2019 Pharmacy Education

Reversal of AnticoagulationCHS Pharmacy Education Series

ProCE, Inc.www.ProCE.com 1

2019 Pharmacy Education Series

May 15, 2019Reversal of Anticoagulation

Faculty Speakers:Jessica M. Rimsans, PharmD, BCPSHeather Weese, PharmD, MSHI, BCPS, BCPPS

Submission of an online post‐test and evaluation is the only way to obtain CE credit for this webinar

Go to www.ProCE.com/CHSRx

Print your CE statement of completion online

– Credit for live or enduring (not both)

Deadline: June 14, 2019

Pharmacists and Pharmacy Technicians: CE credit uploaded to CPE Monitor

– User must complete the “claim credit” step

Online Evaluation, Self-Assessmentand CE Credit

Attendance Code

Code will be provided at the end of today’s activity 2



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2019 Pharmacy Education Series

It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. None of the presenters have any relevant commercial or financial relationships to disclose.

Disclosure: The information contained in the presentation is for Community Health System employees and hospital affiliates and is not for external distribution and/or use. The presentation may contain information that is proprietary, confidential, or legally privileged or protected. It is intended only for the use of Community Health System employees and hospital affiliates. Do not deliver, distribute or copy the presentation and do not disclose its contents or take any action in reliance on the information it contains outside of Community Health Systems and hospital affiliates.

Please note: The opinions expressed in this activity should not be construed as those of the CME/CE provider. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include unlabeled indications. Use of drugs and devices outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature.

May 15, 2019Reversal of Anticoagulation

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CE Activity Information & Accreditation

ProCE, Inc. (Pharmacist and Pharmacy Technician CE)This CE activity is jointly provided by ProCE, Inc. and CHSPSC, LLC. ProCE is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number 0221‐9999‐19‐161‐L01‐P/T has been assigned to this knowledge‐based live CE activity (initial release date 5‐15‐19). This CE activity is approved for 2.0 contact hours (0.2 CEU) in states that recognize ACPE providers. This CE activity is provided at no cost to participants. Successful completion of the online post‐test and evaluation at www.ProCE.com/CHSRx is required to receive CE credit. CE credit will be uploaded to NABP/CPE Monitor. No partial credit will be given.

Funding:This activity is self‐funded through CHSPSC.

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Reversal of Anticoagulation

Jessica Rimsans, PharmD, BCPS

Hemostatic Antithrombotic Stewardship

Brigham and Women’s Hospital, Boston, MA

Community Health Systems & ProCE

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Conflicts of Interest

Speaker has no conflicts of interest

Disclosures

There will be off‐label and/or investigational

discussion

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Pharmacist Objectives

At the conclusion of this activity, participants will be able to:

1. Discuss the differences in bleeding profiles of the direct acting oral anticoagulants (DOACs) and vitamin K antagonists (VKAs).

2. Compare strategies to reverse anticoagulant‐induced life threatening bleeding or for emergency surgery.

3. Develop a periprocedural management plan for patients on oral anticoagulants (AC).

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Pharmacy Technician Objectives

At the conclusion of this activity, participants will be able to:

1. Understand the urgency of life threatening major bleeding.

2. List current available medications used to reverse bleeding caused by oral anticoagulants.

3. Describe how reversal agents such as PCC, idarucizumab, and andexanet are stored, prepared, and administered.

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DOACs vs Vitamin K Antagonists

• Proposed benefits of DOACs• rapid onset of action

• ease of administration

• overall less bleeding (less major bleeding, less ICH*)

• lack of routine laboratory monitoring required

• at least non‐inferior efficacy compared with VKAs

• However, spontaneous and traumatic bleeding events do occur requiring urgent/emergent reversal

*ICH: intracranial hemorrhage Barra M, et al. Am J Med. 2016;129, 1198‐1204.

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Major Bleeding Outcomes in NVAF Clinical Trials

Indicates increased bleeding with warfarin

Indicates increased bleeding with DOAC

Bleeding outcomes reported as DOAC vs warfarin (titrated to target INR 2‐3); % per year

Hellenbart E, et al. Vasc Health Risk Manag. 2017;13:325–342. NVAF: non‐valvular atrial fibrillation12



Real‐World Bleeding Data NVAF

• Large US insurance database (Optum)

• 3 propensity score matched cohorts comparing each DOAC to warfarin

• Major bleeding• Lower with apixaban & dabigatran

• Rivaroxaban equivalent

Yao X, et a. J Am Heart Assoc. 2016;5:e003725.

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Clotting Cascade

http://usmlewiki.org/index.php?title=Image:Coagulation_cascade.png

Factor XaInhibitorsRivaroxabanApixabanEdoxabanBetrixaban

Thrombin InhibitorsArgatrobanBivalirudinDabigatran

Heparin (IIa/Xa)Low molecular weight heparin (Xa/IIa)Fondaparinux (Xa)

Warfarin

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Coagulation Tests

Adock DM, et al. Thrombosis Research. 2015;36:7-12.

1Anti‐Xa assays with Heparin/LMWH standards can be used to exclude the presence of drug, but not to quantify drug level 2Drug‐specific anti‐Xa 3Includes HEMOCLOT assay 3If calibrated in laboratory using rivaroxaban standard. Limited data on Betrixaban, extrapolated from other anti‐Xa Inhibitors.

TT= thrombin time, aPTT = activated partial thromboplastin time, ECA = ecarin chromogenic assay, ECT = Ecarin clotting time

Clinical Scenario

Drug

Exclude Relevant

Anticoagulant Effect

Deter Over‐Anticoagulation

Monitor Drug Activity

Dabigatran TT aPTT, TT, ECA, ECT Dilute TT3, ECA, ECT

Rivaroxaban anti‐Xa1 PT3, Anti‐Xa2 Anti‐Xa2

Apixaban anti‐Xa1 Anti‐Xa2 Anti‐Xa2

Edoxaban anti‐Xa1 Anti‐Xa2 Anti‐Xa2

Betrixaban anti‐Xa1 Anti‐Xa2 Anti‐Xa2

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Patient Case

PATRICK G.71 year old man presenting to the ED with S/Sx ICH on apixaban

PRESENTATION

• Presents with a left facial droop, confusion and found to have a right basal ganglia IPH

• History obtained from son and wife: • At his baseline this am after awakening at 6am

• Awoke from a nap at ~10am with frontal HA

• Ate lunch and family returned home approximately 1hour later and noted patient with facial droop, incontinent of urine and had not taken afternoon meds (which is atypical for him)

• Noted he appears weaker on left, increased hesitancy with answering question and talking quietly

• No witnessed fall, cough, sob, chest pain, palpitations or fever

Height: 5’7”

Weight: 81.6 kg

BMI: 26.9 kg/m2

CrCl: 77mL/min

Current time: 1:05pm

PAST MEDICAL HISTORY• Multiple ischemic strokes (mild residual

deficits)• Atrial fibrillation on apixaban and aspirin• Type 2 diabetes• HTN• HLD

MEDICATIONS• apixaban 5mg twice daily• aspirin 81mg daily• atorvastatin 80 MG daily• hydrochlorothiazide 25mg daily• insulin glargine 20 units BID• insulin lispro 10 units AC plus slideing scale• lisinopril 20mg daily

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Patient Case

PATRICK G.71 year old man presenting to the ED with S/Sx ICH on apixaban

ED COURSE

• Review of Systems (notable) by PA• Neurological: Positive for facial asymmetry, speech difficulty, weakness and headaches.

Negative for light‐headedness.

• All other systems reviewed and are negative

• Neurology Exam• Worsening LLE weakness, new L facial and likely rest was deficient at baseline, suspect a

delta‐NIHSS of 3.

• CT shows an IPH, likely hypertensive with superimposed coagulopathy from both apixaban and aspirin

• Imaging• CT/CTA notable for basal ganglia hemorrhage

• Medication Dosing• Aspirin 81mg daily (last dose 7:30am)

• Apixaban 5mg BID (last dose 7:30am)

Height: 5’7”

Weight: 81.6 kg

BMI: 26.9 kg/m2

CrCl: 77mL/min

Current time: 3:05pm

TREATMENT PLAN• Based on presentation and time of last apixaban dose, should the patients

anticoagulation be reversed?• What agent should be used as 1st line?• What other options are available?• Other considerations? 17

Anticoagulation reversal in the setting of life threatening bleeding

Overview Approach

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General Principles

• Determine urgency of reversal

• Obtain information from patient or caregiver (if available)

• Non‐pharmacological measures• Discontinuation of drug (and confounding medications like antiplatelet agents)

• Estimate half‐life and duration of effect• Obtain appropriate baseline labs (do not wait for results to manage)

• Supportive measures• Mechanical pressure or surgical measures (EVD, evacuation)• Fluids, blood products / pro‐hemostatic agents, adjunctive agents (e.g. TXA, FFP)

• Manage comorbidities that could exacerbate bleeding (e.g. hypothermia, cirrhosis, acidosis)

• Drug removal

• Concentrated clotting factors

• Targeted reversal agentsTomaselli GF, et al. J Am Coll Cardiol. 2017. 70:3042‐67.

Piran S, et al. Blood. 2019;133(5):425‐435.

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Indications for Use of Reversal Agents

• Life threatening bleeding: critical space, or uncontrollable hemorrhage by conventional measures (eg: PRBC, FFP, topical hemostatics)

• hemodynamically unstable• clinically overt bleeding with a Hb drop of ≥2 g/dl or the need for 2+ units of PRBC transfusion

• Bleeding in closed space/critical organ:• ICH• Intraspinal• Intraocular• Pericardial• Pulmonary• Retroperitoneal• Intramuscular with compartment syndrome

• Need for urgent/emergent surgery that is associated with high risk of bleeding and cannot be delayed to allow for drug clearance

Levy JH: J Thromb Haemost. 2016 Mar;14(3):623‐7.

Not for use in those: • Epistaxis• Elective surgery• Intraluminal GIB• GIB controlled by supportive measures• High drug levels in absence of bleeding • Surgery that can be delayed to allow

drug clearance (1‐3 days)

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Major Bleeding – Critical Sites

Critical Site Potential Signs/Symptoms Potential Consequences

ICHUnusually intense headache, emesis, altered mental status, ”stroke‐like” symptoms – vision changes, numbness, weakness, aphasia, ataxia, vertigo, seizures

Coma, permanent neurologic dysfunction, death

Other CNSIntraocular: monocular eye pain, vision changes, blindnessSpinal: back pain, bilateral extremity weakness or numbness, bowel or bladder dysfunction, respiratory failure

Intraocular: permanent vision lossSpinal: permanent disability, paraplegia, quadriplegia, death

Cardiac tamponadeShortness of breath, tachypnea, pulsus paradoxus, Beck’s triad: hypotension, jugular venous distension, muffled heart sounds. Low voltage QRS complexes throughout EKG

Cardiogenic shock, death

Thoracic (hemothorax)Tachypnea, tachycardia, hypotension, decreased chest expansion, dullness to percussion and reduced breath sounds, diffuse opacification on supine chest X‐ray

Respiratory failure (intubation), cardiac arrest, death

Airway (including posterior epistaxis)

Hemoptysis, shortness of breath, hypoxia, profuse epistaxisRespiratory failure (intubation), cardiac arrest, death

Intra‐abdominal or RPHAbdominal pain, unexplained distension, back/flank/hip pain (RPH), tachycardia, hypotension

Femoral neuropathy (RPH), hypovolemic shock, death

Extremities (intramuscular or intraarticular)

Intramuscular: pain, swelling, pallor, paresthesia, weakness, diminished distal pulsesIntraarticular: joint pain, swelling, decreased range of motion

Intramuscular: compartment syndrome, paralysis, limb lossIntraarticular: irreversible joint damage

Tomaselli GF, et al. J Am Coll Cardiol. 2017. 70:3042-67.EKG = electrocardiogram

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Oral Anticoagulation Reversal Options

FDA Approved Options

• Idarucizumab for dabigatran reversal only

• Andexanet alfa for apixaban and rivaroxaban only

• 4PCC VKA‐reversal only

Off Label / Alternative Options

• 3PCC • 4PCC• aPCC (Factor VIII inhibitor bypassing activity)

• Recombinant activated factor VII• Plasmapheresis• Hemodialysis for dabigatran reversal only

• Activated charcoal

Also may use Vitamin K and Fresh Frozen Plasma (FFP) for Warfarin reversalVitamin K and FFP will not overcome/reverse DOAC effect

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Concentrated Clotting Factors

• Prothrombin Complex Concentrates (PCC)• Four factor PCC (4PCC)

• Contains non‐activated vitamin K‐dependent coagulation Factors II, VII, IX, and X and antithrombotic Proteins C and S* (and a small amount of heparin)

• Three factor PCC (3PCC)• Contains non‐activated factors II, IX, X and trace amounts of factor VII

• Requires concomitant administration of FFP for source factor VII

• Activated Prothrombin Complex Concentrates (aPCC)• Four factor aPCC

• Contains mainly non‐activated factors II, IX, X and activated factor VII

• Activated recombinant factor VII (rVIIa)• Contains only activated factor VII

Nutescu EA, et al. Am J Health Syst Pharm. 2013;70(21):1914‐29.

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Anticoagulation reversal in the setting of life threatening major bleeding

VKA Reversal

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Guideline Recommendations ‐ VKA Reversal

Frontera JA, et al. Crit Care Med 2016; 44:2251‐2257.Tomaselli GF, et al. J Am Coll Cardiol. 2017;70(24):3042‐3067.

Critical Care Guidelines2016

Expert Consensus Decision Pathway 2017

Recommend discontinuation of VKA if ICH is present/suspected Agreement

Recommend urgent reversal of VKA in patients with ICH (exceptions for risk vs benefit assessment*)

Agreement

Recommend administration of vitamin K

a.) Dose: 10mg IV x1 w/follow‐up INR

b.) If INR ≥ 1.4 within 23‐48 hrs, suggest redosing

Agreement

Not specifically addressed for ICH

Recommend 3PCC or 4PCC over FFP

a.) Recommend 4PCC over 3PCC

b.) PCC dosing should be weight based and vary according to admission INR and type of PCC used

Agreement

Guidance for INR/weight‐based dosing or low fixed‐dose option (1500 units

for ICH)

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Management of Warfarin‐Related Life Threatening Bleeding

• FDA approval 4PCC• Reversal of life threatening

bleeding or requiring surgery on patients taking warfarin

• Package label dosing: 25‐50 units/kg based on INR

• Off label fixed low dose: 1500 units for ICH (or 2000 units*)

• Risk of thromboembolic events is not clear

• Recommended dose = 10mg slow IV Push

• IV over PO

• Slower onset, but sustained effect

• Combination with 4PCC

Lubetsky A, et al. Arch Intern Med. 2003;163:2469‐2473.

Vitamin K4PCC (Kcentra®)

Other options include: 3PCC +/‐ FFP or rFVIIa if 4PCC not available

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Warfarin Reversal Agents

Nutescu EA, et al. Am J Health Syst Pharm. 2013;70(21):1914‐29.Frontera JA, et al. Crit Care Med. 2016; 44:2251–2257.

Hanke AA, et al. Br J Anaesth. 2013;110(5):764‐72.

Drug Onset of Effect Duration of Effect

Vitamin K (PO) 24 hours Days

Vitamin K (IV) 8‐12 hours Days

FFP Immediate post infusion 12‐24 hours

4PCC* Immediate post infusion 12‐24 hours

• Re‐dosing may be required based on INR post‐reversal and sustained decline in the 1st 24‐48 hours post ICH to prevent hematoma expansion

*Potentially higher thrombotic rate vs FFP (reported at 1.8%)

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4PCC Dosing for VKA Reversal – Variable dosing

Sarode R, et al. Circulation. 2013;128:1234‐124.

Baseline INR

4PCC dose

Plasma dose

2‐ < 425

units/kg10 mL/kg

4‐635

units/kg12 mL/kg

> 650

units/kg15 mL/kg

Max doses

5000 units

1500 mLs

• Phase IIIb, multicenter, open‐label, noninferiority trial, nonsurgical patients • Variable dosing based on presenting INR and patient weight

Outcomes4PCC(n = 98)

Plasma (n=104)

Difference (95% CI)

Effective Hemostatic Efficacy (No, %)

71 (72.4)

68 (65.4) 7.1 (‐5.8 to 19.9)

Rapid INR Reduction*

61 (62.2)

10 (9.6)52.6 (39.4 to

65.9)

Adverse Events

Thromboembolic Events

8 (7.8) 7 (6.4) N/A

Related thromboembolic Events

4 (3.9) 3 (2.8) N/A

Serious adverse events

32 (31.1)

26 (23.9) N/A

*INR ≤1.3 at 0.5 h after end of infusion

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4PCC Dosing for VKA Reversal– Fixed Dosing

• Low fixed‐dose options (ACC 2017 Guideline Recommendations)• 1,000 units for any major bleed, 1500 units for ICH

• Multiple evaluations of fixed dosing from 1000 units to 1500 units

• Retrospective analysis from University of New Mexico 2018

Astrup G, et al. J Thromb Thrombolysis. 2018;45:300–305.

Outcomes Result

INR ≤ 1.5 post 4PCC 74.3% (26/35)

INR ≤ 1.5 post 4PCC – initial INR > 5

60% (6/10)

INR ≤ 2.0 post 4PCC 100% (30/30)

Thromboembolic Events 0

• 37 patients reviewed• Fixed dose 1500 units; median 20 units/kg• Indication for reversal

• Emergent bleeding 78.4%• ICH 45.9%• GI 13.5%

• Urgent surgery 18.9%• Initial INR (median) = 3.06 (range 1.17 to > 16)• Concomitant Medications

• Vitamin K 81.1%• FFP 24.3%

One patient required 2nd dose of 4PCC 2 days after initial dose

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Dabigatran

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Guideline Recommendations ‐ Oral DTI Reversal


Cuker A, et al. Am J Hematol. 2019 Mar 27. [Epub ahead of print] Review.


Expert Consensus Decision Pathway

2017

AC Forum Consensus Document 2019

Recommend discontinuation of DTI when ICH is present or suspected

Agreement Agreement

Recommend obtain time and amount of last dose, renal function and medication interactions to estimate degree of anticoagulation

Agreement Agreement

Suggest activated charcoal (50g) to intubated ICH with enteral access or low risk for aspiration within 2 hours of ingestion

Agreement (within 2‐4 hours of

ingestion)

Agreement

Recommend idarucizumab (5g IV in 2 doses)

a.) dabigatran administered within 3‐5 half‐lives and no evidence of renal failureb.) renal insufficiency leading to drug exposure beyond 3‐5 half‐lives

Agreement Agreement

Suggest 4PCC (50 units/kg) or aPCC (50 units/kg) if ICH if idarucizumab is not available

Agreement aPCC 50 units/kg

Suggest redosing idarucizumab and/or hemodialysis if evidence of ongoing clinically significant bleeding

Not addressed Agreement

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Idarucizumab (Praxbind®)

• FDA Approved October 2015• Human monoclonal antibody fragment that binds free and thrombin‐bound dabigatran

• 300 x higher affinity for dabigatran than dabigatran has for thrombin

• Renally eliminated

• Indication• Emergency surgery / urgent procedures

• Life‐threatening or uncontrolled bleeding

• Dose• 5gm dose administered as 2.5gm x2 IV bolus within 15 minutes

• May require repeat dosing due to dabigatran Vd (rare)

• Cost – approximately $3500 per dose

Gm: grams; VD: Volume of distributionArbit B, et al. Int J of Cardiol. 2016;223: 244–250.

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RE‐VERSE AD Trial

• Design: Multicenter, prospective, open‐label study

• Objective: Does 5 grams idarucizumab reverse the anticoagulant effect of dabigatran

• Group A: Uncontrolled bleeding (n= 301)

• GI bleeding (n = 137, 45.5%)• ICH (n =98, 32.6%)

• Group B: urgent procedure (n = 202)

Pollack CV, et al. N Engl J Med. 2017;377:431‐441.33

RE‐VERSE AD Endpoints

• Median maximum percentage reversal of dabigatran was 100% by either ecarin clotting time (ECT) or dilute thrombin time (dTT)

• Group A: median time to the cessation of bleeding was 2.5 hours

• Group B: periprocedural hemostasis was assessed as normal in 93.4% of the patients

• At 90 days:

• Thrombotic events occurred in 6.3% Group A and 7.4% in Group B

• Mortality rate was 18.8% and 18.9% in Group A and Group B respectively

• No serious adverse safety signals

• 8 patients required 2nd dose of idarucizumab

Pollack CV, et al. N Engl J Med. 2017;377:431‐441.

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aPCC for Dabigatran ReversalStudy Patient Population Dosing and Outcomes

Engelbart JM, et al. 2019Safety and effectiveness of FEIBA for DOAC‐related hemorrhage reversal

• 42 patients with bleeding on rivaroxaban, apixaban, anddabigatran(n = 5)

• Median dose 30 units/kg *Protocolized 25‐50 units/kg • 71% overall had ICH (2 were on dabigatran)• 86% had no hematoma expansion s/p aPCC admin; 17% surgical

intervention • 10% (4) experienced TE complication• 10% (4) had hematoma expansion s/p aPCC and surgical intervention• 29% in hospital mortality

Dager W, et al. 2019Effect of low and moderate dose FEIBA to reverse major bleeding in patientson direct oral anticoagulants

• 64 patients with major bleeding on rivaroxaban, apixaban, anddabigatran(n = 16)

• 16 dabigatran patients • 29% ICH‐related bleeding• 12 Low dose ~ 10 units/kg, and 4 moderate dose ~ 25 units/kg• Six patients received idarucizumab; 1 patient required repeat FEIBA • 25% (n = 4) mortality in dabigatran group (2 received concomitant

idarucizumab)• 2 patients (12%) had a thrombotic event

Schulman S, et al. 2017Reversal of dabigatran associated major bleeding with APCC

• 14 patients with bleeding on dabigatran

• Prospective cohort study

• Median aPCC dose 4099 units, or 44 units/kg (Range 1828‐1525 units)• 5 patients had ICH (35%)• 4 patients required second dose 53 units/kg (Range 29‐69 units/kg) • 64% good hemostatic effectiveness, 36% moderate, 0% poor

• Similar in ICH subgroup• No thrombotic events at 30 days

Dager W, et al. 2016Urgent DOAC Reversal with Low or moderate dose FEIBA in major bleeding

• 45 bleeding patients, apixaban, dabigatranand rivaroxaban, 19 pt had ICH

• Low dose aPCC (mean 10.3 units/kg ) or moderate (mean 24 units/kg ) • 6 patients died prior to discharge• Follow‐up imaging did not reveal any clinically concerning active

bleeding or hematoma expansion• 1 pt had expansion, aPCC dose of 50 units/kg

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Apixaban & Rivaroxaban

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Guideline RecommendationsOral Xa Inhibitor Reversal


Cuker A, et al. Am J Hematol. 2019 Mar 27. [Epub ahead of print] Review.



Recommend discontinuation of factor Xa inhibitor when ICH is present or suspected

Agreement

Recommend obtain time of last dose of factor Xa inhibitor and medication interactions to estimate anticoagulation exposure

Agreement


Agreement (within 2‐4 hours of ingestion)

Suggest 4PCC (50 units/kg) or aPCC (50 units/kg) if ICH within 3‐5 terminal half‐lives of drug or in the context of liver failure

Administer 4PCC 50 units/kg IV

If 4PCC not available, consider aPCC 50 units/kg IV

Suggest 4PCC or aPCC over rFVIIa due to lower risk of thromboembolic events

Not addressed

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Guideline RecommendationsOral Xa Inhibitor Reversal




Recommend discontinuation of factor Xa inhibitor when ICH is present or suspected

Agreement

Recommend obtain time of last dose of factor Xa inhibitor and medication interactions to estimate anticoagulation exposure

Agreement


Agreement (within 2‐4 hours of ingestion)

Suggest 4PCC (50 units/kg) or aPCC (50 units/kg) if ICH within 3‐5 terminal half‐lives of drug or in the context of liver failure

Administer 4PCC 50 units/kg IV

If 4PCC not available, consider aPCC50 units/kg IV

Suggest 4PCC or aPCC over rFVIIa due to lower risk of thromboembolic events

Not addressed

2018 ACC Updated Guidance for Anticoagulation Reversal

First line (when available) for apixaban and rivaroxaban Andexanet alfa

2019 AC Forum Guidance Document

First line (when available) for apixaban and rivaroxaban Andexanet alfa

If not available, 4PCC Fixed Dose 2000 units for life threatening bleeding

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Andexanet Alfa (Andexxa®)

Coagulation factor Xa (recombinant), inactivated‐zhzo (Andexxa®), is a recombinant modified human factor Xa decoy protein that is catalytically inactive but that retains the ability to bind factor Xa inhibitors in the active site with high affinity

Andexxa (andexanet alfa) prescribing information. Portola Pharmaceuticals. 2018.

FDA approved May 2018 Only for life threatening bleeding with Rivaroxaban and Apixaban

Different dosing strategy for agent, dose, and time since last dose

Availability Initially restricted to early supply program

Gen2 product approved Dec 2018 expanded to national distribution 39

ANNEXA 4 Trial – Design and Baseline

Characteristic SafetyPopulation(N = 352)

Primary indication AF 80%

Primary Xa inhibitor

Rivaroxaban 36%

Apixaban 55%

Enoxaparin 6%

Edoxaban 3%

Site of bleeding ICH 64%

Connolly SJ, et al. N Engl J Med. 2019 [Epub ahead of print].

Pharmacodynamic half‐life is approximately 1 hour; requires bolus plus infusion for sustained effect

Included patients taking Apixaban, rivaroxaban, enoxaparin, edoxabanExcluded PCC, aPCC

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ANNEXA 4 Trial –Outcomes

Co‐Primary Outcome: Effective Hemostasis at 12 hours Post andexanet alfa

Number of Major BleedsAdjudicated

Excellent or Good Hemostasis (n, %)

95% CI Excellent Hemostasis (n, %)

Good Hemostasis (n, %)

249 204 (82%) 77% ‐ 87% 171 (84%) 33 (16%)


Outcome Total (n, %) < 6 days from andexanet

administration

6‐14 days from andexanet

administration

15‐30 days from andexanet

administration

Thrombotic events 34 (10) 11 11 12

Mortality within 30 days

49 (14) 8 21 20

ICH – 80% excellent or good efficacy (hematoma volume expansion </= 35%)Compared with GI bleeding with 85% with excellent or good efficacy

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ANNEXA 4 Trial – Efficacy Outcomes

• Apixaban • 92% reduction in anti‐xalevels from baseline to the end of the bolus

• Sustained until 2‐4 hours post end of infusion and then rebounded

• Rivaroxaban • 92% reduction in anti‐xalevels from baseline to end of the bolus

• Sustained until 2‐4 hours post end of infusion and then rebounded


There was no significant relationship between reduction in anti‐factor Xa activity and hemostatic effectiveness

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Prothrombin Complex Concentrate Products

Thorsten et al.,Stroke.2017;48:1432–1437

4PCC (Kcentra®)

aPCC(FEIBA ®)

Contents Dosing Potential Benefit

Contains inactivated form of

factor II,IX,X and activatedfactor VII

Guidelines 50 units/kg ICH

Studies• Low Dose 10‐20 units/k

Majority 25‐50 units/k

Early studies in healthy volunteers show faster time to thrombin generation

Lower doses aid in less TE risk

Inactivated coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S, AT and heparin

Guidelines vary from 2000 fixed dose to 50 units/k

Studies• Fixed dose 2,000 units• Majority 25‐50 units/k

Inactivated factor VII mayresult in less TE risk

“Balanced product” may also result in lower TE risk

Onset 5‐15 minutes Duration: 12‐24 hours + based on half‐lives of clotting factors

K: kgTE: thromboembolic

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4PCC to Reverse Xa InhibitorsStudy Patient Population and Dosing Dosing and Outcomes

Delony L, et al. 2019 SCCM abstract4PCC Major Bleeding Oral FXai

• 31 patients received 4PCC for apixaban or rivaroxaban

• 58% ICH• Dose 25 units/kg (35%) or 50 units/kg (55%)

• Hemostatic effectiveness 81%• No thrombotic events during hospital stay• 16% mortality from major bleeding• 2 ICH ineffective hemostasis (11%)

Santibanez M, et al. 2018

Tolerability and effectiveness 4F‐PCC for warfarin and non‐warfarin reversals

• 165 received 4PCC for major bleed, 32 patients on rivaroxaban or apixaban

• 64.2% of major bleeds were ICH (106 patients)

• 88.1% DOAC pts received 25 units/kg

• Hemostatic effectiveness 68% for major bleed; 81.3% in DOAC major bleed patients; 77.9% for ICH

• Thrombotic events occurred in 8.5% major bleed patients; 5.6% of DOAC major bleed patients

• Major bleed mortality for major bleeding 26.4%

Tao J, et al. 2018Safety of 4F‐PCC for emergent reversal of Fxai

• 43 patients on rivaroxaban & apixaban for emergency surgery, inv. procedures major bleeding

• ICH 32.7%• Doses ranged 25‐50 u/kg (51.2% 25 units/kg)

• Hemostatic efficacy determined by treating physician

• 6.9 % (3pt) continued to have active bleeding; 2 died of hemorrhage

• PT‐INR returned to normal limits in 60%• 1 patient (2%) thromboembolism (UE DVT) post

ICH

Schulman S, et al. 2018PCC for Major Bleeding on Factor Xa Inhibitors: Prospective Cohort

• 66 patients on rivaroxaban (56%) or apixaban(44%) with major bleeding

• ICH 55% • 4F‐PCC fixed 2000 units

• Hemostatic effectiveness ‘good’ in 65%, moderate 20%

• ICH: hemostatic effectiveness ‘good’ in 67%, moderate 17%

• Safety: 9 deaths (14%), 5 thromboembolism (8%)

Majeed A, et al. 2017Mgmt of rivaroxaban or apixaban major bleeding w/PCC: cohort study

• 84 bleeding patients (39 apixaban, 45 rivaroxaban)

• ICH 70%• Median dose 2000 units (1500‐2000u); 25

units/kg

• Hemostatic effectiveness 69%, 73% in ICH• 61.5% of ineffective hemostasis was in ICH• 32% mortality (27 pts, 74% were ICH)• 4% thromboembolism (3 pts)

Arachchillage et al, 2019• Major bleeding (ICH/GIB) on Fxai (n=80)

• 4PCC 2000 units (range 1000‐4500 units)• Effectiveness: ~75% for FXAi, no difference in

rebleeding

Sin et al, 2016• Major bleeding (11) and surgery (3) on Fxai (n=14)

• 4PCC ~25 units/kg • Effectiveness: 100% rivaroxaban, 66.7% apixaban

44



aPCC to Reverse Xa InhibitorsStudy Patient Population Dosing and Outcomes

Dager W, et al. 2019Effect of low and moderate dose FEIBA to reverse major bleeding for DOACs

• 64 patients; apixaban (20), rivaroxaban (28)

• 38 low dose (10 units/kg)• 26 moderate dose (24.3

units/kg)• ICH 29%

• 6 patients received a 2nd dose (2 ICH 50 units/kg)• 5 thromboembolic events (8%); 3 LD and 2 HD• 9 patients died within 30 days (14%)• 12 of 28 ICH patients received low dose

Engelbart JM, et al. 2019Safety and effectiveness of FEIBA for DOAC‐related hemorrhage reversal

• 42 patients with bleeding on rivaroxaban (55%), apixaban (33%), and dabigatran (12%)

• 71% ICH• Median dose 30 units/kg

*Protocolized 25‐50 units/kg

• 86% had no hematoma expansion s/p aPCC administration; 17% surgical intervention

• 10% (4) experienced thromboembolism• 10% (4) had hematoma expansion s/p aPCC and surgical

intervention• 29% in hospital mortality

Mao G, et al. 2017FEIBA for reversal of TSAOC in life threatening ICH

• 11 patients with ICH on apixaban/rivaroxaban

• aPCC 20 units/kg within 2 hr of arrival

• INR and aPTT normalized s/p aPCC• 55% stable head CT s/p aPCC; 36% had worsening; 18% had

surgical evacuation • 27% in hospital mortality• 2 thromboembolic events (18%)

Dager W, et al. 2016Urgent DOAC Reversal with Low or moderate dose FEIBA in major bleeding

• 45 patients, apixaban, dabigatran and rivaroxaban, 19 pt had ICH

• Low dose aPCC (mean 10.3 u/k) or moderate (mean 24 u/k)

• 6 patients died prior to discharge• Follow‐up imaging did not reveal any clinically concerning

active bleeding or hematoma expansion• 1 pt had expansion, aPCC dose of 50 u/kg

45

Andexanet Alfa or 4PCC for Reversal of Bleeding Associated with Xa‐inhibitors

Study ANNEXA‐4 (n=67) Majeed et al 2017 (n=84) prospective

Schulman et al 2018 (n=66) prospective

Reversal agent Andexanet alfa 4PCC 4PCC

Age (years) 77.1±10.0 75.0±10.9 76.9±10.4

ICH 67% 70% 55%

Time since last dose(hours)

R 12.3 (5.1)A 12.1 (4.6)

12.5 (9‐16) 16.9 (12‐21)

Effectiveness for CNS bleeds excellent or good

204 (82%) 43 (73%) 25 (76%)

Thromboticevents

34 (10%) 3 (4%) 5 (8%)

Death 49 (14%) 27 (32%) 9 (14%)

Trial of Andexanet in ICH Patients Receiving an Oral Fxai , comparing andexanet to standard of care 46



Getting the Medication to the Patient

Patient arrives

Situation assessed, medication history, last dose, labs

Decision to treat

Correct medication and dose ordered

Pharmacist reviews and processes the order

Pharmacist alerts technicians of the medication processed to be started in production

Medication delivered immediately upon completion to patient for administration

Medication infused

Andexanet alfaaPCC4PCC

Idarucizumab

Utilize multidisciplinary institution developed

guidelines

47

Storage & Inventory Management

• Store blood products in appropriate temperature• Ensure Omnicell/Pyxis are re‐stocked if stored

• 500 unit vials +/‐ 1000 unit vials

• Stored in fridge or at room temperature

• Monitoring of inventory • Consignment • Auto‐renewal ordering• Set PAR for high‐use products• Dedicated pharmacist to manage inventory of factors

48



Preparation & Administration Considerations

• PCC• Locating the correct product based on FIX components (rounding vial sizes)• Bedside push or in one IV infusion bag,• Administer with infusion smart pump

• Idarucizumab• Locating the vials • Bedside push

• Andexanet• Availability• Reconstitute in one IV bag vs. two• 100mg vials vs. 200mg vials (only takes ~30 minutes)

• 200mg vials are in a box of four: 5 vials for low dose, 9 vials for high dose

• Documenting waste appropriately• Given with an infusion smart pump

49

Periprocedural Anticoagulation Management

50



Guideline Recommendations – 2017 ACC

General Approach to Management:

• Estimate thromboembolic risk• Different registries exist to aid (eg: NVAF vs.

Valves)

• Estimate bleeding risk• Dependent on bleed and surgical approach as

well as patient specific characteristics (eg: age, renal or hepatic dysfunction)

• Determine timing of anticoagulant interruption

• Determine whether to use IV anticoagulant bridging

Picture from: Doherty JU, et al. J Am Coll Cardiol. 2017 Feb 21;69(7):871‐89851

Guideline Recommendations – DOAC

• Low risk procedures• Continue DOAC

• Time procedure at ‘trough’

• Moderate to High risk procedures• Duration of hold dependent on CrCl and intermediate or high bleed risk

• Restarting DOAC post procedure • No bridge required for DOACs

• May start with a short acting agent 1st

such as CI UFH monitor for hemostasis

CI UFH: continuous infusion unfractionated heparin

Doherty JU, et al. J Am Coll Cardiol. 2017 Feb 21;69(7):871‐89852



Guideline Recommendations – VKA

• Low risk procedures• Perform uninterrupted on therapeutic

warfarin

• Moderate to High risk procedures• Hold warfarin therapy

• Decide whether to bridge?

• To bridge or not to bridge?• All depends on Chads2Vasc and recent event

of TIA, Stroke, SSE in previous 3 months

Doherty JU, et al. J Am Coll Cardiol. 2017 Feb 21;69(7):871‐89853

Guideline Recommendations – Bridging

Chads2Vasc 5‐6 or prior thrombotic event >3 months: CONSIDER BRIDGE

Chads2Vasc >6 or prior thrombotic event within 3 months & no maj bleeding = BRIDGE Doherty JU, et al. J Am Coll Cardiol. 2017 Feb 21;69(7):871‐898

54



PAUSE Trial• The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study

• Prospective study of 3,000 NVAF patients (23 sites) undergoing elective procedures requiring interruption to AC therapy

• 33.5% high bleeding risk surgery/procedure

• 1257 apixaban, 1082 rivaroxaban, 668 dabigatran

• Strategy for holding AC resulted in:

• minimal or no residual DOAC level at the time of surgery

• low rates of perioperative major bleeding (<2%)

• low rates of acute thrombotic events (<1%)

Thromb Haemost. 2017 Dec;117(12):2415-242455

Conclusions

• Regardless which reversal agent is given, life threatening major bleeding is associated with high morbidity and mortality.

• When considering anticoagulation reversal, decide if appropriate, and obtain a thorough patient history including OAC/last dose, evaluate risk of bleeding vs risk of thrombosis, get appropriate labs.

• Guideline Reversal Recommendations: • VKA reversal: 4PCC & IV Vitamin K

• Oral DTI reversal: Idarucizumab aPCC 25‐50 units/kg (lower doses observed in the literature)

• FXai inhibitor Reversal: Andexanet alfa 4PCC 2000 units, 4PCC/aPCC 25‐50u/kg

• ALL patients on OAC are at increased risk for thromboembolic events at baseline due to underlying etiology for anticoagulation.

• Re‐initiation of oral anticoagulation should be strongly considered when appropriate (IV or PO)

• Most patients requiring surgery do not require IV AC bridging.• Only bridge VKA patients if high Chads2Vasc or recent thrombotic events

• PAUSE trial has shown positive outcomes for both bleeding and thrombosis in those receiving DOACs

56




Thank you for your time and attention.

57


Jessica Rimsans, PharmD, BCPS

Hemostatic Antithrombotic Stewardship

Brigham and Women’s Hospital, Boston, MA

Community Health Systems & ProCE

58



Anticoagulation Reversal – CHS Resources and Recommendations

Heather Weese, PharmD, MSHI, BCPS, BCPPS

Senior Director, Pharmacy Services

59

Conflicts of Interest

Speaker has no conflicts of interest

Disclosures

There will be off‐label and/or investigational

discussion

60



Learning Objectives

• Describe and apply the CHS resources available to support anticoagulation reversal strategies

61

CHS Resources Available• Adult Anticoagulant/Antiplatelet Reversal Protocol

– Order set

• Andexxa® (andexanetalfa) Toolkit

• Anticoagulant Management Toolkit– National Patient Safety Goal for Anticoagulant Therapy

62



Adult Anticoagulant/Antiplatelet Reversal Protocol

• Provides guidance and evidence‐based support for reversal or management of bleeding complications

• Includes:– Adverse Drug Event reporting requirements– Critical Bleeding Management Flowchart– Guidance for Reversal of:

• Vitamin K Antagonists• Heparin • Low Molecular Weight Heparin and Pentasaccharides• Thrombolytics• Direct Thrombin Inhibitors• Factor Xa Inhibitors• Antiplatelets

63

Format for RecommendationDrug Class Being Reversed

Recommended reversal agents and important information

64



Format for Recommendation

• Table with Considerations, Management and Monitoring recommendations:

65

Protocol Location

• Legacy:

– Clinical Pharmacy ‐> Clinical Resources ‐> Protocols ‐> Anticoag Reversal Protocol

• CHS14:

– Clinical Protocols and Guidelines ‐> AnticoagReversal Protocol

66



Order Set

• Anticoagulant Reversal, Adult

• Organized by drug with appropriate reversal agents, doses, and routes listed

• Guidance for choosing the most appropriate reversal agent is also provided

*entire order set not represented67

Andexxa® (andexanet alfa) Toolkit

• Supports the use of Kcentra as the preferred product over Andexxa for the reversal of rivaroxabanand apixabanassociated bleeding

68



Toolkit Highlights

• Efficacy– Andexxa:

• Healthy volunteers (ANNEXA‐A and ANNEXA‐R)

• Patients with acute major bleeding (ANNEXA‐4)

– Kcentra:• Patients with acute major bleeding:

– Hemostasis

– Hemorrhage progression

• Safety– Thromboembolic complications

69

CHS Strategy

• Kcentra will be recommended as the preferred product available for urgent reversal of factor Xa inhibitor associated bleeding

– FEIBA – second line if Kcentra unavailable

70



Rationale

• Currently available literature on Andexxa® (andexanet alfa) does not examine outcomes data and the current published study in acute bleeding is limited to a single study of 254 patients for efficacy evaluation.

• Current study of andexanet alfa does not include an active comparator such as 4F‐PCC.

• Currently available literature concerning safety (ANNEXA‐4) identifies a 10% risk of thrombotic events including myocardial infarction, stroke, and venous thromboembolism in patients who have received andexanet alfa (34 out of 352 patients).

• Cost of Andexxa® therapy is substantial with an initial acquisition cost of up to $55,000 and a cost of between $24,750 and $49,500 per treatment regimen.

• Exclusion of Andexxa® from formulary is widespread with many other hospitals, including large, academic medical centers and not‐for profit and for‐profit health system electing to not stock Andexxa® at this time.

• Literature regarding comparative agents in similar patient populations is inconclusive regarding the superiority of Andexxa® over traditionally recommended therapies.

71

Who isn’t stocking

• States and Major Medical Centers

• No major medical centers in:

– Alabama

– Alaska

– New Mexico

– Tennessee

72



Toolkit Location

• Legacy:

– Clinical Resources ‐> Clinical Initiatives ‐> Andexxa(andexanet alfa)

• CHS14:

– Formulary Resources ‐> Cardiovascular ‐> AndexxaToolkit

73

Anticoagulation Management Toolkit

• Provides evidence‐based guidance for anticoagulant use– Direct‐acting oral anticoagulants (dabigatran, apixaban, edoxaban, rivaroxaban)

– Warfarin

– Parenteral anticoagulants (heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin)

• In depth recommendations for – Perioperative management

– Transitioning between anticoagulants

74



Toolkit Location

• PENDING APPROVAL FROM CLINICAL PHARMACY COUNCIL

75

Anticoagulation Reversal – CHS Resources and Recommendations



76



77

Disclosure: The information contained in the presentation is for Community Health System employees and hospital affiliates and is not for external distribution and/or use. The presentation may contain information that is proprietary, confidential, or legally privileged or protected. It is intended only for the use of Community Health System employees and hospital affiliates. Do not deliver, distribute or copy the presentation and do not disclose its contents or take any action in reliance on the information it contains outside of Community Health Systems and hospital affiliates.



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