1. Initiation of Warfarin in Pharmacotherapy Munzur Morshed, Pharm- D. candidate 2011Arnold & Marie Schwartz College of Pharmacy and Health SciencesJames J. Peters VA Medical CenterInstitutional-Advanced Pharmacy Practice 10/5/2010 1

2. 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 10/5/2010 2

3. Introduction Discovered in University of Wisconsin- 1948 Cattles experienced hemorrhagic deaths after eating spoiled sweet clover Wisconsin Alumni Research Foundation + coumARIN suffix J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010 10/5/2010 3

4. 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-coagulants 10/5/2010 4

5. 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 10/5/2010 5

6. 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 10/5/2010 6

7. 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 hours 10/5/2010 7 J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010

8. 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 10/5/2010 8

9. 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 10/5/2010 9 J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010

10. 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 10/5/2010 10

11. 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 J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010 10/5/2010 11

12. 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 J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010 10/5/2010 12

13. 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 10/5/2010 13 J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010

14. www.warfarindosing.org 14 10/5/2010

15. 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 INR 10/5/2010 15

16. 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. J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010 10/5/2010 16 Stewart A. Am J Health-Syst Pharm 2010; 67: 901-904

17. Warfarin Toxicity cont… Purple toe syndrome 3 to 8 weeks after initiation of treatment Cholesterol embolization Little recommendation in treatment J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010 10/5/2010 17

18. 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 10/5/2010 18

19. 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 10/5/2010 19 Gage BF, et al. Am Heart J. 2006; 151(3):713-719

20. Bleeding Risk Drugs Concomitant anti-coagulation Antiplatelet agent Cranberry Juice Fish oils Herbal products Garlic Ginger Licorice root Red Clover Ginko 10/5/2010 20

21. 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/kg 10/5/2010 21

22. 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 hours Ansell J, et al. Chest. 2008;133:160S-198S 10/5/2010 22

23. Drug-Drug Interactions Decreased effect Carbamazepine Phenobarbital Phenytoin Rifabutin Vitamin K Increased effect Amiodarone Cimetidine Ciprofloxacin Erythromycin Omeprazole Sulfamethaxazole 10/5/2010 23

24. Content of Vitamin K 10/5/2010 24 J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010

25. 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 J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010 10/5/2010 25

26. 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 ethnicities 10/5/2010 Reider MJ, et al. NEJM. 2005;352(22):2285-2293 26

27. 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 10/5/2010 27

28. 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. 10/5/2010 28

29. 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 10/5/2010 29

30. Case Presentation cont… 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 10/5/2010 30

31. Case Presentation cont… Diagnostic Tests in ER INR: 6.54 Therapy on admission 2L/Min O2 N/C Cardiac Monitor IVF D5 NS at 200cc/hr 10/5/2010 31

32. 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 10/5/2010 32

33. 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 10/5/2010 33

34. 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 10/5/2010 34

35. Other Active Complications Elevated WBC- Unclear source Flare up Myasthenia Gravis Acute Renal Failure Altered mental status 10/5/2010 35

36. 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 10/5/2010 36

37. Etiology of elevated INR Inappropriate Dose Elderly Drug-Drug Interactions Aspirin Omeprazole 10/5/2010 37

38. 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 accordingly 10/5/2010 38

39. Thank You!