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

WARFARIN Historical 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 fibrillation



Prosthetic

heart valves



Deep venous thrombosis



Pulmonary 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 warfarin

very 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 Interactions

Drugs 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

DVT/PE Atrial Fibrillation Myocardial Infarction Mechanical Heart Valves

INR Range

2.0-3.0

2.0-3.0 2.0-3.0

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 Therapy Inpatient (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 Therapy

Out 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

10 mg 1 mg 2mg 3 mg 5mg 4mg

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/107/12/169 2?eaf

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