Download Outpatient Anticoagulation management

Outpatient
Anticoagulation
Management
Evaluating the pharmacist’s role
in the past, present, and future
Jill Hiers, Pharm.D., BCPS
NHPA CE program
December 4, 2016
Outline
• Definition of anticoagulation and brief review of
clotting cascade
• Indications for anticoagulation (CHEST guidelines)
• Oral anticoagulants review
• Mechanism of action, laboratory monitoring,
pharmacokinetics, dosing, adverse effects, reversal, drug
interactions, and dietary considerations
• Outpatient anticoagulation management
• Past
• Present
• Future
Objectives
At the end of this presentation, you will be able to:
1.
Understand the coagulation process and indications for
anticoagulation
2.
Calculate a CHA2Ds2-VASc score for a patient with atrial
fibrillation
3.
Know the oral anticoagulants that are currently available for use,
including dosing, monitoring, adverse effects, reversal, drug
interactions, and dietary considerations
4.
Determine an appropriate oral anticoagulant for a patient
5.
Discuss the pharmacist’s current and future role in outpatient
anticoagulation management
About me
• Graduate of University of Connecticut School of Pharmacy
• PGY-1 residency at Lahey Clinic (focus in ambulatory care)
• Elliot Health System clinical pharmacist since 2007
• Started ambulatory care program in 2008
• Elliot Senior Health Center: medication therapy management,
disease management, medication adherence program for
seniors (MAPS)
• Started residency program in 2008
• 3 residents (one with focus in ambulatory care)
• Expansion of anticoagulation clinic program
• Outpatient management of anticoagulation therapy
Elliot Health System
Anticoagulation Clinics
• 2002
• One pharmacist managing INR lab results via phone at one
primary care office
• 2007
• One anticoagulation certified nurse performing point of care
(POC) finger stick INR testing and managing results using
protocol
• 50 POC tests/week
• Pharmacist oversight and consultation
• 2016
• Four anticoagulation certified nurses working at four different
sites, performing POC testing and adjusting warfarin doses per
protocol
• ~850-1000 POC tests/month (in addition to over-the-phone
monitoring)
• Pharmacist oversight and consultation has continued
Why Anticoagulation
Clinics?
• Physician managed anticoagulation versus
anticoagulation clinics
• Literature shows improved time in therapeutic range
with anticoagulation clinic management over physician
management for patients receiving warfarin therapy
• Literature also shows improved satisfaction with
anticoagulation clinic management over physician
management
• Literature supports collaboration with pharmacists,
nurses, and physicians (Elliot Health System model)
Young S, Bishop L, Twells L et al. “Comparison of pharmacist managed anticoagulation with usual medical care in
a family medicine clinic”. BMC Fam Pract. 2011. 12:88 doi: 10.1186/1471-2296-12-88
Anticoagulation
• What is anticoagulation?
• Anti = against coagulation = clotting
• Coagulation is a complex process that allows blood to
clot
• What are anticoagulants?
• Medications that prolong the time it takes for blood to
clot
Clotting cascade
http://www.neurology.org/content/78/7/501/F2.large.jpg. Accessed June 21, 2016.
Chest guidelines
• Published by the American College of Chest
Physicians
• Provide guidelines for anticoagulation based on
comprehensive literature reviews
• February 2012: 9th edition published
• January 2016: Updated edition released (VTE)
• Updated 12 topics from 2012 version
Anticoagulation
indications
• Venous thromboembolism
• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
• Atrial fibrillation
• Mechanical or bioprosthetic heart valve
• Inherited thrombophilias
• Genetic predisposition to clotting
• Cardioembolic ischemic stroke
• Myocardial infarction (MI)
Thrombotic disease
burden
• Over 900,000 cases of VTE annually
• Estimate 1/3 will have reoccurrence over the next 10 years
• Approximately 5-8% of the population has an inherited
thrombophilia
• 2.7-6.1 million Americans have atrial fibrillation
• 9% of people over the age of 65
Data and Statistics. http://www.cdc.gov/ncbddd/dvt/data.html. Last accessed September 30, 2016
Atrial fibrillation
• Irregular heart rhythm characterized by rapid and
irregular heart beats
• Irregular rhythm causes blood stasis in the left atrium,
which increases risk of stroke
True or False
Everyone with atrial fibrillation needs to be on an
anticoagulant to reduce the risk of a thromboembolic
event
FALSE!!!!
CHA2Ds2-VASc
Condition
Points
C
Congestive heart failure (or LV systolic dysfunction)
1
H
Hypertension
1
A2
Age greater than or equal to 75
2
D
Diabetes mellitus
1
S2
Prior stroke or TIA or thromboembolism
2
V
Vascular disease
1
A
Age 65-74
1
Sc
Female
1
http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016.
Annual stroke risk
CHA2DS2-VASC Score
Stroke risk %
0
0
1
1.3
2
2.2
3
3.2
4
4.0
5
6.7
6
9.8
http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016.
CHA2Ds2-VASc
SCORE
RISK
ANTICOAGULATION THERAPY
0
Low
None (consider adding aspirin 75-325 mg
daily)
1
Moderate
Oral anticoagulation or aspirin (above dosing)
2 or greater
High
Oral anticoagulation
http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016.
Patient case
AW is a 74 year old female recently diagnosed with atrial
fibrillation. She has a history of hypertension and her
blood pressure is well-controlled with lisinopril 10 mg
daily. She also takes a calcium and vitamin D
supplement daily. She is going to start on metoprolol XL
25 mg daily for rate control.
What is her CHA2DS2-VASc?
Would you manage her with an anticoagulant?
Patient case
AW is a 74 year old female recently diagnosed with atrial
fibrillation. She has a history of hypertension and her
BP is well-controlled with lisinopril 10 mg daily. She
also takes a calcium and vitamin D supplement daily.
CHA2DS2-VASc score:
1 point for hypertension, 1 point for age, and 1 point for
being female = score of 3
Would you manage her with an anticoagulant?
Yes!
CHA2Ds2-VASc
Calculator
• CHA2DS2-VASc Calculator
http://www.mdcalc.com/cha2ds2-vasc-score-for-atrial-fibrillation-stroke-risk/. Last accessed September 27, 2016.
Anticoagulants
• ISMP* high-risk medication
• Bear heightened risk of causing significant patient harm when
they are use.
• The Joint Commission: Hospital national patient safety goal
number 3
• Reduce the likelihood of patient harm associated with the use
of anticoagulant therapy
• Use approved protocols for management of anticoagulant
therapy
• Obtain baseline laboratory work and provide ongoing lab
monitoring (have policy)
• Provide ongoing education to prescribers, staff, patients, and
families
*Institute for Safe Medication Practices
http://www.ismp.org/selfassessments/hospital/2011/definitions.pdf. Last accessed September 27, 2016
http://www.jointcommission.org/assets/1/6/2015_NPSG_HAP.pdf. Last accessed September 27, 2016
True or false
Anticoagulants dissolve blood clots
FALSE!!!!
Anticoagulants prevent new blood clots from forming
and prevent existing blood clots from getting bigger
Patient case
It’s the year 2009…
ML is a 64-year-old male with history of hypertension
who is seen in the emergency department (ED) for
increased shortness of breath. He is diagnosed with 6
pulmonary emboli (PE). He is started on enoxaparin
(Lovenox®) 1 mg/kg BID in the ED, and needs to be
discharged on an oral medication.
How would this patient’s PE be managed back in 2009?
Oral
anticoagulants
Prior to 2010:
• Warfarin (Jantoven®, Coumadin®)
Warfarin
• Approved for human use in 1954
• Brand names: Jantoven®, Coumadin®
• Available in the following strengths (daily dose varies):
• Same color for different strengths regardless of
manufacturer: “Please let Greg Brown bring peaches to your
wedding”
Warfarin
Mechanism of action: inhibits vitamin K epoxide
reductase vitamin K-dependent clotting factors II, VII,
IX, and X, as well as anticoagulant proteins C and S
Warfarin
pharmacokinetics
• Warfarin is an enantiomer (S is 3-5x more potent than R)
• Absorption:
• Complete oral absorption, peak concentrations in 4 hours
• Distribution:
• Small volume of distribution, highly protein bound (99%)
• Metabolism:
• CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4
• Elimination:
• Inactive metabolites excreted in urine;
• R-warfarin half-life 37-89 hours; S-warfarin half-life 21-43
hours
Warfarin
Depletion of factors II, VII, IX and X takes time
• Factor VII half-life: 4-6 hours
• Factor IX half-life: 24 hours
• Factor X half-life: 48-72 hours
• Factor II half-life: 60 hours
• Protein C half-life: 8 hours
• Protein S half-life: 30 hours
Risk of hypercoaguable state during first few days of
treatment due to depletion of protein C and S
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Warfarin
• Administration:
• Take po (by mouth) once daily with or without food
(usually in the evening)
• Take at same time every day
• Pregnancy/Breastfeeding
• Pregnancy category X
• Major congenital malformations, fatal fetal hemorrhage, and
an increased risk of spontaneous abortion and fetal mortality
• Compatible with breastfeeding
https://www.drugs.com/pro/warfarin.html. Last accessed September 27, 2016.
Warfarin
Lab monitoring
• Warfarin prolongs prothrombin time (dependent on
factors II, VII and X)
• International Normalized Ratio (INR)
• Standardized measurement of how long it takes blood to
clot
• INR = (prothrombintest / prothrombincontrol)ISI
• ISI = international sensitivity index
• Warfarin dosing depends on INR results
http://www.myvmc.com/investigations/blood-clotting-international-normalised-ratio-inr/ Last accessed September 27, 2016.
Warfarin indications
and INR range
Indication
INR goal range
Venous thromboembolism
(VTE):
Deep vein thrombosis (DVT)
or pulmonary embolism (PE)
2.0-3.0
Atrial fibrillation
CHA2DS2-VASc score 1 or
greater
2.0-3.0
Cardioversion to normal sinus
rhythm
2.0-3.0
Comments
Enoxaparin
preferred for VTE
with malignancy
3 weeks precardioversion and 4
weeks post
Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy: Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST.
2012;141:e152s-184s.
http://www.uwhealth.org/files/uwhealth/docs/pdf2/Ambulatory_Warfarin_Guideline.pdf Last accessed September 27, 2016
Warfarin indications
and INR range
Indication
INR goal range
Comments
Valvular heart disease
Mechanical heart valves
2.0-3.0 (aortic)
2.5-3.5 (mitral)
Bioprosthetic valves
aspirin or short-term
warfarin then aspirin
Ischemic stroke
Cardioembolic stroke or TIA
2.0-3.0
Non-cardioembolicuse antiplatelet
Can use aspirin 81-325
mg daily
Thrombophilias:
Antiphospholipid Syndrome
Homozygous Factor V Leiden
Deficiency of Protein C, S or
Anti- Thrombin
2.0-3.0
Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy: Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST.
2012;141:e152s-184s.
http://www.uwhealth.org/files/uwhealth/docs/pdf2/Ambulatory_Warfarin_Guideline.pdf Last accessed September 27, 2016
Warfarin duration
of therapy
Indication
Duration of therapy
VTE
At least 3 months then re-evaluate
Extended for second episode of unprovoked
Atrial fibrillation
Long-term
Mechanical heart valves
Long-term
Ischemic stroke
Cardioembolic stroke or TIA
3-6 months; long-term
Thrombophilias
Indefinite
Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy: Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST.
2012;141:e152s-184s.
http://www.uwhealth.org/files/uwhealth/docs/pdf2/Ambulatory_Warfarin_Guideline.pdf Last accessed September 27, 2016
Warfarin adverse
effects
• Common (greater than 10%)
• Bleeding
• Rare (less than 1%)
• Intracranial bleeding
• Skin necrosis
• Tissue necrosis
• Purple toe syndrome
• Usually occurs within 3-8 weeks of warfarin initiation
• Bleeding into blood vessel plaque  cholesterol embolization
in feet (and sometimes hands)
• Must stop warfarin!
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Purple toe syndrome
Bleeding
• Signs and symptoms of bleeding:
•
•
•
•
•
•
•
•
•
•
Nosebleeds
Bleeding gums
Coughing up blood
Abnormal vaginal bleeding
Bright red blood when using restroom
“Coffee ground” vomit
Black, tarry stools (ask about iron!)
Bloody or brown urine
Unexplained bruising
Severe headache
Clotting
• Signs and symptoms of clotting:
•
•
•
•
•
•
•
Severe pain/swelling/redness in arms or legs
Sudden shortness of breath
Chest pain
Severe headache/dizziness
Slurred speech
Sudden changes in vision
STROKE!
Sudden weakness in arms or legs
HAS-BLED
• From a one year observational study of over 5000
atrial fibrillation patients on anticoagulation
• Estimates risk over 1 year of major bleeding
• Major bleeding: bleeding requiring hospitalization,
decrease in hemoglobin more than 2 g/L, and/or patient
requiring transfusion
• Assigns 1 point for different risk factors
• Points correlate with risk of bleeding while on
anticoagulants
http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016.
HAS-BLED
• Hypertension
• Abnormal renal and liver function
• Stroke
• Bleeding
• Labile INRs
• Elderly
• Drugs or alcohol
http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016.
HAS-BLED
Condition
Points
H
Hypertension (uncontrolled; systolic over 160 mmHg)
1
A
Abnormal renal function (dialysis, transplant, SCr* over 2.26 mg/dl)
Abnormal liver function (cirrhosis, bilirubin 2x upper limit of
normal, AST/ALT/AP 3X upper limit of normal)
1
1
S
Stroke (prior history of stroke)
1
B
Bleeding (predisposition to bleeding or prior major bleeding)
1
L
Labile INRs (time in therapeutic range less than 60%)
1
E
Elderly (age over 65)
1
D
Drugs (medication usage that predisposes to bleeding)
Alcohol (greater than 8 drinks per week)
1
1
*SCr = serum creatinine
http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016.
HAS-BLED
HAS-BLED
score
Risk
0
0.9% over 1 year; 1 major bleed per 100 patients; low risk
1
3.4% over 1 year; 1 major bleed per 100 patients; low risk
2
4.1% over 1 year; 2 major bleeds per 100 patients; moderate risk
3
5.8% over 1 year; ~4 major bleeds per 100 patients; high risk
4
8.9% over 1 year; ~9 major bleeds per 100 patients; high risk
5
9.1% over 1 year; 12 major bleeds per 100 patients; high risk
6-9
Scores over 5 too rare to determine risk
http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/
HAS-BLED calculator
• http://www.mdcalc.com/has-bled-score-for-majorbleeding-risk/
http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016.
HAS-BLED score
• RG is an 81 year old recently diagnosed with atrial
fibrillation with a CHA2DS2-VASc score indicating
anticoagulation therapy. She has a history of hypertension
(BP well controlled with SBP less than 140 mmHg) and
spinal stenosis for which she uses acetaminophen 500 mg
BID with effect. She was previously taking NSAIDs, but
had a major GI bleed and discontinued therapy. Her only
other medications include hydrochlorothiazide 25 mg daily
for hypertension and calcium/vitamin D. Her recent SCR
and CrCl were within normal limits. She occasionally
drinks ETOH (1 drink/week). She is concerned about
bleeding side effects from anticoagulation therapy.
• What is RG’s HAS-BLED score?
HAS-BLED score
• 1 point for age (over 65)
• 1 point for history of previous major bleed
• Her hypertension is controlled, so no points
• HAS-BLED score = 2 (moderate bleeding risk)
• Would start anticoagulation therapy, but educate
patient on signs and symptoms of bleeding to watch
out for
http://www.mdcalc.com/has-bled-score-for-major-bleeding-risk/ Last accessed September 27, 2016.
Warfarin reversal
• Indications for reversal of warfarin anticoagulation:
• Severe bleeding
• Surgery
• Supratherapeutic INR
Warfarin reversal
Garcia and Crowther. Reversal of warfarin. Circulation. 2012;125 (23)
Warfarin reversal
No significant bleeding
INR less than 10
No vitamin K
INR greater than 10
Consider 2.5-5 mg oral vitamin K
Urgent reversal with any INR elevation
*Severe/major bleeding
* Life threatening hemorrhage
*Urgent surgery required
Vitamin K 10 mg IV piggy back over 30 minutes AND
3 factor PCC (Profilnine®) AND
1-2 units of fresh frozen plasma
Prothrombin complex
concentrates
• 3-PCC (Profilnine ®, Bebulin®)
• Contains factors II, IX and X with minimal factor VII
• Usually used in combination with factor VII and FFP
and vitamin K
• 4-PCC (Kcentra®)
• Contains therapeutic concentrations of factors II, VII, IX
and X
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Warfarin
interruption
• Sometimes anticoagulant therapy need to be stopped
for a planned procedure
• Warfarin interruption depends on the bleeding risk
associated with the procedure
Procedure bleeding
risk
High bleeding risk
Low bleeding risk
Minimal bleeding risk
Cancer surgery
Major orthopedic
Reconstructive
Transurethral prostate
resection, bladder resection
or tumor ablation
Nephrectomy, kidney
biopsy
Colonic polyp resection
Bowel resection
(PEG) placement, ERCP
Procedure duration >45
minutes)
Pacemaker implant*
Minor dental procedures
Cutaneous/lymph node
biopsy
Shoulder/foot/hand
surgery
Coronary angiograph
Gastrointestinal endoscopy
or Colonoscopy +/- biopsy
Abdominal hysterectomy
Lap. Cholecystectomy
Abdominal hernia repair
Hemorrhoidal surgery
Bronchoscopy +/- biopsy
Epidural inj w/ INR <1.2
Pacemaker battery change
Arthroscopy
Minor derm procedures
Cataracts
Dental cleanings and
fillings
*Recent evidence suggests lower risk
Management of anticoagulation in the per-procedural periodhttp://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016
Warfarin
interruption
• Do not interrupt warfarin for minimal bleeding
procedures
• Warfarin interruption for low and high risk bleeding
procedures also depends on patient’s thromboembolic
risk
Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016
Warfarin
interruption
High risk bleed
Low risk bleed
High risk clot
• Any mechanical mitral valve
• Stroke w/in last 6 months (valve)
• CHA2DS2-VASc greater than 5
• Stroke w/in last 3 months (AF)
• VTE last 3 months
• Thrombophilias
Interrupt warfarin
therapy and bridge with
LMWH*
Consider interrupting
warfarin; bridge if
interrupting warfarin
therapy
Medium risk clot
• Aortic valve with high stroke risk
• CHA2DS2-VASc 3-4
• VTE last 3-12 months
• Recurrent VTE
• Cancer
Interrupt warfarin
therapy and consider
bridge with LMWH
Consider interrupting
with or without
LMWH bridge
Low risk clot
• Aortic valve with low stroke risk
• CHA2DS2-VASc less than 2
• VTE more than 12 months ago
Interrupt warfarin;
bridge not indicated
Interrupt warfarin;
bridging not necessary
*low molecular weight heparin
Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016
Warfarin
interruption
• Hold warfarin 5 days prior to procedure
• If indicated, bridge with LMWH
• Enoxaparin (Lovenox®) 1 mg /kg BID (1 mg/kg daily if CrCl
less than 30 ml/min)
• Baseline platelets, H/H, serum creatinine
• Start LMWH when INR is less than 2.0
• Last dose of LMWH at least 24 hours prior to procedure
• Resume warfarin in the evening after procedure
• Resume LMWH on day 1 post procedure (low bleeding
risk) or day 2 post procedure (high bleeding risk)
Douketis JD, Spyropolous AC, Spencer FA et al. “Perioperative Management of Antithrombotic Therapy:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines”. Chest. 2012;141(2_suppl):e326S-e350S.
Warfarin
drug interactions
Risk of increased INR
Acetaminophen (vitamin K cycle)
Macrolides (2C9 inhibition)
Allopurinol (2C9 inhibition)
Metronidazole (2C9/3A4 inhibition)
Amiodarone (2C9 inhibition)
Phenytoin (displaces protein binding
sites)
Antibiotics (decrease gut flora that
produces vitamin K)
Proton pump inhibitors (2C9
inhibition)
Corticosteroids (unknown)
Quetiapine (2C9/3A4 inhibition)
Fluconazole (2C9 inhibition)
*SSRIs
Fluoroquinolones (2C9 inhibition)
TCAs (increased warfarin absorption)
Levothyroxine (increased metabolism
of clotting factors)
Trimethoprim/sulfamethoxazole
(2C9 inhibition)
(some 2C9 inhibition; also
decreased platelet aggregation)
*SSRIs selective serotonin reuptake inhibitors **TCAs tricyclic antidepressants
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Warfarin
drug interactions
Risk of decreased INR
Anti-thyroid medication (decreased
metabolism of clotting factors)
Phenytoin (2C9 induction)
Barbiturates (2C9 induction)
Rifampin (2C9 induction)
Bile acid sequestrants (decreased
warfarin absorption)
St John’s Wart (2C9 induction)
Carbamazepine (2C9 induction)
Sucralfate (decreased warfarin
absorption)
Diuretics* (increased concentration
of clotting factors)
Therapeutic multivitamins (if
contain vitamin K
Nafcillin (2C9 induction)
*Ethacrynic acid displaces warfarin from binding sites and can increase INR
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Warfarin
drug interactions
Increased risk of bleeding
Aspirin
Anti-platelet agents
Non-steroidal anti-inflammatory drugs (NSAIDs)
Fish oil
SSRIs
SNRIs (selective norepinephrine reuptake inhibitors)
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
True or False
Patients taking warfarin should never eat foods rich in
vitamin K since vitamin K decreases the effectiveness of
warfarin
FALSE!!!!
Vitamin K rich foods can decrease the INR, but the key
is consistency in diet and monitoring
Warfarin dietary
interactions
Foods the decrease INR
Foods that increase INR
Vitamin K containing foods*
Cranberries (sauce, juice, etc.)
High protein food/drinks
Grapefruit (fruit, juice, etc.)
Foods containing bromelain
(pineapple, other tropical fruits)
Alcohol
Dietary consistency is key to keeping INR in therapeutic range!
*see vitamin K resource for comprehensive list of vitamin K containing foods:
QAS vitamin K registry. http://www.pkdiet.com/pdf/vit/vitkreg.pdf. Last accessed September 27, 2016
Vitamin K
containing foods
Low vitamin K
(0-9 mcg)
Medium vitamin K
(10-24 mcg)
High vitamin K
(25 or more mcg)
Apples
Blackberries/blueberries
Asparagus
Berries
(strawberries/raspberries)
Celery
Avocado
Corn
Cucumber (with skin)
Broccoli
Cucumber (without skin)
Grapes (red or green)
Brussel sprouts
Lettuce (butterhead)
Lettuce (iceberg/romaine)
Cabbage
Oil (olive, peanut)
Oil (vegetable)
Kale
Onions
Peppers (green/red-cooked)
Mayonnaise
Peaches
Pistachios
Peas
Peppers (green/red-raw)
Plums (canned)
Pumpkin (canned)
Tomatoes
Tomato paste
Spinach
Tea (chamomile, decaf)
Vegetable juice (canned)
Tea leaves (black, green)
QAS vitamin K registry. http://www.pkdiet.com/pdf/vit/vitkreg.pdf. Last accessed September 27, 2016
Warfarin
Other factors that can affect INR
Activity level
Bowel habits
Fluid status
Smoking
Patient case
It’s the year 2009…
ML is a 64-year-old male with history of hypertension
who is seen in the emergency department (ED) for
increased shortness of breath. He is diagnosed with 6
pulmonary emboli (PE). He is started on enoxaparin
(Lovenox®) 1 mg/kg BID in the ED, and needs to be
discharged on an oral medication.
How would this patient’s PE be managed?
Patient case
• Patient would be started on warfarin for outpatient
anticoagulation for PE
• What dose of warfarin would you start the patient on?
• Would you continue the enoxaparin?
• If yes, for how long?
Warfarin initiation
• CHEST guidelines: 10 mg x 2 days then 5 mg daily for
“healthy” patients
• Elliot protocol:
• Start patients on 5 mg daily
• Initiate patients on 2.5 mg if patient is elderly, under 50
kg, or on severely interacting medications
Patient case
• What dose of warfarin would you start the patient on?
• 5 mg daily
• Would you continue the enoxaparin?
• Yes
• If yes, for how long?
• Until INR is over 2.0, or for 5 days total
• Subsequent warfarin daily dosing will depend on INR
results
Patient case
• ML is discharged from the hospital on Lovenox 1
mg/kg BID and warfarin 5 mg daily
• He is referred to the Anticoagulation clinic for further
management
Anticoagulation
clinics-The past
• Point of care testing
• Warfarin dosing per protocol
• Patient assessment
• Initial and ongoing education
• Over the phone management:
• PT/INR laboratory monitoring
• Visiting nurse point of care testing
• Patient home testing
Patient case
It’s the year 2016…
ML is a 64-year-old male with history of hypertension
who is seen in the emergency department (ED) for
increased shortness of breath. He is diagnosed with 6
pulmonary emboli (PE). He needs to be started on an
oral anticoagulant.
How would this patient’s PE be managed in the present
day?
Current oral
anticoagulants
• Warfarin (Jantoven®, Coumadin®)
• Dabigatran (Pradaxa®)
• Rivaroxaban (Xarelto®)
• Apixaban (Eliquis®)
• Edoxaban (Savaysa®)
DOACs
NOACs
TSOACs
DOACS/NOACs/TSOACs
• DOAC = Direct-acting oral anticoagulant
• NOAC = Novel oral anticoagulant
• NOAC = New oral anticoagulant
• NOAC = Non-vitamin K antagonist oral anticoagulant
• NOAC = Non-vitamin K oral anticoagulant
• TSOAC= Target-specific oral anticoagulant
NOACs
• Dabigatran (Pradaxa®)
• Rivaroxaban (Xarelto®)
• Apixaban (Eliquis®)
• Edoxaban (Savaysa®)
Dabigatran
• Brand name: Pradaxa
• Approved: 2010 (non-valvular atrial fibrillation); expanded in
2014 (VTE treatment)
• Pivotal trial
• RE-LY
• Randomized Evaluation of Long-Term Anticoagulation Therapy
• Dabigatran low-dose non-inferior to warfarin for stroke prevention;
high-dose superior to warfarin; similar bleeding rates
• RELY-ABLE continuation study
Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous
thromboembolism following total hip or knee arthroplasty: A meta-analysis. Thromb Haemost 2009;101(1):77-85.
Dabigatran
Mechanism of action: Direct thrombin inhibitor that
inhibits both free and clot-bound thrombin
Dabigatran
pharmacokinetics
• Absorption:
• Pro-drug
• Bioavailability is only 3-7%
• Distribution:
• Only 35% protein bound
• Metabolism:
• Substrate of P-glycoprotein (P-gp)
• Active metabolites
• Elimination:
• Primarily excreted in the urine
• Half-life 12-17 hours
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Dabigatran
• Available strengths: 75 mg and 150 mg capsules
• 110 mg capsule available in Europe and Canada
• Atrial fibrillation dosing:
•
•
•
•
Creatinine clearance (CrCl) more than 30 ml/min:150 mg po twice daily
CrCl 15-30 ml/min: 75 mg po twice daily
CrCl less than 15 ml/min: not recommended
CrCl 30-50 ml/min with co-administration of P-gp inhibitor: 75 mg po
twice daily
• CrCl less than 30 ml/min: Avoid co-administration
• VTE dosing is the same
• Beers criteria recommends against using in patients over age 75
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Creatinine clearance
• Estimation of renal function
• Used for drug dosing adjustment
• Cockcroft-gault equation:
• CrCl = [(140 - age) x weight*] / (Scr^ x 72) (x 0.85 for females)
*Weight: Use IBW (ideal body weight)
• Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
• Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.
• If ABW (actual body weight) is less than the IBW use ABW
• Use adjusted body weight (AjBW) if patient obese
• AjBW = IBW + 0.4 (ABW – IBW)
^SCr = serum creatinine
Creatinine clearance
calculator
• http://www.glob
alrph.com/multi
ple_crcl_2012.ht
m
True or False
• Dabigatran can be put in a weekly medi-planner with a
patient’s other medications
FALSE!!!!
Dabigatran requires special storage…
Dabigatran
• Storage:
• Must remain in original packaging
• Use within 4 months of opening container
• Administration:
• Take with or without food
• Swallow capsules wholes
• Pregnancy/Breastfeeding
• Pregnancy Category C
• Breastfeeding risk unknown
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Dabigatran
• Lab monitoring
• No routine anticoagulation monitoring required
• Can prolong aPTT and ECT
• Monitor serum creatinine and adjust doses as necessary
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Dabigatran
adverse effects
• Common (greater than 10%)
• Bleeding
• Infrequent (1-10%)
•
•
•
•
•
GI bleeding
Edema
Dyspepsia
Pruritus
Rash
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Dabigatran reversal
• Idarucizumab (Praxbind®)
• Humanized monoclonal antibody that binds to
dabigatran and its metabolites
• 5 mg IV (provided as 2.5 mg/50 ml)
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Dabigatran reversal
Moderate bleeding
Symptomatic treatment
Fluid replacement
Mechanical compressions
Blood product transfusion
Consider FFP
Urgent reversal
*Severe/major bleeding
* Life threatening hemorrhage
*Urgent surgery required
Praxbind ® 2.5 grams x 2 doses
OR
3F-PCC (Profilnine®) and 1-2 units of FFP
Dabigatran
interruption
Renal
Function
Low
bleeding risk
High
bleeding risk
Resumption- Resumptionlow bleeding high
risk
bleeding risk
CrCl greater
than 50
ml/min
Last dose 2
days before
procedure
Last dose 3
days before
procedure
Day after
procedure
2-3 days after
procedure
CrCl 30-50
ml/min
Last dose 3
days before
procedure
Last dose 4-5
days before
procedure
Day after
procedure
2-3 days after
procedure
Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016
Dabigatran drug
interactions
• P-gp inducers
• P-gp inhibitors
• Medications that increase bleeding risk
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
P-gp inducers
P-gp inducers
Avasimibe
Carbamazepine
Phenobarbital (primidone)
Phenytoin (fosphenytoin)
Rifampin
St. John’s wort
Tipranavir/ritonavir
Drug development and drug interactions: table of substrates, inhibitors, and inducers.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664
.htm. Last accessed September 27, 2016
P-gp inhibitors
P-gp Inhibitors
Amiodarone
Macrolides (azithromycin,
clarithromycin, erythromycin,
telithromycin)
Cycylosporine
CCB (diltiazem, felodipine,
nifedipine, verapamil)
PPIs ((lansoprazole, omeprazole,
pantoprazole)
Dronaderone
Ranolazine
Grapefruit juice
Quinidine
Ketoconazole (and other anti-fungal) Saquinavir
Lopinavir
Statins (atorvastatin, lovastatin,
simvastatin
Drug development and drug interactions: table of substrates, inhibitors, and inducers.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664
.htm. Last accessed September 27, 2016
Dabigatran drug
interactions
Medications that increase bleeding risk
Aspirin
Anti-platelets
NSAIDs
SSRIs
SNRIs
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Dabigatran dietary
considerations
• Avoid grapefruit juice
• Limit alcohol intake
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Rivaroxaban
• Brand name: Xarelto ®
• Approved in 2011 (non-valvular atrial fibrillation, VTE
prophylaxis) and expanded in 2012 (VTE treatment)
• Pivotal trial
• ROCKET-AF
• Rivaroxaban Once Daily Oral Direct Factor Xa
Inhibition Compared with Vitamin K Antagonism for
Prevention of Stroke and Embolism Trial in Atrial
Fibrillation
• Rivaroxaban non-inferior to warfarin in preventing stroke
or systemic embolism with less bleeding
Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEJM. 2011 Sep
8;365(10):883-91
Rivaroxaban
• Mechanism of action: factor Xa inhibitor
Rivaroxaban
pharmacokinetics
• Absorption
• Bioavailability 80-100% for 10 mg dose with or without food
• 15-20 mg dosage should be taken with food to increase
bioavailability
• Distribution
• 92-95% protein bound
• Metabolism
• CYP 3A4 and P-gp substrate
• Elimination
• 35% excreted unchanged in urine
• Half life 5-9 hours (11-13 hours in elderly)
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Rivaroxaban
• Available strengths: 10 mg, 15 mg, 20 mg
• Atrial fibrillation dosing: 20 mg daily with evening meal
• CrCl 15-50 ml/min: 15 mg daily with evening meal
• CrCl less than 15 ml/min: avoid use
• VTE treatment: 15 mg BID with food for 21 days, then 20 mg daily with
evening meal
• 20 mg daily with evening meal for extended VTE treatment
• CrCl less than 30 ml/min: avoid use
• VTE prophylaxis: 10 mg daily for 12 days post knee surgery or 35 days
post hip surgery
• CrCl less than 30 ml/min: avoid use
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Rivaroxaban
• Special instructions:
• Do not administer to patients receiving a combined P-gp
and moderate 3A4 inhibitor (if CrCl 15-80 ml/min)
• Administration:
• 10 mg with or without food; 15 and 20 mg with evening
meal
• Tablets can be crushed (crushed tablets stable up to 4
hours)
• Pregnancy/Breastfeeding:
• Pregnancy category C
• Not recommended with breastfeeding
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Rivaroxaban
• Lab monitoring:
• No routine anticoagulation monitoring required
• Can affect INR
• Anti-FXa
• Monitor serum creatinine and adjust doses as necessary
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Rivaroxaban
adverse effects
• Infrequent (1-10%)
•
•
•
•
•
Bleeding (including GI bleeding)
Back pain
Dyspepsia
Muscle cramps
Pruritus
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Rivaroxaban
reversal
Moderate bleeding
Symptomatic treatment
Fluid replacement
Mechanical compressions
Blood product transfusion
Consider FFP
Urgent reversal
*Severe/major bleeding
* Life threatening hemorrhage
*Urgent surgery required
3F-PCC (Profilnine®) and 1-2 units of FFP
Rivaroxaban
reversal
• Andexanet alfa (AndexXa®)
• Recombinant modified human factor Xa decoy protein
(intravenous injection)
• Decreases anti-Xa activity by 89%
• Not FDA approved yet as of 9/2016
Rivaroxaban
interruption
Renal
Function
Low
bleeding risk
High
bleeding risk
Resumption- Resumptionlow bleeding high
risk
bleeding risk
CrCl greater
than 50
ml/min
Last dose 2
days before
procedure
Last dose 3
days before
procedure
Day after
procedure
2-3 days after
procedure
CrCl 30-50
ml/min
Last dose 2
days before
procedure
Last dose 3
days before
procedure
Day after
procedure
2-3 days after
procedure
CrCl 15-29
ml/min
Last dose 3
days before
procedure
Last dose 4
days before
procedure
Day after
procedure
2-3 days after
procedure
Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016
Rivaroxaban
drug interactions
• P-gp substrate
• P-gp inhibitors and inducers
• See dabigatran tables
• 3A4 substrate
• 3A4 inhibitors
• 3A4 inducers
• Medications that increase bleeding risk
• See dabigatran table
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
3A4 inhibitors
Strong 3A4
inhibitors
Boceprevir,
clarithromycin,
conivaptan,
grapefruit juice, indinavir,
itraconazole, ketoconazole,
lopinavir/ritonavir,
mibefradil,
nefazodone, nelfinavir,
posaconazole, ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole
Moderate 3A4
inhibitors
Amprenavir, aprepitant,
atazanavir, ciprofloxacin,
darunavir/ritonavir,
diltiazem, erythromycin,
fluconazole,
fosamprenavir, grapefruit
juice,
imatinib, verapamil
Mild 3A4 inhibitors
Alprazolam, amiodarone,
amlodipine, atorvastatin,
bicalutamide, cilostazol,
cimetidine,
cyclosporine, fluoxetine,
fluvoxamine, ginkgo,(5)
goldenseal,(5)
isoniazid, nilotinib,
oral contraceptives,
ranitidine, ranolazine,
tipranavir/ritonavir,
zileuton
Drug development and drug interactions: table of substrates, inhibitors, and inducers.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664
.htm. Last accessed September 27, 2016
3A4 inducers
Strong 3A4 inducers
Moderate 3A4 inducers
Avasimibe,
Bosentan, efavirenz,
carbamazepine,
etravirine, modafinil,
phenytoin, rifampin, St. nafcillin
John’s wort
Mild 3A4 incuders
Amprenavir, aprepitant,
armodafinil,
echinacea,pioglitazone,
prednisone, rufinamide
Drug development and drug interactions: table of substrates, inhibitors, and inducers.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664
.htm. Last accessed September 27, 2016
Rivaroxaban dietary
considerations
• Avoid grapefruit juice
• Take 15 mg and 20 mg dosages with food
• Limit alcohol intake
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Apixaban
• Brand name: Eliquis ®
• Approved: 2014 (non-valvular atrial fibrillation, VTE
prophylaxis, VTE treatment)
• Pivotal trial:
• ARISTOTLE
• Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation
• Apixaban superior to warfarin in preventing stroke and
systemic embolism with less intracranial bleeding (similar
GI bleeding rates)
Granger CB, Alexander JH, McMurray JJV et al. “Apixaban versus Warfarin in Patients with Atrial Fibrillation”. NEJM.
2011; 365:981-992
Apixaban
• Mechanism of action: factor Xa inhibitor
Apixaban
pharmacokinetics
• Absorption
• Bioavailability 50 %
• Absorption not affected by food
• Distribution
• Protein binding 87%
• Metabolism
• Metabolized by CYP-3A4
• Also a substrate of P-gp
• No active metabolites
• Elimination
• Some urine and fecal
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Apixaban
• Available strengths: 2.5 mg, 5 mg
• VTE dosing:
• 10 mg (2 of the 5 mg tablets) twice daily x 7 days, then 5 mg twice daily
• VTE prophylaxis following treatment:
• 2.5 mg twice daily
• VTE prophylaxis knee and hip surgery:
• Knee: 2.5 mg twice daily for 12 days starting 12-24 hours post surgery
• Hip: 2.5 mg twice daily for 35 days starting 12-24 hours post surgery
• Atrial fibrillation:
• 5 mg twice daily
• 2.5 mg twice daily if age 80 or greater, serum creatinine 1.5 or greater,
body weight 60 kg or less
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Apixaban
• Administration:
• With or without food
• NPO (nothing by mouth): Crush and suspend the tablet
in 60 ml 5% dextrose solution; administer immediately
through a nasogastric tube (no data for oral
administration of suspension)
• Pregnancy/Breastfeeding:
• Pregnancy category B (increased risk of maternal
bleeding in rats)
• Not recommended in breast-feeding
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Apixaban
• Lab monitoring:
• No routine anticoagulation lab monitoring required
• Anti-factor Xa activity
• Can also affect INR
• Monitor serum creatinine and adjust doses as necessary
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Apixaban
adverse effects
• Infrequent (1-10%)
• Bleeding
•
•
•
•
•
Epistaxis
Hematoma
Hematuria
Hemoptysis
Vaginal bleeding
• Anemia
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Apixaban reversal
Moderate bleeding
Symptomatic treatment
Fluid replacement
Mechanical compressions
Blood product transfusion
Consider FFP
Urgent reversal
*Severe/major bleeding
* Life threatening hemorrhage
*Urgent surgery required
3F-PCC (Profilnine®) and 1-2 units of FFP
Apixaban reversal
• Andexanet alfa (AndexXa®)
• Recombinant modified human factor Xa decoy protein
(intravenous injection)
• Decreases anti-Xa activity by 93%
• Not FDA approved yet as of 9/2016
Apixaban
interruption
Renal
Function
Low
bleeding risk
High
bleeding risk
Resumption- Resumptionlow bleeding high
risk
bleeding risk
CrCl greater
than 50
ml/min
Last dose 2
days before
procedure
Last dose 3
days before
procedure
Day after
procedure
2-3 days after
procedure
CrCl 30-50
ml/min
Last dose 3
days before
procedure
Last dose 4
days before
procedure
Day after
procedure
2-3 days after
procedure
Management of anticoagulation in the per-procedural period. http://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016
Apixaban
drug interactions
• P-gp substrate
• P-gp inhibitors and inducers
• See dabigatran list
• 3A4 substrate
• 3A4 inhibitors and inducers
• See rivaroxaban list
• Medications that increase bleeding risk
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Apixaban dietary
considerations
• Avoid grapefruit juice
• Limit alcohol intake
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Edoxaban
• Brand name: Savaysa ®
• Approved: 2015 for non-valvular atrial fibrillation and
VTE
• Pivotal trial
• ENGAGE AF-TIMI 48
• The Effective Anticoagulation with Factor Xa Next
Generation in Atrial Fibrillation–Thrombolysis in
Myocardial Infarction 48
• Non-inferior to warfarin with less major bleeding and
intracranial bleeding (more GI bleeding with higher dose)
Giugliano RP, Ruff CT, Braunwald E et al. “Edoxaban versus Warfarin in Patients with Atrial Fibrillation”.
NEJM. 2013; 369:2093-2104
Edoxaban
• Mechanism of action: factor Xa inhibitor
Edoxaban
pharmacokinetics
• Absorption
• Bioavailability 62%, not affected by food
• Distribution
• Low protein binding
• Metabolism
• Minimally metabolized by CYP 3A4
• P-gp substrate
• Elimination
• Primarily excreted unchanged in urine
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Edoxaban
• Available strengths: 15 mg, 30 mg, 60 mg
• Non-valvular atrial fibrillation dosing:
• CrCl 51-94 ml/min: 60 mg daily
• CrCl 15-50 ml/min: 30 mg daily
• CrCl over 95 ml/min: DO NOT USE
• VTE treatment:
• Greater than 60 kg: 60 mg daily following 5-10 days of
initial treatment with parenteral anticoagulant
• Less than 60 kg: 30 mg daily following 5-10 days of
initial treatment with parenteral anticoagulant
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Edoxaban
• Administration:
• May be taken with or without food
• Pregnancy/Breastfeeding:
• Pregnancy category C
• Breastfeeding: unknown effects
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Edoxaban
• Lab monitoring:
• No routine anticoagulation monitoring required
• Can prolong PT/INR and aPTT
• Anti-FXa activity
• Monitor serum creatinine and adjust doses as necessary
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Edoxaban
adverse effects
• Infrequent (1-10%)
• Bleeding
•
•
•
•
Epistaxis
GI bleeding
Hematuria
Vaginal bleeding
• Anemia
• Elevated hepatic enzymes
• Rash
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Edoxaban reversal
Moderate bleeding
Symptomatic treatment
Fluid replacement
Mechanical compressions
Blood product transfusion
Consider FFP
Urgent reversal
*Severe/major bleeding
* Life threatening hemorrhage
*Urgent surgery required
3F-PCC (Profilnine®) and 1-2 units of FFP
Edoxaban reversal
• Aripazine (aka ciraparantag and PER977)
• Cationic molecule designed to bind specifically to
novel oral anticoagulants
• Currently in clinical trials (FDA fast track in 2015)
Edoxaban
interruption
Renal
Function
Low
bleeding risk
High
bleeding risk
Resumption- Resumptionlow bleeding high
risk
bleeding risk
CrCl greater
than 50
ml/min
Last dose 2
days before
procedure
Last dose 3
days before
procedure
Day after
procedure
Management of anticoagulation in the per-procedural periodhttp://qio.ipro.org/wpcontent/uploads/2015/10/AQIN_MAP_5-1-2014.pdf Last accessed September 27, 2016
2-3 days after
procedure
Edoxaban
drug interactions
• P-gp inhibitors and inducers
• See dabigatran table
• Drugs that increase risk of bleeding:
• Aspirin
• Anti-platelets
• NSAIDs
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Edoxaban dietary
considerations
• Avoid grapefruit juice
• Limit alcohol intake
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Anticoagulant
comparison
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Generic
Yes
No
No
No
No
Average cost
per month*
$10.72
$340.20
$344.60
$346.01
$292.61
FDA approval
date
Pre-1982
October 2010
July 2011
Dec 2012
Jan 2015
FDA approved
indications
AF (w/ valves) AF (no valves)
VTE treatment VTE treatment
& prophylaxis
AF (no valves)
VTE treatment
& prophylaxis
AF (no valves)
VTE treatment
& prophylaxis
AF (no valves)
VTE treatment
& prophylaxis
Dosage
Variable
75 or 150 mg
10, 15, 20 mg
2.5 or 5 mg
30, 60 mg
Dosage
frequency
Daily
BID
Daily
(BID loading
dose VTE)
BID
Daily
Onset
Slow
Rapid
Rapid
Rapid
Rapid
*Average cost per insurance claim made. https://masshealthdruglist.ehs.state.ma.us/MHDL/pubtheradetail.do?id=110
Last accessed September 28, 2016
Anticoagulant
comparison
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Kidney
function
No
Yes (kidney
function
affects dose)
Yes (kidney
function
affects dose)
Yes (kidney
function
affects dose)
Yes (kidney
function
affects dose)
Pregnancy/bre
astfeeding
Preg: X
BF: Yes
Preg: C
BF: No
Preg: C
BF: No
Preg: B
BF: No
Preg: C
BF: No
Drug
interactions
Many
Some
Some
Some
Some
Dietary
interactions
Yes, many
GFJ
ETOH
GFJ
ETOH
GFJ
ETOH
GFJ
ETOH
Lab
monitoring
(anticoag)
Yes
No
No
No
No
Reversal
Vitamin K
PCC and FFP
Praxbind
PCC and FFP
PCC and FFP
PCC and FFP
PCC and FFP
Patient case
It’s the year 2016…
ML is a 64-year-old male with history of hypertension
who is seen in the emergency department (ED) for
increased shortness of breath. He is diagnosed with 6
pulmonary emboli (PE). He needs to be started on an
oral anticoagulant.
How would this patient’s PE be managed in the present
day?
Current oral
anticoagulants
• Warfarin (Jantoven®, Coumadin®)
• Dabigatran (Pradaxa®)
• Rivaroxaban (Xarelto®)
• Apixaban (Eliquis®)
• Edoxaban (Savaysa®)
Chest guidelines
• CHEST guidelines VTE 2016 update
• In patients with DVT of the leg or PE and no cancer, as
long-term (first 3 months) anticoagulant therapy, we suggest
dabigatran, rivaroxaban, apixaban, or edoxaban over
vitamin K antagonist (VKA) therapy (warfarin)
• Initial parenteral anticoagulation is given before dabigatran
and edoxaban, is not given before rivaroxaban and
apixaban, and is overlapped with VKA therapy.
• In patients with DVT of the leg or PE who receive extended
therapy, we suggest that there is no need to change the
choice of anticoagulant after the first 3 months
Kearon C, Akl EA, Ornelas J et al. “Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel
Report”. Chest. 2016;149(2):315-352
Patient case
• ML was started on Xarelto® (rivaroxaban) 15 mg po
BID with food x 21 days then transitioned to 20 mg
daily
• He was not referred to an anticoagulation clinic and
was given minimal education on his new high-risk
medication
Anticoagulation
clinics-The Present
• Point of care testing/over the phone management
• Warfarin dosing per protocol
• Patient assessment
• Initial and ongoing warfarin education
• Enoxaparin bridging recommendations
• Support for switching between warfarin and NOACs
Switching therapies
Switching from dabigatran to warfarin:
Creatinine clearance
Instructions
CrCl greater than 50 ml/min
Start warfarin 3 days before
discontinuing dabigatran
CrCl 31-50 ml/min
Start warfarin 2 days before
discontinuing dabigatran
CrCl 15-30 ml/min
Start warfarin 1 day before
discontinuing dabigatran
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Switching therapies
Switching from warfarin to dabigatran:
• Discontinue warfarin and wait until INR is less than
2.0, then start dabigatran as follows:
Creatinine clearance
Dabigatran dosing
CrCl greater than 30 ml/min
150 mg twice daily
CrCl 15-30 ml/min
75 mg twice daily
CrCl less than 15 ml/min
Not recommended
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Switching therapies
Switching from rivaroxaban to warfarin:
• Stop rivaroxaban and administer LMWH + warfarin
when next dose of rivaroxaban was due (rivaroxaban
can affect INR)
• Continue LMWH until INR is over 2.0
Switching from warfarin to rivaroxaban:
• Stop warfarin and start rivaroxaban once INR is less
than 3.0
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Switching therapies
Switching from apixaban to warfarin:
• If continuous anticoagulation is needed, discontinue
apixaban and start warfarin + LMWH until INR
therapeutic (apixaban can affect INR)
Switching from warfarin to apixaban:
• Discontinue warfarin and start apixaban when INR is
less than 2.0
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Switching therapies
• Switching from edoxaban to warfarin:
• For patients taking edoxaban 60 mg daily, decrease
dosage to 30 mg daily and start warfarin; discontinue
edoxaban when INR is over 2.0
• For patients taking edoxaban 30 mg daily, decrease
dosage to 15 mg daily and start warfarin; discontinue
edoxaban when INR is over 2.0
• Switching from warfarin to edoxaban:
• Stop warfarin and start edoxaban when INR is less than
2.5
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinical pharmacology.com. Updated
August 2016.
Savaysa® patient package insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf Last accessed
September 28, 2016
Patient case
• ML continues on Xarelto 20 mg daily
• He has received minimal education from his
physician’s office regarding this high risk medication
• How can anticoagulation clinics help patients like ML?
Anticoagulation
Clinics: The Future
For patients taking warfarin seen in office*:
• Assess compliance
• Deliver patient education
• Evaluate for diet and drug interactions
• Assess for falls, bleeding or clotting adverse effects
• Reduce risk of complications associated with
anticoagulation therapy
• POC INR and adjust dose as appropriate
• Set up follow-up appointment
*Same for phone managed patients, minus POC testing
Anticoagulation
Clinics: The Future
For patients taking NOACs seen in the office:
• Assess compliance
• Deliver patient education
• Evaluate for diet and drug interactions
• Assess for falls, bleeding or clotting adverse effects
• Evaluate serum creatinine, CrCl, liver function and hemoglobin
• Establish appropriate dose and make adjustments when needed
• Reduce risk of complications associated with anticoagulation
therapy
Anticoagulation
clinics
How can we make the future start now?
• Billing
• Expansion of protocols
• Pilot program
Conclusion
• Coagulation is a complicated process, and anticoagulation
therapy can also be complex
• There are several indications for anticoagulation therapy
• Anticoagulants are high-risk medications, and they require
close monitoring and patient education to ensure proper usage
• There are currently five oral anticoagulants available
• Anticoagulation clinics should consider expanding beyond
patients taking warfarin and offer support for patients taking
newer anticoagulant agents
Questions?
Contact info
Jill Hiers, Pharm.D., BCPS
[email protected]
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