Download stroke-presentation-dec2015 - Pharmacy Clinical References

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.
Circulation. 2015;131:e29-e322.
Stroke. 2013;44:2361-2375.
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.)
Stroke. 2013;44:2361-2375.
Stroke. 2014; 45: 3754-3832.
Non-modifiable
• Age
• Sex
• Race/ Ethnicity
• Genetic Factors
• Family History of CVD at a
young age
• Proinflammatory and
prothrombotic factors
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
JACC. 2014; 64(21): e1-76.
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.
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-andantiplatelets-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
Nonresponse and resistance to aspirin. Uptodate.
NSAIDs (including aspirin): Primary prevention of
gastroduodenal toxicity. 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
• Warfarin (Coumadin)
Vitamin K epoxide,
inhibiting synthesis of
vitamin K dependent
clotting factors 2, 7, 9,
10, and the
anticoagulant proteins C
and S.
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
Atrial fibrillation: Anticoagulant therapy to prevent embolization. Uptodate.
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
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 • Do NOT use with
days prior to
other
invasive procedure
anticoagulants
or surgery.
– Based on renal function
and bleeding risk of
procedure.
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 • Side Effects:
– Increased bleeding
days prior to
– GI hemorrhage
– Epidural hematoma
invasive procedure
or surgery.
– Based on renal function
and bleeding risk of
procedure.
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 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)
Apixaban (Eliquis)
• Discontinue use 14 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 Risk
Letter
Clinical
Characteristic
Points
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
Points
0
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.
• 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.
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)
• DOSE – 5gm IV given as a • Adverse reactions:
push or infusion
• Hypokalemia
• No dose adjustments
needed
• CAUTION - hereditary
fructose intolerance
• Consider restarting
dabigatran within 24
hours of administration
• $3500 per dose
•
•
•
•
•
Constipation
Delirium
PNA
Fever
Hypersensitivity reaction
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.