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Antiplatelet & Anticoagulant Considerations for

Repair of Aneurysms

And Reversal Options…

Kiffon M. Keigher, MSN, ACNP-BC, BSN

Rush University Medical Center

Chicago, IL

Disclosures

• The Joint Commission, Stroke

Program Reviewer

• Cure 4 Stroke Foundation, Co-

Founder & Board Member

Objectives

• Describe indications for use of antiplatelets for neurovascular procedures

• Understand basic platelet aggregation process and binding of receptors

• List risk factors associated with antiplatelet use

• Name commonly used antiplatelet and anticoagulant medications and reversal options

• Describe considerations for patients prior to initiating antiplatelet therapies for unruptured and ruptured aneurysm repair

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The Intracranial Aneurysm

• Key Considerations

– Ruptured vs Unruptured

– Size, location, morphology

• Risk Factors

– Hypertension

– Smoking

– Family History

• Mechanism: blood pressure tension of the wall exceeds the strength of wall itself

– Wall degeneration: pressure and sheer stress

• Inflammation is clearly associated with degenerated and ruptured walls

– Luminal thrombus

• Impaired endothelial function and high oxidative stress

Starke, R. et al. The Role of Oxidative Stress in Cerebral Aneurysm Formation and Rupture. Current Neurovascular Research. 2013

Dormant����Active

Activated platelets

undergo 3 consecutive

processes:

1. Shape change2. Secretion

3. Aggregation

The Platelet

Formation of platelet plug

Activated platelets

undergo 3

consecutive

processes:

1. Shape change

2. Secretion3. Aggregation

• Fibrinogen

• ADP

• 5 H-T

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Formation of platelet plug

Aggregation

Final pathway of

cross-linking of

activated GPIIb/IIIa

to macromolecules

(primarily

fibrinogen and

vonWillebrand

What Causes Platelet Activation?

Blood Vessel Wall Injury

TraumaIntroduction of Catheters, GuideWires

Placement of

Implants

HOW?????

• Endothelial Artery Wall Damage

– Multiple passes

– Inability to properly appose implant to artery wall

– Multiple attempts to resheath devices/implants

– Difficulty “crossing” the lesion

– Improper sizing of devices (too big)

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Aneurysm Considerations

• Size and shape

– Small vs giant

– Saccular, fusiform, mycotic, dissecting

• Wide vs narrow neck

• Thrombosis within the sac

Question to ask… do we anticipate the need for stent

assisted coiling or flow diversion for treatment?

Indications for Antiplatelet

• Wide neck aneurysms

• Fusiform aneurysms

• Dissecting or Pseudoaneurysms

• Carotid or Vertebral artery stenosis

• Venous sinus stenosis or thrombosis

• Iatrogenic dissections

• Stroke

• TIA

• Fibromuscular

dysplasia

• MoyaMoya syndrome

• Other—bailout, coil

prolapse

Antiplatelets

• Indication– Primary Prevention of ischemic stroke

• Ten year risk for CV disease is 6% or more

• High risk women over 65 yrs greatest benefit

• Asprin 81 mg preferred (minimize bleeding, no other antiplatelet agent have indications for primary prevention)

– Secondary prevention• New stroke event-failed therapy

• TIA

• Prevention of thrombosis for placement of intraluminal stents

• Adverse Reactions

– Most common is bleeding

• Contraindications

– Active bleeding

– Known allergy—could consider desensitization in some cases

Goldstein et al., 2011)

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Antiplatelets

• Interactions

– Medications that may synergistically increase bleeding risk

• Anticoagulants, NSAIDS, Herbals (gingko, ginger, ginseng)• Monitoring

– Bleeding

– Drug Resistance

• More common with Clopidogrel vs aspirin

• Testing and dose adjustments varies among providers and organizations

– Accumetrics (VerifyNow) most common: ARU and PRU

– TEG and Rotem: provide measure of response to antiplatelet and relative hemorrhage or thrombotic risk, measure of hemostasis

• Other Considerations

– NSAID’s in general best to avoid but no definitive interaction w/aspirin

– No clinically significant results showing should NOT use PPI with Clopidogrel. May be worse problem with known poor metabolizers

Commonly Used Oral Agents

• Aspirin (Thromboxane inhibitor)

– Dose: 81 and 325 mg daily

– Considerations: Inhibits for life of platelet (5-7 days), GI bleed most common risk

• Clopidogrel (ADP Inhibitor)

– Dose: 75 mg daily (loading doses may vary from 150, 300, 600 mg)

– Considerations: Irreversible-inhibits for life of platelet (5-7 days). Pro-drug-CYP conversion to active metabolite, some patients may be resistant

• Aspirin/Dypirdamole (PDE Inhibitor)

– Dose: 200 mg/25 mg BID

– Considerations: Irreversible-inhibits for life of platelet. Up to 40% of patients will experience headaches

Antiplatelets: Commonly Used Oral Agents

High Potency P2Y12/ADP Inhibitors are:

Both have ONLY acute coronary syndrome indications

• Ticagrelor– Dose: Loading dose: 180 mg x1, followed by 90 mg BID, after 12 months can consider decreasing to 60 mg

BID

– Considerations: Can be used with aspirin dose of 75-100 mg only, contraindicated in patients w/history of ICH, shown to prevent stent thrombosis but in ACS patients only

• Prasugrel– Dose: Loading dose: 60 mg x1, followed by 10 mg daily, except for patients <60kg dose is 5 mg daily

– Considerations: BLACK BOX WARNING TO BE USED IN PATIENTS WITH TIA OR STROKE, not recommended for patients >75yo. Take with daily aspirin 75-325 mg tab

Less commonly used (older drug)

• Ticolpidine (Adenosine diphosphate inhibitor)– Dose: 250 mg BID

– Considerations: Pro drug—CYP to convert to active metabolite. Irreversible for life of platelet. Associated with more adverse reactions: GI intolerance, neutropenia, aplastic anemia and thrombotic thrombocytopenic purpura (must monitor labs)

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P2Y12�Clopidogrel

� Prasugrel

� Ticagrelor

�Cangrelor

TXA2

�Aspirin

GPIIb/IIIa� Abciximab

� Integrilin

� Aggrastat

Ticagrelor (oral) and cangrelor (IV) are non-thienopyridine reversible antagonist of P2Y12

ADP receptor

Blocking P2Y12 Receptors Inhibit ADP-Induced

Platelet Activation

17Source: Bhatt D. N Engl J Med 2007;357:2078.

Commonly Used IV AgentsBoth are GPIIb/IIIa Inhibitors

Most commonly used during endovascular procedures for prevention of stent thrombosis and stroke prevention

• Abciximab

– Dose: 0.25 mg/kg bolus, followed by infusion at 0.125 mcg/kg/min for 12 hours typical up to max dose of 10 mcg/kg. Short half life.

• Eptifibatide

– Dose: for ACS--180 mcg/kg bolus over 1-2 minutes, then IV drip of 2 mcg/kg/min up to 72 hours. Given concomitantly with heparin. Should be given with daily aspirin 160-325 mg daily. Need to adjust dose for patients with renal disease

Adenosine Diphosphate Inhibitor (ADP inhibitor)—active drug---DOES NOT require metabolic conversion

• Cangrelor

– Dose: Bolus of 30mcg/kg, followed by infusion of 4 mcg/kg/min for at least 2 hours but no more than 4 hours (duration of procedure)

– Considerations: indicated for ACS only, not indicated for patient who have taken oral P2Y12 agent or with planned use of GPIIb/IIIa agent, must bridge to oral dose of ADP inhibitor, reversible half-life of 3-6 minutes

– Reversible.

– Common adverse reaction includes dyspnea and respiratory issues

– VERY EXPENSIVE!!

Biggest Concern is for Bleeding: Close Monitoring in ICU Setting Crucial

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Transition to Oral P2Y12 Inhibitors

C-Phoenix – Study Design

Anti-Platelet Protocol:Anticipating stent placement typically…

Pre-Operative

– Loading Dose--options:

• Aspirin 325mg and Clopidogrel 75mg daily for 5-7 days prior to endovascular

procedure

• Aspirin 325mg and Clopidogrel 600mg once day before endovascular

procedure

• Other=provider preference

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Anti-Platelet Protocol

• Intra-operative

– Check if levels therapeutic via Point of Care Testing (pre stent placement)

– Decide if post-operative additional load dose is needed

– Determine if additional antiplatelet agent, such as Abciximab, needed

for prevention of thromboembolic event

– Sub-therapeutic and concerns for thromboembolic complications: Consider

additional drug: i.e. Reopro Load administered during procedure by MD

Point of Care Testing

Measures level of

platelet inhibition

provided by:

Therapeutic Levels Are (target

varies by institution):

1. Aspirin

• ARU <550

2. Plavix or other P2Y12 agent

• PRU <230

• ARU=Aspirin Reaction Units

• PRU=P2Y12 Reaction Units

Red Thrombus Vs.. White Thrombus

RED Thrombus=VENOUS=ANTICOAGULANT

• Fibrin rich clots

• Low Pressure, Slow Flow

• Can break into embolus move into

systemic circulation

WHITE Thrombus=ARTERIAL=ANTIPLATELET

• Platelet rich clots

• High Shear Pressure, High Flow

• Interruption of blood flow causes

ischemia and/or death

Anticoagulation Antiplatelet

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Anticoagulants

• Indications– Prevention of cardioembolic stroke

– Nonvalvular atrial fibrillation

– Venous thromboembolism

• Mechanism: decrease clot formation via different pathways– Decrease activation of Vitamin K dependent clotting factors (II, VII, IX, X)

– Direct thrombin and direct Xa inhibitors

• Adverse reactions– Most common: bleeding

– Bruising

– Respiratory issues: dyspnea

• Contraindications– Acute bleeding

– Severe organ impairment (renal and hepatic impairment)

• Interactions– NSAIDS, antiplatelets, herbals

• Monitoring– Monitor for bleeding, target INR

Anticoagulation: To Bridge or Not To Bridge

• Considerations: Why Is the Patient on OAC?– Mechanical heart valve

– Atrial Fibrillation

– VTE

– Other??

• What is the larger risk?– Hemorrhage vs Thromboembolic

• Monitoring– Coagulation Studies: PT/INR, PTT

– EKG

– Hemodynamic and Neurological Assessments

Rechenmacher, S.J. et al. J Am Coll Cardiol. 2015;

66(12): 1392-402

To Bridge

To Interrupt

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Anticoagulants: Common oral

• Warfarin—vitamin K antagonist– Dose: Variable—titrate to INR 2-3

– Antidote: : Vitamin K, FFP, PCC (prothrombin complex concentrate)

Novel Oral anticoagulants:Indications include nonvalvular afib and VTE treatment

• Dabigatran—direct thrombin inhibitor– Dose: 75-150 mg BID

• Rivaroxaban-direct Xa inhibitor

– Dose: 20 mg PO daily

• Apixaban-Direct Xa inhibitor

– Dose: 2.5-5 mg PO BID

Anticoagulant: IV

• Heparin

– Dose: variable—depends on indication for therapy and adjusted to

achieve goal PTT

– Half-life: 1.5 hour

– Mechanism of action: acts at multiple sites, binds to antithrombin III,

inactivates thrombin and other clotting factors

– Reversal: Protamine Sulfate 1-1.5mg IV per 100 units of heparin. Max

Dose is 50mg/dose. Rate 5mg/min

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SAH & ICH: Correct Coagulopathies

� Antiplatelets: Any type�Reversal Agents: No antidote, give platelets

� Heparin�Reversal Agent: Protamine 1mg/100 units heparin, max dose 50 mg

� Warfarin: Vitamin K antagonist

�Half-Life: 20-60 hour (variable)

�Reversal Agents: Vitamin K, Fresh Frozen Plasma (FFP), Prothrombin Complex Concentrate (PCC)

� Dabigatran: Direct Thrombin Inhibitor

�Half-Life: 12-17 hours

�Reversal Agent: Idarucizumab-very $$$, PCC or Activated recombinant factor VII (rFVII)

� Rivaroxaban, Apixaban: Direct Xa Inhibitor

�Half-Life: 5-13 hours (Rivaroxaban), 8-15 hours (Apixaban)

�Reversal Agent: No Antidote, PCC or Activated recombinant factor VII (rFVII)

Elective vs. Emergent Aneurysm Repair

• Opportunity to time procedure for the “right time”

• More time to educate patient and family

• Allows for time to discuss past medical history that may

contraindicate or prompt further workup of antiplatelet

therapy

• Provides time to give a “soft” load vs a large loading dose or to

bridge with a drip

• No EVD’s, tracheostomies, g-tubes or other invasive lines or

procedures to consider

Out-Patient Considerations

• Pending Procedures or Surgeries

– Dental procedures, colonoscopies, biopsies, etc…

– Orthopedic or other invasive planned surgeries

• History of GI bleed or Peptic Ulcer Disease

– Not a contraindication but may need further workup

– Consider Protonix or other PPI prophylaxis

• Allergy to antiplatelets

• Chronic epistaxis

• Anticoagulant use for other medical condition

– Interrupt & Bridge or Not

– Triple therapy considerations

www.fda.gov. 2016

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Acute Phase Considerations• Coil vs Stent and Coil vs Flow Diversion vs Clipping????????

• External Ventricular Drains– Does patient have an EVD in place? Is it functional and draining well?

– Do you anticipate your patient will need an EVD? Timing of EVD vs starting antiplatelet

• Pending surgical procedures– Will patient require additional surgeries during hospital stay?

• Tracheostomy, g-tube, VPS

• Other critical care issues– Does patient have other underlying medical conditions concerning for increased risk of

bleeding?• Thrombocytopenia

• Profound anemia

• Acute blood loss--postoperative

• GI bleed

• Hypercoaguable disorder

• Hemophilia or other blood clotting issue (i.e. VonWillebrands)

• Post stroke-post IV tPA

Nursing Implications

• Understanding the Therapy– Administer all doses of anti-platelets

• Do not hold doses unless indicated

• Know what is indicated!

– Platelet Counts

– Punctures and procedures post IV antiplatelets, anticoagulants

• Monitoring– Signs of bleeding

– Signs of thromboembolic events• Neurological changes

• Know reversal agents

• Educating the Patient– Do not skip doses, do not stop medications prematurely w/o first speaking to surgeon/interventionalist—

call if having procedures requiring stopping medication

– Do not double doses

– Maintain safety & educate on increased bleeding risks

– Educate to monitor for excessive bruising

– Review possible medication interactions

– Bruising risks

Summary

• The platelet has many receptors allowing for different types of drugs to be

effective platelet inhibitors

• Multiple indications for use of antiplatelets

• Endovascular procedures themselves contribute to endothelial wall damage

• Some patients may need to have their anticoagulation medications adjusted

for treatment-must decide to bridge or not and determine triple therapy

• Treatment approach for the hemorrhagic stroke patient is often more

conservative and has potential higher risk in setting of antiplatelet use

• Education of patient and families is critical

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Thank You

To Visit or Participate in Further Training at RUMC Contact: kiffon_keigher@rush.edu OR

kkeigher@cure4stroke.com