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Presented by: Manar LashkarSamah Al-shehriPharm.D candidates

Supervised by:

Dr.Mohammad Elfaour

King Faisal Specialist Hospital and Research Center

(2007-1428)

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Introduction

The American College of Chest Physicians (ACCP) recommends treating these patients with oral warfarin to maintain an international normalized ratio (INR) of 2.0–3.0.

Oral warfarin is the standard of care for patients requiring long-term anticoagulation due to venous thromboembolic disease.

Achieving a therapeutic INR may be complicated by many factors, such as drug-drug interactions, drug-food interactions, and inadequate absorption of drugs.

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Introduction

Normally Warfarin sodium is completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.

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Introduction Patients with Crohn's disease may have

reduced absorption of warfarin in the small bowel due to loss of effective surface area secondary to:

chronic inflammation ulcerative lesions resection

In such cases the oral anticoagulant

therapy is not applicable.

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Introduction So, the usual alternative

outpatient anticoagulation is achieved by subcutaneous low molecular weight heparin (LMW heparin) e.g. enoxaparin and tinzaparin.

What about if

LMW heparin is contraindicated?!

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Introduction In cases like pyoderma gangrenosum

(which is a complication of Crohn’s disease that causes tissue to become necrotic causing deep ulcers and worsened by subcutaneous injections),

oral warfarin and SC LMW heparin are not useful…

What is the alternative?!

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Intravenous Warfarin as an Alternative for

Anticoagulation

In this presentation we will discuss a case report published in Pharmacotherapy Journal in 2007 that describes the successful use of intravenous warfarin in a patient with upper extremity thrombosis who was resistant to oral warfarin and cannot tolerate the SC LMW heparin.

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Case Report Patient information: A 27-year-old, 40-kg, Caucasian woman

Complain:Malnourishment secondary to end-stage Crohn's disease.Blocked central venous catheter line that had been inserted 6 weeks earlier for administration of total parenteral nutrition (TPN).

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Case Report Medical History:• Multiple surgical procedures, including a

colectomy with a primary closure for her Crohn's disease.

• Pyoderma gangrenosumDrug administration on admission:• Hydromorphone IV• Dimenhydrinate IV• Furosemide IV• Total parenteral nutrition• Sublingual lorazepam

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Case Report Lab results: Hepatic transaminase levels and platelet

count were within normal limits and remained stable throughout her admission.

Diagnostic tools:Doppler ultrasonography confirmed that the patient had developed an upper extremity thrombosis extending from the right jugular to the subclavian vein, secondary to her central line.

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Thromboembolic Treatment

New central line was inserted, and anticoagulation with an intravenous heparin infusion along with oral warfarin was started.

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Ora

l D

aily

Warf

ari

n D

ose

s (m

g)

DayDay

INR

Vitamin K discontinued

Warfarin

INR

High doses of warfarin were potentially dangerous if sudden absorption were to occur

patient was still receiving vitamin K 10 mg/week in her TPN

Next doses failed to produce a significant increase in the patient's INRINR

remained subtherapeutic

The patient

did respond

to therapy So oral warfarin

should be discontinued

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Since

Therapy was started

An alternative anticoagulant was required

The hospital's purchasing group ordered IV warfarin on hospital day 28; it arrived the next morning

IV heparin was not an option for outpatient management of the thrombus

LMW heparin was contraindicateddue to her history of pyoderma gangrenosum

The decision was made to use IV warfarin

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WarfarinINR

Day

IV D

aily

Warf

ari

n D

ose

s (m

g)

Heparin DC

INR

IV warfarin was started at 5 mg dose.

The patient began to respond to warfarin.The patient achieved her therapeutic INR

The patient stabilized on 4mg/day IV warfarin and was discharged.

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Discussion

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Warfarin Resistance

1) Hereditary.. very rare 2) Acquired: more common

Poor compliance. Exogenous vit. K intake. Increased warfarin clearance (intrinsic or

due to enzyme inducers) Decreased warfarin absorption.

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The patient was in the inpatient setting.

Achievement therapeutic INR while receiving warfarin intravenously.

vitamin K was removed from the TPN.

Patient drugs were reviewed.

Hereditary

Poor Compliance

Vitamin K intake

Drug-drug Interactions

Determining Warfarin Resistance Cause

in our Case

Increased clearance

xxxxx

Decreased absorption

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Pharmacological Facts Warfarin is an anticoagulant that inhibits

activation of vitamin K–dependent clotting factors II, VII, IX, and X and proteins C and S.

So, it works on the extrinsic clotting system which is measured by the INR.

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It is completely absorbed from the GIT and its effect is produced within 36–72 hours and lasts from 4–6 days.

Intravenous warfarin, approved for use the FDA, provides an alternative administration route for patients who cannot receive the oral formulation and cannot use subcutaneous low-molecular-weight heparins due to adverse effects

Pharmacological Facts

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But is there any differences between IV and oral warfarin??

vs

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Pharmacologically:

The efficacy and toxicity of IV warfarin is similar to that of the oral form and it is monitored by INR, prothrombin time and hemoglobin levels

Pharmacokinetically:

It should provide the patient with the same concentration of an equal oral dose.

But maximum plasma concentration will be reached earlier.

Coumadin® for Injection

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However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72-96 hours after dosing.

So, IV warfarin should not provide any increased biological effect or earlier onset of action.

Warfarin for injection should be administered as a slow bolus over 1–2 minutes into a peripheral vein.

It is not to be given intramuscularly and is not approved for direct intravenous push.

Coumadin® for Injection

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However, clinical experience, including the experience with our patient, suggests that it can be administered as a direct intravenous push injection without complications.

The vial must be reconstituted with 2.7 mL of sterile water for Injection to yield 2mg/mL. So, net contents 5.4 mg of warfarin lyophilized powder.

It must be protected from light.

Coumadin® for Injection

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Coumadin® for Injection

After reconstitution, COUMADIN® for Injection is chemically and physically stable for 4 hours at room temperature.

It does not contain any antimicrobial preservative.

The vial is not recommended for multiple use and unused solution should be discarded.

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ConclusionIn this complicated patient who was resistant to oral warfarin and unable to receive subcutaneous low-molecular-weight heparin, therapeutic anticoagulation was achieved with intravenous warfarin.

Further clinical experience and reports are needed to better understand the role of intravenous warfarin in anticoagulation management.

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Criticism The title was interesting and useful in our clinical

practice. (Intravenous Warfarin as an Alternative for Anticoagulation)

The case follows a standard format (Introduction, description of the case, discussion and references).

The case described clearly and it stated the clinical importance for reporting this case.

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Criticism The patient data were reported adequately.

The treatment plan was appropriate for the problem and other options were discussed .

The author indicates direction for future management of similar cases.

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However, the article doesn’t state the exact date of patient admission and the hospital name and place.

Criticism

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References Gellatly R. Intravenous Warfarin as an Alternative for Anticoagulation.

Pharmacotherapy. 2007;27(6):933-935

Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. The

seventh ACCP conference on antithrombotic and thrombolytic therapy: antithrombotic therapy for venous thromboembolic disease. Chest 2004;126(3):401S–28.

DiDomenico RJ. Coagulants and anticoagulants. In: Anderson PO, Knoben JE, Troutman WG, eds. Handbook of clinical drug data, 10th ed. New York: McGraw-Hill Companies, Inc., 2002:615–17.

Porter RS, Sawyer WT. Warfarin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied pharmacokinetics: principles of therapeutic drug monitoring, 3rd ed. Vancouver, WA: Applied Therapeutics, Inc., 1992:31-1–31-46.

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References

Hulse ML. Warfarin resistance: diagnosis and therapeutic alternatives. Pharmacotherapy 1996;16(6):1009–17.

Brophy DF, Ford SL, Crouch MA. Warfarin resistance in a patient with short bowel syndrome. Pharmacotherapy 1998;18(3):646–9.

Brystol-Myers Squibb Canada, Inc. Coumadin (warfarin sodium) product monograph. Montreal, Quebec, Canada; 2005.

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Manar Lashkar Samah Al-shehri