Transcript Reversal - Squarespace

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.
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
Increased risk of drug induced bleeding:
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> 65 YO
< 50 kg
Renal dysfx
Liver dysfx
Prior hemorrhage
Stroke Hx
PUD
ETOH abuse
High fall risk
Meds: AC, Antiplatelets, others
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/TraumaFibrinogen/D-Dimer
• PT/PTT Mixing
study
• Factor deficiency
• Thromboelastogra
m (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
TXA
Trauma – Roberts 2013
CRASH-2
Epistaxis – Zahed 2013
Hyphema – Jahadi Hosseini 2014
Gingival – 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 replacement
1:1:1 > 1:1:2
Less exsanguination, more hemostasis
No difference in transfusion complications
H.E.M.O.R.R.H.A.G.E.
• Help
• Initial consults
• F/U w/ consults
• Poison Control
• 1-800-2221222
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:
Drug
Half-life
Asa < 300mg
Asa Overdose
<3 hours
15-30 hours
• ticagrelor – 30% LESS platelet inhibition 2.5 days after discontinuing
Clopidogrel parent
• dipyridamole, NSAIDs, SSRIs
Active metab
• 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
6 hours
< 1 hour
Prasugrel active
metab
~7 hours
Ticagrelor parent
Active metab
~7 hours
~9 hours
Vorapaxar parent
Active 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 cases
Half-life
Duration
Metabolism
Elimination
Enoxaparin
4.5-7h
~12h
Hepatic
Renal
Dalteparin
2-5h
>12h
Hepatic & RES
Renal
Factor Xa Inhibitor
• Fondaparinux
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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 510mg 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 FFP
4F-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&S
Set 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, transfusionassociated 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?
• Drug removal
Imminent risk of death or disability?
Anti-Xa level?
• 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
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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
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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%)
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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.boehringeringelheim.com/news_events/press_releases/press_release_archive/2014/06-26-14-boehringer-ingelheim-investigational-antidote-pradaxa-dabigatranetexilate-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