Practical Approach to Warfarin Therapy

Craig Ernst MHS, PA-C

Richard Freeman MD MPH

Lock Haven University

2013

Anticoagulation

Definition: Use of a medication to directly or indirectly

inhibit the action of one or more of the clotting factors

Medication are called ANTICOAGULANTs or ANTITHROMBOTICs

NOT THROMBOLYTICS

ANTICOAGULANTS Prevention:-Prophylactic intensity

Require Risk stratification Examples:

immobilized patient (hospitalized) Atrial fibrillation Orthopedic surgery Genetic coagulation anomalies

Treatment: -=Therapeutic intensity Examples

DVT PE Arterial thromboembolisms

FDA approved ANTICOAGULANTS

Unfractionated Heparin activates antithrombin III

Low molecular weight heparin-Enoxaparin Fondaparinux (Arixta)-

Factor Xa inhibitor-Subcutaneous Warfarin (Coumadin)

Oral Inhibitorof production of Vit K dependent factors Dabigatran (Pradaxa)

oral direct thrombin inhibitor Rivaoxaban (Xarelto)

Oral direct factor Xa inhibitor

WARFARINHistorical Background

Spoiled clover silage caused bleeding in cattle

Causative agent: dicoumarol Warfarin is a derivative of dicoumarol

Primarily used as a rodenticide-Decon Clinical Trials: warfarin safe for human use EXCEPT IN PREGNANCY-Category X-

crosses placenta

Mechanism of Action

Warfarin partially blocks the re-use of Vit K-liver

Vitamin K dependent procoagulants: Prothrombin (Factor II) Factor VII Factor IX Factor X

Vitamin K dependent Anticoagulants: Proteins S and C.

Indications

Long-term thrombosis prophylaxis

Atrial fibrillationProsthetic heart valvesDeep venous thrombosisPulmonary emboli

Warfarin is not a thrombolytic!

Warfarin- positives

Well studied- been around a LONG time Relatively inexpensive (covered by most 3

party payers) Given ORALLY Comes in multiple strengths Effects “Can” be Reversed

Warfarin-Negatives Bleeding complications- frequent Slow onset of action-- 3-5 days Requires ongoing monitoring—PT INR

May require frequent dosage changes MULTIPLE drug interactions Effected by diet-Vit K containing

Dark green leafy; fish oils Reversing effects with Vit K may take days Normal gut flora needed for Vit K

conversion/absorption Broad spectrum -antibiotics inhibit

Pharmacokinetics

Many Therapeutic challenges Delayed optimal anticoagulant effect

Has no effect on currently circulating clotting factors No anticoagulant effect until these decay

5-7 days until clotting factors are at a minimal level

Warfarin half-life of 36 to 48 hours Persistent anticoagulant effect after warfarin is

discontinued THERAPUETIC INDEX- NARROW Initial Prothrombotic effect-slight problem

Protein C and S are Vit K dependent

Other Considerations

Patient’s liver stasis- hepatitis, cirrhosis, and cancers that degrade liver

function already result in a deficiency of clotting factors

Providers – not knowledgeable in usage WARFARIN CLINICS

Oral Formulations

Warfarin ~13 different generic companies

Jantoven Generic name brand

Coumadin Most widely used formulation of warfarin

Contraindications to warfarinvery similar to thrombolytic contraindications

history of hemorrhagic stroke < 2 months CNS neoplasm, AV malformation, or aneurysm, or

CNS surgery < 2months Severe uncontrolled hypertension

(over 200/130 or complicated by retinovascular disease or encephalopathy)

ongoing (active/current) bleeding s/p recent significant surgery, pending surgery Pregnancy MI due to aortic dissection allergy many relative contraindications

Drug InteractionsDrugs That May

Lengthen PT Antibiotics

azithromycin

Antiarrhythmics Others

Anabolic steroids Omeprazole Cimetidine Phenytoin Clofibrate Tamoxifen Disulfiram Thyroxine Statins- lovastatin Vitamin E (large doses)

Drugs That May Shorten PT

Alcohol Antacids Antihistamines Spironolactone Barbiturates Sucralfate Carbamazepine Trazodone others

Monitoring

Prothrombin Time a.k.a—Protime, PT, INR

Used to assess Extrinsic Pathway Factor VII Normal range 12-15 seconds Normal range NOT SAME as therapeutic range INR-Standardized Test Must use INR for Coumadin Dosing

“normal” range for the INR is 0.8-1.2

Monitoring Warfarin is a narrow therapeutic index drug (NTI). When the INR falls below 2.0 thrombosis risk increases and

when the INR rises above 4.0 serious bleeding risk increases.

Target INR ranges: Disease INR Range

DVT/PE 2.0-3.0Atrial Fibrillation 2.0-3.0 Myocardial Infarction 2.0-3.0Mechanical Heart Valves 2.5-3.5

Initiating Therapy ASSESS FOR CONTRAINDICATIONS HISTORY AND PHYSICAL EXAM Initiating a Plan:

Pt Education Diet- do not vary – see slide Timing- EVENING Warning signs- abnormal bleeding:

bowel/bladder, epistaxis, gum, petechia/ purpura

Laboratory findings Baseline PT INR, aPTT, platelet count Arrange schedule for Follow-up PT INR

If patient can not comply reconsider using warfarin

Co-morbid Conditions Expect a LONGER baseline prothrombin time in patients with: CHF, hepatitis, liver failure, diarrhea, extensive cancer connective tissue disease.

Metabolic alterations can affect the prothrombin time.

Expect a longer prothrombin time in ELDERLY patients.

Dietary Interactions

Patients taking warfarin should eat a diet that is CONSTANT in vitamin K.

MINIMIZE CHANGES in intake of green leafy vegetables (spinach, greens, and broccoli), green peas, and oriental green tea

Initiating Warfarin Therapy

Initiate therapy with the estimated daily maintenance dose

2-5 mg daily Large loading doses do not markedly shorten the

time to achieve a full therapeutic effect.

Elderly or debilitated patients often require lower daily doses of warfarin (2-4 mg daily).

Initiating Warfarin TherapyInpatient (hospitalized)

Check daily PT- INR 5mg Day 1 5mg Day 2 2-5mg Day 3 2-5 mg Day 4

Concurrent LMWH or Heparin management

Initiating Warfarin TherapyOut patient 2-5 mg daily Check INR on days 3, 4, 5

Insure anticoagulation therapeutic range and stable

If therapeutic -- Recheck one week from initiation Additional anticoagulant?

Urgent anticoagulation needed-DVT Concurrent LMWH or Heparin UNTIL INR THERAPUETIC

Non-urgent anticoagulation Start with anticipated daily dose

Case 1

80 y/o female with SOB, tachypnea, tachycardia, hypoxia. Found to have PE on CT angiogram.

PMH: Prior DVT- no workup, DM, HTN

WHAT DO YOU DO???.

Case 1

80 y/o female with SOB, tachypnea, tachycardia, and mild hypoxia. Found to have large PE on CT angiogram.

PMH: Prior DVT no workup, DM, HTN.

Day 3 INR is 2.0 What do you do? Day 4 INR is 3.2 What do you do?

Case 2

70 y/o male with new dx atrial fibrillation. Hemodynamically stable, HR 70 bpm.

PMH: CAD Habits: occasional beer, eats a healthy diet.

What do you do?

Case 3

55 y/o healthy female. Recently returned from visiting France . Found to have unilateral R leg swelling, U/S comes back confirming R DVT.

PMH: G2 P2 not currently pregnant

What do you do?

Altering Chronic Therapy

Significant changes in INR can usually be achieved by small changes in dose (15% or less).

4-5 days are required after any dose change or any new diet or drug interaction to reach the new antithrombotic steady state. Recheck PT INR

Patients are confused by multiple dosages of pills.

Case 2

70 y/o male with new dx atrial fibrillation. Hemodynamically stable, HR 70 bpm.

PMH: CAD Habits: occasional beer, eats a healthy diet. Pt returns for monthly “protime”

Coumadin 4 mg daily (28 mg/week) INR history within therapeutic range for last 3

months INR today: 1.8

Case 3

55 y/o healthy female. Recently returned from visiting France . Found to have unilateral R leg swelling, U/S comes back confirming R DVT.

PMH: G2 P2 Coumadin 5 mg daily (35 mg/week) Stable INR history for past 6 weeks INR today 3.5

1 mg

2mg

3 mg

4mg

5mg

10 mg

Complications

HEMORRHAGE Warfarin necrosis

Protein C deficiency Massive thrombosis

Osteoporosis Purple toe syndrome

Embolic cholesterol deposits

Hemorrhage management

Stop Warfarin Fresh Frozen Plasma Administer Packed Red Blood cells- if

indicated

Aqua-Mephyton(Vit K) difficult to re-establish a therapeutic INR

Dr. Freeman & PA- death of a patient

DABIGATRAN-Pradaxa

Direct Thrombin inhibitor Oral Indications:

Stroke prevention AF patients DVT prophy- hip and knee surgeries Used as an alternative to poorer controlled Warfarin

users (nothing gained if controlled) DOES NOT REQUIRE INR MONITORING Complications:

Higher risk for GI bleeding BUT overall life threatening bleeds are less

RIVAROXABAN-Xarelto

Direct Factor Xa inhibitor- onset 4 hours Oral Indications:

Prevention and treatment of DVT Orthopedic hip and knee replacements Long term DVT recurrence prevention

Nonvalular Atrial fib-stroke prophylaxis

Resources

Clotting Cascade Web based aid to help determine dose

http://warfarindosing.org/Source/Home.aspx    ACC foundation guide to therapy

http://circ.ahajournals.org/cgi/content/full/107/12/1692?eaf

Excellent Resource for managing Warfarin http://www.med.umich.edu/cvc/services/site_anticoag/healthprof.html