Practical Aspects of Novel Oral Anticoagulants (NOACs)

Practical Aspects of Novel Oral Anticoagulants (NOACs) Edith Nutescu, Pharm.D., FCCP Clinical Professor University of Illinois at Chicago College of Pharmacy University of Illinois Hospital & Health Sciences System Objectives Compare pharmacokinetic and pharmacodynamics characteristics of novel oral anticoagulants. Review clinical trial data for stroke prevention in atrial fibrillation and venous thrombosis treatment with novel oral anticoagulants. Highlight practical patient management issues with novel oral anticoagulants. Ideal Oral Anticoagulant Are the NOACs Ideal? Oral route of administration Once daily dosing Fixed dose Predictable pharmacokinetics & pharmacodynamics with fixed dosing Well-defined kinetics in renal or hepatic disease Rapid onset/offset of action No Bridging No drug or food interactions Wide therapeutic window No need for routine monitoring Low risk of bleeding Easily reversible Affordable

Novel Oral Anticoagulants X TF VIIa IX Dabigatran II VIIIa Xa Va IXa IIa Rivaroxaban Edoxaban Betrixaban Darexaban Fibrinogen Fibrin NOACs: Comparison FDA Approved Indications Available tablet/capsule strengths (Eliquis) Atrial Fibrillation VTE Prevention (Hip and Knee Replacement Surgery) Dabigatran (Pradaxa) Atrial Fibrillation VTE Treatment Rivaroxaban (Xarelto) Atrial Fibrillation VTE Prevention (Hip and Knee Replacement Surgery) VTE Treatment 5mg; 2.5mg 150mg; 75mg 10mg; 15mg; 20mg Overview and Pharmacology of NOACs Drug class (Eliquis) Direct factor Xa inhibitor Dabigatran (Pradaxa) Direct factor IIa inhibitor Bioavailability 50% 3%-7% Rivaroxaban (Xarelto) Direct factor Xa inhibitor 80%-100% for 10-mg dose 66% for 20-mg dose Tmax 3-4 hours 1-2 hours 2-4 hours Onset of anticoagulant effect Within 3 hours Within 2 hours Within 4 hours CYP metabolism 25% CYP3A4 No 30% CYP3A4, CYP2J2 P-gp transport Yes Yes Yes Renal excretion 27% 80% 36% Dialyzable No Yes No Half-life 8-15 hours 12-17 hours 5-9 hours; 11-13hrs elderly Dosage form Tablet Capsule Tablet Dosing frequency BID BID Once daily Antidote No No No CYP=cytochrome P450; Tmax=time to maximum concentration

Novel Oral Agents: Phase III Trials Total Hip Replacement Total Knee Replacement Dabigatran Rivaroxaban RE-NOVATE RE-NOVATE II RE-MOBILIZE RE-MODEL RECORD 1 RECORD 2 RECORD 3 RECORD 4 ADVANCE-3 ADVANCE-1 ADVANCE-2 VTE Prophylaxis in Medical Patients MAGELLAN ADOPT VTE Treatment RE-COVER a RE-MEDY c RE-SONATE a EINSTEIN-DVT b EINSTEIN-EXT c EINSTEIN-PE e AMPLIFYa AMPLIFY-EXT c Atrial Fibrillation Acute Coronary Syndrome RE-LY ROCKET-AF ATLAS ACS TIMI 51 AVERROES d ARISTOTLE APPRAISE-2 a DVT & PE treatment b DVT treatment c DVT and PE extended treatment d vs. Aspirin e Acute Sx PE + DVT Novel Anticoagulants for AF Study Designs Study characteristic RELY ROCKET-AF AVERROES ARISTOTLE Study design Open label RCT Double-blind RCT Double-blind RCT Double-blind RCT Sample size 18,113 14,264 5,599 18,201 Treatment group Dabigatran 150mg BID Rivaroxaban 20mg/d 5mg BID 5mg BID Dabigatran 110mg BID Rivaroxaban 15mg/d CrCl 30 50ml/min 2.5mg BID Age > 80y, Wt < 60kg, or Cr > 1.5mg/dl 2.5mg BID Age > 80y, Wt < 60kg, or Cr > 1.5mg/dl Control group Warfarin Warfarin Aspirin Warfarin ConnollySJ, et al. N Engl J Med 2009;361:1139-51. ConnollySJ, et al. N Engl J Med 2011;364:806-17. Patel MR, et al. N Engl J Med 2011;265:883-91. GrangerCB, et al. N Engl J Med 2011;365:981-92. Novel Anticoagulants for SPAF Primary Endpoint: Stroke or Thromboembolism RELY ROCKET-AF AVERROES ARISTOTLE NNT 172 333 (ITT) 48 303 200 (PP) p<0.001 (sup) p<0.001 (NI) p=0.01 (sup) p<0.001 (sup) ConnollySJ, et al. N Engl J Med 2009;361:1139-51. ConnollySJ, et al. N Engl J Med 2011;364:806-17. Patel MR, et al. N Engl J Med 2011;265:883-91. GrangerCB, et al. N Engl J Med 2011;365:981-92.

Novel Anticoagulants for SPAF Safety Endpoint: Major Bleeding RELY ROCKET-AF AVERROES ARISTOTLE GI bleed: p<0.001 GI bleed: p<0.001 p<0.01 ICH: p<0.001 ICH: p=0.02 ConnollySJ, et al. N Engl J Med 2009;361:1139-51. ConnollySJ, et al. N Engl J Med 2011;364:806-17. Patel MR, et al. N Engl J Med 2011;265:883-91. GrangerCB, et al. N Engl J Med 2011;365:981-92. NOAC vs Warfarin: Mortality 1. Connolly SJ et al. N Engl J Med. 2009;361(12):1139-1151. 2. Patel MR et al. N Engl J Med 2011; 365:883-891. 3. Granger CB et al. NEngl J Med. 2011;365(11):981-992.. Novel Oral Anticoagulants for SPAF: Myocardial Infarction RE-LY ROCKET - AF ARISTOTLE Dabigatran 150 mg BID: 0.74%/yr Rivaroxaban 20 mg QD: 1.02%/yr 5mg BID: 0.53%/yr Warfarin: 0.53%/yr Warfarin: 1.11%/yr Warfarin: 0.61%/yr P = 0.048 P = 0.46 P = 0.37 HR: 1.38 HR = 0.91 HR = 0.88 RE-LY: NEJM 2009;361:1139-1151. ROCKET-AF: NEJM 2011;365:883-891. ARISTOTLE: NEJM 2011;365:981-92.

Dabigatran Association With Higher Risk of Acute Coronary Events Arch Intern Med. 2012;172(5):397-402. doi:10.1001/archinternmed.2011.1666 NOACs for SPAF: Efficacy and Safety Dabigatran Rivaroxaban TE: superior MB: superior Mortality: superior TE: superior MB: similar Mortality: similar TE: non-inferior MB: similar Mortality: similar GI: similar MI: similar GI: inferior MI: inferior GI: inferior MI: similar Choice of agent will \depend on renal function, patient adherence, drug interactions, & cost/tier/copays VTE Treatment Current VTE treatment LMWH * Bridging VKA DABIGATRAN LMWH Dabigatran 150 mg BID Switching Day 1 Day 6-11 At least 3 months RIVAROXABAN; APIXABAN Rivaroxaban 15 mg BID X 3 weeks, then 20 mg QD 10 mg BID X 1 week, then 5 mg BID Day 1 Single drug approach At least 3 months *Or UFH or fondaparinux

NOACs for VTE Treatment: Efficacy and Safety Dabigatran Rivaroxaban AMPLIFY (n=5395) 10 mg bid x 7 days, then 5 mg bid x 6 months vs warfarin with enoxaparin initially Efficacy (Recurrent VTE or death related to VTE): noninferior Safety (Major bleeding): superior RE-COVER (n=2539) Dabigatran 150 mg bid vs. warfarin, both with initial parenteral anticoagulation Efficacy (recurrent VTE): noninferior Safety (Major bleeding): equivalent EINSTEIN DVT (n=3,449) EINSTEIN PE (n=4832) Rivaroxaban 15 mg bid x 21 days, then 20 mg qd vs warfarin with enoxaparin Efficacy (Recurrent VTE): noninferior Safety (Major or clinical relevant non-major bleeding): equivalent Safety (Major bleeding EINSTEN PE): Superior Importance of Patient Selection Appropriate Candidates for VTE treatment Poor Candidates for VTE treatment with NOACs with NOACs No evidence of hepatic disease or Hepatic impairment or hepatic disease coagulopathy with associated coagulopathy CrCl > 30 ml/min Renal dysfunction (CrCl < 30 ml/min) Strong adherence with medications History of medication non-compliance No drug interactions with Rivaroxaban Drug interactions with Rivaroxaban Insurance coverage, access/affordability of Lack of insurance, difficulty with Rx Rx cost/co-pay cost-co-payments Difficulty with regular INR monitoring, or Women who are pregnant or unstable INRs not caused by nonadherence breastfeeding Patients taking NOACs DO require periodic monitoring of renal function, liver function, adherence status, and potential introduction of interacting medications NOACs: Dosing Regimens Drug Dose Dabigatran (AF) CrCl >30 ml/m: 150 mg po BID CrCl 15-29 ml/m: 75 mg po BID CrCl <15 ml/m: not recommended Rivaroxaban AF: CrCl 50 ml/m: 20 mg po QD CrCl 15-49 ml/m: 15 mg po QD CrCl <15 ml/m: not recommended VTE Prophylaxis: CrCl 30 ml/m: 10 mg po QD; CrCl <30 ml/m: CI VTE Treatment: CrCl 30 ml/m: 15mg po BID x 21 days, then 20mg po QD; CrCl <30 ml/m: CI (AF) 5 mg po BID dose adjusted to 2.5 mg po BID for patients with 2 of: 80 years, weight 60 kg, or Cr 1.5 mg/dl; patients on strong dual inhibitors of CYP3A4 and P-gp

Dosing of NOACs: Formulation Issues, Food Effects Dabigatran Rivaroxaban Formulation No information Capsules cannot be: crushed (no feeding tube), broken, or chewed Expires 4 mo after bottle is opened May be crushed and mixed with applesauce in a feeding tube (Gtube) Food Effects Bioavailability not affected by food May be taken with or without food 10-mg tablet: may be taken with/without food 15-mg and 20-mg tablets: should take with largest meal of the day NOACs: A New Drug Interaction Mindset Warfarin Drug interactions can be managed through increased monitoring and dose adjustment Interacting drugs are not contraindicated NOACs Drug interactions are contraindications or precautions No ability to monitor and adjust dose based on response NOACs Metabolic Fate Cytochrome P450 enzymes CYP3A4, CYP3A5 Rivaroxaban CYP2J2 Rivaroxaban P-Glycoprotein Substrate Dabigatran Rivaroxaban * Dabigatran metabolized by esterases to active form

NOACs: Drug Interactions Inducer CYP3A4 Inhibitor Carbamazepine Amiodarone Itraconazole Efavirenz Aprepitant Ketoconazole Glucocorticoids Cimetidine Nefazodone Nevirapine Clarithromycin Protease inhibitors Phenobarbital Cyclosporine Verapamil Phenytoin Diltiazem Voriconazole Primidone Rifampin Rifapentine St. John s wort Erythromycin Fluconazole Fluoxetine Fluvoxamine Inducer Midazolam P-Glycoprotein Inhibitor Amiodarone Dronaderone Nifedipine Nifedipine Ceftriaxone Propranolol Phenobarbital Clarithromycin Quinidine Phenytoin Cyclosporine Tacrolimus Rifampin Diltiazem Verapamil St. John s wort Dipyridamole Erythromycin Hydrocortisone Itraconazole Ketoconazole Drug Interactions & Product Labeling Dabigatran P-glycoprotein inducers (e.g. Rifampin) - AVOID P-glycoprotein inhibitors Ketoconazole or dronedarone & CrCl 30-50 ml/min: dose to 75 mg BID AVOID if CrCl < 30 ml/min Rivaroxaban Combined strong CYP3A4 & p-glycoprotein inducers - AVOID rifampin, carbamazepine, phenytoin, St John s wort Combined CYP3A4 & p-glycoprotein inhibitors Strong: Avoid (ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, conivaptan) Weak-moderate and Renal Insufficiency: use only if benefit outweighs risks Combined strong dual CYP3A4 & p-glycoprotein inducers - AVOID rifampin, carbamazepine, phenytoin, St John s wort Combined strong dual CYP3A4 & p-glycoprotein inhibitors ketoconazole, itraconazole, ritonavir, clarithromycin Decrease dose to 2.5mg bid; in patients already on 2.5 mg bid AVOID ALL: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic nonsteroidal antiinflammatory drugs increases the risk of bleeding Periprocedural Management of NOACs Timing of Interruption of NOACs Before Surgery or Invasive Procedures Calculated CrCl, ml/min Dabigatran Half-life, h Timing of Last Dose Before Surgery Standard Risk of Bleeding a High Risk of Bleeding b >80 14 24 h 2 d 50-79 17 24 h 2 d >31-49 19 2 d 4 d 30 28 4 d 6 d /Rivaroxaban Apix Riva >80 15 8 24 h 2 d 50-79 15 9 1-2d 3-4 d >31-49 17 9 1-2 d 3-4 d 30 18 10 2d 4d a Examples: cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, uncomplicated laparoscopic procedures b Examples: major cardiac/cancer/urologic/vascular surgery, insertion of pacemakers/defibrillators, neurosurgery, large hernia surgery

Recommended Strategy for Conversion: NOACs to/from Warfarin Suggested Strategy for Conversion from NOACs to Warfarin Calculated CrCl (ml/min) Dabigatran: Start Day with Warfarin a Rivaroxaban: Start Day with Warfarin a,b >50 If continuous anticoagulation is necessary, Day -3 Day -4 31-50 discontinue apixaban and begin both a parenteral anticoagulant and warfarinat the time the next dose Day -2 Day -3 15-30 of apixaban would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range. Day -1 Day -2 Suggested Strategy for Conversion from Warfarin to NOACs Dabigatran Rivaroxaban Start when INR is <2 Start when INR is <2 Do not use point-of-care monitors to assess INR during transitions Start when INR is <3 a Dabigatran/Rivaroxaban is stopped on day 0; the longer overlap with rivaroxaban is justified by the half-life being shorter than that of dabigatran and by the concern about thromboembolic events shortly after transitioning from rivaroxaban to warfarin b Strategy recommended in rivaroxaban product labeling is to transition to an injectable anticoagulant Unresolved Issues No established methods of monitoring No known therapeutic ranges Lack of an antidote Management of bleeding Long term safety The ideal anticoagulant drug... does not require laboratory monitoring but should be measurable

Monitoring vs. Measuring Monitoring implies dose adjustment according to test result Measuring (or quantifying) the drug or drug effect may be useful in Overdosage Questions of compliance Urgent surgery, interventions, thrombolysis Extreme body weights Renal insufficiency Hematology Testing: The New Oral Anticoagulants Usefulness of lab test Dabigatran Rivaroxaban Lab tests Strong ECT Chromogenic anti-xa Chromogenic anti-xa TT aptt, PT aptt Weak PT/INR Adapted from Am J Hematol 2012; s127-s132. Interpretation of Coagulation Assays of Patients on NOACs Heidbuchel H et.al. Europace 2013;15:625-651

Reversal Considerations of New Agents Supportive care Discontinuation of drug Likely sufficient for many patients Dabigatran Rivaroxaban Oral activated charcoal Yes Yes Yes Hemodialysis Yes No No Hemoperfusion with activated charcoal Yes Possible Possible FFP No No No Activated factor VIIa Unclear Unclear Unclear 3-factor PCC Unclear Unclear Unclear 4-factor PCC Possible Possible Possible Kaatz S Am J Hematol. 2012;87:s141-145. Effects of Nonspecific Reversal Agents on Anticoagulant Activity in an Ex-Vivo Model Measured Effect on Thrombin Generation: AUC, Peak, Time to Peak, and Lag Time Nonspecific Reversal Agent rfviia: NovoSeven 0.5,1.5,3 ug/ml Conclusions: If immediate reversal is needed, currently no clear evidence for any reversal agent clinically Feiba effective for rivaroxaban ex-vivo, but higher doses are associated with more thrombin generation; clinically may cause more thrombosis Marlu R, et al. Thromb Haemost. 2012;108:217-224. Not tested apcc: Feiba 0.25,0.5,1,2 U/mL Not tested 4-factor PCC a : Kanokad 0.25,0.5,1 U/mL Not tested + (lag time) + (lag time) Dabigatran 150 mg + (increased AUC) + (lag time) Rivaroxaban 20 mg +++ (AUC, peak, lag time, and time to peak) ++ (strongly corrected AUC, modest peak) a PCCs contain significant quantities of factors II, IX, and X; 4-factor PCCs (not yet available in the US) also contain factor VII rfviia=recombinant activated clotting factor VII

Management of Bleeding in Patients taking NOACs Heidbuchel H et.al. Europace 2013;15:625-651 Click here to add text Therapeutic Interventions for Reversal of Oral Anticoagulants Based on Urgency Level of Urgency WARFARIN DABIGATRAN RIVAROXABAN OR APIXABAN Emergent (<1 hr) Withhold drug high-dose i.v. Vit K (depending on anticipated need to restart warfarin) consider clotting factor supplement: PCC4 Build PCC4 [with PCC3 + rfviia] apcc PCC3 rfviia FFP Withhold drug give activated charcoal if last dose within past 2 hr hemodialysis (>2 hr) consider clotting factor supplement: apcc PCC4 Build PCC4 [with PCC3 plus rfviia] Nutescu EA, et.al. Am J Health Syst Pharm. 2013;70(21):1914-29 Withhold drug give activated charcoal if last dose within past 2 hr, repeat after 6 hr after the last dose consider clotting factor supplement: PCC4 apcc Build PCC4 [with PCC3 plus rfviia] PCC3

Reversal Agent Dose(s) for Reversal of Specific Anticoagulant Warfarin Dabigatran Rivaroxaban PCC3 25-50 units/kg 50 units/kg PCC4 25-50 units/kg 25-50 units/kg 25-50 units/kg rfviia 17.7-53.4 µg/kg 20-120 µg/kg 20-120 µg/kg apcc Up to 25 units/kg initially with subsequent doses based on response; Up to 25 units/kg initially; no data available in patients with active bleeding; PCC3 50 units/kg + rfviia 1mg; Building of PCC4 if rfviia not available, addition of small dose FFP (1-2 units) could be considered No data available; possibly extrapolate doses from warfarin reversal No data available; possibly extrapolate doses from warfarin reversal Nutescu EA, et.al. Am J Health Syst Pharm. 2013;70(21):1914-29 New Oral Anticoagulant Educational Points Anticoagulation Basics Risk Benefit Self Care Accessing Health Care Adherence Indicate the reason for initiating anticoagulation. Review the name of the anticoagulant drug (generic and trade), how they workto reduce complications, onset, duration, and reversibility. Duration of therapy. Commonsigns and symptoms of bleedingand whatto do whenthey occur. Common signs and symptoms of a blood clot and what to do when they occur. The need for birth control for women of child bearing age Precautionary measures to reduce the risk of trauma or bleeding (e.g. shaving, toothbrushing, acceptable physical activities). Common side effects or allergic type reactions Which healthcare providers (e.g. physicians, dentists) to notifying of the use of anticoagulant therapy. When to notify an anticoagulation provider (dental, surgical, or invasive procedures or hospitalizations are scheduled). Carrying identification (e.g. identification card, medical bracelet/necklace). Potential drug interactions. Consequences of non-adherence or taking too much When to take an anticoagulant medication and what to do if a dose is missed. Warfarin Educational Points Lab Monitoring The meaning and significance of the International Normalized Ratio. The need for frequent INR testing and the target INR values appropriate for treatment. The narrow therapeutic index and the emphasis on regular monitoring as a way to minimize bleeding and thrombosis risk. The influence of dietary vitamin K use. Diet and Lifestyle The need to limit or avoid alcohol Topic in Dabigatran/Rivaroxaban/ Medication Guide Ideal Oral Anticoagulant Are the NOACs Ideal? Oral route of administration Once daily dosing Fixed dose Predictable pharmacokinetics & pharmacodynamics with fixed dosing Well-defined kinetics in renal or hepatic disease Rapid onset/offset of action No Bridging No drug or food interactions Wide therapeutic window No need for routine monitoring Low risk of bleeding Easily reversible Affordable

Structured Follow-Up of Patients on NOACs Heidbuchel H et.al. Europace 2013;15:625-651 Checklist During Follow-Up of Patients on NOACs Heidbuchel H et.al. Europace 2013;15:625-651 NOACs: Risk/Benefit Profiles Favor warfarin Mitral stenosis Mechanical valves TTR >70% + patient desire CrCl <30 ml/m Weight <50 kg or >150 kg (?) High GI bleed risk (?) CAD +/- PCI (?) Cost Adherence/monitoring Favor NOAC No contraindications Access to drug ($/insurance) TTR <65% Frequent interruption Monitoring is difficult DRUG INTERACTIONS CAD, coronary artery disease; GI, gastrointestinal; PCI, percutaneous cardiac intervention.

NOACs: Clinical Implications 1. Careful patient selection based on risk assessment 2. Consider patient-related and OAC-related factors and provider knowledge Comorbidities (eg, renal dysfunction) Extreme weights Adherence issues PK/PD, dosing, drug interactions Bleeding/Reversibility Periprocedure management 3. Choose the best agent for the patient, and provide: Patient education Ongoing risk assessment and support Communication Efficacy and safety in practice will not mimic clinicaltrial results without careful thought and patient monitoring Discussion