Advances in An+coagula+on

Advances in An+coagula+on Laurajo Ryan PharmD, MSc, BCPS, CDE Clinical Associate Professor The University of Texas at Aus+n College of Pharmacy UTHSCSA School of Medicine Pharmcotherapy Research Educa+on Center ryanl@uthscsa.edu

Accredita+on & Disclosures Advances in An+coagula+on is accredited for 1.5 contact hours by: ACPE for pharmacists, ACPE 154-0000- 15-042- L01- P Technicians, ACPE 154-0000- 15-042- L01- T Laurajo Ryan has not disclosed any financial or conflicts of interest in rela+on to this program

Learning Objec+ves By the end of this session, the par+cipant should be able to: Review recent developments in an+coagula+on therapy List the key prescribing points and safety concerns for new an+coagulants Iden+fy op+ons for reversal of new an+coagulants Discuss transi+on between new an+coagulants

Thromboembolisms: The Problem United States Precise numbers unknown Es+mated at 300-600K/year 1-2/1000 1/100 >80 YOA Mortality 60 100K/year 25% of pa+ents with PE present with sudden death ½ with DVT Long- term complica+ons 10 years ~33% recurrence CDC: hcp://www.cdc.gov/ncbddd/dvt/data.html

An+coagulan+on Does newer = becer?

An+coagula+on Cascade Adapted from: Ryan. In Acridge, Miller, Moote, Ryan eds. Internal Medicine: A Guide to Clinical Therapeu+cs. McGraw- Hill 2013

An+coagulants Warfarin (Coumadin ) Inhibits clokng factors Heparins II, VII, IX, X Proteins C & S Unfrac+onated (UFH) Factor IIa Xa Low Molecular Weight (LMWH) Factor Xa >>> IIa Factor Xa inhibitors Fondaparinux (Arixtra ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Direct thrombin inhibitors Argatroban Bivalirudin (Angiomax ) Dabigatran (Pradaxa )

An+coagulant Site of Ac+on Adapted from: Ryan. In Acridge, Miller, Moote, Ryan eds. Internal Medicine: A Guide to Clinical Therapeu+cs. McGraw- Hill 2013

An+coagulants Does newer = becer?

VITAMIN K ANTAGONIST

Warfarin Pros Many years of clinical data Ability to monitor effect Reliable reversal agent Vitamin K Cheap Once daily dosing

Warfarin Cons Inferior bleeding profile in some studies Delay in an+coagula+on ac+on Monitoring requirements Drug/diet interac+ons Gene+c variability

Risks & Reversibility Bleeding risk with INR GI tract Cerebral hemorrhage Elderly at higher risk An+dote Vitamin K Fresh frozen plasma FFP Prothrombin complex concentrate (II, VII, IX, X) PCC Recombinant factor VIIa Chest 2012;141(Suppl 2):e152S

FACTOR Xa INHIBITORS

An+coagulant Site of Ac+on Adapted from: Ryan. In Acridge, Miller, Moote, Ryan eds. Internal Medicine: A Guide to Clinical Therapeu+cs. McGraw- Hill 2013

Rivaroxaban (Xarelto ) Oral Xa inhibitor Reversible Renally cleared Must adjust Doses 15mg/day; take with food t½ ~ 10 hours DVT treatment 15mg BID X3 weeks Then 20mg QD Contraindicated <30mL/min Non- valvular afib 20mg QD CrCl 30 50mL/min 15mg QD Crcl <15mL/min Contraindicated Post- op PPX (hip/knee) 10mg QD Crcl <30mL/min Contraindicated

Rivaroxaban No specific an+dote Not dialyzable High protein binding Life- threatening bleed Packed RBC Aggressive bleeding management 4- factor PCC Drug interac+ons 3A4 metabolism risk of bleed An+coagulants NSAIDs An+- platelet agents Thromboly+cs 3A4 inhibitors effects Strong 3A4 inducers P- glycoprotein inducers St. Johns wort

Rivaroxaban Pros Once daily dosing No monitoring VTE treatment Does not require bridging with parenteral agent Cons Renally eliminated Short t½ Non- compliance issues Non- inferior to warfarin for afib More bleeding in general VTE prophylaxis popula+on Limited reversal op+ons No widely available monitoring Drug interac+ons Expensive ~$300 for 30 day supply

Apixaban (Eliquis ) Oral Xa inhibitor Reversible t½ ~ 8-15 hours DVT treatment 10mg BID X7 days Then 5mg BID 2.5mg BID azer 6 months Non- valvular atrial fibrilla+on 5mg BID 2.5mg BID if any 2: Scr 1.5mg/dL Age 80 Weight 60kg Post- op PPX (hip/knee) 2.5mg BID

Apixaban No specific an+dote Not dialyzable High protein binding Life- threatening bleed Packed RBC Aggressive bleeding management Prothrombin complex concentrate (PCC) Drug interac+ons 3A4 metabolism risk of bleed An+coagulants NSAIDs An+- platelet agents Thromboly+cs 3A4 inhibitors effects 3A4 inducers P- glycoprotein inducers St. Johns wort

Apixaban Pros Oral agent No monitoring No need for bridging therapy Data in afib >>> vs. warfarin Lowest compara+ve bleeding risk of NOACs Cons Dose- adjustment rubric No monitoring No specific an+dote Short t½ Non- compliance risks More GI bleeds vs. warfarin No reliable reversal agent Licle data available Cost

Edoxaban (Savaysa ) Oral Xa inhibitor Reversible t½ ~ 8-15 hours DVT treatment 60mg QD azer 5-10 days parenteral tx 60kg = 30mg If using P- gp inhibitor reduce to 30mg QD Renally eliminated Do NOT use if CrCl >95mL/min CrCl 15-50mL/min 30mg QD Avoid if CrCl <15mL/min

Edoxaban Pros Oral agent No monitoring No need for bridging therapy Cons Dose- adjustment for drug interac+ons No monitoring No specific an+dote No reliable reversal agent Licle data available Cost

DIRECT THROMBIN INHIBITORS

An+coagulant Site of Ac+on Adapted from: Ryan. In Acridge, Miller, Moote, Ryan eds. Internal Medicine: A Guide to Clinical Therapeu+cs. McGraw- Hill 2013

Direct Thrombin Inhibitors Inhibit thrombin Circula+ng & fibrin- bound Do not need an+- thrombin as co- factor HIT No cross- reac+vity with heparin products No specific an+dote

Dabigatran (Pradaxa ) Oral reversible thrombin inhibitor RELY trial compared to warfarin in afib Decreased stroke risk Similar overall bleeding No superiority if good warfarin control 2X é GI bleed» Bioavailability? ê risk intracranial bleed Non- valvular atrial fibrilla+on 150mg BID Renal clearance 75mg BID ClCr 15 30mL/min Contraindicated <15mL/min DVT/PE 150mg BID Azer parenteral an+coagulant

Dabigatran Hygroscopic capsules Dispense/store in original packaging Discard 4 months azer opening Do not break or open capsule é bioavailability t½ ~ 12-17 hours Adverse effects Bleeding GI distress No an+dote May be reversed by prothrombin complex concentrate (PCC) Provides factor II Removed by hemodialysis

Dabigatran Drug interac+ons P- glycoprotein inducers ê dabigatran concentra+ons Avoid combina+on with strong inducers Rifampin Elderly Increased bleeding risk; no specific dosing guidelines Disease- related concerns Variability in hepa+c impairment Use in advanced liver disease not recommended Renal dysfunc+on Concentra+on é up to 3X with moderate ê func+on American College of Chest Physicians (ACCP)*» Clcr <30mL/min contraindicated

Dabigatran In the News BMJ inves+ga+on States recommenda+ons for dabigatran may be flawed Manufacturers withheld informa+on showing drug concentra+on monitoring may improved safety Op+mally used (= +trated) dabigatran has the poten+al to provide pa+ents an even becer efficacy and safety profile than fixed dose dabigatran and also a becer safety and efficacy profile than a matched warfarin group. BMJ 2014;349

Dabigatran Pros Oral agent No monitoring More effec+ve vs. warfarin for stroke & VTE No lifestyle limita+ons Cons No monitoring* Drug interac+ons with p- glycoprotein inducers Renally eliminated No specific an+dote Increased GI bleeding Short t½ Non- compliance risks BID dosing Capsule instability Cost

REVERSAL OPTIONS

Current Reversal Op+ons Agent Vitamin K Protamine Sulfate Fresh Frozen Plasma (FFP) Comments Cheapest agent, most data; only effec+ve against warfarin Binds to heparin; cheap Must be thawed, high volume; contains all clokng factors Prothrombin Complex Concentrates (PCC) Recombinant ac+vated factor VII *per977 *andexanet alfa (Annexa- R) *idracizumab Profilnine /Bebulin - - ac+vated factors II/IX/X $$ Kcentra /Feiba - - non- ac+vated factors II/IX/X + ac+vated fvii $$ $$$$$$$ Directly combines with NOACs, LMWH, UFH without binding coagula+on factors IV modified Xa molecule acts as a decoy; targets & sequesters Xa inhibitors (rivaroxaban, apixaban, edoxaban) IV an+body fragment binds & inac+vates dabigatran *currently in clinical trials

NOAC DOSING & CONVERSION

Typical Dosing Regimens Factor Xa Inhibitors Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Dabigatran (Pradaxa ) Afib: 20mg QDay VTE: 15mg BID X 21days; then 20mg QDay DVT PPX: 10mg QDay up to 35 days post- op Afib: 5mg BID VTE: 10mg BID X 7days; 5mg BID X6 months; 2.5mg BID if con+nuing therapy DVT PPX: 2.5mg BID up to 35 days post- op Afib: 60mg QDay VTE: 60mg QDay azer 5-10 days parenteral tx Direct Thrombin Inhibitor Afib: 150mg BID VTE: 150mg BID azer 5-10 days parenteral tx

Conversions.to NOAC. From warfarin Start NOAC when INR < 2 Edoxaban when INR 2.5 From SQ an+coagulant Start NOAC 2 hours before the next scheduled SC injec+on At scheduled +me for edoxaban From IV an+coagulant Start NOAC when infusion is stopped 4 hours azer DC for edoxaban from NOAC to Parenteral an+coagulant Wait 12 24 hours azer last NOAC dose Warfarin CrCl > 50 ml/min: Start warfarin 3 days before NOAC D/C CrCl 30 50 ml/min: Start warfarin 2 days before NOAC D/C Apixaban affects INR Ini+ate warfarin AND parenteral agent 24 azer DC Edoxaban drop dose to 15mg & ini+ate warfarin; DC when INR stable 2

NOAC Periopera+ve Management Bleed Risk Examples Stopping strategy Re- Start Strategy High Risk Cancer surgery Major ortho surgery Cardiac/spinal/cranial surgery Surgery > 45 min Renal biopsy CrCl >50mL/min; last dose 3 days before procedure CrCl 30-50mL/min; last dose 4 days before procedure Restart 48-72h postop Low Risk Minor dental procedure Lymph node biopsy Shoulder/hand surgery Lap Cholecystectomy Colonoscopy CrCl >50mL/min; last dose 2 days before procedure CrCl 30-50mL/min; last dose 3 days before procedure Restart 24h postop

Oral An+coagulant Summary Drug Dosing Monitor? Dose adjust? Drug intx? Specific anhdote? Warfarin PO, daily INR, food Yes $ Cost Rivaroxaban PO, daily* No Renal No $$$ Apixaban PO, BID No Renal, wt No $$$ Edoxaban PO, daily No Renal* No $$$ Dabigatran PO, BID No Renal No* $$$

NOAC Summary Pros No need for bridging with injectables for some NOACs Less lifestyle intrusions compared to warfarin Less bleeding compared to warfarin? Cons $$$$ Limited reversal agents Mul+ple day dosing Limited clinical informa+on Drug interac+ons exist, but <<< vs. warfarin

NOAC Summary Many new an+coagulants have entered or will enter the market in the future decade A clear understanding of pros/cons of NOACs required for safe use Affordable reversal strategies s+ll needed for NOACs Warfarin s+ll viable op+on for many pa+ents, but use is decreasing