An#coagulant Choices in Renal Impairment

An#coagulant Choices in Renal Impairment Karen Shalansky, Pharm.D. Pharmacotherapeu#c Specialist, Nephrology Vancouver General Hospital Clinical Professor Faculty of Pharmaceu#cal Sciences, UBC karen.shalansky@vch.ca April 18, 2012

Disclosures I have no known or real conflicts of interest to declare

Outline Review mechanisms of ac0on of an0coagulants Compare the new oral an0coagulants dabigatran, rivaroxaban, apixaban Discuss an0coagulant op0ons in renal impairment Focus on LMWH use in renal impairment Role of an0- Xa monitoring cases with clinical use of LMWH in dialysis Long- term 0nzaparin and an0- Xa levels Triple an0coagulant therapy Bridge Therapy Prophylac0c therapy with dalteparin

XII An#coagulant Sites of Ac#on XI Unfrac#onated Heparin IX VIII X VII Factor Xa Inhibitors rivaroxaban, apixaban, fondaparinux Low Molecular Weight Heparin V II Warfarin I Direct Thrombin (IIa) Inhibitors - dabigatran, argatroban Fibrin Clot

Compara#ve Features of New Oral An#coagulants Target Inhibi#on Coag Assay* Dabigatran etexilate Rivaroxaban Apixaban Factor IIa (Thrombin) Both free and clot bound Thrombin #me (27x) aptt (2-3x); INR 40% Factor Xa Xa inhibi0on (68%) aptt 40%; INR 40% Factor Xa Xa inhibi0on aptt; INR Oral Bioavailabilty 6-7% 60-80% 50% T (max) 1-3 h 2-4 h 1-3 h Half- life 14-17 h 9-13 h 8-15 h 66% renal (36% Metabolism / 80% renal 25% renal unchanged) Elimina#on 20% biliary 75% biliary 33% biliary Dialyzable Yes No (92-95% PB) Unlikely (87% PB) Hold Prior to Surgery egfr > 50 ml/min Minor surgery: 1 day Major surgery: 3 days Minor surgery : 1 day Major surgery: 2 days? Similar to Rivaroxaban CYP Metabolism No 30% CYP3A4 15% CYP3A4 P- glycoprotein Substrate Yes Yes Yes * To assess toxicity only (Pharmacotherapy 201;31:1175-91; Blood 2010;115:15-20)

P- Glycoprotein Drug Interac#ons with NOA P- glycoprotein (P- gp) is a transport protein that func0ons as an efflux pump to prevent absorp0on of certain drugs, including the new oral an0coagulants Inhibitors of P- gp increase absorp0on of NOA Azole antifungals* Ritonavir* amiodarone verapamil quinidine cyclosporin tacrolimus Clarithro/Erythro* Inducers Rifampin** Phenytoin** Carbamazepine** Phenobarbital** Dexamethasone Doxorubicin St. John s Wort** Inhibitors * Also CYP3A4 inhibitor - rivaroxaban ** Also CYP3A4 inducers - rivaroxaban

New Oral An#coagulant (NOA) Trials Orthopedic Prophylaxis (Total Hip and Knee Replacement) Stroke preven0on in Atrial Fibrilla0on Dabigatran Rivaroxaban Apixaban ü RE- MOBILIZE RE- MODEL RE- NOVATE ü RE- LY (W) ü RECORD 1 RECORD 2 RECORD 3 RECORD 4 ü ROCKET AF (W) ü ADVANCE 1 ADVANCE 2 ADVANCE 3 AVERROES (ASA) ARISTOTLE (W) VTE Treatment RECOVER REMEDY EINSTEIN PE EINSTEIN DVT EINSTEIN- EXT AMPLIFY AMPLIFY- EXT ü Approved use in Canada

Canadian Dosing Guidelines for NOA Dabigatran Rivaroxaban Apixaban Orthopedic Prophylaxis (TKR = x 14 days; THR = x 35 days) > 50 ml/min 220 mg daily 10 mg daily 2.5 mg BID 30-50 ml/min 150 mg daily 10 mg daily (Cau0on) 2.5 mg BID 15-29 ml/ min Avoid (black box) Avoid 2.5 mg BID (Cau0on) (AUC 44%) < 15 ml/min Avoid Avoid Avoid Stroke Preven#on in Atrial Fibrilla#on > 50 ml/min 150 mg BID 20 mg daily 30-50 ml/min 150 mg BID (if 75 yrs + risk factor for bleeding, consider 110 mg BID) 15 mg daily < 30 ml/ min Avoid Avoid

Advantages of New Oral An#coagulants Fixed dosing Monitoring of an0coagulant effect not required Fewer drug interac0ons compared to warfarin

Limita#ons of New Oral An#coagulants Inability to Measure an0coagulant effect Poten0al for increased risk of stroke or embolism if poor compliance Poten0al for increased risk of bleed if reduced renal func0on/di (Dabigatran - 260 fatal bleeding events worldwide Mar 08 to Oct 11) Lack of specific an0dote Prothrombin complex concentrate (Octaplex ) for intracranial hemorrhage (Octaplex plasma derived, purified Factors II, VII, IX, X, protein C and S) Some drug interac0ons p- glycoprotein inhibitors/inducers Dose adjustments required in renal dysfunc0on Should not be prescribed for egfr < 30 ml/min (BLACK BOX for dabigatran) Cost Rivaroxaban covered for orthopedic prophylaxis (Circula0on 2012;125:165070)

An#coagulant Op#ons in Renal Failure Drugs with no significant renal clearance Unfrac0onated heparin (UFH) Warfarin Direct Thrombin Inhibitors: argatroban Direct Factor Xa inhibitors: apixaban (avoid < 15 ml/min) Drugs with significant dependence on renal clearance Low molecular weight heparins (LMWHs) Factor Xa inhibitors: Indirect - Pentasaccharide: fondaparinux Direct rivaroxaban Heparinoids: danaparoid Direct Thrombin Inhibitors: lepirudin, bivalirudin, dabigatran

Factor Xa Inhibitors FON D Indirect Inhibitors Fondaparinux Idraparinux Direct Inhibitors Rivaroxaban Apixaban Edoxaban Betrixaban

Fondaparinux Regional Approval Unstable angina/non- STEMI (2.5 mg SC daily) Management of HIT Tx VTE: 5-10 mg SC daily; Prophylaxis VTE: 2.5 mg SC daily Easier to administer vs argatroban (con0nuous infusion) Elimina0on t/12 = 17-21 hrs; Elimina0on = 77% unchanged urine Renal Dosing (hemodialysis) case reports Tx VTE: 2.5 mg SC every 2 days (monitor an0- Xa levels 3 h peak 0.5-1.5; trough < 0.5) Give dose ater dialysis (Am J Health- Syst Pharm 2010;67:1075-9)

LMWH Use in Renal Impairment

2012 ACCP Guidelines Appropriate dose of LMWH in pa0ents with severe renal insufficiency (< 30 ml/min) is uncertain Clearance of the an#- Xa effect of LMWH correlates with CrCl (enoxaparin, nadroparin, dalteparin) Excep#on: Tinzaparin not shown to correlate with CrCl If severe renal insufficiency and therapeu0c an0coagula0on required, suggest UFH over LMWH If LMWH is used in pa0ents with severe renal insufficiency for therapeu0c an0coagula0on, suggest monitor an0- Xa levels Garcia et al. Parenteral An0coagulants. Chest 2012;141:24s- 43s.

An#- Xa Monitoring (not an exact science) Measure in pa0ents with renal failue (CrCl < 30 ml/min) or obesity Measure peak effect (4 hours) 3-4 hours ater twice daily dosing 4-5 hours ater once daily dosing Twice daily: 0.6-1 units/ml Once daily: 1-2 units/ml (Tinzaparin 0.6-1.5 U/mL*) Trough levels < 0.5 units/ml (Semin Thromb Hemost 2001;27:519-22; *Drug Safety 2002;25:725-33)

Mean Peak An#- Xa Levels (Normal Renal Func0on) Units/kg Q12H Units/kg daily (Semin Thromb Hemost 2001;27:519-22)

Heparin and LMWHs Pentasaccharide sequence binds to AT and accelerates its inhibitory ac0vity Factor Xa requires only pentasaccharide Thrombin requires 18 saccharide units LMWHs have less ac0vity against thrombin as longer chain length required Weitz N Engl J Med 1997.

Clearance of UFH and LMWHs Agent Average MW (daltons) An0Xa:IIa Ra0o UFH 15,000 1:1 Tinzaparin 6,500 1.9:1 Dalteparin 5,600 2.0 2.7:1 Enoxaparin 4,500 2.7 4.1:1 Nadroparin 4,300 3.2 3.7:1 Higher MW chains are cleared by dose- dependent hepa0c mechanism Lower MW chains are cleared by dose- independent renal route (Pharmacotherapy 2001;21:218-34; Pharmacotherapy 2005; 25:881-5)

Tinzaparin Highest MW may be less dependent upon renal clearance Closest an0- Xa:IIa ac0vity compared to heparin Agent Average MW (daltons) An#Xa:IIa Ra#o Heparin 15,000 1:1 No Dose Adjustment CrCl < 30 ml/min Tinzaparin 6500 1.9:1 No (short- term) Dalteparin 5600 2.0-2.7:1? Enoxaparin 4500 2.7-4.1:1 Yes (50% - per CPS) Nadroparin 4300 3.2-3.7:1 Yes (no guidelines)

Tinzaparin Full Dose (175 units/kg/day) Trial Popula#on Dura#on Outcome Drug Safety 2002:25:725-33 Thromb Haemost 2000;84: 800-4 Blood 2006; 108:884 (abstract) 200 elderly VTEpts ~25% Cr Cl 20-35 ml/min 30 elderly VTE pts ~25% CrCl 20-29 ml/min 78 pts with VTE and varying CrCl including HD Up to 30 d (mean 19 d) 88% peaks < 1.5 U/mL (Day 1, qweek) - No correla0on to CrCl 10 days All peaks < 1.1 U/mL (Days 1, 2, 7, 10) 5-7 days - No correla0on to CrCl 94% troughs < 0.5 U/mL (Days 3, 5, 7) - No correla0on to CrCl Thromb Res 2011;128:27-34 (IRIS) MC, OL, R cf UFH 539 elderly with DVT and CKD (25% pts with CrCl< 30 ml/min) 5-10 days, then warfarin (f/ u = 90 d) - Study stopped early due to mortality in Tinza arm at day 28 (11.9% vs 6.3%, p=0.035) - CA, sepsis in pts 90 yrs - Imbalance in randomiza0on

Enoxaparin Dose Adjustment Linear correla0on between an0- Xa levels and CrCl Prolonged t 1/2 (2.94 vs 5.12 hrs CrCl 5-21 ml/min) CPS dose adjustment for CrCl < 30 ml/min Treatment: 1 mg/kg SC Q24H Prophylaxis: 30 mg SC Q24H Poten0ally low peak and trough levels (up to 26%) (Pharmacother 2007;27:1347; Thromb Res 2005;116;41) Pharmacokine0c trials Treatment: 0.5-0.75 mg/kg Q12H (Am Heart J 2004;148:582) No outcome data for VTE with reduced renal func0on

Case 1. Long- Term Tinzaparin A case of Calciphylaxis and Atrial Fibrilla#on

Case 1. Calciphylaxis and A Fib 79 yo female, 75 kg admiyed with calciphylaxis & atrial fibrilla0on D/C warfarin, daily HD (5/7), hyperbaric unit, sodium thiosulphate, lanthanum Started on 0nzaparin 14,000 units SC daily (75 kg x 175 units/kg = 13, 125 units) Peak An#- Xa levels (6h): Day 3 = 0.85 units/ml Day 16 = 0.88 units/ml Day 37 = 0.78 units/ml NOTE: Intradialy0c heparin discon0nued

Case 2. Long- Term Tinzaparin and Triple An#coagulant Therapy A case of An#- phospholipid syndrome and MI

Case 2: 73 yo female, 80kg on HD PMH: An0phospholipid an0body syndrome (DVT/PE 2000, IVC filter, warfarin failure, a fib) Lifelong 0nzaparin Date Event Tinzaparin Dose (SC) Oct- 06 to Aug- 07 Start HD 14,000 U 10,000 U 7000 U daily (Aug 23/07 peak an0- Xa level = 1.03 U/mL) Aug- 09 Seizure (admission) 7000 units daily + Levateracetam (Keppra ) Aug- 09 Dec- 09 Feb- 10 Pneumonia- ICU NSTEMI x 2 Let upper arm hematoma Right upper arm hematoma (readmit); Heme consult 7000 units SC daily + ASA 81mg PO daily + Clopidogrel 75 mg PO daily ASA + Plavix held; Discharged Jan- 10 to RN home on triple therapy above D/C Tinzaparin and Clopidogrel ASA 81mg daily + Heparin 5000 units SC BID Sept- 10 Humerus # - fall Deceased (?PE vs sudden cardiac death)

Bleed Risk from Single, Dual, or Triple Therapy in Pa#ents with A Fib Variable Warfarin Aspirin RR (95% CI) non- fatal bleed 1 (reference) Crude Rate = 3.6% 0.84 (0.8-0.89) Clopidogrel 0.94 (0.76-1.16) ASA +C W+ASA 1.64 (1.33-2.03) 1.77 (1.66-1.90) Na0onwide Danish registry of 82,854 pa0ents with atrial fib discharged on warfarin, ASA, or clopidogrel (Jan 97- Dec 06) Analyzed risk hospitaliza0on or death due to bleeding 12,191 (10.3%) had non- fatal bleed, primary due to GI W+C W+C+ASA 3.16 (2.48-4.03) 3.93 (3.05-5.05) (Arch Int Med 2010;170:1433-41)

Major Bleeding in HD Pa#ents Retrospec0ve review of 255 pts from Jan 2002- Jan 2004 (1028 person years of exposure) 25/26 major bleeds were upper or lower GI bleed; 1 = CNS Treatment # pts Major Bleed % Major Bleeds None 178 4 0.8% Reference Hazard Model for Time to First Bleed (95% CI) Warfarin 89 15 3.1% 3.9 (1.05-14.6) ASA 107 12 4.4% 5.8 (1.9-18.0) ASA + Warfarin 50 5 6.3% 8.2 (2.2-30.7) Total 255 26 (CJASN 2008;3:105-110)

Cases 3 & 4 Bridge Therapy Two high risk pa#ents

Peri- opera#ve Risk Stra#fica#on (Chest 2012;141:326s- 350s) Thrombosis Risk Mechanical Heart Valve Atrial Fibrilla#on VTE Bridge HIGH Mitral Valve CHADS 2 5-6 VTE < 3 mo Yes (2C) Older aor0c valve (0l0ng disc) Recent (< 6 mo) stroke or TIA Recent (< 3 mo) stroke or TIA Rheuma0c valvular HD Severe thrombophilia MODERATE Bileaflet aor0c valve + one of: a fib, stroke, TIA, HT, DM, CHF, > 75 CHADS 2 3-4 VTE 3-12 mo Recurrent VTE Ac0ve cancer Full dose or Prophylac0c dose or No bridge LOW Bileaflet aor0c valve & no risk factors for stroke CHADS 2 0-2 VTE > 12 mos and no other risk factors No bridge (2C)

How to Bridge with LMWH (Circula#on 2004;110:1658-63; Chest 2012;141:326s- 350s) Stop Warf Start LMWH Stop LMWH am / pm Start Warf 12-24h post- sx Start LMWH am / pm Stop LMWH when INR therapeu#c Day - 5 Day - 3 Day - 1 Day 0 Day +1 to +3 Full dose OD or BID or prophylactic dose OD No dose within 24 h (or ½ dose in am); INR >1.5 Vit K 1mg po Restart depends on adequate hemostasis

Temporary Discon#nua#on of Warfarin: INR Decay with Target Range 2-3 4 Mean INR 2.6 INR 3 2 Mean INR 1.6 Mean INR 1.1 Age 55 yrs Age > 55 yrs 1 0 20 40 60 80 100 120 140 160 180 Hours N= 22 pa0ents; serial INRs done at 2.7 and 4.7 days ater D/C (Ann Intern Med 1995;122:40-2)

Case 3: 72 yo, 91 kg male Recent bilateral PE July 4/11; Hx of PE and DVT x 2 Pt had been off warfarin AMA prior to recent event Requires fistuloplasty July 19/11 Date Day Action July 14 Day - 5 Stop Warfarin (INR = 2.7) July 15-17 Day - 4 to - 2 (low dose ID heparin) Start Tinzaparin 14,000 units qpm (175 units x 91kg = 15,925 units) July 18 Day - 1 No Tinzaparin; INR = 1.0 July 19 July 27 Day 0 (if okay by vascular) Day + 8 (end of 10 day Pharmacare coverage) Restart Warfarin in evening Restart Tinzaparin in evening Last dose Tinzaparin (INR = 1.9)

Case 4: Accidental Overdose 74 yo, 58 kg male with PE July 27/10; Hx of pulmonary fibrosis Date Event Tinzaparin Dose Aug 6 Discharged INR = 1.2 10,000 units daily Aug 7-9 Patient error with dose; was dispensed 3 x 20,000 unit/2 ml vial (instead of 10,000 unit syringe) 20,000 units daily x 3 Aug 10 Ran out of Tinzaparin None Aug 11 INR = 1.3; error discovered; Anti-Xa level ordered (43 h post) 5000 units Aug 12 Anti-Xa Level = 0.26 units/ml 10,000 units Aug 13 INR = 2.1 Discontinue tinzaparin

Case 5. LMWH Prophylaxis A paraplegic pa0ent

Dalteparin Prophylaxis Trial: DIRECT (Arch Intern Med 2008;168:1805-12) 138 ICU pa0ents, CrCl < 30mL/min (mean 18.9mL/min) 9.4% on dialysis Dalteparin 5000 U SC daily < 30 days (median 7 days; IQR 4-12 days) Trough an0- Xa levels on days 3, 10, 17 Results: All trough an0- Xa levels < 0.4 units/ml No evidence of accumula0on DVT = 5.1% Major bleeding = 7.2% Risk Factors: ASA use, INR

VTE Prophylaxis Guidelines: VCH/PHC Dalteparin 5000 units SC daily (egfr > 10 ml/min) If pa0ent has egfr 10-30 ml/min and therapy to extend beyond 10 days, consider switch to heparin Q12H Heparin 5000 units SC Q12h (egfr < 10 ml/min) Weight Range Dalteparin (egfr > 10mL/min ) Heparin (egfr < 10 ml/min) 40 kg or less 2500 units SC daily 2500 units SC Q12H 41 kg to BMI 40 kg/m 2 5000 units SC daily 5000 units SC Q12H BMI > 40 kg/m 2 5000 units SC Q12H 5000 units SC Q8H

Case 5: Dalteparin Prophylaxis 57 yo male, 95 kg, paraplegic Date Event Anticoagulation Apr 2, 2010 Apr 22 Admitted for LOC ICU intubation x 2 weeks CKD 2 diabetic nephropathy Dialysis initiated R IJ inserted - radiologist noted incidental finding of R IJ vein thrombosis (from previous ICU catheter) Heparin 5000 units SC Q8H Heparin 5000 units SC Q8H May 1 June 2 June 5 Heme consult Doppler R neck negative Anti-Xa Level > 2 units/ml (13 h post dose) Patient discharged Dalteparin 5000 units SC daily Hold x 24 h, then Dalteparin 2500 U SC OD

Conclusion An#coagulant Choices in Renal Impairment (egfr < 30 ml/min) VTE Treatment Unfrac0onated heparin IV preferred in hospital LMWH (monitor an0- Xa levels with long- term therapy) Tinzaparin full dose (up to 10d) Enoxaparin 1/2 dose (1 mg/kg SC daily) VTE Prophylaxis Heparin 5000 units SC Q8-12H Apixaban Avoid < 15 ml/min LMWH Tinzaparin no dose restric0ons Dalteparin 5000 units SC OD up to 10 days ( 2500 units if low risk) Enoxaparin 30 mg SC daily (1/2 dose)