OMG my pa*ent is bleeding pa*ent is on NOACs!! Bryan Poon, PharmD Clinical Quality Manager UT Southwestern Medical Center at Dallas

OMG my pa*ent is bleeding pa*ent is on NOACs!! Bryan Poon, PharmD Clinical Quality Manager UT Southwestern Medical Center at Dallas

Disclosure Financial disclosure: NONE Off label drug use disclosure: YES

Objec*ves (Pharmacists) Review the current usage of novel oral an*coagulants (NOACs) Discuss the bleeding risk associated with NOACs Discuss various strategies used in controlling bleeding when NOAC is on board Discuss poten*al reversal agents that can be used in the event of life threatening bleeding

Objec*ves (Technicians) Familiar with the current usage of novel oral an*coagulants (NOACs) Describe the bleeding risk associated with NOACs Outline various strategies used in controlling bleeding when NOAC is on board List poten*al reversal agents that can be used in the event of life threatening bleeding

Let s talk about our good ole friend - warfarin

Warfarin (coumadin) Inhibits hepa*c conversion of vitamin K to vitamin K epoxide Inhibit produc*on of II, VII, IX, and X Inhibit produc*on of protein C and S Used widely for stroke preven*on in NVAF and those with mechanical valves, VTE treatment and preven*on, etc for a long *me Target mostly 2 3; but for mechanical valve: 2.5 3.5. Range may be lower for some specific pa*ent groups Due to long half- life of circula*ng cloang factors, esp factor II, full an*thrombo*c state won t be established for at least 5 days acer ini*a*on of therapy

Y Anon. hdp://www.frca.co.uk/ar*cle.aspx?ar*cleid=100096. Accessed 10/21/2011.

Now, let s take AF as an example (which usually requires paaents to be on it for a very long Ame)

Why warfarin for AF? RRR = 64% RR (vs ASA) = 15-36% Hart RG, et al. Ann Intern Med. 2007;146:857-67. ACCF/AHA/HRS guidelines. Circula*on 2011;123:e269- e367

An unmet need AF scenario Baker WL, et al. J Manag Care Pharm 2009;15(3):244-52.

Why don t eligible pa*ents take warfarin? frequent drug level (INR) monitoring mul*ple drug- drug interac*ons mul*ple drug- food interac*ons gene*c variability (CYP2C9 and VKORC1 muta*ons) delayed onset/offset fears of bleeding, eg fall risk bad impression/publicity

So, we need alternaaves Novel Oral AnA- Coagulant (NOACs)

Current INDICATED use of NOACs Dabigatran (Pradaxa) Stroke preven*on in NVAF (RE- LY) Treatment of DVT/PE (RE- COVER I, RE- COVER II) Rivaroxaban (Xarelto) Stroke preven*on in NVAF (ROCKET- AF) Treatment of DVT/PE (EINSTEIN- DVT, EINSTEIN- PE, EINSTEIN- EXT) VTE ppx acer hip and knee replacement surgery (RECORD) Apixaban (Eliquis) Stroke preven*on in NVAF (ARISTOTLE) Treatment of DVT/PE (AMPLIFY, AMPLIFY- EXT) VTE ppx acer hip and knee replacement surgery (ADVANCE) Edoxaban (being reviewed by the FDA) Betrixaban (being studied)

How do these NOACs work?

Y FXa inhibitors: Rivaroxaban, Apixaban, Edoxaban, Betrixaban Direct Thrombin Inhibitor: Dabigatran Anon. hdp://www.frca.co.uk/ar*cle.aspx?ar*cleid=100096. Accessed 10/21/2011.

NOACs efficacy in NVAF

Dabigatran Apixaban RRR = 34%* RRR = 21% Rivaroxaban Edoxaban* RRR 12% RRR = 23% ITT: HR 0.88 (0.75-1.03), p<0.001 (non- inferiority), p=0.12 (superiority) Average TTR: RELY 64%; ROCKET AF 55%; ARISTOTLE 62.2%; ENGAGE AF 64.9% (being reviewed by the FDA) Connolly SJ, et al. NEJM 2009;361:1139-51; Patel MR, et al. NEJM 2011;365:883-91; Granger CB, et al. NEJM 2011;365:981-92;

Why are we considering NOACs? Ease of use - Oral administra*on Quick onset - NO need to bridge Rela*vely quick offset good vs bad? NO need for rou*ne monitoring LESS drug- drug, drug food interac*ons Great DTC adver*sement (?)

Wow, sounds good let s go over one dialogue I had with a paaent

A conversa*on pt hey, i want to start on that new medica*on adver*sed on TV... me which one? pt you know, that blood thinner... me you mean pradaxa? pt that s the one... the one that doesn t require any blood tes*ng... me hmmm... well...

He didn t pay me!!! Unpaid model, original pa*ent was 3 days post burr holes 2/2 SDH while on ASA and clopidogrel.

Oops that s a problem and what else

Problems with NOACs NO specific an*dote Quick onset/offset Problems with bridging and resump*on Lack of experience Dosing varies among NOACs and indica*ons NO known monitoring scheme Great DTC adver*sement (?)

Dosing can be confusing IndicaAon Dabigatran Rivaroxaban Apixaban Stroke preven*on in NVAF Treatment of VTE VTE ppx acer knee replacement VTE ppx acer hip replacement CLcr >30ml/min: 150mg BID CLcr 15-30ml/min: 75mg BID IF on dronedarone or ketoconazole CLcr 30-50ml/min: 75mg BID CLcr < 30ml/min: AVOID AFTER 5-10days of parenteral tx, then CLcr >30ml/min: 150mg BID CLcr <30ml/min: AVOID Not approved Not approved CLcr >50ml/min: 20mg daily CLcr 15-50ml/min: 15mg daily CauAon: ketoconazole, ritonavir, clarithromycin CLcr >/=30ml/min: 15mg BID X 21days, then 20mg daily CLcr <30ml/min: AVOID CLcr >/=30ml/min: 10mg daily X 12days CLcr >/=30ml/min: 10mg daily X 35days Non- HD: 5mg BID unless 2/3+ of the following: age >/=80, body wt </=60kg, Scr >/=1.5: 2.5mg BID HD: 5mg BID, unless 1/2+ of the following: age >/=80, body wt </=60kg: 2.5mg BID IF on ketoconazole, itraconazole, ritonavir, clarithromycin: 2.5mg BID 10mg BID X 7days, then 5mg BID (reduce dose by 50% if on keto, itra, ritonavir, clarithro); 2.5mg BID if >/=6mos of in*al tx (avoid if on K, I, R, C) 2.5mg BID X 12days (avoid if on K, I, R, C) 2.5mg BID X 35days (avoid if on K, I, R, C) Anon. Product Informa*on: dabigatran (Pradaxa). Boehringer Ingelheim Pharmaceu*cals, Inc. Ridgefield, CT. 2014 Anon. Product Informa*on: rivaroxaban (Xarelto). Janssen Pharmaceu*cals, Inc. Titusville, NJ. 2014 Anon. Product Informa*on: apixaban (Eliquis). Bristol- Myers Squibb Pharma Company.

What about using dabigatran off- label for mechanical heart valves?? BAD!! Eikelboom JW, et al. NEJM 2013;369:1206-14.

OK what exactly are the bleeding risks, if we use it on- label?

Major bleeding risks Study (D, R, A, E) Drug (%) Comparator (%) Comments RE- LY (D) 3.11/yr 3.36/yr ICH: 0.3%/yr vs 0.74%/yr NVAF VTE TX & extended ppx VTE ppx (TKR/THR) ROCKET- AF (R) 3.60/yr 3.4/yr ICH: 0.5%/yr vs 0.7%/yr ARISTOTLE (A) 2.13/yr 3.09/yr ICH: 0.33%/yr vs 0.8%/yr ENGAGE AF (E*) 2.75/yr (60mg daily), 1.61/yr (30mg daily) 3.43/yr RECOVER I (D) 1.6 1.9 RECOVER II (D) 1.2 1.7 EINSTEIN- DVT (R) 0.8 1.2 EINSTEIN- PE (R) 1.1 2.2 AMPLIFY (A) 0.6 1.8 RECORD (R) 0.1-0.7 0.1-0.5 ADVANCE (A) 0.6-0.8 0.7-1.4 ICH (60mg): 0.39%/yr vs 0.85%/yr ICH (30mg): 0.26%/yr vs 0.85%/yr D = dabigatran; R = rivaroxaban; A = apixaban; E* = edoxaban (being evaluated by the FDA) Connolly SJ, et al. NEJM 2009;361:1139-51; Patel MR, et al. NEJM 2011;365:883-91; Granger CB, et al. NEJM 2011;365:981-92; hdp://www.an*coagulant- trials.eu/introduc*on.html. Accessed 12/22/2014

RE- LY - *me to bleeds * Hemorrhagic transforma*on was NOT considered hemorrhagic stroke; ICH includes hemorrhagic stroke, SDH, SAH. Eikelboom JW, et al. Circula*on 2011;123:2363-72.

RE- LY - bleeding by age p=0.002 Higher risk of major bleeding for pa*ent >/= 75 years * Hemorrhagic transforma*on was NOT considered hemorrhagic stroke; ICH includes hemorrhagic stroke, SDH, SAH. Eikelboom JW, et al. Circula*on 2011;123:2363-72.

So, is it bad?... Depends on how you look at it

Something you DON T want to see 81 year old female, on eliquis (apixaban) 2.5mg BID (Dose adjusted for > 80 years old and weight 53kg), s/p GLF.

Or this 69 year old female, s/p VP shunt placement, started on xarelto 10mg daily (at outside facility).

Or this That s only 1 of 3 bags Elderly male, h/o afib, s/p stent placement (?), on pradaxa, ASA, and plavix, s/p fall, face down, bleeding from nose

OMG what can we do?...

General strategies STOP the drug Ac*vated charcoal? PRBC transfusion if needed Evaluate where the bleeding is Damage control, if feasible Adempt to increase renal clearance (dabigatran and rivaroxaban (?)) HD for dabigatran Manage other meds that may exaggerate bleeding FFP? Thrombo*c agents PCC, FEIBA, rfviia, combo Specific an*dotes being evaluated, not available yet

Daelen, SV, et al. Expert Rev Cardiovasc Ther. 2015;13(1):95-103.

Pharmacokine*cs of NOACs (Being reviewed by the FDA) Heidbuchel H, et al. Europace 2013;15:625-51; Babilonia K, et al. Thrombosis Journal 2014;12(8). hdp://www.thrombosisjournal.com/content/pdf/1477-9560- 12-8.pdf. Accessed 12/22/2014.

Can we at least monitor the drug?... Technically NO, but

Dabigatran monitoring* BID dosing of all dosages (Trough) *aptt is recommended per package insert; Van Ryn J, et al. Thromb Haemost 2010;103:1116-27.

Rivaroxaban monitoring steady state with rivaroxaban 20mg dose * neoplas*n PT used hdp://www.fda.gov/downloads/advisorycommidees/commideesmee*ngmaterials/drugs/cardiovascularandrenaldrugsadvisorycommidee/ UCM272005.pdf. accessed 10/21/2011.

Apixaban - monitoring chromogenic an*- Xa assay with LMWH (or apixaban) calibra*on may be effec*ve in evalua*ng apixaban ac*vity Becker RC, et al. J Thromb Thrombolysis 2011;32(2):183-7.

What about that fancy ROTEM?...

Anderson, L et al. Transfusion Medicine. 2006;16:31-39. ROTEM won t be able to detect NOACs YET!?

Adelmann D et al. Thrombosis Research 2014;134:918-23. LowTF- ROTEM

Can we dialyze the drug out?... May be

Unfortunately, NOT for all NOACs Only dabigatran is dialyzable: Low protein binding: 35% High flux dialyzer: Qb 200ml/min, Qd 700ml/hr, 49% clearance over 4hrs Qb 300ml/min, Qd 700ml/hr, 57% clearance Rebound (redistribu*on): 7-15% Vd 50-70L Both rivaroxaban and apixaban has high protein binding, >87%, which makes HD not usable Anon. Product Informa*on: dabigatran (Pradaxa). Boehringer Ingelheim Pharmaceu*cals, Inc. Ridgefield, CT. 2014 Anon. Product Informa*on: rivaroxaban (Xarelto). Janssen Pharmaceu*cals, Inc. Titusville, NJ. 2014 Anon. Product Informa*on: apixaban (Eliquis). Bristol- Myers Squibb Pharma Company.

Baseline data/tx given Singh T, et al. Clin J Am Soc Nephrol 2013;8:1533-1539.

Singh T, et al. Clin J Am Soc Nephrol 2013;8:1533-1539. Dialysis seangs

Excorporeal removal of dabigatran Singh T, et al. Clin J Am Soc Nephrol 2013;8:1533-1539. Don t forget the redistribu*on phase!!

What else can we do?...

Lots of aracles let s look at 2 of them

Eerenberg ES, et al. Circula*on 2011;124:1573-79.

PCC (Cofact) 1. cofact is a 4-factor PCC 2. reconstitution: 500unit/20ml SW 3. dose: 50unit/kg X 1, NO additional blood product or rfviia given 4. PT, aptt, TT, ECT were used as surrogate markers, ie NOT clinical bleeding Eerenberg ES, et al. Circula*on 2011;124:1573-79.

Effects of Cofact on coag *me 1. after rivaroxaban: PT 15.8+/-1.3 sec (p<0.001) 2. after cofact: 12.8+/-1.0 sec (p<0.001) 3. normalization sustained X 24 hrs 1. after dabigatran: aptt 59.4+/-15.8sec (p<0.001), TT >120sec 2. after cofact: NO effects on aptt, TT, ECT Eerenberg ES, et al. Circula*on 2011;124:1573-79.

Comments on the study All healthy volunteers Xarelto dosing was 2X afib, 4X orthopedic Cofact is a 4- factor PCC, NOT available in US PCC was given at peak, NOT likely in emergency Coagula*on assays as surrogate markers, NOT actual bleeding NO long term evalua*on for thrombo*c effects

Marlu R, et al. Thromb Haemost 2012; 108:217-24.

FEIBA/PCC/rFVIIa on *me for thrombin genera*on 2hrs acer rivaroxaban 2hrs acer dabigatran H0 = NO an*coagulants; H2 = 2hrs AFTER riva (LEFT) or dabi (RIGHT); PCC = kanokad (4- factors) Dosing (reflec*on): PCC 50unit/kg, FEIBA 160unit/kg, rfviia 120mcg/kg Marlu R, et al. Thromb Haemost 2012; 108:217-24.

Effects of FEIBA on ETP overcorrec*on overcorrec*on ETP = endogenous thrombin poten*al; H0 = NO an*coagulants; H2 = 2hrs AFTER riva (LEFT) or dabi (RIGHT); PCC = kanokad (4- factors) (#) denotes NS (vs H0) and (*) denotes p<0.001 (vs H2) Marlu R, et al. Thromb Haemost 2012; 108:217-24.

Effects of FEIBA on LT LT = Lag Time; H0 = NO an*coagulants; H2 = 2hrs AFTER riva (LEFT) or dabi (RIGHT); PCC = kanokad (4- factors) (#) denotes NS (vs H0) and (*) denotes p<0.001 (vs H2) Marlu R, et al. Thromb Haemost 2012; 108:217-24.

Ex vivo data Comments on the study Peak concentra*on evaluated NOT at steady state, ONE dose study Kanokad is a 4- factor PCC, NOT available in US ETP/LT as surrogate markers, NOT actual bleeding NO evalua*on of thrombo*c poten*al

So, what actually did we do to the 2 paaents with ICH

First pa*ent 81 year old female, on eliquis (apixaban) 2.5mg BID, s/p GLF, AFTER Profilnine 1660unit (34unit/kg) X 1 with rfviia 1mg (20mg/kg) X 1, NO FFP, emergent RIGHT frontotemporal craniotomy

Trend of LMWH an*- Xa level

And the second pa*ent 69 year old female, s/p VP shunt placement, started on xarelto 10mg daily (at outside facility). s/p emergent EVD, intraventricular tpa 2mg daily X 2 doses

Is there anything in the horizon?

Some poten*al an*dotes AnAcoagulants Idarucizumab (BI655075) Andexanet Alfa (PRT4445) Dabigatran X X Rivaroxaban X X Apixaban X X UFH LMWH? X Fondaparinux? X Aripazine (?) (PER977) X Cos*n J, et al. Postgraudate Medicine, 2014;126(7):19-24. Shah N, et al. AMSRJ, 2014;1(1):16-28.

Andexanet alfa

How does andexanet work? Anon. Portola Pharmaceu*cals. hdps://www.youtube.com/watch?v=lxa7aiaa7yq. Accessed 1/2/2015.

Retains high affinity for factor Xa inhibitors Serine to Alanine eliminates cataly*c ac*vity and prothrombin cleavage Removal of GLA domain prevent an*coagulant effect Shah N, et al. AMSRJ, 2014;1(1):16-28. Crowther M. hdp://my.americanheart.org/idc/groups/ahamah- public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf. Accessed 1/2/2015; Crowther M. hdp://my.americanheart.org/idc/groups/ahamah- public/@wcm/@sop/@scon/documents/downloadable/ucm_469594.pdf. Accesed 1/2/2015; Cocchio C.hdp://www.pharmacy*mes.com/contributor/craig- cocchio- pharmd/2014/11/one- step- closer- towards- reversing- an*- xa- inhibitors. Accessed 1/2/2015.

ANNEXA studies ANNEXA- A Part 1: 400mg IV bolus only Part 2: 400mg IV bolus + 4mg/min infusion ANNEXA- R Part 1: bolus only Part 2: bolus + infusion Crowther M. hdp://my.americanheart.org/idc/groups/ahamah- public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf. Accessed 1/2/2015; Crowther M. hdp://my.americanheart.org/idc/groups/ahamah- public/@wcm/@sop/@scon/documents/downloadable/ucm_469594.pdf. Accesed 1/2/2015; Cocchio C.hdp://www.pharmacy*mes.com/contributor/craig- cocchio- pharmd/2014/11/one- step- closer- towards- reversing- an*- xa- inhibitors. Accessed 1/2/2015.

ANNEXA- A (part 1) Part of phase 3 study presented at AHA scien*fic sessions 2014 N=33 (9 placebo, 24 andexanet) Age 50-75 Apixaban 5mg BID X 4 days Andexanet 400mg IV X 1 or placebo given 3hrs post apixaban dose Primary endpoint: % change an*- factor Xa Results: Change in an*- factor Xa = 94% (vs ~22% with placebo, p<0.0001), within 2 mins All subjects achieved >/= 90% reversal (secondary endpoint) Effects lasted 1-2hrs Safety: NO thrombo*c events NO an*bodies to factor X or factor Xa noted Crowther M. hdp://my.americanheart.org/idc/groups/ahamah- public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf. Accessed 1/2/2015; Crowther M. hdp://my.americanheart.org/idc/groups/ahamah- public/@wcm/@sop/@scon/documents/downloadable/ucm_469594.pdf. Accesed 1/2/2015; Cocchio C.hdp://www.pharmacy*mes.com/contributor/craig- cocchio- pharmd/2014/11/one- step- closer- towards- reversing- an*- xa- inhibitors. Accessed 1/2/2015.

PER977

Ansell JE, et al. NEJM 2014. 371(22):2141-42. Some data on PER977

Ansell JE, et al. NEJM 2014. 371(22):2141-42.

Idarucizumab

Some data on idarucizumab Fab fragment against dabigatran Safety, tolerability, PK/PD study presented at ASH. December 2014 N=46 (male/female, eclcr 30-59 or 60-89) Dabigatran 220mg BID X 4 days 150mg BID X 4 days Idarucizumab 1gm, 2.5gm, 5gm, 2X 2.5gm (1hr apart) all given as 5min IV infusion, 2hrs acer last dose of dabigatran Endpoints: unbound dabi concentra*on, diluted TT, ECT, aptt, resump*on acer 24hrs Results: PK measurements of unbound dabigatran occurred right acer end of infusion All cloang assays reversed to baseline at of infusion Part return of dabigatran effect about 2-4hrs acer infusion (1gm dose) Dabigatran effect can be re- established 24hrs acer idarucizumab Further study: RE- VERSE AD trial (5gm dose) Glund S, et al. hdps://ash.ocnfex.com/ash/2014/webprogram/paper74960.html. Accessed 1/2/2015.

In the absence of a specific anadote and an established monitoring scheme, we should

MINIMIZE THE RISK OF BLEEDING!!!

How can we minimize the risk? Proper pa*ent selec*on Adequate pa*ent educa*on Frequent monitoring of renal and hepa*c func*on Con*nued surveillance for drug- drug interac*ons Understand the pharmacological proper*es of each NOACs Use guidelines to determine how long to hold NOACs before procedure

OK, I know it is a long lecture several of you are soundly asleep But, sall, do you have any quesaon?