1. Oral Anticoagulant and Antiplatelet Medications: Pharmacology Update
Stroke Fair 2015

2. 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.

3. 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.
Increased prevalence of obesity  increases in both HTN and DM
Increased stroke burden among younger adults could increase dramatically
Optimal treatment of risk factors critical to reduce stroke burden on society/individuals.
Circulation. 2015;131:e29-e322.
Stroke. 2013;44:

4. Risk Factors Modifiable Non-modifiable Age Sex Race/ Ethnicity
Physical inactivity
Dyslipidemia
Diet and nutrition
Hypertension
Obesity
Diabetes Mellitus
Smoking
Atrial Fibrillation
Other cardiac conditions (MI, cardiomyopathy, valvular heart disease, etc.)
Age
Sex
Race/ Ethnicity
Genetic Factors
Family History of CVD at a young age
Proinflammatory and prothrombotic factors
>76 % of strokes are new events
HTN considered most important, well-documented modifiable stroke risk factor
Glycemic control reduces microvascular complications of DM, but inadequate evidence that improved control reduces risk of incident stroke.
Effective prevention remains the best approach for reducing the burden of stroke.
Age > 80
Black > white
Usually women > men
Stroke. 2013;44:
Stroke. 2014; 45:

5. 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
Mechanical mitral valve: INR low dose aspirin
Bioprosthetic: aspirin + warfarin for first 3 months
DM – several trials show no benefit vs no asa
Stroke. 2014; 45:

6. 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.

7. CHA2DS2-VASc Risk Stratification for Nonvalvular AF
Risk Factor
Score
Congestive HF 1
Hypertension
Age >/= 75 y/o 2
Diabetes mellitus
Stroke/TIA/TE
Vascular disease (prior MI, PAD, or aortic plaque)
Age y
Sex (female)
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 ( % rate) or prior stroke or TIA
Oral anticoagulation recommended.
When compared with the CHADS2 score, the CHA2DS2-
VASc score for nonvalvular AF has a broader score
range (0 to 9) and includes a larger number of risk factors
(female sex, 65 to 74 years of age, and vascular disease)
In a nationwide Danish registry from 1997 to 2008, the CHA2DS2-VASc index better discriminated stroke risk among subjects with a baseline CHADS2 score of 0 to 1 with an improved predictive ability.
JACC. 2014; 64(21): e1-76.

8. 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.

9. 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
Clopidogrel – reasonable in place of ASA or Aggrenox; also in case of ASA allergy
Clopidogrel + ASA – x21 days if initiated within 24hr of minor ischemic stroke or TIA (long-term use not recommended)
Stroke. 2014; 45:

10. 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:

11. Antiplatelets vs. Anticoagulants

12. Antiplatelets
Keep blood clots from forming by preventing platelet aggregation.
Aspirin
Cilostazol (Pletal)
Clopidogrel (Plavix)
Dipyridamole + Aspirin (Aggrenox)
Prasugrel (Effient)
Ticagrelor (Brilinta)
Ticlopidine (Ticlid)

13. 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
GI injury severe enough to induce bleeding is thought to reflect systemic effects, not just local effects.
Enteric coated ASA: should not be used for acute events – if used, should be crushed or chewed. For chronic administration, doses higher than 81mg may be necessary.
Nonresponse and resistance to aspirin. Uptodate.
NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity. Uptodate.

14. 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 mg.
Higher doses associated with highest risk of GI toxicity.
Side effects: GI upset, GI bleeding
Low doses (</= 325mg) ASA at prolonged intervals  annual risk of serious GI hemmorhage is ~0.4% (2.5 x the risk for non-users)
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15. 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:

16. 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.

17. 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:

18. 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
Carriers of at least 1 CYP2C19 reduced-function allele had a relative reduction of 32% in plasma exposure to the active metabolite of clopidogrel compared with noncarriers (P<0.001).

19. 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.
3 randomized trials in patients with cerebrovascular disease: superior to placebo in one, superior to ASA in one, no benefit compared to ASA in the third
Stroke. 2014;45:

20. 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

21. 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:

22. 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
Do not use aspirin dose > 100mg daily.
Potential reduced efficacy of ticagrelor
ACS= unstable angina, NSTEMI, STEMI

23. 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)

24. Clotting Cascade

25. 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)

26. 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.
For patients with tilting disk or bileaflet mechanical valve in the mitral position or caged ball or caged disk valves (combination with aspirin), a target INR of 3 (range, 2.5 to 3.5) is recommended

27. 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

28. 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

29. 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
Reduced major bleeding: significant for Apixaban, edoxaban
Reduced hemorrhagic stroke: All
Significant reduction in stroke/ systemic embolism: superiority shown for dabigatran, apixaban; Noninferiority for rivaroxaban, edoxaban
Atrial fibrillation: Anticoagulant therapy to prevent embolization. Uptodate.

30. NOACs Advantages Disadvantages Convenience
Lack of dietary interactions
Fewer drug interactions
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.

31. Direct Thrombin Inhibitor
Prevents formation of clots by directly blocking thrombin.
Can be reversed with
Praxbind 5mg once
Dabigatran (Pradaxa)

32. 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
Twice daily med – must remain in blister pack until used for stability reasons. If drug is still in manufactuerer bottle it is good for 4 months from the date the bottle was opened

33. 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
Apcc – activated prothrombin complex concentrate – has been approved and is available at BHE but not much data available for its use – it is a possible reversal agent for emergent bleeds, it contains 4 clotting factors
PRAXBIND – just approved

34. 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)
This includes epidurals
Should not be used with anticoagulants but may see it used with antiplatelet agents

35. Factor Xa Inhibitors Prevents clots by inhibiting factor Xa
“Oral Arixtra”
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Edoxaban (Savaysa)
In development: betrixaban

36. 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 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.
Reduced bioavailability if administered into proximal intestine.

37. 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)
Apcc – activated prothrombin compex concentrate – has been approved and is available at BHE but not much data available for its use – it is a possible reversal agent for emergent bleeds, it contains 4 clotting factors
Don’t use with other anticoagulants but may see this used with antiplatelet agents

38. 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
This includes epidurals

39. Apixaban (Eliquis) Oral anticoagulant approved for: Dose – 5mg BID
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.

40. Apixaban (Eliquis) 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)
This includes epidurals

41. Apixaban (Eliquis) Side Effects
Bleeding
GI hemorrhage
Intracranial hemorrhage
Discontinue use 1-4 days prior to invasive procedure or surgery.
Based on renal function and bleeding risk of procedure.
This includes epidurals

42. Edoxaban (Savaysa) Newest oral anticoagulant approved for:
Stroke prevention in atrial fibrillation
DVT/ PE
Dose – 60 mg once daily
Crcl 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.

43. 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)

44. Edoxaban (Savaysa) Discontinue prior to surgery Side Effects: Bleeding
At least 24 hours prior to procedure
Reinstate once adequate hemostasis is established
Side Effects:
Bleeding
Rash
Abnormal liver function tests

45. 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.

46. Bleeding Risk
Letter
Clinical Characteristic
Points H
Hypertension 1 A
Abnormal liver or renal function
1 or 2 S
Stroke B
Bleeding L
Labile INR E
Elderly (age>65) D
Drugs or Alcohol
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.
Bleeding risk scores to quantify hemorrhage risk
include HAS-BLED (Hypertension, Abnormal renal/liver
function, Stroke, Bleeding history or predisposition,
Labile INR, Elderly, Drugs/alcohol concomitantly), RIETE
(Computerized Registry of Patients With Venous Thromboembolism),
HEMORR2HAGES (Hepatic or Renal Disease,
Ethanol Abuse, Malignancy, Older Age, Reduced
Platelet Count or Function, Rebleeding, Hypertension,
Anemia, Genetic Factors, Excessive Fall Risk and Stroke),
and ATRIA (Anticoagulation and Risk Factors in Atrial
Fibrillation)
Points 1 2 3 4 5
Annual bleed rate
0.9%
3.4%
4.1%
5.8%
8.9%
9.1%
JACC. 2014; 64(21): e1-76.

47. 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
FEIBA for warfarin:
INR</= 5 = 500 units IV (do not exceed 2 units/kg/min infusion rate)
INR > 5 OR intracranial bleed = 1000 units IV (do not exceed infusion rate of 2 units/kg/min)
Recheck INR in 30 minutes, if > 1.5 contact physician to determine if another 500 units is needed.

48. 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
FFP if bleeding still not controlled
Activated charcoal (if within 8hrs of ingestion)
Dialysis not useful for factor Xa inhibitors due to high protein-binding

49. 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.
FDA indications for hemophilia A or B – prophylaxis or control of bleeding (with factor VIII or IX inhibitors)
Increased thrombosis risk – evidence comes from studies involving hemophilia patients. Theoretically, higher risk with patients on anticoagulant due to pt’s baseline higher risk of thrombosis (reason for anticoagulation initially)

50. 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

51. 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
REVERSE-AD: used dilute thrombin times and ecarin clotting times to evaluate efficacy
Management of bleeding in patients receiving direct oral anticoagulants. Uptodate.
N Engl J Med 2015;373:

52. Idarucizumab (Praxbind)
DOSE – 5gm IV given as a push or infusion
Adverse reactions:
Hypokalemia
No dose adjustments needed
Constipation
Delirium
CAUTION - hereditary fructose intolerance
PNA
Fever
Consider restarting dabigatran within 24 hours of administration
Hypersensitivity reaction
$3500 per dose

53. 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.