CHALLENGES AND OPPORTUNITIES IN CLINICAL USE OF THE NEW ORAL ANTICOAGULANTS. Amy Giovino, PharmD Formulary Coordinator Sarasota Memorial Hospital

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1 CHALLENGES AND OPPORTUNITIES IN CLINICAL USE OF THE NEW ORAL ANTICOAGULANTS Amy Giovino, PharmD Formulary Coordinator Sarasota Memorial Hospital 1

2 2 Disclosure I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation.

3 3 Objective Review clinical considerations of prescribing the new oral anticoagulants (NOACs) Mechanism of action Pharmacokinetics Indications and dosing Lab monitoring (qualitative vs quantitative) Reversal strategies

4 Anticoagulation Prior to 21 ST Century: Warfarin Strengths Frequent monitoring Prescriber familiarity Reversible Low cost to patients Broad indications Limitations Frequent monitoring Patient-specific dosing Narrow therapeutic window Interactions Drug-drug Drug-food Slow onset Bridge therapy 4

5 Anticoagulation Today New Oral Anticoagulants (NOACs) Strengths Short half-life No monitoring Predictable dose response No bridge therapy Minimal drug interactions Non-inferior /superior to warfarin Lower risk of ICH Limitations Short half-life Lack of lab monitoring Lack of prescriber familiarity Peri-operative management No specific reversal agent Lack of studies for treatment of severe hemorrhage 5

6 Black Box Warning Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim, Inc; Revised: January 2015 Xarelto [package insert]. Titusville, NJ: Jansen Pharmaceuticals; Revised: January 2015 Eliquis [package insert]. Princeton, NJ: Bristol-Meyers Squibb, Inc; Revised: August 2014 Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo; January

7 Coagulation Cascade Prothrombin Complex Concentrates as Reversal Agents for New Oral Anticoagulants Dickneite, Gerhard, PhD, Clinics in Laboratory Medicine, Volume 34, Issue 3, Copyright 2014 Elsevier Inc.

8 Pharmacokinetics Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Target Thrombin Xa Xa Xa T ½ (hrs) Tmax (hrs) Protein Binding Renal Clearance 35% >90% 87% 55% 80% 66% 25% 50% Dialyzable Yes No No No AWP* (30-day) * Average wholesale price $ $ $ $332 McMahon, B. Kwaan, H. Semin Thromb Hemost 2015;41: Greinacher et al. Thrombosis and Haemostasis 2015;113(5):

9 Indication and Dosing No renal or hepatic disease Dabigatran Rivaroxaban Apixaban Edoxaban VTE/stroke Prevention in Non-valve Afib 150 mg BID with or w/o food 20 mg daily with evening meal 5 mg BID with or w/o food 60mg daily with or w/o food VTE Treatment 150 mg BID after 5-10d of parenteral anticoagulation 15 mg BID w/food x 21d then 20 mg daily w/food 10 mg BID x 7d, then 5 mg BID 60 mg BID after 5-10d of parenteral anticoagulation Prevention of Recurrent VTE 150 mg BID after 5-10d of parenteral anticoagulation 20 mg daily with food 2.5 mg BID after 6 months of initial VTE treatment N/A VTE Prevention Post Hip or Knee Replacement N/A 10 mg daily with or w/o food: 35d (hip), 12d (knee) 2.5 mg BID 35d (hip), 12d (knee) N/A Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim, Inc; Revised: January 2015 Xarelto [package insert]. Titusville, NJ: Jansen Pharmaceuticals; Revised: January 2015 Eliquis [package insert]. Princeton, NJ: Bristol-Meyers Squibb, Inc; Revised: August 2014 Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo; January

10 Indication and Dosing Renal or hepatic disease Dabigatran Rivaroxaban Apixaban Edoxaban VTE/stroke Prevention in Non-valve Afib CrCl 15-30: 75 mg BID CrCl <15: avoid CrCl 15-50: 15 mg daily CrCl <15: avoid 2.5 mg BID if 2 of the following: age 80yr weight < 60kg SCr > 1.5 CrCl > 95: avoid CrCl 15-30: 30 mg daily CrCl <15: avoid VTE Treatment CrCl <30: avoid CrCl <30: avoid No dose adjustment CrCl 15-30: 30 mg daily CrCl <15: avoid Prevention of Recurrent VTE CrCl <30: avoid CrCl <30: avoid No dose adjustment N/A VTE Prevention Post Hip or Knee Replacement N/A CrCl <30: avoid No dose adjustment N/A Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim, Inc; Revised: January 2015 Xarelto [package insert]. Titusville, NJ: Jansen Pharmaceuticals; Revised: January 2015 Eliquis [package insert]. Princeton, NJ: Bristol-Meyers Squibb, Inc; Revised: August 2014 Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo; January

11 Interactions and Tube Administration Dabigatran Rivaroxaban Apixaban Edoxaban Drug-Drug Interactions Dose Adjustments Non-valvular Afib: CrCl & P-gp inh: 75 mg BID CrCl <30 & P-gp inh: avoid Prevention of Recurrent VTE: CrCL <50 & P-gp inh: avoid Avoid concomitant use with: Other anticoagulants P-gp inducers or inhibitors Strong CYP3A4 inhibitors or inducers Strong dual inhibitors of CYP3A4 & P-gp: 2.5mg BID Avoid if already taking 2.5 mg BID Strong dual inhibitors of CYP3A4 & P-gp: 30 mg daily Administration via Tube Cannot be given via tube; breaking, chewing or opening capsule will absorption by 75% 15 mg or 20 mg tabs may be crushed and suspended in 50 ml water via gastric tube (requires acidic ph) and follow with enteral feeding May be crushed and suspended in 60 ml D5W and given through NGT No data available Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim, Inc; Revised: January 2015 Xarelto [package insert]. Titusville, NJ: Jansen Pharmaceuticals; Revised: January 2015 Eliquis [package insert]. Princeton, NJ: Bristol-Meyers Squibb, Inc; Revised: August 2014 Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo; January

12 Anti-Xa in Pipeline - Betrixaban Betrixaban (phase III) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Bioavailability 35% 80% 60% 50% T ½ (hrs) Tmax (hrs) Take with food Renal Clearance Maybe Yes No No 7% 66% 25% 35-50% CYP 3A4 No No No No P-gp inh Yes Yes Yes Yes McMahon, B., Kwaan, H. Semin Thromb Hemost 2015;41: Greinacher et al. Thrombosis and Haemostasis 2015;113(5):

13 Betrixaban Phase III (APEX Trial) Title Design Groups Efficacy and Safety Study Comparing Extended Duration Betrixaban With Standard of Care Enoxaparin for the Prevention of Venous Thromboembolism in Acute Medically Ill Patients Active-controlled, randomized, double-blind, double-dummy, multicenter clinical trial Betrixaban 160mg PO once followed by 80mg PO daily for 35 days Vs. Enoxaparin 40mg SQ daily for 10 ± 4 days Recruiting Approx 7,000 medically ill adult patients at risk for VTE Outcomes Primary: Composite of VTE (DVT and/or PE) and VTE Death through day 35 Secondary: Number of patients with symptomatic VTE through day 35 SMH Study site. Investigator: Dr. Concha Betrixaban. NCT Accessed: 5/14/

14 LABORATORY MONITORING 14

15 Anticoagulant Monitoring Assays Direct Thrombin Inhibitors Xa Inhibitors Qualitative d TT a > aptt a > PT a PT Quantitative dtt b, ECT b, ECA b, Chromagenic anti-xa c aptt, activated partial thromboplastin time; dtt, dilute thrombin time; ECA, ecarin clotting assay; ECT, ecarin clotting time; PT, prothrombin time; TT, thrombin time a. Therapeutic ranges have not been established b. These assay are not FDA approved and are not routinely available c. Care must be taken to use appropriate calibrator d. Values may be abnormally high even at clinically insignificant levels Modified with permission from Dr. Christopher Tormey Arch Pathol Lab Med, May

16 Patient Case 65yo male with history of Afib admitted for cardiac ablation Day 0 PT (sec) INR Warfarin Rivaroxaban Day 1 (0500) X X Day 1 (0900) X X Pt seen in anticipation of possible discharge today. This morning, his INR is elevated at 7.02, so we have ordered a stat repeat. The patient as noted is somewhat anxious regarding this. Warfarin d/c. Discharged on rivaroxaban. 16

17 REVERSAL STRATEGIES: 1) Stop anticoagulant Antiplatelet? 2) Dabigatran HD removes 60% in one 4 hr session 3) Activated charcoal 4) No specific reversal agents 5) Supportive measures Fluids, RBC, FFP, Platelet 6) Consider: PCC, apcc Nutescu, E. Am J Health-Syst Pharm. 2014;70:

18 Reversal Agents Type Brand Factors and Proteins FFP -- Coagulation factors / proteins rfviia NovoSeven FVII 3 factor PCC Bebulin VH FII, FIX, FX, Heparin Profiline SD FII, FIX, FX 4 factor PCC Kcentra FII, FVII, FIX, FX, Proteins C & S, Heparin Activated PCC Feiba NF II, activated FVII, FIX, FX, Protein C Pinto et al. Current Drug Safety, 2015;10(2):

19 Fresh Frozen Plasma (FFP) Contains coagulation factors in normal serum concentrations Indications: Coagulation factor deficiencies or major bleeding Dose: ml/kg Limitations Must be thawed ABO matching required Administration requires large volume Adverse Effects Fluid overload Infectious disease risk Transfusion related acute lung injury Allergic reactions Risk of thromboembolism 19

20 Recombinant Factor VII (rfviia) Non-plasma form of factor VII similar to human plasma Activates factor X leading to thrombin generation FDA approved indications: Patient with factor VII deficiency or hemophilia A or B Dose: mcg/kg every 2-6 hours, based on indication Minimum effective dose has not been determined Conflicting results reversal of NOACs Limitations Recent data recommends against off-label use Short half-life may require frequent administration Increased risk of thrombosis Cost NovoSeven RT [package insert]. Bagsvaerd, Denmark; Novo Nordisk; Revised July,

21 4F-PCC: KCentra FDA approved: Urgent reversal of VKA* (warfarin) therapy in adult patients with: Acute major bleeding Need for urgent surgery or other invasive procedure Baseline INR IUnits/ kg (based on FIX) 2 - <4 25 (max 2500units) (max 3500units) >6 50 (max 5000units) Contraindicated: HIT and DIC CHEST 2012 Guidelines: VKA associated major bleeding, 4F-PCC is preferred over FFP *vitamin K antagonist CHEST 2012; 141(2)(Suppl):e152S e184s. Kcentra [package insert]. Marburg, Germany; CSL Behring GmbH; Revised 08/

22 Prothrombin Complex Concentrate (PCC) Title Population Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled crossover study in healthy subjects. 12 healthy male volunteers (24 ± 4 yrs. old) Average BMI 23 kg/m 2 Design Coagulation tests Randomized, double-blind, placebo-controlled crossover study Dabigatran: aptt, TT, ECT Rivaroxaban: PT, ETP Blood drawn at baseline, 15 min., 30 min., and 1, 2, 4, 6, and 24 hours after infusion Eerenberg ES, et al. Circ. 2011;124:

23 RESULTS Rivaroxaban PT ETP Baseline Cofact (PCC) Saline (Placebo) Unchanged Unchanged Dabigatran Baseline Cofact (PCC) Saline (Placebo) aptt Unchanged Unchanged ETP lag time TT ECT Unchanged Unchanged Unchanged Unchanged Unchanged unchanged Eerenberg ES, et al. Circ. 2011;124:

24 LIMITATIONS Inclusion criteria - Healthy subject Small sample size Short duration of follow up PCC agent and dose Cofact not approved in US Coagulation Assays how does this translate into clinical outcomes Eerenberg ES, et al. Circ. 2011;124:

25 ACTIVATED 4F-PCC: FEIBA FACTOR EIGHT INHIBITOR BYPASSING ACTIVITY FDA approved: Hemophilia A+B patients w/ inhibitors ( units/kg q 6-12 hrs) Unlabeled use: Life-threatening hemorrhage associated with NOACs ( units/kg) Adverse Effects Thrombosis hyper/hypotension tachycardia flushing DIC Allergic reactions FEIBA NF [package insert]. Westlake Village, CA; Baxter Healthcare Corporation; Revised February,

26 Studies for Reversal of Dabigatran Siegal, D., J Thromb Thrombolysis. 2015;39: Copied with permission Dr. Deborah Siegal 26

27 Studies for Reversal of Factor Xa Inhibitors Siegal, D., J Thromb Thrombolysis. 2015;39: Copied with permission: Dr. Deborah Siegal 27

28 REVERSAL AGENTS IN PIPELINE Type Brand Factors / Proteins Idarucizumab (adabi-fab) Humanized monoclonal antibody that inhibits dabigatran Andexanet alpha PRT Modified recombinant form of factor Xa Aripazine PER977 Small molecule directly binds anticoagulant Pinto, I. et al. Current Drug Safety. 2015;10(2):

29 IDARUCIZUMAB (adabi-fab) Monoclonal antibody fragment derived from mouse Approximately 350 times the affinity for dabigatran vs thrombin Animal studies Immediate reversal of dabigatran No pro-coagulant properties displayed Phase 1 healthy volunteers Corrected: TT, aptt, ECT, ACT Phase III RE-VERSE AD Trial Open label. Case series. Uncontrolled bleeding or requiring emergent reversal for procedure Idarucizumab 5gm IV Schiele, F., et al. Blood, 2013;121(18): McMahon, B., Kwaan,H. Semin Throm Hemost 2015;41: Idarucizumab. NCT accessed 05/06/

30 ANDEXANET (PRT064445) Recombinant factor Xa molecule Enzymatically modified inactive Directly binds and reverses factor Xa inhibitors Phase 3 trials ANNEXA Study Andexanet Alpha in Patients Receiving a Factor Xa Inhibitor who have Acute Major Bleeding Prospective, Open-Label Reversal of apixaban, rivaroxaban or enoxaparin All patients will receive active drug (n=250) Bolus followed by 2 hour infusion Primary investigator: Dr. Concha Gomez-Outes et al. Recent Patent on Cardiovascular Drug Discovery. 2014;2: Andexanet. Accessed 05/06/

31 ARIPAZINE (PER977, CIRAPARANTAG) Synthetic small molecule that has activity against various anticoagulants UH, LMWH DTI, Xa Inhibitors (direct and indirect) Directly binds to the anticoagulant drug and not blood coagulation factors or other proteins in the blood One study of 80 healthy male subjects received one dose of edoxaban followed by IV PER977 10minutes following IV dose, whole blood clotting times returned to within 10% of baseline Investigational-Broad-Spectrum-Anticoagulant-Reversal-Agent 31

32 SUMMARY: Appropriate patient selection with NOACs is key Know differences Medication compliance crucial Use FDA approved doses Reversal PCC no outcome data, minimal data Optimal dose and agent unknown Weigh risk / benefit Concurrent antiplatelet? ICH Treat as stroke alert Target specific reversal agents on the horizon! 32

33 Dabigatran Patient Case 87 yo M, 75kg c/o progressive R. sided weakness, paresis, and aphasia PMH: HTN, CAD, TIA (3 weeks prior to admission), HIT S/P TIA, patient was converted from rivaroxaban to dabigatran Last dabigatran dose 14 hours prior to arrival Allergies: Ampicillin, heparin Which are possible treatment options? A. Activated charcoal B. Hemodialysis C. FEIBA 50 units/kg once D. KCentra 50 units/kg once E. B and C F. All of the above. 33