Initiation Of Warfarin Pharmacotherapy Final Version

Initiation of Warfarin in Pharmacotherapy

Munzur Morshed, Pharm- D. candidate 2011

Arnold & Marie Schwartz College of Pharmacy and Health Sciences

James J. Peters VA Medical CenterInstitutional-Advanced Pharmacy Practice04/12/2023

1

Objectives At the end of this presentation you should

be able to Understand the pharmacokinetics of warfarin Describe how to initiate and monitor warfarin

therapy in tx. naive patients Identify INR goal based on patients medical

history and co-morbidities Dose adjust warfarin based on patients INR level Understand how genetic polymorphism effects

the dosing of warfarin among various patients population

04/12/2023 2

Introduction Discovered in University of Wisconsin-

1948 Cattles experienced hemorrhagic deaths after

eating spoiled sweet cloverWisconsin Alumni Research Foundation

+ coumARIN suffix

J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/201004/12/2023 3

Pharmacology The liver synthesizes factors II, VII, IX, and X as well

as proteins C, S, and Z with the help of Vitamin K Factors II, VII, IX, and X- Pro-Coagulants of the body Proteins C, S, and Z- Anti-Coagulants of the body The coagulation factors requires carboxylation for

their biological activity Vitamin K help influence carboxylation process into

producing the coagulant effect Warfarin inhibits the carboxylation process and

produces Anticoagulant activity by inhibiting production of pro-

coagulants Pro-coagulant activity by inhibiting the production of body’s

natural anti-coagulants04/12/2023 4

Pharmacokinetics- Absorption

A racemic mixture of two stereoisomers S- enantiomer- more potent R-enantiomer

Rapidly absorbed from the GI F= 77.6- 100%-PO F varies based on the product used Peak= 60-90 minutes

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Pharmacokinetics- Distribution

Binds to plasma albumin- 97-99.9% Vd- 0.12 L/kg (0.09 – 0.17 L/kg) Renal failure- alters protein binding

Increased free fraction

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Pharmacokinetics- Metabolism

Extensively metabolized via the liver Reduction, hydroxylation, dehydration To hydroxywarfarin + warfarin alcohols▪ metabolites possess minimal intrinsic activity

S-enantiomer CYP 450 2C9, 2C8, 2C18, 2C19 T ½ = 33 hours

R-enantiomer CYP450 3A4, 1A2, 1A1, 2E1, 2C8, 2C18, 2C19 T1/2= 45.2 hours04/12/2023 7

J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010

Pharmacokinetics- Elimination Eliminated in the urine Decrease renal function increases non-

renal clearance Accumulation of metabolites in nephron

Renal failure + Bleeding Desmopressin- 0.3mcg/kg IV over 30 minutes

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Onset of Effect Dependent upon the clearance of active clotting

factors Protein C- 6-8 hours Protein S- 40-60 hours Factor VII- 4-6 hours Factor IX- 20-30 hours Factor X- 24-48 hours Factor II- 60-100 hours

Full antithrombotic effect Depletion of factor II

Takes several days to observe prolongation of the INR Overlap with heparin for at least 5 days Stable therapeutic INR overlap for two consecutive days

04/12/2023 9J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010

Therapeutic Range

Normal Person- 1 Atrial Fibrillation- 2 to 3 Acute myocardial infarction- 2 to 3

Left ventricular dysfunction- 2.5 to 3.5 Prophylaxis/treatment of VTE- 2 to 3 Bioprosthetic heart valve- 2 to 3 Mechanical heart valve- 2.5 to 3.5

Aortic position PLUS no risk factors for stroke- 2 to 3

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Warfarin Dosing Day # 1

Start with 5 mg in most patients Start with 2.5 mg in patients who:▪ ≥ 65 years old▪ Has liver disease, hypothyroidism, CHF, or low body

weight (< 50kg)▪ Malnourished or low albumin level▪ Identified genetic variation▪ Asian decent more sensitive to warfarin

▪ Identified drug-drug interaction or drug-nutrient interaction which will decrease the metabolism or elimination of warfarin


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Warfarin Dosing Day #2 and # 3

INR Day #2 < 1.5 – no dose change 1.5-1.9- decrease initial dose by 25-50% 2.0 – 2.5- decrease initial dose by 50-75% INR > 2.5 hold next dose

INR Day # 3 < 1.5 – increase dose by 0-25% 1.5-1.9 – no dosage change 2.0.2.5 – decrease dose by 25 – 50% > 2.5 – decrease dose by 50% or hold next dose


Warfarin Dosing day 4 and 5

INR day # 4 < 1.5 – increase dose by 0-25% 1.5-1.9 – no dose change or increase by 10 -25% 2.0 – 3.0- no dosage change or decrease by 25% if at

high end of range > 3.0- decrease dose by 50% or hold next dose

INR day # 5 < 1.5- increase dose by 25% 1.5-1.9- increase dose by 0-25% 2.0 – 3.0 no dosage change or decrease by 10-25% if at

high end of range > 3.0- decrease dose by 25-50 % or hold next dose


www.warfarindosing.org

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Monitoring Parameters

PT Measures activity of factor II, VII and X Widely variable among institutions

INR Developed by the WHO to minimize variability among

institutions INR= (Patients PT(sec)/ MRI PT)^ ISI▪ PT- Prothrombin Time▪ MRI- Mean of Reference Interval ▪ ISI- International Sensitivity Index

Measured 8-14 hours after administration Should be monitored frequently until

therapeutic INR04/12/2023 15

Warfarin Toxicity Skin Necrosis

3-10 days after initiation of treatment

Depletion of Protein C Necrosis of the extremities,

adipose tissues, female breasts, penis, buttocks, thighs, abdomen

Can progress to gangrene Management: Protein C

100U/Kg of ABW bolus followed by 84U/Kg of ABW X 48 H.


04/12/2023 16Stewart A. Am J Health-Syst Pharm 2010; 67: 901-904

Warfarin Toxicity cont…

Purple toe syndrome 3 to 8 weeks after

initiation of treatment Cholesterol

embolization Little recommendation

in treatment


Risk factors of bleeding

INR > 4 First few weeks of therapy Antiplatelet or Aspirin use concomitantly Hx. of GIB, recent surgery or trauma Renal Failure, hepatic failure Increase fall risk Alcohol use

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Determining the risk of bleeding

HEMORRHAGES Hepatic or renal disease▪ Cirrhosis, CrCl < 30ml/min

Ethanol use Malignancy▪ Metastatic cancer

Older age (>75 years) Reduced Platelet count or

function▪ Plt < 75,000, NSAID, or ASA

use R2-Rebleeding risk( prior

bleeding event) Hypertension▪ SBP ≥ 160mmHg

Anemia▪ Hg < 10g/dL, or HCT< 30

HEMORRHAGES Genetic factors▪ CYP2C9*2 or CYP2C9*3

Excessive fall risk▪ PD, AD, schizophrenia, etc

Stroke Total Score: 0-12 Increase risk as follows:

0 points- 1.9 1 point- 2.5 2 points- 5.3 4 points- 8.4 4 points- 10.4 ≥ 5 points- 12.3

04/12/2023 19Gage BF, et al. Am Heart J. 2006; 151(3):713-719

Bleeding Risk Drugs

Concomitant anti-coagulation

Antiplatelet agent Cranberry Juice Fish oils

Herbal products Garlic Ginger Licorice root Red Clover Ginko

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Management of Warfarin Toxicity

Vitamin K1 2.5-25 mg PO/IV; repeat w/in 12-48 h if unsatisfactory

PT. OOA- 6 to 12 hours

Fresh Frozen Plasma OOA- 1 to 2 hours Contains all clotting factors Dose: 15-20 mL/kg

Plasma derived products rFactor VII Prothrombin Complex Concentrate (PCC)▪ Contains II, VII, IX, and X▪ Dose: 25-50mcg/kg04/12/2023 21

Vitamin K1 INR 2.1-4.9 and no bleeding

Skip and lower the dose INR 5.1- 8.9 and no bleed

Skip dose or vitamin K1 1 to 2.5 mg INR 5.1 to 8.9 and surgery

Vitamin K1 2-5 mg INR > 9 and no signs of bleeding

Vitamin K1 2.5-5 mg Rapid Reversal needed

FFP, Vitamin K1 10 mg PCC, rFactor VIIa

Check INR within 12-24 hoursAnsell J, et al. Chest. 2008;133:160S-198S04/12/2023 22

Drug-Drug Interactions

Increased effect Amiodarone Cimetidine Ciprofloxacin Erythromycin Omeprazole Sulfamethaxazole

Decreased effect Carbamazepine Phenobarbital Phenytoin Rifabutin Vitamin K

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Content of Vitamin K

Very High(>200 mcg)-Omit

High (100-200 mcg)-Omit

Medium( 50-100mcg)

Low (<50 mcg)

Brussel Sprouts Broccoli Green Apples Red Apples

Spinach Cabbage Cauliflower Beans

Green or Black Tea

Cucumber Pistachio nuts Dairy Products

Turnip Greens Green Onions Squash Tomato

Chick peas Lettuce Asparagus Eggs


Genetic Polymorphism

CYP 450 2C9 N= 561 patients treated with warfarin▪ Mean dose to achieve an INR of 2.5 varied

according to genotype▪ *1*1 wild-type (70% of the patients)- 5 mg▪ *1*2 heterozygote (19% of group)- 4.3 mg▪ *1*3 heterozygote (9% of group)- 4 mg▪ *2*3 heterozygote (1% of group)- 4.1 mg▪ *2*2 homozygote (0.5% of group)- 3 mg

Aithal GIP, et al. Lancet. 1999;2353(9154):717-719


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Genetic Polymorphism cont…

VKORC1 Genetic Variations Retrospective Study (N=186) To determine the effect of VKORC1 haplotypes on warfarin dose Group A- Low-dose haplotype Group B- High dose haplotype Three haplotype group combination and the mean maintenance

dose of warfarin▪ Group A/A - 2.7 +/- 0.2mg/day▪ Group A/B - 4.9 +/- 0.2mg/day▪ Group B/B – 6.2 +/- 0.3mg/day▪ Asian-Americans had higher percentage of group A haplotypes▪ African-Americans had a higher percentage of group B haplotypes

Conclusion▪ Can be used to stratify patients among low, intermediate, and high dose

warfarin group▪ Explains the difference in dose requirements among patients of different

ethnicitiesReider MJ, et al. NEJM. 2005;352(22):2285-2293

04/12/202326

Special Situations

PREGNANCY

Avoid all form’s of oral anticoagulants throughout pregnancy Risk of embryopathy

greatest during six to twelve weeks of gestation

Heparin or LMWH preferred

MAJOR SURGERY

Stop warfarin 5 days prior to surgery Low dose vitamin K may

be utilized to shorten the interval

Check INR prior to the procedure INR < 1.4

Resume warfarin on day of or after surgery

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Case Presentation LC is a 77 Y/O AAM veteran with PMH of myasthenia gravis,

thymectomy, dementia, depression, and anemia, who was brought in to the ER because of experiencing dizziness and near syncope in the elevator. The patient was admitted at the VA on August 29th due to chest pain radiating to his left shoulder. ACS was ruled out upon 3 negative troponins.ECG changes were notable for A-Fib. Patient was started on anticoagulation with warfarin to follow up with clinic upon discharge. He came to the clinic on September 10 for continuation of his recent anticoagulation therapy due to onset of A-Fib and INR at the time was reading at 6.54. On the way home, he felt palpitations, lightheaded, dizzy and almost collapsed in the elevator. Upon examination in ER, patient reported he on and off has palpitations, chronic right sided pain and never felt dizzy like today. Patient reported no chest pain, SOB, headaches, abdominal pain, blood per rectum, or melena.

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Case Presentation cont…

Meds PTA Acetaminophen 325mg-1 t po

q6h prf pain/fever Aspirin 81mg- 1 t po qd Cholecalciferol 1000 unit- 1 t

po qd Aricept 5mg- 1 t po qhs Felodopine 10 mg- 1 t po qd Ferrous SO4- 1 t po bid Finasteride 5 mg- 1 t po qd Hydrocortisone 1% cream Meclizine 25mg- ½ t po q8h prf

dizziness Mycophenelate Mofetil 250mg –

4 c po bid Omeprazole 20mg- 1 c po

before breakfast

Oxybutynin Chloride SR 10 mg- 1 t po qd

KCL 20mEq-2 t po qd Prednisone 5 mg- 2 t po qd Pyrodistigmine 60mg- 1 and

a ½ t po tid Seroquel 25 mg- 1 t po qhs Spirinolactone 25 mg- 1 t

po bid Tamsulosin 0.4 mg- 2 c po

qd Vardenafil 20 mg- 1 t po prn

1 hr prior to sexual activity Warfarin 5 mg- 1 t po qhs

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SOC Hx. + tobacco ETOH 30+ years Currently lives with spouse

ROS/PE Temp: 99 F, HR 58bpm, BP 96/53, RR 16 breaths/min Gen: WDWN M in NAD HEENT: MMM CV: irreg/irreg Lungs: + fine crackles at L base Abd: +BS, soft, NT Ext: slight edema

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Diagnostic Tests in ER

INR: 6.54 Therapy on admission

2L/Min O2 N/C Cardiac Monitor IVF D5 NS at 200cc/hr04/12/2023 31

Interval history

09/10- Patient admitted to ER due to syncope, elevated INR

09/11- INR still elevated, Hgb continued to drop▪ No signs of bleeding▪ Patient transferred to the floor-8B▪ Hgb dropping▪ Guaiac negative▪ No vitamin K administered, Coumadin put on

hold

04/12/2023 32

Interval History cont…

09/12- Pt. was found lying on the floor, laceration on forehead. The Morse Fall scale was performed and score was 35.

This is indicative of moderate risk for falls. On assessment patient noted to have left sided weakness. INR 4.63, Hgb 7.1, Hct 21.8 and s/p fall CT Scan- enlargement of the left gluteal and upper thigh

and diagnosed of intramuscular hematoma Head CT-Scan- negative bleeding Patient was then transfer to ICU for close monitoring Hgb dropped to 7 gm/dl, then to 5.4 and his INR was 3.94.

Given sub-q vitamin k to reverse warfarin and ASA stopped

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Interval History cont… 9/12 cont-ICU Labs : WBC 12.8, Hgb 5.4, Hct 16.5, PLT 94, INR

2.99, glucose 146. H/H continued to drop S/2 intramuscular bleeding Aspirin put on hold Transfused 4-5 units of PRBC 2 units of FFP

9/13- Received second unit of blood transfusion Pre-transfusion H&H: Hgb 8.1 & Hct 23.7 Post-transfusion H&H: Hgb 10.2& Hct 30

9/14- Hgb, INR Stable Hgb- 10.4, INR-0.9

9/14-9/27- Hgb, Hct, INR remained stable 9/27- Patient discharged

Taken off of AC S/2 fall risk Discharged on Aspirin only 04/12/2023 34

Other Active Complications

Elevated WBC- Unclear source Flare up Myasthenia Gravis Acute Renal Failure Altered mental status

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Inpatient Meds APAP 650mg po q6h prn Atropine/Diphenoxylate 1 tablet po qd Calcium Gluconate Inj, Soln 4.6 MEQ in NaCl

0.9% 50mL –infuse over 90 minutes Cholecalciferol cap/tab 1000 units po qd Epoetin Alfa Inj, Soln 5000unit/2.5ml sc Folic Acid 1 mg po qd Phytonadione Inj 2.5 mg sc now Pyridostigmine Inj. Soln 3mg IV q4h Quetiapine Fumarate Tab 25mg po qhs Prednisone tab 10mg po qd

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Etiology of elevated INR

Inappropriate Dose Elderly

Drug-Drug Interactions Aspirin Omeprazole

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Conclusion

warfarin is a very complex drug to utilize in practice

Many factors must be taken into account prior to initiating therapy Age Co-morbidities Genetic Factors

Imperative to monitor each patient on a daily basis and manage therapy accordingly04/12/2023 38

Thank You!

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Initiation Of Warfarin Pharmacotherapy Final Version