H.E.M.O.R.R.H.A.G.E For Drug Induced Bleeding Emergency Medicine Residency Conference Clinical Pharmacy Lecture October 21, 2015 Matt Perciavalle, Pharm.D.

H.E.M.O.R.R.H.A.G.EFor Drug Induced Bleeding

Emergency Medicine Residency ConferenceClinical Pharmacy Lecture

October 21, 2015Matt Perciavalle, Pharm.D.

Stony Brook Medicine

H.E.M.O.R.R.H.A.G.E. • Hemodynamics

• The Basics• Vitals• Perfusion• Hypotensive

Resuscitation?• Airway• Patient specific• Stabilize

H.E.M.O.R.R.H.A.G.E. • Explain

• H & P • Find source• Scans

> 65 YO < 50 kg Renal dysfx Liver dysfx Prior hemorrhage Stroke Hx PUD ETOH abuse High fall risk Meds: AC, Antiplatelets, others

Increased risk of drug induced bleeding:

H.E.M.O.R.R.H.A.G.E. • Medication List

• Pharmacist!• Chart review• Patient/Family• External Rx Hx• Last dose?

Antiplatelet: aspirin, clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), vorapaxar (Zontivity), aspirin/dipyridamole

(Aggrenox), NSAIDs, SSRIs, nitrates, calcium channel blockers Oral Anticoagulants

warfarin (Coumadin), dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) Parenteral Anticoagulants

unfractionated heparin, enoxaparin (Lovenox), dalteparin (Fragmin), fondaparinux (Arixtra) Toxins

Superwarfarins AKA commercial rat poisons

H.E.M.O.R.R.H.A.G.E. • Obtain initial labs/consults

• Chem• CBC• aPTT/ PT/ INR• Others

• LFT• Bleeding Time• Sepsis/Trauma-

Fibrinogen/D-Dimer• PT/PTT Mixing study• Factor deficiency• Thromboelastogram

(TEG) – future • Poison Control • 1-800-222-1222

H.E.M.O.R.R.H.A.G.E. • Reversal

• Phytonadione• Protamine• 4F-PCC• FFP?• Idarucizumab• Antifibrinolytics

• TXA• Aminocaproate

• Pipeline agents• Andexanet

alpha

TXATrauma – Roberts 2013

CRASH-2Epistaxis – Zahed 2013

Hyphema – Jahadi Hosseini 2014Gingival – Nuvvula 2014

H.E.M.O.R.R.H.A.G.E. • Replacement

• What’s goes where?• Crystalloids• Colloids?• Platelets- 1st • RBCs• Plasma PROPPR Trial Holcomb 2015

Trauma replacement1:1:1 > 1:1:2

Less exsanguination, more hemostasisNo difference in transfusion complications

H.E.M.O.R.R.H.A.G.E. • Help

• Initial consults• F/U w/ consults• Poison Control• 1-800-222-

1222

H.E.M.O.R.R.H.A.G.E. • Assess/ Admit

• Frequent assessments• Where does this

patient need to go?

H.E.M.O.R.R.H.A.G.E. • Goals

• Patient specific• Agent specific• Immediate• Intermediate• Long term

H.E.M.O.R.R.H.A.G.E. • Extra work up

• F/U labs• Additional

scans

Antiplatelet Medications• What can we do?• Irreversible platelet inhibition:

• aspirin, clopidogrel, prasugrel – 100% inhibition for 5-7 days• Reversible platelet inhibition:

• ticagrelor – 30% LESS platelet inhibition 2.5 days after discontinuing• dipyridamole, NSAIDs, SSRIs

• Reversible platelet inhibition but not really• vorapaxar – significant inhibition 4 weeks after discontinuation

• No specific reversal agents• Stop the bleed other wise• Risk V Benefit assessment of stopping drug• Platelet infusion? Maybe• DDAVP? Probably not

Drug Half-life

Asa < 300mgAsa Overdose

<3 hours15-30 hours

Clopidogrel parentActive metab

6 hours< 1 hour

Prasugrel active metab

~7 hours

Ticagrelor parentActive metab

~7 hours~9 hours

Vorapaxar parentActive metab

3-4 days~8 days

Dipyridamole ~11 hours

Vitamin K Antagonist• Warfarin

• MOA: Inhibition of Vitamin K epOxide Reductase Complex 1 (VKORC1), depleting functional vitamin K stores, reducing production of coagulation factors II, VII, IX, & X; Also inhibits proteins C & S (natural anticoagulants)

• Duration: 2-5 days • Drug interactions: Too many to list- consult a pharmacist• Therapeutic monitoring: INR

• Superwarfarins AKA commercially available rat poisons• MUCH MORE POTENT than warfarin• brodifacoum, bromadiolone, difenacoum, and flocoumafen chlorophacinone

• Tecarfarin • Pipeline VKORC1 inhibitor, designed with intent of less drug interactions, avoids renal

elimination, and less patient to patient variability

Factor Xa Inhibitors• Apixaban, Rivaroxaban, Edoxaban• MOA: Inhibits platelet activation and fibrin clot formation via direct, selective and

reversible inhibition of free and clot-bound factor Xa • Drug interactions: not as many as warfarin, but significant – consult a pharmacist• Prolonged elimination in renal dysfunction• Therapeutic monitoring: N/A

Half-life Metabolism & Transport Excretion

Apixaban ~12h CYP3A4 major, others, P-gp Renal

Rivaroxaban 5-9h, 11-13h elderly CYP3A4/5, 2J2, P-gp Renal, minor fecal

Edoxaban 10-14h CYP3A4 minor, P-gp Renal

Direct Thrombin (FIIa) Inhibitors (DTI)• Dabigatran Etexilate• MOA: Prodrug converted to the active dabigatran, a specific, reversible, direct thrombin

inhibitor. Inhibits free and fibrin-bound thrombin. Inhibits coagulation by preventing thrombin-mediated effects, including cleavage of fibrinogen to fibrin monomers, activation of downstream factors, and inhibition of thrombin-induced platelet aggregation.• Half-life:

• 12-17 hours; Elderly: 14-17 hours; Longer with p-glycoprotein inhibitors• Mild-to-mod renal impairment: 15-18 hours; Severe renal impairment: 28 hours

• Elimination: Renal; 62% dialyzable• Therapeutic monitoring: N/A

Unfractionated Heparin• Heparin• MOA: Binds reversibly to anti-thrombin III (ATIII) and causes inactivation of factors IIa

and Xa.• Half-life: dose dependent, ~1.5 hours• Therapeutic monitoring: aPTT

Low Molecular Weight Heparins• Enoxaparin, Dalteparin• MOA: Inhibits FXa and FIIa with a higher ratio of anti-FXa to anti-FIIa activity than

unfractionated heparin• Elimination: renal; significant for enoxaparin, less significant for dalteparin• Therapeutic monitoring:

• small effect on aPTT, monitoring not required, Anti-FXa in select casesHalf-life Duration Metabolism Elimination

Enoxaparin 4.5-7h ~12h Hepatic Renal

Dalteparin 2-5h >12h Hepatic & RES Renal

Factor Xa Inhibitor• Fondaparinux• MOA: See previous slides• Half-life: 17-21 hours• Elimination: Renal – significant; prolonged half-life in renal impairment and elderly• Therapeutic monitoring: not generally recommended

• Can monitor anti-Xa level in select cases• Reversal: minimal data

• 4F-PCC 50units/kg ? • rFVIIa (Novoseven) 90mcg/kg ?

• Higher risk of thromboembolic event

ACCP 2012 Guidelines for VKA reversal• INR above therapeutic range to < 4.5, no evidence of bleeding: lower/ hold

dose, monitor• INR 4.5-10, no evidence of bleeding: • Routine use of vitamin K NOT recommended; hold, watch, wait and monitor;

• May consider 1-2.5mg ORAL vitamin K if other risk factors for bleeding (ACCP 2008)

• INR > 10, no evidence of bleeding:• Recommend administration of ORAL vitamin K – no specified dose– hold, watch, wait

and monitor• Usually 2.5-5mg. May give additional if necessary

• Minor bleeding at ANY INR elevation: • Give ORAL vitamin K 2.5-5mg; hold, watch, wait, monitor; may repeat if necessary

• Major bleeding at ANY INR elevation: • Administer four-factor prothrombin complex concentrate (PCC) and IV vitamin K 5-

10mg by slow infusion (may repeat vitamin K in 12 hours); hold VKA, monitor

Phytonadione (Vitamin K1)• MOA: Promotes liver synthesis of clotting factors II, VII, IX, X• Onset: • Oral: 6-10 hours; IV: 1-2 hours

• Peak effects on INR• Oral: ~24 hours; IV: ~12 hours

• Administration: • Oral: tablets, can be crushed; can use IV solution orally • IV: SLOW infusion preferred (in 50ml NS or D5W) over 20-30 minutes

• Max rate: 1 mg/minute; filter if ampoule

• Hypersensitivity reactions! • IV for MAJOR bleeds• No role for SC or IM

4-Factor Prothrombin Complex Concentrate• MOA: AKA Factor IX Complex Concentrate

• Provides vitamin K-dependent coagulation factors (II, VII, IX, and X) and protein C & S. Leads to downstream clot formation.

• FDA Indication:• Urgent reversal of acquired coagulation factor deficiency induced by VKA therapy in patients

with acute major bleeding or a need for an urgent surgery or an invasive procedure

• Onset: Rapid, decreased INR seen within 10 minutes• Duration: 6-8 hours; may see rebound effect after 12-24 hours if used alone• Administration:

• IV infusion, max rate ~210 units per minute (~8.4 ml/min); do not allow blood to backflow into the line

• Administer IV vitamin K concurrently to maintain clotting factor levels after effects of PCC have diminished

• Baseline PT/INR in all patients; Recommended to repeat PT/INR 30 minutes after completion of infusion

4 Factor PCC• Warnings:• Contains Heparin- Contraindicated with history of heparin allergy (HIT)• Thromboembolic events - Black Boxed Warning:

• No significant adverse events from clinical trials, but anecdotal reports (usually > 48h post)• Use has not been evaluated in patients who have experienced a thromboembolic event, MI, DIC, CVA,

TIA, unstable angina, or severe peripheral vascular disease within the prior 3 months.

• Tazarourte, et al. Critical Care 2014 (EPAHK study): • Protocol based PCC + Vitamin K administration within 8 hours associated with 2x

decrease in seven day mortality overall and a 3x decrease in ICH population

4F-PCC vs FFP4F-PCC FFP

Volume infused Small (500units/20ml) Large (1unit/200-250ml)

Dose INR & Weight based (see previous) Weight based (~10-20ml/kg)

Infusion time Quick (210units/ml)Quicker preparation time

Varies based on clinical hx (30min to multiple hrs/unit)May take longer to be available

INR Reduction Significant within 30 minutes Varies based on infusion time and # of units given, but can take hours to see significant reversal

Cost $$$$$$$$$$$$$$$$$ $

Components II, VII, IX, X, Protein C&SSet range of variation

All coagulant factors, fibrinogen, plasma proteins, electrolytes, proteins C & S, antithrombin

Risks Hypersensitivity reaction, VTE, HIT, transmission of blood born diseases

Hypersensitivity reactions, transmission of blood born diseases, transfusion-related acute lung injury, transfusion-associated volume overload

Hickey, et al. Circulation 2013: PCC has less serious adverse events, quicker INR reversal, less PRBC transfusions than FFP, but similar HLOS

Goldstein, et al. Lancet 2015: 4F-PCC superior to FFP in terms of achieving hemostasis and rapid INR reduction, which similar AE profile.

Superwarfarin ingestion• MUCH MORE POTENT (>100x) than rx warfarin

• Brodifacoum, bromadiolone, difenacoum, and flocoumafen chlorophacinone• Laboratory levels

• Similar onset as warfarin 24-72 hours• Prolonged PT/INR may persist for WEEKS to MONTHS

• May require MUCH HIGHER DOSES of phytonadione if coagulopathy• > 100mg/day reported in literature• Dose may need to be titrated to response of bleeding & factor deficiency

• In ED would be acceptable to start 10mg IV and repeat q4-8 hours based on response • Typically treated for many weeks months

• Initial 4FPCC may be warranted for acute life threatening bleeding

• What is the Poison Control Center Phone Number?

“Reversal” of NOACs• Mixed data due to lack of high quality evidence from randomized trials; Off-label use

of 4FPCC• Possible reversal strategies:

• Minor Vs Major Bleeding? Imminent risk of death or disability? Anti-Xa level? • Drug removal

• HD for dabigatran – may see rebound levels! • charcoal if previous dose within 2 hours for all; can consider if within up to 6 hours

• Pro-hemostatic agents (tranexamic acid, aminocaproic acid, DDAVP?)• No significant studies for this strategy

• Anti-Xa inhibitors and Dabigatran: 4F-PCC (Kcentra) – 25-50 units/kg • Few animal and human studies, but mostly in healthy subjects, looking at PT/INR as endpoint of reversal• No evidence to support repeat dosing

• Dabigatran: a4F-PCC (FEIBA) – 25-100 units/kg – may be associated with higher risk of thrombosis• Few animal and human studies (not available in this institution)

• Avoid FFP- no evidence for any benefit, except with when used as part of MTP (trauma, dilutional coagulopathy)

• No role for vitamin K administration unless underlying vitamin K deficiency known/suspected

Dabigatran Reversal• Idarucizumab, Boehringer Ingelheim – FDA APPROVED 10/16/2015• Monoclonal antibody fragment designed to bind dabigatran and ceases inhibition of

thrombin• Pollack C. et al. NEJM 2015: interim analysis of RE-VERSE-AD

• Significant reversal of thrombin time and ecarin clotting time, significant binding of free drug• Group A (uncontrollable bleeding): clinical assessment of bleeding stopped ~11 hours• Group B (need for urgent surgery within 8 hours): Normal hemostasis in 92% • 1 thromboembolic event in 72 hours (n=90); 4 events > 72 h – no patients were on AC

• 2 x 2.5g/50 mL bolus infusion < 15 minutes apart (total 5 grams)• Can repeat if re-bound coagulation/bleeding or need for another procedure

• Clinical judgement: At 24 hours, 79% patients with minimal unbound dabigatran• Dabigatran can be restarted 24 hours after adm if necessary; No pro-coagulant effects alone

• Hypersensitivity? Hereditary fructose intolerance?

Pipeline Reversal Agents for NOAC

• Andexanet alpha, Portola Pharma• Modified F-Xa molecule designed as antidote for reversal of anti-Xa inhibitors (oral and

injectable)• F-Xa decoy, binds drug allowing real F-Xa to restore normal hemostatic processes• Phase 3 studies: ANNEXA-A & ANNEXA-R - early review both achieved primary endpoints

• > 90% anti-Xa level reversal and binding of free drug in plasma• IV continuous infusion, very short half-life

• FDA Accelerated Approval Pathway- currently in late phase 3 studies

Protamine• MOA:• Basic protamine binds acidic heparin forming salt complex, inhibiting anticoagulation

• FDA Indication: Neutralization of unfractionated heparin• Reversal of enoxaparin or dalteparin – OFF-LABEL

• Onset: ~5 minutes• Duration: ~ 2 hours (when used with UFH)• Administration: IV – slow infusion; max 5mg/min• Warnings• Heparin rebound – may be seen > 10 hours after administration• Infusion reactions – hypotension, anaphylatoid reactions/ hypersensitivity reactions

• Can give 5mg test dose; can pre-treat with antihistamines/steroids if necessary

Protamine• Heparin reversal (100%)

• 1mg protamine IV/ ~100 units UFH SC or IV; 50mg max single dose• If CIV need to account for last 2-2.5 hours of heparin• If heparin stopped > 30 minutes ago, required dose of protamine drops• If SC heparin, can give half dose as “slow bolus infusion” followed by prolonged infusion of rest of dose• May need to repeat if persistent bleeding or elevated aPTT

• Enoxaparin or Dalteparin reversal (60-70%)• Last dose < 8 hours: 1mg protamine IV /1mg enoxaparin/ 100 units dalteparin; 50mg max single dose• Last dose 8-12 hours ago: 0.5mg protamine IV / 1mg of enoxaparin / 100 units dalteparin; 50mg max

single dose• aPTT elevated after 2-4 hours or bleeding: May repeated dose as 0.5mg protamine IV /1mg of

enoxaparin / 100 units Dalteparin; 50 mg max dose• Last dose > 12 hours ago: not recommended- can consider 25mg IV fixed dose if deemed necessary

Summary• H.E.M.O.R.R.H.A.G.E.

For drug induced bleeding• Know your meds

• Choose the right reversal strategy• Save some lives

References• Ageno W. Oral Anticoagulant therapy Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians Evidence-

Based Clinical Practice Guidelines.” Chest 2012; 141.2 Suppl e44s-e88s. • Van der Meer FJM, et al. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med. 1993;15313:1557-

1562.• Ansell, Jack, et al. “Pharmacology and Management of the Vitamin K Antagonists. American College of Chest Physicians Evidence-Based Clinical

Practice Guidelines.” CHEST Journal 133.6_suppl (2008): 160S-198S.• Holbrook, Anne, et al. “Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis:

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.” Chest 141.2 Suppl (2012): e152S-e184S.• Lubetsky, Aharon, et al. “Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective

randomized controlled study.” Archives of internal medicine 163.20 (2003): 2469.• Crowther, Mark A., et al. “Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment

of warfarin-associated coagulopathyA randomized, controlled trial.” Annals of internal medicine 2002.• Tazarourte, Karim, et al. “Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased

mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study).” Critical Care 2014.• Majeed, Ammar, et al. “Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin

coagulopathy.”Thrombosis research 129.2 (2012): 146-151.• Hickey, Michael, et al. “Outcomes of Urgent Warfarin Reversal Using Fresh Frozen Plasma versus Prothrombin Complex Concentrate in the

Emergency Department.” Circulation 2013.• Goldstein JN, et al. Four Factor PCC vs Plasma for rapid VKA reversal in patients needing urgent surgical or invasive interventions: a phase 3b,

open label non-inferiority, randomized trial. Lancet 2014. • Eerenberg, Elise S., et al. “Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled,

crossover study in healthy subjects.” Circulation 2011.• Schulman, Sam, et al. “Activated prothrombin complex concentrate for dabigatran associated bleeding.” ‐ British journal of haematology 2014.

References• Ageno W. Oral Anticoagulant therapy Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians Evidence-Based

Clinical Practice Guidelines.” Chest 2012; 141.2 Suppl e44s-e88s. • Barron, Bridget. “The Effectiveness of Prothrombin Complex Concentrate in Reversing the Anticoagulant Activity of the Oral Director Thrombin

Inhibitor Dabigatran (Pradaxa®): A Review of Human Studies.” (2013).• Zahir, Hamim, et al. “Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex

Concentrate.” Circulation(2014): CIRCULATIONAHA-114.• Portola Pharmaceuticals Initiates Phase 4 Study to Support Accelerated Approval of Andexanet Alfa- Its Breakthrough Designed Factor Xa Inhibitor

Antidote. Portola Globe Newswire. Available at: http://investors.portola.com/mobile.view?c=198136&v=203&d=1&id=2006796. Accessed Sept 20, 2015.

• Portola Announces Phase 3 ANNEXA-R Study of Andexanet Alfa and Factor Xa Inhibitor XARELTO Met Primary Endpoint With High Statistical Significance. Portola Globe Newswire. Availabe at: http://investors.portola.com/mobile.view?c=198136&v=203&d=1&id=2005429. Accessed September 20, 2015

• Cocchio, Craig. One Step Closer to Reversing Anti-Xa Inhibitors. Pharmacy Times. November 18, 2014. • Boehringer Ingelheim’s Investigational Antidote for Pradaxa Receives FDA Breakthrough Therapy Desgination. Available At: http://us.boehringer-

ingelheim.com/news_events/press_releases/press_release_archive/2014/06-26-14-boehringer-ingelheim-investigational-antidote-pradaxa-dabigatran-etexilate-mesylate-fda-breakthrough-therapy-designation.html. Accessed September 20, 2015

• Pollack C. Idarucizumab for Dabigatran Reversal. NEJM. 2015; 373:511-20. • Roberts I. The CRASH-2 Trial. Health Technol Assess. 2013 Mar; 17 (10):1-79. • Zahed R. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized control trial. Am J Emerg

Med 2013. 31 (9): 1389-1392• Jahadi Hosseini S. Comparison between topical and oral TXA in management of traumatic hyphema. Iran J Med Sci. 2014. 39: 178-83• Nuvvula S. Efficacy of TXA mouthwash as an alternative for factor replacement in gingival bleeding during dental scaling in cases of hemophilia: a

randomized clinical trial. Contemp Clin Dent. 2014 Jan. 5(1):49-53. • Dias J. et al. Use of TEG for Detection of NOACs. Arch Pathol Lab Med. 2015. 139: 665-673