5/21/2012. Perioperative Use Issues. On admission: During hospitalization:

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1 Dabigatran and Rivaroxaban: Challenges in the Perioperative Setting Claudia Swenson, Pharm.D., CDE, BC-ADM, FASHP Central Washington Hospital Wenatchee, WA Dabigatran and Rivaroxaban: Challenges in the Perioperative Setting - Objectives Review pharmacology, kinetics, laboratory monitoring of dabigatran & rivaroxaban Describe current management options for urgent procedures/surgery On admission: Perioperative Use Issues Assuring dabigatran/rivaroxaban have been held appropriately prior to planned procedure During hospitalization: Urgent surgery/procedures 1

2 Dabigatran (Pradaxa ) Pharmacology Oral direct thrombin inhibitor (DTI) Indication: nonvalvular atrial fibrillation (AF), VTE prophylaxis (Europe) AF (ReLY): noninferior to warfarin,(150mg vs. 110mg bid superior) Major bleeding same but 50% ICH, GI bleeding. No quantitative monitoring test (ECT research), TT or DTI assay better correlation with therapeutic effect. UW: DTI assay therapeutic range is secs. INR/aPTT elevated (trough aptt 1.5X control if normal CrCl) but not proportionate to drug level at supratherapeutic levels. Dabigatran Pharmacology Renally cleared. Holding drug prior to procedures is determined by renal function. Renal failure, dialysis removes 60%. If dose/overdose within 2hrs, activated charcoal. Dosing: CrCl >30ml/min: 150mg bid CrCl 15-30ml/min:75mg bid CrCl< 15ml/min: contraindicated Suggestions for Periprocedural Management of Dabigatran: UWACC CrCl >80ml/min Half life 14hrs Time of last dose before Standard Risk of Bleeding At least 24hrs of dabigatran procedure High Risk of Bleeding (major surgery, spinal/epidural placement, Spinal puncture other high risk) 2-3 days 50-80ml/min 30-50ml/min 17hrs 19hrs <30 27hrs At least 24hrs At least 48hrs 2-4 days 4 days 2-5 days >,= 5 days 2

3 Dabigatran Case #1 Case #1: 80yo female, AF, unwilling to comply with warfarin monitoring. Scr 1.1 mg/dl, estimated CrCl 45ml/min, dabigatran 150mg bid initiated Pt developed bradycardia, hospitalized for pacemaker insertion, Scr = 4.5 (renal failure with poor perfusion). Options?? Dabigatran - Case #1 Hospital course: aptt elevated, INR 4.0. UWACC consulted: Consider hemodialysis, blood products. Patient on isoproterenol drip in ICU, poor response. Day 2: inserted temporary pacemaker, no serious bleeding complications. Day 7: patient stabilized, serum creatinine back to baseline. Warfarin reinitiated. Rivaroxaban (Xarelto ) - Pharmacology Oral direct Xa inhibitor (like fondaparinux, LMWH) Increases aptt, factor Xa, INR no predictive value of these parameters for bleeding risk or efficacy 3 fold variation INR depending on thromboplastin Holding for procedure: If aptt/protime normal, no rivaroxaban effect. Expect rivaroxaban specific monitoring tests (mptt) and reversal agent in next year Cleared renally but not dialyzable FDA approved for DVT prophylaxis post-operatively operatively and non- valvular atrial fibrillation (Rocket AF trial) Cost : pharmacy acquisition cost ($6-$12/day) $12/day) lower than generic enoxaparin ($17-$26/day) $26/day) High copays and stocking issues in pharmacies. 3

4 Rivaroxaban Pharmacology VTE prophylaxis: THA,TKA Rivaroxaban 10mg daily if CrCl >30ml/min Avoid use in patients with severe renal impairment CrCl < 30 ml/min Observe closely/evaluate s/sx of blood loss in patients with moderate renal impairment (CrCl ml/min) No clear periprocedural hold information as procedure unlikely during 14-30days of prophylaxis: reoperation rates 0.1% to 0.4% Hold at least 24hrs. No reversal agent except blood products. Oral charcoal if dose<2hrs. Rivaroxaban Pharmacology Atrial Fibrillation Atrial Fibrillation: rivaroxaban vs. warfarin Results: noninferior to warfarin Warfarin group poor INR control Major bleeding rate same: higher GI bleed rate, ICH 50% lower Dosing 20mg at dinner if CrCl >50ml/min 15mg at dinner if CrCl 15-50ml/min50ml/min No information about stopping prior to surgery/procedures other than 24hrs. Suggestions for Periprocedural Management of Rivaroxaban: UWACC CrCl Half life Time of last dose before Standard Risk of Bleeding of rivaroxaban procedure High Risk of Bleeding (major surgery, spinal/epidural placement, Spinal puncture other high risk) >,=30ml/min 24hrs 24-48hrs 4

5 Case #2: 87yo female on dabigatran for AF, hospitalized with Hip Fracture. Estimated CrCl=40-54ml/min (Scr: ), INR elevated (1.4), needs surgery. Options? Vitamin K for elevated INR? Orthopedic surgeon ordered, not effective Dialysis to remove dabigatran vs. delay 48 hrs? (risk/benefit) Chose Transfusion /48hrs delay as renal function WNL. Post surgery: rivaroxaban 15mg daily at dinner for VTE prophylaxis and AF No current antidote available for either agent If <2hrs from ingestion, activated charcoal FFP, prbc may help Hemodialysis removes 64-68% of dabigatran but will not remove rivaroxaban (highly protein bound) Others: mechanical compression, surgery, hemodynamic support, fluid replacement Treatment Life-Threatening Bleeding PCC and recombinant Factor VII (rviia): reserve for life-threatening/organ threatening bleeding 12 normal volunteers given Rivaroxaban 20mg bid or Dabigatran 150mg bid x 2.5 days. Reversal: PCC (Cofact -4 factor PCC not available in US) or saline. U.S. PCC is 3 factor product (Profilnine SD). PCC completely reversed effects of rivaroxaban but not dabigatran: Normalized prothrombin time (15.8 secs to 12.3 secs) and endogenous thrombin potential (51% on riva vs. 92% baseline) Dabigatran effects on aptt, ECT and thrombin time unchanged. (Eerenberg et al) 5

6 To warfarin Converting Between Anticoagulants Dabigatran CrCl 50mL/min,start warfarin 3 days before stopping dabigatran CrCl ml/min, start warfarin 2 days before stopping dabigatran CrCl 15-30mL/min, start warfarin 1day before stopping dabigatran Rivaroxaban Start warfarin and stop rivaroxaban 3 days later. From warfarin Start when INR below 2.0 Start when INR below 2.0 To parenteral anticoagulant (heparin or enoxaparin) CrCl 30mL/min, start 12 hours after last dabigatran dose CrCl <30mL/min, start 24hours after last dabigatran dose Stop rivaroxaban, administer 1 st dose of parenteral anticoagulant when next dose rivaroxaban due. From heparin drip Start when drip stopped Start when drip stopped From LMWH (i.e. enoxaparin) or fondaparinux Start dabigatran 0-2 hours before next dose due Start rivaroxaban 0-2 hours before next dose due Summary Drug Use CrCl (ml/min) and Dosing Holding for Surgery or Procedure Dabigatran AF >30:150mg bid 15-30:75mg bid <15: contraindicated CrCl>50:STD risk - 24hrs High risk: 2-4days CrCl<50: STD risk - 48hrs Bleeding: usual Oral charcoal if <2hrs prior. care + intvns Consider dialysis (60% (Life threatening) removal)/blood products. (rviia) Rivaroxaban VTE prophylaxis/af VTE prophylaxis: >30: 10mg daily <30: contraindicated AF: >50: 20mg daily 15-50: 50: 15mg daily <15: contraindicated STD risk: 24hrs High risk: hrs Oral charcoal If <2hrs prior.(pcc* or rviia) References: 1. Ageno, W et al. Oral Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis. 9 th Ed: ACCP Chest 2012;e62S-e88s. 2. Van Ryn, J et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor; Interpretation of coagulation assays and reversal of anticoagulant activity. Thrombosis and Haemostasis 2010;103: Eerenberg, ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. A randomized, placebocontrolled, crossover study in healthy subjects. Circulation 2011; 124: University of Washington Anticoagulation Clinic website. 6