The ED Pharmacists is IN: Anticoagulant Reversal Agents and other FAQs

By: DeAngelo Price, PharmD, BCPS, BCCCP

Emergency Medicine Clinical Pharmacist

Disclosures

Learning Objectives

• List resources for drug dilutions

• Discuss medications with unique mixing procedures

• Describe the different types of anticoagulation reversal agents commonly used in the emergency department

• Compare common practice with best practice of IV push

Learning Objective 1: List resources for drug dilutions

Definitions

• Tertiary Literature

• Summaries or condensed versions of materials

• Usually with references to primary or secondary sources

• Good place to look up facts or get a general overview of a subject

• Secondary Literature

• Summarizes and synthesizes primary literature

• Usually broader and less current than primary literature

• Primary Literature

• Original research and/or new scientific discoveries

• Often includes analysis of data collected in the field or laboratory

Examples

• IV Red Book

• Package Inserts

• Micromedex

• Clinical Pharmacology

• LexiROM

• www.globalrph.com

• Drug Information Handbook

• Original Research Papers

Learning Objective 2: Discuss medications with unique mixing

procedures

Patient Case: Alteplase

• Patient DP is a 64 y/o male who is brought into the ER for stroke like symptoms. Patient NIHSS is 24 and CT came back negative for hemorrhagic stroke. After speaking with the Stroke team, they recommend for alteplase. Patient has no contraindications for the drug and patient is weighed at 110 kg.

Poll Question 1

• What would be the dose (Bolus + Infusion) for patient DP?

• A. 9mg Bolus + 81mg Infusion

• B. 9.9mg Bolus + 89.1mg Infusion

• C. 81mg Bolus + 9mg Infusion

• D. 89.1mg Bolus + 9.9mg Infusion

Demonstration

Patient Case: Kcentra

• Patient CM is a 55 y/o female who is brought into the ER comatose. Family members stated that during dinner, she was complaining of a very severe HA and all of a sudden pass out. Husband states that she only takes warfarin for A.Fib. Lab is significant for elevated INR (13) and imagining shows that the patient has a severe intracranial bleed. Neurosurgery recommends Kcentra before getting the patient into the OR. Patient weighs 50kg.

Poll Question 2

• True or False: Kcentra is less concentrated than FFP

• A. True

• B. False

Demonstration

Patient Case: Crofab

• Patient AR is a 23 y/o male who is brought into the ER after getting bitten by a snake at Traders Joe. The bite was on the patient’s right ankle and the snake was identified as a copperhead. Bite wound looked moderately-severe. Poison control recommended Crofab for this patient.

Poll Question 3

• True or False: Dosing of CroFab is based off patient’s weight

• A. True

• B. False

Demonstration

Patient Case: CyanoKit

• Patient AB is 27 y/o male who was brought to the ER pulseless (PEA). Patient was intubated and ACLS was initiated for the patient. EMS stated that there was a bottle of cyanide next to the patient’s bottle at the scene. Poison control recommended CyanoKit (Hydroxocobalamin).

Poll Question 4

• Hydroxocobalamin makes _______ when combined with cyanide

• A. Vitamin B1

• B. Vitamin B6

• C. Vitamin B12

• D. Vitamin C

Demonstration

Learning Objective 3: Describe the different types of

anticoagulation reversal agents commonly used in the emergency department

List of Reversal Agents

• Protamine

• Phytonadione (Vitamin K)

• Idarucizumab (Praxbind)

• Prothrombin Complex Concentrate (PCC)

• Andexanet Alfa (Andexxa)

Protamine

• MOA: Binds to heparin and forms a stable salt = Inactivates heparin

• Use: Reversal of UFH and LMWH

• Side effects: Hypotension, bradycardia, dyspnea, or anaphylactic reactions with rapid administration

• Monitoring: aPTT

• Special Consideration: If hypersensitive: Pretreat with corticosteroids and antihistamines. Max single dose is 50mg

Protamine

Time since IV UF

administration

Protamine dose per 100 units UFH

< 30 min 1 mg

30-60 min 0.75 mg

60-120 min 0.5 mg

> 120 min 0.375 mg

> 180 min Protamine is not necessary

Time since LMWH

administration

Protamine dose per 1 mg of

LMWH

< 8 hours 1 mg

8-12 hours 0.5mg

> 12 hours Protamine may not be

necessary. Consider in renal

dysfunction

Phytonadione (Vitamin K)

• MOA: Provides the necessary substrate to synthesize specific coagulation factors (II, VII, IX, and X) blocked by warfarin

• Use: Reversal of Warfarin

• Side effects: Anaphylactiod reaction with intravenous administration (incidence is only 3 per 10,000 doses). Reducing the infusion rate help reduce risk

• Monitoring: INR, BP, Active Bleeding

• Special Consideration: Avoid Subq and IM administration

Phytonadione (Vitamin K)

Idarucizumab (Praxbind)

• MAO: Humanized monoclonal antibody fragment (Fab) that binds andsequesters dabigatran

• Monitor: Signs and symptoms of hemostasis or thrombosis

• Dosing:

• 5 g vial (typically two separate vials)

• IV Push: Inject 5 grams

• Infusion: Hang both vials and administer 5 grams as two consecutive infusions no later than 15 minutes apart

Andexanet Alfa (Andexxa)

• MAO: Binds and sequesters Factor Xa inhibitors, inhibits Tissue Factor pathway

• Monitor: Signs and symptoms of hemostasis or thrombosis

Timing of last DOAC

DOAC Last Dose < 8 hours or Unknown ≥ 8 Hours

Apixaban (Eliquis) ≤ 5mg Low Dose

Low Dose> 5mg/unknown High Dose

Rivaroxaban (Xarelto) ≤ 5mg Low Dose

>10mg/ unknown High Dose

Low Dose : 400mg IV Bolus followed by 4mg/minute IV infusion for up to 120 minutes

High Dose: 800mg IV Bolus followed by 8mg/minute IV infusion for up to 120 minutes

Prothrombin Complex Concentrate (PCC)3Factor or 4 Factor

• MOA:

• 3F: Replaces coagulation factors II, IX, and X

• 4F: Replaces coagulation factors II, VII, IX and X and protein C and S

• Use: Severe, life –threatening bleeds for warfarin and DOACS (off label)

• Dosing: Weight/INR Based, Fixed Dosing

• Contraindications: hypersensitivity to concentrate, history of heparin induced thrombocytopenia

• US Boxed Warning: May predispose the patient to thromboembolic complications

Learning Objective 4: Compare common practice with best

practice of IV push

Common Practice Issues of IV Push

• Lack of Patient Information

• Lack of Drug Information

• Communication of Drug Information

• Drug Labeling, Packaging, and Nomenclature

• Drug Storage, Stock, Standardization, and Distribution

• Device Use

• Environment, Staffing, and Workflow

• Staff Education and Competency

• Risk Management and Quality Improvement Challenges

Best Practices of IV Push Medications

• 1. Acquisition and Distribution of IV Push Medications

• 2. Aseptic Technique

• 3. Clinical Preparation

• 4. Labeling

• 5. Clinician Administration

• 6. Drug Information Resources

• 7. Competency Assessment

• 8. Error Reporting

Acquisition and Distribution of IV Push Medications

• 1.1: To the greatest extent possible, provide IV Push medications in a ready-to-administer form

• 1.2: Use only commercially available or pharmacy prefilled syringes of appropriate IV solution to flush and lock vascular access devices

Aseptic Technique

•2.1: Use aseptic technique when preparing and administering IV push medications, flush/locking solutions, and other parenteral solutions administered by direct IV injection.

Clinical Preparation

• 3.1: Withdraw IV push medications from glass ampules using a filter needle or straw

• 3.2: Only dilute IV push medications when recommended by the manufacturer, supported by evidence in peer-reviewed biomedical literature, or in accordance with approved institutional guidelines.

• 3.3: If dilution or reconstitution of an IV push medication becomes necessary outside of the pharmacy sterile compounding area, perform these tasks immediately prior to administration in a clean, uncluttered, and functionally separate location using organization-approved, readily-available drug information resources and sterile equipment and supplies

Clinical Preparation

• 3.4: Provide instructions and access to the proper diluent when reconstitution or dilution is necessary outside of he pharmacy sterile compounding area.

• 3.5: Do not withdraw IV Push medications from commercially available, cartridge-type syringes into anther syringe for administration

• 3.6: Do not dilute or reconstitute IV push medications by drawing up the contents into a commercially available, prefilled flush syringe or 0.9% sodium chloride

• 3.7: When necessary to prepare more than one medication in a single syringe for IV push administration, limit preparation to the pharmacy

• 3.8: Never use IV solutions in containers intended for infusion, including mini bags, as common source containers to prepare IV flush syringes or to dilute or reconstitute medications for one or more patients in clinical care areas

Labeling

• 4.1: Appropriately label all clinician-prepared syringes of IV push medications or solutions, unless the medication or solution is prepared at the patient’s bedside and immediately administered to the patient

• 4.2: Provide clinical units with blank or printed, ready-to-apply labels, including sterilized labels where needed, to support safe labeling practices

• 4.3: Immediately discard any unattended, unlabeled syringes containing any type of solution

• 4.4: Never pre-label empty syringes in anticipation of use

Clinical Administration

• 5.1 Perform an appropriate clinical and vascular access site assessment of the patient prior to and following the administration of IV push medications

• 5.2 Unless its use would result in a clinically significant delay and potential patient harm, use barcode scanning or similar technology immediately prior to the administration of IV push medications to confirm patient identification and the correct medication

• 5.3 Administer IV push medications and any subsequent IV flush at the rate recommended by the manufacturer, supported by evidence in peer-reviewed biomedical literature, or in accordance with approved institutional guidelines. Use an appropriate volume of the subsequent IV flush to ensure that the entire drug dose has been administered

Clinical Administration

• 5.4: Assess central line patency using at minimum, a 10 mL diameter-sized syringe filled with preservative-free 0.9% sodium chloride. Once patency has been confirmed, IV push administration of the medication can be given in a syringe appropriately sized to measure and administer the required dose

• 5.5 When administering IV push medications through an existing IV infusion line, use a needleless connector that is proximal to the patient, unless contraindicated in current evidence-based literature, or if the proximal site is inaccessible for use, such as during a sterile procedure

Drug Information Resources

• 6.1: Standardized, facility-approved IV push medication resources are readily available at the point of care to guide the safe practice of IV push medication administration. Resources should include any special considerations for the preparation and administration of IV push medications and for unique practice locations where medications may be administered IV push to ensure effective patient monitoring

Competency Assessment

• 7.1: Competency assessments for IV push medication preparation and administration are standardized across disciplines within healthcare organizations and validated through an initial assessment and on an ongoing basis.

Error Reporting

• 8.1: Report adverse events, close calls, and hazardous conditions associated with IV push medications internally within the healthcare organizations as well as in confidence to external safety organizations such as ISMP for shared learning

• 8.2: Use internal and external information about adverse events, close calls, and hazardous conditions associated with IV push medications for continuous quality improvement

References

• Institute for Safe Medication Practices. Some I.V. medications are diluted unnecessarily in patient areas, creating undue risk. ISMP Medication Safety Alert! 2014;19(12):1-5

• Konstantinos NA and Hylek EM. Who, when and how to reverse non-vitamin K oral anticoagulants. J Thromb Thrombolysis. 2016;41 (2): 253-72

• Pollack CV, Reilly PA, Ekelboom J, et al. Idarucizumab for Dabigatran reversal N Engl J Med. 373 (6); 511-20

• Siegal DM, Curnutte JT <Connolly SJ, Et al. Andexanet alfa fort he reversal of Factor Xa inhibitor activity. N engl J Med. 2015; 373 (25): 2413-2424

Questions