARISTOTLE Subgroup Analysis Subgroup Apixaban n=9,120 Warfarin n=9,081 HR (95% CI) 30 P-Value for Interaction Yearly Event Rate for Stroke/Systemic Embolism > 80 ml/min 0.99 %/year 1.12 %/year 0.88 (0.64-1.22) 51-80 ml/min 1.24 %/year 1.69 %/year 0.74 (0.56-0.97) < 50 ml/min 2.11 %/year 2.67 %/year 0.79 (0.55-1.14) 0.705 Yearly Event Rate for Major Bleeding > 80 ml/min 1.46 %/year 1.84 %/year 0.80 (0.61-1.04) 51-80 ml/min 2.45 %/year 3.21 %/year 0.77 (0.62-0.94) < 50 ml/min 3.21 %/year 6.44 %/year 0.50 (0.38-0.66) 0.030 Eur Heart J. 2012;33(22):2821-30. 15

AMPLIFY Subgroup Analysis Recurrent Symptomatic VTE/VTERelated Death Adjudicated Major Bleeding Subgroup Apixaban N=2609 LMWH-Warfarin N=2635 > 80 ml/min 2.26% (38/1676) 2.44% (42/1719) 51-80 ml/min 2.64% (14/531) 2.26% (12/530) < 50 ml/min 4.14% (7/169) 4.43 % (7/158) Subgroup Apixaban N=2676 LMWH-Warfarin N=2689 > 80 ml/min 0.29% (5/1720) 1.42% (25/1756) 51-80 ml/min 0.91% (5/549) 1.84% (10/544) < 50 ml/min 2.86% (5/175) 5.52% (9/163) 31 P-Value for Interaction 0.8757 P-Value for Interaction 0.3606 N Engl J Med. 2013;369(9):799-808 Apixaban Takeaways 32 In patients with a CrCl between 51 and 80 ml/min, apixaban was associated with a reduced risk of stroke and major bleeding compared to warfarin in patients with NVAF In patients with a CrCl between 25 and 50 ml/min, apixaban was similar to warfarin in preventing stroke in NVAF and treating VTE. In patients with CrCl between 25 and 30 ml/min, apixaban was associated with a 50% reduction in bleeding risk. Overall, apixaban may be a safer alternative to warfarin in patients with CrCl between 25 and 30 ml/min. 16

Edoxaban Landmark Trials 33 ENGAGE-AF TIMI-48 2013 Hokusai-VTE 2013 Endpoints Stroke/systemic embolism in NVAF Recurrent VTE Thromboembolism vs. warfarin Stroke or systemic embolism = Recurrent symptomatic VTE or related death Bleeding vs. warfarin Bleeding Bleeding N Engl J Med. 2013;369(22):2093-104. N Engl J Med. 2013;369(15):1406-15. ENGAGE-AF TIMI 48 Subgroup Analysis 34 Stroke/ Systemic Embolism Ischemic Stroke Hemorrhagic Stroke Major Bleeding 81 95 ml/min 1.1 vs. 1.0 %/year 1.05 (0.61, 1.82) 0.8 vs. 0.7 %/year 1.11 (0.58, 2.12) 0.2 vs. 0.3 %/year 0.76 (0.24, 2.38) 2.44 vs. 2.85 %/year 0.86 (0.60, 1.22) 51 80 ml/min 1.1 vs. 2.0 %/year 0.53 (0.40, 0.70) 0.8 vs. 1.2 %/year 0.63 (0.44, 0.89) 0.3 vs. 0.7 %/year 0.38 (0.22, 0.67) 3.08 vs. 3.49 %/year 0.88 (0.73, 1.07) 30-50 ml/min 1.8 vs. 2.0 %/year 0.90 (0.60, 1.34) 1.2 vs. 1.1 %/year 1.11 (0.66, 1.84) 0.5 vs. 0.7 %/year 0.66 (0.32, 1.36) 3.83 vs. 5.07 %/year 0.76 (0.58, 0.99) < 95 ml/min 1.2 vs. 1.8 %/year 0.68 (0.55, 0.84) 0.9 vs. 1.1 %/year 0.80 (0.62, 1.04) 0.3 vs. 0.6 %/year 0.50 (0.33, 0.75) 3.1 vs. 3.7 %/year 0.84 (0.73, 0.97) Savaysa(R) [package insert]. Basking Ridge,NJ: Daiichi Sankyo, Inc.; 2017 17

Hokusai-VTE Subgroup Analysis Subgroup Edoxaban n=4118 Warfarin n=4122 35 P-Value for Interaction Recurrent Symptomatic VTE >50 ml/min 3.2% (122/3850) 3.4% (130/3849) 30-50 ml/min 3.0% (8/268) 5.9% (16/273) 0.1581 Major and Clinically Relevant Non-Major Bleeding >50 ml/min 8.3% (321/3850) 10.0% (384/3849) 30-50 ml/min 10.4% (28/268) 14.3% (39/273) 0.5926 N Engl J Med. 2013;369(15):1406-15. Edoxaban Takeaways 36 In patients with NVAF and CrCl between 51 and 80 ml/min, edoxaban was associated with less stroke/systemic embolism and similar bleeding risk compared to warfarin. In patients with CrCl between 30 and 50 ml/min, edoxaban was associated with decreased bleeding risk compared to warfarin in NVAF. In patients with CrCl between 30 and 50 ml/min, recurrent symptomatic VTE and bleeding rates were less than that of warfarin. Overall, edoxaban is a reasonable alternative to warfarin in patients with CrCl between 30 and 95 ml/min. 18

Betrixaban Landmark Trial 37 APEX 2016 Endpoints VTE in the setting of extended thromboprophylaxis in acutely ill medical patients VTE vs. enoxaparin In patients with elevated D-dimer level and at least 75 years of age Bleeding vs. enoxaparin Major/clinically relevant non-major bleeding N Engl J Med. 2016;375(6):534-44. APEX Baseline Characteristics Renal Function (ml/min) Percent of Patients > 90 18.5 % 60-89 35.2 % 30-59 41.7 % 15-29 4.3 % < 15 < 0.1 % 38 N Engl J Med. 2016;375(6):534-44. 19

DOACs in Patients Receiving Dialysis Dabigatran and Rivaroxaban in Hemodialysis Event Rate per 100 Patient-Years Outcomes in Patients with NVAF 39 40 Unadjusted Rate Ratios Dabigatran n=281 Rivaroxaban n=244 Warfarin n=8064 Dabigatran vs. Warfarin (95% CI) Rivaroxaban vs. Warfarin (95% CI) Stroke/ Arterial Embolism 10.6 11.2 6.2 1.71 (0.97-2.99) 1.80 (0.89-3.64) Major Bleeding 83.1 68.4 47.1 1.76 (1.44-2.15) 1.45 (1.09-1.93) Circulation 2015;131:972 979. 20

Apixaban in Dialysis Study Design Purpose Population Characteristics Retrospective cohort Determine patterns and outcomes associated with apixaban use in patients with AF undergoing dialysis. Medicare beneficiaries with ESRD undergoing dialysis. Diagnosed with AF within 1 year prior to anticoagulant therapy N= 25,523 (Apixaban: n=2351 vs. Warfarin: n=23,172) Apixaban 5 mg BID: 44% Apixaban 2.5 mg BID: 56% Time Period October 2010 through December 2015 Comparison Apixaban versus warfarin, matched 1:3 Endpoints 41 Ischemic stroke or systemic embolism Major bleeding, GI bleeding, Intracranial bleeding Mortality Circulation. 2018; In Press Apixaban in Dialysis Apixaban N=2,351 Outcome 42 Warfarin N=7,053 Event Rate per 100 Person-Years HR (95% CI) P Value Stroke/Systemic Embolism 12.4 11.8 0.88 (0.69-1.12) 0.29 Major Bleeding 19.7 22.9 0.72 (0.59-0.87) < 0.001 GI Bleeding 23.8 23.4 0.86 (0.72-1.02) 0.09 Intracranial Bleeding 3.1 3.5 0.79 (0.49-1.26) 0.32 Mortality 23.7 24.9 0.85 (0.71-1.01) 0.06 Circulation. 2018; In Press 21

Summary of DOACs in Dialysis 43 Dabigatran and rivaroxaban were each associated with an increased risk of bleeding compared to warfarin in patients with NVAF on hemodialysis. Retrospective data in NVAF suggest that apixaban may be as effective as warfarin in patients with NVAF on dialysis. Other Considerations 44 CrCl Calculation Cockcroft-Gault Formula Actual Body Weight Age Weight Hepatic Dysfunction Valvular Heart Disease CHA2DS2VASc and HAS-BLED Scores in NVAF Drug-Drug Interactions Cost 22

Take Home Points 45 Hemostasis in patients with CKD is impaired, increasing the risk of both thrombosis and bleeding. Highest quality evidence stems from subgroup analyses and retrospective cohorts. Dabigatran should not be used for stroke prevention in NVAF in patients with severe renal impairment and ESRD. Rivaroxaban may be considered in patients with a CrCl between 30 and 50 ml/min. Apixaban is associated with less bleeding risk compared to warfarin patients with moderate to severe renal impairment and in patients on hemodialysis. In addition to renal impairment, other factors must be considered when selecting oral anticoagulation in patients with CKD. Patient LW 46 LW is a 65 year-old African American woman with a history of DM, CKD, HTN, epilepsy and NVAF who presented to the ED with progressively worsening palpitations. Her calculated CrCl based on actual weight is 40 ml/min. Home Medications: Metoprolol succinate 50 mg daily Lisinopril 20 mg daily Carbamazepine 200 mg twice daily Sitagliptin 50 mg daily 23

Assessment Question 47 Which oral anticoagulant would be most appropriate in patient LW? A. B. C. D. Rivaroxaban Apixaban Warfarin Edoxaban Practical Considerations for Using Oral Anticoagulants in Patients with Chronic Kidney Disease Cyrille K. Cornelio, Pharm.D. PGY2 Cardiology Pharmacy Resident The University of Oklahoma College of Pharmacy Oklahoma Society for Health-System Pharmacists Fall Meeting September 14, 2018 24