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(1)

Anticoagulants for venous

thromboembolic disease-

Optimizing the old, ushering in the new.

Daniel A. Forman, DO

RPS Hematology Oncology

daniel.forman@readinghealth.org

(2)

RHS Anticoagulation Clinic

Opening in November 2013.

Doctors office building. 3

rd

floor.

Patient will need to be referred by a physician with basic

information (EPIC).

Pharmacy consult on first visit. Twice year visit.

You are still in charge! (holding, discontinuation, etc.)

Point of care testing available.

(3)

Goals

Discuss ways to improve the safety and more

convenient administration of warfarin.

Review efficacy and pharmacologic issues

associated with the newer oral

(4)

Warfarin Basics

VII, XI, X, II Protein C & S

Inhibits Vitamin K Oxide

Reductase (“recycles” Vit. K)

Lack vitamin K prohibits

carboxylation of clotting

factors

(Inactive clotting factors produced)

Genetic factors can predict

warfarin sensitivity or

resistance

VKORC1 genotypes

CYP2C9 polymorphism

(5)

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

All factors need to be suppressed for

anticoagulant effect (takes two days after

INR therapeutic)!

(6)

Avoid loading doses.

INR reflective of rapid

decline in factor VII.

Confounds the patient’s

“real dose.”

(7)

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/d

(8)

You 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.

(9)

Newly diagnosed VTE disease case:

If the INR = 1.0 on Day 3 then double starting dose.

LMWH is better than UFH for VTE Disease!

No lab testing, Less risk HIT, more clot regression, lower

recurrence, lower bleeding, less deaths

One study reported 60% patient on UFH failed to achieve adequate

aPTT response in 24 hours.

ACCP 2B recommendation.

Arch Intern Med 1988; 148:1321 Chest 2012; 141: e495S

(10)

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.

(11)

Low dose vitamin k for erratic patients

• Multiple studies have suggested that daily low dose vitamin k improves INR

control • 100-200 Mcg day

• Increasing dietary intake of vitamin K may suffice • Not recommended for routine use.

(12)

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.

(13)

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

(14)
(15)

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.

(16)

Give your patient a break!

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).

(17)

What is the best way to determine a patient’s

warfarin dose if he was previously on this

medication?

A. Genetic testing for VKOR1 polymorphisms.

B. Genetic testing for Cytochrome P450

CYP2C9 polymorphisms.

C. Dose based upon age, weight, and sex.

D. Find out his/her previous dose.

(18)

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?

A. 1%

B. 5%

C. 10%

D. 20%

(19)

Supratherapeutic INR’s

Risk of major bleeding is low (1%) when single

INR 5-9.

Spurious INR suspected if doesn’t make sense.

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: e44

(20)

Reversing warfarin without bleeding

Wait it out: INR will fall from 6-10 to < 4 in 2.4 days.

Vitamin K

1

(phytonadione) given orally takes about 1.4 days to

bring INR 6-10 to <4.

Follow CHEST Guidelines

(21)

Rapid Correction of warfarin in an

unstable patient or ICH

Vitamin K

1

10 mg iv

FFP 15ml/kg (4-8 units)

Prothrombin Complex Concentrates

3 Factor (II, IX, X) & 4 Factor (II, VII, IX, X)

Effective, but thrombogenic

Recommended over FFP by ACCP guidelines.

rFactor VIIa-

Not FDA approved for reversal

(22)

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.

(23)

Idiopathic Clot

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)

Big Picture:

First 3 months: Vigilant therapeutic anticoagulation

(24)

Ideal anticoagulant

Safe and effective

Rapid acting

Available p.o. and parenteral

Rapid elimination

Free of drug interactions

Predictable effect and wide therapeutic window

No need for monitoring

Minimal toxicity and side effects

Reversible with an antidote

(25)

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)

(26)

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

Edoxaban

(27)
(28)

Drug CYP 3A4 P-gp

Dabigatran

(Pradaxa) Yes

Rivaroxaban

(Xarelto) Yes Yes

Apixaban

(29)

Dabigatran (Pradaxa)

Direct thrombin inhibitor

Renal excretion

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

(30)

Rivaroxaban (Xarelto)

Once daily with food

(BID

for acute VTE x 3wk)

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)

No need for overlapping

parenteral Tx

(ex. LMWH)

(31)

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.

(32)

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)

(33)

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%

(34)

Edoxaban

Once daily (60mg)

– 30mg/d. Cr.Cl 30-50 or weight less than 60kg.

Approx. 10% < 60 kg

Approx. 10% > 75 y.o.

More effective than

warfarin in patients with

high risk PE.

(RV enlargement, elevated BNP).

(35)

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

(36)

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: 1362

(37)

Future 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

One week in the hospital

Numerous tests

Exposure to sick patients

Discharged on therapeutic

warfarin

Outpatient labs, risk of over

and under dosing.

Missed work, bills, etc.

“Future”

Start rivoroxaban BID for

three weeks then daily.

Discharge from the ED or

(38)
(39)

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

http://www.mayoclinicproceedings.org/article

/PIIS002561961300222X/fulltext

Good Review on the newer anticoagulants

Pragmatic advice about how long to hold

these agents prior to surgery, changing to

warfarin while on these agents, etc.

(40)

Summary

Try to avoid unnecessary adjustments when

managing warfarin.

Stable patients on warfarin need less frequent

testing .

The newer agents appear to be well tolerated

with similar , or less bleeding risk.

Be careful with potential serious drug

interactions, and watch organ function

with the newer agents.

(41)

References

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