Oral Anticoagulant and Antiplatelet Medications: Pharmacology Update

Stroke Fair 2015

Objectives

• Discuss guideline recommendations regarding use of oral antiplatelet and anticoagulant medications for stroke prevention.

• Review oral antiplatelet medications used for stroke prevention.

• Review oral anticoagulant medications used for stroke prevention.

Stroke

• Currently 5th leading cause of death in the US and a leading cause of disability.– ~1 of every 20 deaths in the US

• ~795,000 strokes per year.– 610,000 new– 185,000 recurrent– >690,000 ischemic

• By 2030, 3.88% of US population > 18 y/o is projected to have had a stroke.

Stroke. 2013;44:2361-2375.

Circulation. 2015;131:e29-e322.

Risk Factors

Modifiable• Physical inactivity• Dyslipidemia• Diet and nutrition• Hypertension• Obesity• Diabetes Mellitus• Smoking• Atrial Fibrillation• Other cardiac conditions (MI,

cardiomyopathy, valvular heart disease, etc.)

Non-modifiable• Age• Sex• Race/ Ethnicity• Genetic Factors• Family History of CVD at a

young age• Proinflammatory and

prothrombotic factors

Stroke. 2014; 45: 3754-3832.

Stroke. 2013;44:2361-2375.

Antithrombotics for Primary Prevention

• Atrial Fibrillation– Anticoagulant or antiplatelet depending on risk

factors• Diabetes Mellitus

– Aspirin (unclear benefit for stroke prevention)• Mechanical valves

– Warfarin + aspirin• Bioprosthetic valves

– Aspirin +/- warfarin

Stroke. 2014; 45: 2160-2236.

Atrial Fibrillation

• Non-valvular AF is associated with a 5-fold increased risk of stroke.

• AF-related stroke is likely to be more severe than non–AF-related stroke.– Greater disability and mortality.– Greater risk of recurrent stroke.

• Antithrombotic regimen is selected based on balance of risks and benefits.

JACC. 2014; 64(21): e1-76.

CHA2DS2-VASc Risk Stratification for Nonvalvular AF

Risk Factor Score

Congestive HF 1

Hypertension 1

Age >/= 75 y/o 2

Diabetes mellitus 1

Stroke/TIA/TE 2

Vascular disease (prior MI, PAD, or aortic plaque)

1

Age 65-74 y 1

Sex (female) 1

2014 AHA/ACC/HRS Guidelines for patients with non-valvular AF: •Score = 0 (0.2% ischemic stroke rate per year)

• Reasonable to omit antithrombotic therapy.

•Score = 1 (0.6% rate)• No antithrombotic therapy or

treatment with an oral anticoagulant or aspirin may be considered.

•Score >/= 2 (2.2-12.2% rate) or prior stroke or TIA

• Oral anticoagulation recommended.

JACC. 2014; 64(21): e1-76.

Treatment of Acute Ischemic Stroke and TIA

• Antiplatelet agents– Early initiation of ASA (within 48h)

• Do not administer antithrombotics within 24hr of treatment with IV alteplase

– Combination antiplatelet therapy may be beneficial• Parenteral anticoagulation not recommended

during the first 48 hours of acute ischemic stroke – Increased risk of bleeding complications– May be used for some ischemic stroke subtypes– Limited evidence

Antithrombotic treatment of acute ischemic stroke and transient ischemic attack. Uptodate.

Secondary Prevention• Noncardioembolic ischemic stroke or TIA

– Antiplatelet agent• ASA or ASA + dipyridamole• Clopidogrel• ASA + clopidogrel

– Anticoagulants (not recommended)• Similar rate of vascular events but higher risk of bleeding

with warfarin • Newer anticoagulants not studied in recurrent stroke

• Cardioembolic stroke– Recommendations vary with indication

Stroke. 2014; 45: 2160-2236.

Selecting Antiplatelets for Secondary Prevention

• Individualized decision to consider: patient risk factors, cost, tolerance, relative known efficacy.

• AHA guidelines:– ASA or ASA + dipyridamole– Clopidogrel may be used in place of the above or

when pt is allergic to aspirin.• Combination ASA + clopidogrel

– Can consider for initiation within 24 hr of minor ischemic stroke or TIA and continuation for 21 days.

– Long-term use increases risk of hemmorrhage.

Stroke. 2014;45:2160-2236.

Antiplatelets vs. Anticoagulants

http://www.thrombosisadviser.com/en/acs/anticoagulants-and-antiplatelets-combined/

Antiplatelets

• Keep blood clots from forming by preventing platelet aggregation.

• Aspirin• Cilostazol (Pletal)• Clopidogrel (Plavix)• Dipyridamole + Aspirin

(Aggrenox)• Prasugrel (Effient)• Ticagrelor (Brilinta)• Ticlopidine (Ticlid)

Aspirin• MOA: Inhibits cyclooxygenase, reducing

production of thromboxane A2, a stimulator of platelet aggregation.

• Approved for: CVA, CVA prophylaxis, TIA treatment and prophylaxis.

• Available as immediate release and delayed release (enteric coated)– Enteric coating protects against erosion but does not

reduce GI bleeding incidence in studies– Potential reduced efficacy of enteric coated ASA,

especially at low doses

NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity. Uptodate.

Nonresponse and resistance to aspirin. Uptodate.

Aspirin

• Dose: Most studies have found that lower doses of ASA are as effective as higher doses for secondary stroke prevention.– Magnitude of benefit similar for doses ranging

from 50-1500 mg.– Higher doses associated with highest risk of GI

toxicity.

• Side effects: GI upset, GI bleeding

Stroke. 2014;45:2160-2236.

Dipyridamole + Aspirin (Aggrenox)

• Dipyridamole: Impairs platelet function by inhibiting the activity of adenosine deaminase and phosphodiesterase.

• Beneficial effects of ASA and dipyridamole appear to be additive.

• As effective as ASA for secondary stroke prevention in trials.

Stroke. 2014;45:2160-2236.

Dipyridamole + Aspirin (Aggrenox)

• Dose: ASA 25mg/ dipyridamole 200mg PO twice daily– Do not crush or chew

• Side effects: headache (incidence declines with continued use), GI upset, diarrhea.

• Higher rate of side effects and early discontinuation in clinical trials.

Clopidogrel (Plavix)

• Irreversibly inhibits ADP-dependent platelet aggregation.

• Approved for: cerebrovascular accident prophylaxis.

• Dose: 75mg PO once daily• Compared to ASA and ASA/dipyridamole

(CAPRIE and PRoFESS trials): similar rates of primary outcomes.

Stroke. 2014;45:2160-2236.

Clopidogrel (Plavix)

• Genetic differences in hepatic enzymes or P2Y12 receptor may affect response to clopidogrel.– Not enough evidence to recommend routine genetic

testing.

• Side effects: rash and diarrhea (>ASA); GI upset and GI bleeding (<ASA).

• Proton pump inhibitors may reduce effectiveness of clopidogrel.• H2 blocker or pantoprazole preferred

Ticlopidine (Ticlid)

• Irreversibly alters the function of platelet membranes by preventing ADP from stimuating platelet-fibrinogen binding and subsequent interactions between platelets.

• Approved for: Prevention of thromboembolic stroke.

• Conflicting results in clinical trials.

Stroke. 2014;45:2160-2236.

Ticlopidine (Ticlid)

• Side effects: Rash, diarrhea• May cause severe neutropenia: biweekly CBC

required for 3 months• Not considered first line due to high cost and

side effects

Cilostazol (Pletal)• Phosphodiesterase 3 inhibitor• Non-FDA approved indication: cerebrovascular

accident prevention.• Mainly used for intermittent claudication in

patients with peripheral artery disease.• Controlled trials demonstrate effectiveness in

preventing cerebral infarction (in Asian populations).• Lower rate of intracranial hemorrhages.

• Higher cost, lower tolerability than aspirin.

Stroke. 2014;45:2160-2236.

Other Antiplatelets• NOT approved for stroke prevention• Prasugrel (Effient)

– FDA approved indication: acute coronary syndrome (ACS) managed with percutaneous coronary intervention (PCI).

• Used with aspirin– Do not use in patients with history of TIA or stroke

(increased risk of bleeding).– Not recommended in patients > 75 y/o.

• Ticagrelor (Brilinta)– FDA-approved indication: ACS with or without PCI

• Used with aspirin– Do not use aspirin dose > 100mg daily.

• Potential reduced efficacy of ticagrelor

Oral Anticoagulants

• Disrupt parts of the coagulation cascade, preventing fibrin clots from forming or enlarging.

• Apixaban (Eliquis)• Dabigatran etexilate

(Pradaxa)• Edoxaban (Savaysa)• Rivaroxaban (Xarelto)• Warfarin (Coumadin)

Clotting Cascade

Vitamin K Antagonists

• Blocks regeneration of Vitamin K epoxide, inhibiting synthesis of vitamin K dependent clotting factors 2, 7, 9, 10, and the anticoagulant proteins C and S.

• Warfarin (Coumadin)

Warfarin (Coumadin)

• Oral anticoagulant approved for prophylaxis of thromboembolic disorders related to prosthetic cardiac valve and atrial fibrillation.

• Dose is based on INR (usual target 2-3)• INR may be affected by vitamin K intake.

– Consistent dietary and supplement intake is necessary.

• Multiple drug interactions.

Warfarin (Coumadin)

• Bridge therapy sometimes required

• Routine lab monitoring required

• Reversal agent:– Vitamin K

• Side Effects:– Bleeding– Purple toe syndrome– Alopecia– Nausea/vomiting– Diarrhea– Chills/ feeling cold

Warfarin (Coumadin)

• Discontinue approximately 5 days prior to surgery to provide sufficient time for INR to normalize

• Use with parenteral anticoagulants only for bridge therapy

Novel Oral Anticoagulants (NOACs)• Direct thrombin inhibitors and direct factor Xa

inhibitors.• No blinded head to head trial comparisons

between NOACs• For A. fib, NOACs associated with (compared

to warfarin) – depending on the drug:– Significant reduction in stroke/ systemic embolism– Significant relative reduction in hemorrhagic

stroke and all cause mortality– Reduced major bleeding

Atrial fibrillation: Anticoagulant therapy to prevent embolization. Uptodate.

NOACs

Advantages• Convenience• Lack of dietary interactions• Fewer drug interactions

Disadvantages• Lack of efficacy and safety

data in patients with severe CKD

• Lack of easily available monitoring of blood levels (and compliance)

• Higher cost• Lack of reversal agents• Potential for unanticipated

side effects

Atrial fibrillation: Anticoagulant therapy to prevent embolization. Uptodate.

Direct Thrombin Inhibitor

• Prevents formation of clots by directly blocking thrombin.

• Can be reversed with• Praxbind 5mg once

• Dabigatran (Pradaxa)

Dabigatran (Pradaxa)• Oral anticoagulant approved for stroke prevention in

atrial fibrillation.• Normal dose is 150mg BID

– Renal dose (CrCl<30) 75 mg BID– Do not use with CrCl < 15 or in dialysis patients

• Can be taken without regards to meals• Capsule should never be chewed, crushed, or

opened.– Bioavailability increases 75% when capsule opened

• Must be stored in original packaging– Cannot put in a pill organizer

Dabigatran (Pradaxa)

• No bridge therapy required

• No routine lab monitoring

• Idarucizumab (Praxbind) approved 10/2015 for reversal!

• Side Effects– Esophagitis– Gastritis– GERD– GI hemorrhage– Bleeding– Indigestion

Dabigatran (Pradaxa)

• Discontinue use 1-6 days prior to invasive procedure or surgery.– Based on renal function

and bleeding risk of procedure.

• Do NOT use with other anticoagulants

Anticoagulants..oral and injectable

Heparin Enoxaparin (Lovenox) Fondaparinux (Arixtra) Warfarin Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa)

Factor Xa Inhibitors

• Prevents clots by inhibiting factor Xa– “Oral Arixtra”

• Rivaroxaban (Xarelto)• Apixaban (Eliquis)• Edoxaban (Savaysa)• In development:

betrixaban

Rivaroxaban (Xarelto)• Oral anticoagulant approved for

– DVT prophylaxis post knee and hip surgery– Stroke prevention in atrial fibrillation– DVT and PE treatment and secondary prophylaxis

• Dose differs based on indication– A. fib: 20mg once daily – Crcl 15-50 ml/min: 15 mg once daily– Crcl < 15 ml/min: avoid use

• 15 mg to 20 mg doses should be taken with food to increase absorption.– Take with largest meal of the day (usually supper)

• If crushed, must be administered into the stomach.

Rivaroxaban (Xarelto)

• No bridge therapy required

• No routine lab monitoring

• No reversal agent

• Do NOT use with other anticoagulants

Anticoagulants..oral and injectable

Heparin Enoxaparin (Lovenox) Fondaparinux (Arixtra) Warfarin Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis)

Rivaroxaban (Xarelto)

• Discontinue use 1-4 days prior to invasive procedure or surgery.– Based on renal function

and bleeding risk of procedure.

• Side Effects:– Increased bleeding– GI hemorrhage– Epidural hematoma

Apixaban (Eliquis)• Oral anticoagulant approved for:

– A fib – CVA/embolus prophylaxis– DVT/PE treatment– VTE prophylaxis postop arthroplasty of knee or hip

• Dose – 5mg BID– Do not use with severe hepatic impairment– Decrease to 2.5mg BID IF 2 or more of the following are present

• Age >/= 80• Weight </= 60 kg• Serum Cr >/= 1.5mg/dL

• May be crushed.• May be administered with or without food.

Apixaban (Eliquis)

• No bridge therapy required

• No routine lab monitoring

• No reversal agentAnticoagulants..

oral and injectable Heparin Enoxaparin (Lovenox) Fondaparinux (Arixtra) Warfarin Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa)

• Do NOT use with other anticoagulants

Apixaban (Eliquis)

• Discontinue use 1-4 days prior to invasive procedure or surgery.– Based on renal function

and bleeding risk of procedure.

• Side Effects• Bleeding

• GI hemorrhage

• Intracranial hemorrhage

Edoxaban (Savaysa)• Newest oral anticoagulant approved for:

– Stroke prevention in atrial fibrillation– DVT/ PE

• Dose – 60 mg once daily– Crcl 15-50 ml/min: 30mg once daily– Crcl < 15 ml/min: not recommended– Do not use in moderate or severe hepatic impairment– Do not use for atrial fibrillation if Crcl > 95 ml/min

• Increased risk of ischemic stroke• May be crushed.• Administer with or without food.

Edoxaban (Savaysa)

• No bridge therapy required

• No routine lab monitoring

• No reversal agent

• Do NOT use with other anticoagulants

Anticoagulants..oral and injectable

Heparin Enoxaparin (Lovenox) Fondaparinux (Arixtra) Warfarin Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa)

Edoxaban (Savaysa)

• Discontinue prior to surgery– At least 24 hours prior to

procedure– Reinstate once adequate

hemostasis is established

• Side Effects:– Bleeding– Rash– Abnormal liver function

tests

Betrixaban

• In development• Once daily dosing• Low renal clearance

– Studied in patients with all degrees of renal dysfunction.

• No significant CYP3A4 metabolism• Currently in Phase 3 trial – seeking approval

for hospital and post-discharge prevention of VTE in acute medically ill patients.

Bleeding RiskLetter Clinical

CharacteristicPoints

H Hypertension 1

A Abnormal liver or renal function

1 or 2

S Stroke 1

B Bleeding 1

L Labile INR 1

E Elderly (age>65) 1

D Drugs or Alcohol 1 or 2

• Most common tool used to assess bleeding risk: HAS-BLED score.

• Should be used to identify risk factors or define patients at elevated bleeding risk, not to determine who should or should not receive anticoagulation.

JACC. 2014; 64(21): e1-76.

Points 0 1 2 3 4 5

Annual bleed rate

0.9% 3.4% 4.1% 5.8% 8.9% 9.1%

Emergent Antithrombotic Reversal

• For life-threatening bleeds or emergent surgery• Antiplatelet drugs

– Platelet infusion– No specific reversal agents

• Warfarin– Phytonadione (Vitamin K) 10mg IV– FEIBA (activated prothombin complex concentrate)

• Dose depends on INR and site of bleeding

Emergent Antithrombotic Reversal• Direct thrombin inhibitor

– Idarucizumab (Praxbind)– FEIBA 50 units/kg IV x1– Emergent hemodialysis (removes ~60% in 2-3 hr)– Activated charcoal (if within 2hrs of ingestion)

• Factor Xa inhibitors– FEIBA 50 units/kg IV x1– FFP if bleeding still not controlled– Activated charcoal (if within 8hrs of ingestion)

FEIBA

• Activated prothrombin complex concentrate.– Contains inactivated factors II, IX, and X and

activated factor VII

• No indication and not well studied for treatment of bleeding due to anticoagulants.– Dosing comes from literature, not package insert.

• Should be used for life threatening bleeds only.– Substantial risk for thrombotic and thromboembolic

events.

FEIBA

• Available in 500 unit, 1000 unit, and 2500 unit (approximate) strengths– All units / kg doses will be rounded to the

nearest vial size

• Dispensed from pharmacy:– Volumes ≤ 20mL in syringe– Volumes > 20mL in 50mL empty bag

Targeted Reversal Agents

• Idarucizumab (Praxbind) – FDA approval 10/2015– dabigatran reversal– Humanized dabigatran-specific antibody fragments– RE-VERSE AD study

• Rapidly and completely reversed anticoagulation in 88-98% of patients who had elevated clotting times at baseline

• Andexanet alfa: – Factor Xa inhibitor reversal– Recombinant modified human Factor Xa molecule– Studies underway

Management of bleeding in patients receiving direct oral anticoagulants. Uptodate.

N Engl J Med 2015;373:511-20.

Idarucizumab (Praxbind)

Summary

• Use of antithrombotic therapy for stroke prevention requires careful consideration of a patient’s history and risk factors.

• Multiple antiplatelet and anticoagulant options available to provide individualization of therapy based on patient-specific factors.

• Antithrombotic medications have many other uses not related to stroke prevention.