Anticoagulants for venous
thromboembolic disease-
Optimizing the old, ushering in the new.
Daniel A. Forman, DO
RPS Hematology Oncology
daniel.forman@readinghealth.org
RHS Anticoagulation Clinic
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Opening in November 2013.
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Doctors office building. 3
rdfloor.
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Patient will need to be referred by a physician with basic
information (EPIC).
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Pharmacy consult on first visit. Twice year visit.
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You are still in charge! (holding, discontinuation, etc.)
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Point of care testing available.
Goals
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Discuss ways to improve the safety and more
convenient administration of warfarin.
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Review efficacy and pharmacologic issues
associated with the newer oral
Warfarin Basics
VII, XI, X, II Protein C & S
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Inhibits Vitamin K Oxide
Reductase (“recycles” Vit. K)
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Lack vitamin K prohibits
carboxylation of clotting
factors
(Inactive clotting factors produced)•
Genetic factors can predict
warfarin sensitivity or
resistance
–
VKORC1 genotypes
–
CYP2C9 polymorphism
Warfarin Basics
Protein C Anticoagulant 8 hours Protein S Anticoagulant 30 hours
Factor VII Procoagulant 7 hours
Factor IX Procoagulant 24 hours Factor X Procoagulant 36 hours
Factor II Procoagulant 50 hours
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All factors need to be suppressed for
anticoagulant effect (takes two days after
INR therapeutic)!
Avoid loading doses.
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INR reflective of rapid
decline in factor VII.
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Confounds the patient’s
“real dose.”
Warfarin Dosing
• African-American - 6.0-7.0 mg/d • European - mean ~ 5 mg/d • Asian - lower ~ 3.0-3.5 mg/d • Obese ↑14%/S.D. • Age ↓ 13%/decade • Drugs (100’s interactions) Ex. Amiodarone ↓ 24% ~ 6.0-7.0 mg/d • Asian - lower ~ 3.0-3.5 mg/dYou are treating a 55 y.o. black male presenting with an acute L. lower
extremity DVT with IV Heparin, and warfarin that was started on his first
hospital day. His dose of warfarin is 5 mg daily. His day 3 INR was 1.0. What
is the next best action?
A. Stop IV Heparin, start LMWH at therapeutic dosing.
Continue warfarin 5 mg daily.
B. Change to LMWH as above; but increase warfarin 10 mg
daily.
C. Continue IV Heparin. Continue warfarin 5 mg daily.
D. Continue IV Heparin. Increase warfarin 10 mg daily.
Newly diagnosed VTE disease case:
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If the INR = 1.0 on Day 3 then double starting dose.
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LMWH is better than UFH for VTE Disease!
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No lab testing, Less risk HIT, more clot regression, lower
recurrence, lower bleeding, less deaths
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One study reported 60% patient on UFH failed to achieve adequate
aPTT response in 24 hours.
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ACCP 2B recommendation.
Arch Intern Med 1988; 148:1321 Chest 2012; 141: e495S
Patient is a 50 y.o. male with a mechanic AVR and atrial fibrillation with a
difficult to control INR. The patient’s time in the therapeutic range is less than
40 %. His INR today is 5.0, last week it was 1.5. His dose was changed last
week from 5 mg daily to 5 mg alternating with 7.5 mg. The patient has seen a
dietician and said that he does not eat any vitamin k containing foods. Which of
the following is the most reasonable advice?
A. Stop warfarin and start dabigatran (Pradaxa)
150 mg bid.
B. Continue warfarin at the current dose and
recheck the INR in 4 weeks.
C. Stop warfarin and start aspirin therapy.
D. Start low dose daily vitamin K.
Low dose vitamin k for erratic patients
• Multiple studies have suggested that daily low dose vitamin k improves INRcontrol • 100-200 Mcg day
• Increasing dietary intake of vitamin K may suffice • Not recommended for routine use.
Patient is a 70 year old man on warfarin for recurrent DVT. The first DVT was 15 years ago after surgery, and the second one was idiopathic and occurred 3 years ago. The patient’s INR has been at goal on 5 mg daily. You received a call that his most recent
INR is 1.5. The patient is feeling fine, just got back from a cruise, and reports no health changes. What is the next best action?
A. Start enoxaparin 1mg/kg SQ Q12 hours and
increase dose of warfarin to 7.5mg.
B. Increase dose of warfarin to 6mg daily.
C. Continue same dose warfarin and repeat INR
in two weeks.
INR out of range??
Stable patients with single outlier INR will often fall back into therapeutic range at time of recheck with NO adjustment (60% time)
Guidelines support rechecking 1-2 weeks at same dose (2C)
One Observational study suggests only adjusting warfarin dose if INR is less than 1.7 or greater than 3.3.
Schuman et al Throm Res 2010; 125:393 Rose et al J Throm Haemost 2009; 7:94 Chest 2012; 141S: e44
Next patient is a 42 year old female with multiple dvt’s, a second trimester
miscarriage, and laboratory confirmed Anti-phospholipid Antibody Syndrome (APAS). She has to leave work early for INR testing and it is causing conflict with her employer.
Her INR’s have been therapeutic for 6 months on 3 mg alternating with 4mg warfarin every other day. Which of the following is the best approach for this patient?
A. Change to dabigatran 150mg po bid.
B. Change to aspirin 81mg daily.
C. Change to enoxaparin 1.5 mg/kg/day.
D. Check the INR every 3 months.
Give your patient a break!
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PRINT Study-
Randomized Controlled Trial, Concluded:– Stable patients can have INR’s performed every 12 weeks.
– Less dose change (2% vs. 18%) no increased bleeding.
– Accepted by CHEST guidelines (2B).
– Not for Everyone (CHF, New Disease Development, etc).
What is the best way to determine a patient’s
warfarin dose if he was previously on this
medication?
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A. Genetic testing for VKOR1 polymorphisms.
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B. Genetic testing for Cytochrome P450
CYP2C9 polymorphisms.
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C. Dose based upon age, weight, and sex.
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D. Find out his/her previous dose.
You receive a call from the lab with an INR of 8.6. You call the 70 y.o. patient
with PAF and HTN, and he has no bleeding symptoms. He just started
ciprofloxin last week for sinusitis given to him by a provider at an urgent care
clinic. What is the risk of major bleeding in this patient over the next month?
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A. 1%
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B. 5%
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C. 10%
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D. 20%
Supratherapeutic INR’s
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Risk of major bleeding is low (1%) when single
INR 5-9.
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Spurious INR suspected if doesn’t make sense.
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Bleeding risk scoring systems for warfarin are not
better than clinicians judgment.
Donzé J et al. Am J Med 2012; 125:1095 Ageno et al. Chest 2012; 141S: e44Reversing warfarin without bleeding
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Wait it out: INR will fall from 6-10 to < 4 in 2.4 days.
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Vitamin K
1(phytonadione) given orally takes about 1.4 days to
bring INR 6-10 to <4.
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Follow CHEST Guidelines
Rapid Correction of warfarin in an
unstable patient or ICH
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Vitamin K
110 mg iv
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FFP 15ml/kg (4-8 units)
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Prothrombin Complex Concentrates
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3 Factor (II, IX, X) & 4 Factor (II, VII, IX, X)
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Effective, but thrombogenic
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Recommended over FFP by ACCP guidelines.
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rFactor VIIa-
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Not FDA approved for reversal
Your patient is a 50 y.o. male who presented 6 months ago with syncope due
to an idiopathic PE. He is afraid of dying and does not want to stop warfarin,
but he is an international traveler and is concerned about work related travel
due to his INR testing. His INR’s have not been stable. He takes no other
medications. What is the best option for this patient?
A. Stop warfarin and recommend aspirin.
B. Check INR every 3 months.
C. Change to LMWH.
Idiopathic Clot
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Risk of recurrence 10% per year
( 50% long term)•
New paradigm and recommendations are to
continue indefinite therapy for idiopathic
proximal DVT and PE (ACCP 2B)
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Big Picture:
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First 3 months: Vigilant therapeutic anticoagulation
Ideal anticoagulant
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Safe and effective
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Rapid acting
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Available p.o. and parenteral
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Rapid elimination
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Free of drug interactions
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Predictable effect and wide therapeutic window
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No need for monitoring
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Minimal toxicity and side effects
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Reversible with an antidote
Warfarin VS. Newer Rxs
Features Warfarin Newer Agents
Onset Slow (days) Rapid
Dosing Variable Fixed
Half life Long Short
Food effects Yes No
Drug Interactions Many Few
Monitoring Yes No
Antidote Yes No (but short ½ life)
Newer Anticoagulants FDA Approval
Drug Prophylaxis
(ortho) A. Fib ACUTE DVT Prolonged treatment
DVT/PE Dabigatran (Pradaxa)
x
Rivaroxaban (Xarelto)x
x
x
x
Apixaban (Eliquis)X
x
EdoxabanDrug CYP 3A4 P-gp
Dabigatran
(Pradaxa) Yes
Rivaroxaban
(Xarelto) Yes Yes
Apixaban
Dabigatran (Pradaxa)
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Direct thrombin inhibitor
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Renal excretion
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Not for use with
mechanical heart valves
(increase CVA and
bleeding)
NEJM 2013; 369:1206•
Slight increase for CAD
(0.2%) Circulation 2012; 125:669
Rivaroxaban (Xarelto)
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Once daily with food
(BIDfor acute VTE x 3wk)
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Avoid with medications that
affect both the P-gp and
Cytochrome P450 3A4.
Cyp3A4 inhibitors:
• (HIV protease inhibitors, ketoconazole, voriconazole)
CYP3A4 inducers:
• (Rifampin, carbamazepine, or phenytoin)
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No need for overlapping
parenteral Tx
(ex. LMWH)Patient is a 57 y.o. male school teacher recently
diagnosed with AIDS while admitted for an acute
PE. Which of the following is correct?
A. HIV/AIDS is not a risk factor for VTE disease.
B. Intravenous unfractionated heparin is preferred in HIV
patients with acute VTE disease.
C. Rivaroxaban is contraindicated in patient on protease
inhibitor therapy due to CYP3A inhibition.
Rivaroxaban (Xarelto) vs. Warfarin for acute PE
• Symptomatic PE +/- DVT
• Excluded: Cr clearance < 30, Liver disease, SBP <110 or >180, drugs that affect CYP 3A4 • Average age 57
• 10% treated outpatient • 12% ICU
• Conclusion: Rivaroxaban is non-inferior with similar bleeding risk (less major
bleeding)
Apixaban (Eliquis)
Twice daily
Less bleeding
?
“AMPLIFY”
Major bleeding or clinically relevant for acute DVT/PE
4.3% vs. 9.7%
(warfarin)AMPLIFY EXT for continued therapy after 6-12 months no higher
bleeding then placebo.
Risk of DVT 12 mo. 1.7% 2.5mg, 1.7% 5mg, and 8% placebo
Risk of Death 12mo 3.8%, 4.2%, 11.6%
Edoxaban
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Once daily (60mg)
– 30mg/d. Cr.Cl 30-50 or weight less than 60kg.
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Approx. 10% < 60 kg
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Approx. 10% > 75 y.o.
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More effective than
warfarin in patients with
high risk PE.
(RV enlargement, elevated BNP).Bleeding Patients
• Supportive measures • Last dose?
• Renal or hepatic dysfunction? • Other anticoagulants?
• If PT normal, unlikely any effect of rivaroxaban.
• If PTT is normal, unlikely any effect of dabigatran.
“Oral Anticoagulants: The old and the new.” 2012; American Society of Hematology Webinar
Control of bleeding
Modality Dabigatran Rivaroxaban Apixaban
Charcoal X X X Hemodialysis X Prothrombin Complex Concentrates
X
X
aVII ? ? ? King et al Chest 2013; 143: 1362Future is here:
59 y.o. female with breast cancer.
Oct 24th, 2013 Hi Dr. Dan, I bet you thought I died or something. Just got back from the Italy
trip on Monday night - had a wonderful time. Didn't think that I was going to be able to go. About a month ago, I had such bad chest pain that I thought I was having a heart attack - turned out to be a blood clot on my lung. Was in the hospital for a week until they got my INR levels correct. Now I am
on Warfarin.
Oct 25th, 2013 Dr. Dan , Just had a chemo. treatment today and they checked my pro-time
levels - 3.9 - must have been all that wine I drank in Italy. Dr. Latif told me not to take my warfarin tonight and also tomorrow night, but I am to resume on Sunday, but only 5 mg. not the 7.5 mg.
1950’s- present
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One week in the hospital
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Numerous tests
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Exposure to sick patients
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Discharged on therapeutic
warfarin
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Outpatient labs, risk of over
and under dosing.
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Missed work, bills, etc.
“Future”
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Start rivoroxaban BID for
three weeks then daily.
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Discharge from the ED or
Mayo Clinic Proceedings: Wilson I. Gonsalves, MD, et al.
Volume 88, Issue 5 , Pages 495-511, May 2013 The New Oral Anticoagulants in Clinical Practice