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Initiation Of Warfarin Pharmacotherapy Final Version
- 1. Initiation of Warfarinin PharmacotherapyMunzur Morshed, Pharm- D. candidate 2011Arnold & Marie Schwartz College of Pharmacy and Health SciencesJames J. Peters VA Medical CenterInstitutional-Advanced Pharmacy Practice10/5/20101
- 2. ObjectivesAt the endof this presentation you should be able to Understand the pharmacokinetics of warfarinDescribe how to initiate and monitor warfarin therapy in tx. naive patientsIdentify INR goal based on patients medical history and co-morbiditiesDose adjust warfarin based on patients INR levelUnderstand how genetic polymorphism effects the dosing of warfarin among various patients population10/5/20102
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- 4. PharmacologyThe liver synthesizesfactors II, VII, IX, and X as well as proteins C, S, and Z with the help of Vitamin KFactors II, VII, IX, and X- Pro-Coagulants of the bodyProteins C, S, and Z- Anti-Coagulants of the bodyThe coagulation factors requires carboxylation for their biological activityVitamin K help influence carboxylation process into producing the coagulant effectWarfarin inhibits the carboxylation process and produces Anticoagulant activity by inhibiting production of pro-coagulantsPro-coagulant activity by inhibiting the production of body’s natural anti-coagulants10/5/20104
- 5. Pharmacokinetics- AbsorptionA racemicmixture of two stereoisomersS- enantiomer- more potentR-enantiomerRapidly absorbed from the GIF= 77.6- 100%-PO F varies based on the product usedPeak= 60-90 minutes10/5/20105
- 6. Pharmacokinetics- DistributionBinds toplasma albumin- 97-99.9%Vd- 0.12 L/kg (0.09 – 0.17 L/kg)Renal failure- alters protein bindingIncreased free fraction10/5/20106
- 7. Pharmacokinetics- MetabolismExtensively metabolizedvia the liverReduction, hydroxylation, dehydrationTo hydroxywarfarin + warfarin alcoholsmetabolites possess minimal intrinsic activityS-enantiomerCYP 450 2C9, 2C8, 2C18, 2C19T ½ = 33 hoursR-enantiomerCYP450 3A4, 1A2, 1A1, 2E1, 2C8, 2C18, 2C19T1/2= 45.2 hours10/5/20107J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010
- 8. Pharmacokinetics- EliminationEliminated inthe urineDecrease renal function increases non-renal clearanceAccumulation of metabolites in nephronRenal failure + Bleeding Desmopressin- 0.3mcg/kg IV over 30 minutes10/5/20108
- 9. Onset of EffectDependentupon the clearance of active clotting factorsProtein C- 6-8 hoursProtein S- 40-60 hoursFactor VII- 4-6 hoursFactor IX- 20-30 hoursFactor X- 24-48 hoursFactor II- 60-100 hoursFull antithrombotic effect Depletion of factor IITakes several days to observe prolongation of the INROverlap with heparin for at least 5 daysStable therapeutic INR overlap for two consecutive days10/5/20109J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010
- 10. Therapeutic RangeNormal Person-1Atrial Fibrillation- 2 to 3Acute myocardial infarction- 2 to 3Left ventricular dysfunction- 2.5 to 3.5Prophylaxis/treatment of VTE- 2 to 3Bioprosthetic heart valve- 2 to 3Mechanical heart valve- 2.5 to 3.5Aortic position PLUS no risk factors for stroke- 2 to 3 10/5/201010
- 11. Warfarin Dosing Day# 1Start with 5 mg in most patientsStart with 2.5 mg in patients who:≥ 65 years oldHas liver disease, hypothyroidism, CHF, or low body weight (< 50kg)Malnourished or low albumin levelIdentified genetic variationAsian decent more sensitive to warfarinIdentified drug-drug interaction or drug-nutrient interaction which will decrease the metabolism or elimination of warfarinJ. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/201010/5/201011
- 12. Warfarin Dosing Day#2 and # 3INR Day #2< 1.5 – no dose change1.5-1.9- decrease initial dose by 25-50%2.0 – 2.5- decrease initial dose by 50-75%INR > 2.5 hold next doseINR Day # 3< 1.5 – increase dose by 0-25%1.5-1.9 – no dosage change2.0.2.5 – decrease dose by 25 – 50%> 2.5 – decrease dose by 50% or hold next doseJ. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/201010/5/201012
- 13. Warfarin Dosing day4 and 5INR 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 doseINR 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 dose10/5/201013J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010
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- 15. Monitoring ParametersPTMeasures activityof factor II, VII and XWidely variable among institutionsINRDeveloped by the WHO to minimize variability among institutionsINR= (Patients PT(sec)/ MRI PT)^ ISIPT- Prothrombin TimeMRI- Mean of Reference Interval ISI- International Sensitivity Index Measured 8-14 hours after administrationShould be monitored frequently until therapeutic INR10/5/201015
- 16. Warfarin ToxicitySkin Necrosis3-10days after initiation of treatmentDepletion of Protein CNecrosis of the extremities, adipose tissues, female breasts, penis, buttocks, thighs, abdomenCan progress to gangreneManagement: Protein C100U/Kg of ABW bolus followed by 84U/Kg of ABW X 48 H. J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/201010/5/201016Stewart A. Am J Health-Syst Pharm 2010; 67: 901-904
- 17. Warfarin Toxicity cont…Purpletoe syndrome3 to 8 weeks after initiation of treatmentCholesterol embolizationLittle recommendation in treatmentJ. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/201010/5/201017
- 18. Risk factors ofbleedingINR > 4First few weeks of therapyAntiplatelet or Aspirin use concomitantlyHx. of GIB, recent surgery or traumaRenal Failure, hepatic failureIncrease fall riskAlcohol use10/5/201018
- 19. Determining therisk of bleedingHEMORRHAGESHepatic or renal diseaseCirrhosis, CrCl < 30ml/minEthanol useMalignancyMetastatic cancerOlder age (>75 years)Reduced Platelet count or functionPlt < 75,000, NSAID, or ASA useR2-Rebleeding risk( prior bleeding event)HypertensionSBP ≥ 160mmHgAnemiaHg < 10g/dL, or HCT< 30HEMORRHAGESGenetic factorsCYP2C9*2 or CYP2C9*3Excessive fall riskPD, AD, schizophrenia, etcStrokeTotal Score: 0-12Increase risk as follows:0 points- 1.91 point- 2.52 points- 5.34 points- 8.44 points- 10.4≥ 5 points- 12.310/5/201019Gage BF, et al. Am Heart J. 2006; 151(3):713-719
- 20. Bleeding RiskDrugsConcomitant anti-coagulationAntiplateletagentCranberry JuiceFish oilsHerbal productsGarlicGingerLicorice rootRed CloverGinko10/5/201020
- 21. Management of WarfarinToxicityVitamin K12.5-25 mg PO/IV; repeat w/in 12-48 h if unsatisfactory PT.OOA- 6 to 12 hoursFresh Frozen PlasmaOOA- 1 to 2 hoursContains all clotting factorsDose: 15-20 mL/kgPlasma derived productsrFactor VIIProthrombin Complex Concentrate (PCC)Contains II, VII, IX, and XDose: 25-50mcg/kg10/5/201021
- 22. Vitamin K1INR 2.1-4.9and no bleedingSkip and lower the doseINR 5.1- 8.9 and no bleedSkip dose or vitamin K1 1 to 2.5 mgINR 5.1 to 8.9 and surgeryVitamin K1 2-5 mgINR > 9 and no signs of bleedingVitamin K1 2.5-5 mgRapid Reversal neededFFP, Vitamin K1 10 mgPCC, rFactor VIIaCheck INR within 12-24 hoursAnsell J, et al. Chest. 2008;133:160S-198S10/5/201022
- 23. Drug-Drug InteractionsDecreased effectCarbamazepinePhenobarbitalPhenytoinRifabutinVitaminKIncreased effect AmiodaroneCimetidineCiprofloxacinErythromycinOmeprazoleSulfamethaxazole10/5/201023
- 24. Content of VitaminK10/5/201024J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/2010
- 25. Genetic PolymorphismCYP 4502C9N= 561 patients treated with warfarinMean 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 mgAithal GIP, et al. Lancet. 1999;2353(9154):717-719J. Papadopoulous-PH 412-Principles of Warfarin Pharmacotherapy- 04/21/201010/5/201025
- 26. Genetic Polymorphism cont…VKORC1Genetic VariationsRetrospective Study (N=186)To determine the effect of VKORC1 haplotypes on warfarin doseGroup A- Low-dose haplotypeGroup B- High dose haplotypeThree haplotype group combination and the mean maintenance dose of warfarinGroup A/A - 2.7 +/- 0.2mg/dayGroup A/B - 4.9 +/- 0.2mg/dayGroup B/B – 6.2 +/- 0.3mg/dayAsian-Americans had higher percentage of group A haplotypesAfrican-Americans had a higher percentage of group B haplotypesConclusionCan be used to stratify patients among low, intermediate, and high dose warfarin groupExplains the difference in dose requirements among patients of different ethnicities10/5/2010Reider MJ, et al. NEJM. 2005;352(22):2285-229326
- 27. Special SituationsPregnancyAvoid allform’s of oral anticoagulants throughout pregnancyRisk of embryopathy greatest during six to twelve weeks of gestationHeparin or LMWH preferredMajor SurgeryStop warfarin 5 days prior to surgeryLow dose vitamin K may be utilized to shorten the intervalCheck INR prior to the procedureINR < 1.4Resume warfarin on day of or after surgery10/5/201027
- 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.10/5/201028
- 29. Case Presentation cont…MedsPTAAcetaminophen 325mg-1 t po q6h prf pain/feverAspirin 81mg- 1 t po qdCholecalciferol 1000 unit- 1 t po qdAricept 5mg- 1 t po qhsFelodopine 10 mg- 1 t po qdFerrous SO4- 1 t po bidFinasteride 5 mg- 1 t po qdHydrocortisone 1% creamMeclizine 25mg- ½ t po q8h prf dizzinessMycophenelate Mofetil 250mg – 4 c po bid Omeprazole 20mg- 1 c po before breakfastOxybutynin Chloride SR 10 mg- 1 t po qdKCL 20mEq-2 t po qdPrednisone 5 mg- 2 t po qdPyrodistigmine 60mg- 1 and a ½ t po tidSeroquel 25 mg- 1 t po qhsSpirinolactone 25 mg- 1 t po bidTamsulosin 0.4 mg- 2 c po qdVardenafil 20 mg- 1 t po prn 1 hr prior to sexual activityWarfarin 5 mg- 1 t po qhs10/5/201029
- 30. Case Presentation cont…SOCHx.+ tobaccoETOH 30+ yearsCurrently lives with spouseROS/PETemp: 99 F, HR 58bpm, BP 96/53, RR 16 breaths/minGen: WDWN M in NADHEENT: MMMCV: irreg/irregLungs: + fine crackles at L baseAbd: +BS, soft, NTExt: slight edema10/5/201030
- 31. Case Presentation cont…DiagnosticTests in ERINR: 6.54Therapy on admission2L/Min O2 N/CCardiac MonitorIVF D5 NS at 200cc/hr10/5/201031
- 32. Interval history09/10- Patientadmitted to ER due to syncope, elevated INR09/11- INR still elevated, Hgb continued to dropNo signs of bleedingPatient transferred to the floor-8BHgb droppingGuaiac negativeNo vitamin K administered, Coumadin put on hold10/5/201032
- 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 fallCT Scan- enlargement of the left gluteal and upper thigh and diagnosed of intramuscular hematomaHead CT-Scan- negative bleedingPatient was then transfer to ICU for close monitoringHgb 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 stopped10/5/201033
- 34. Interval History cont…9/12cont-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 bleedingAspirin put on holdTransfused 4-5 units of PRBC2 units of FFP9/13- Received second unit of blood transfusionPre-transfusion H&H: Hgb 8.1 & Hct 23.7Post-transfusion H&H: Hgb 10.2& Hct 309/14- Hgb, INR StableHgb- 10.4, INR-0.99/14-9/27- Hgb, Hct, INR remained stable9/27- Patient dischargedTaken off of AC S/2 fall riskDischarged on Aspirin only 10/5/201034
- 35. Other Active ComplicationsElevatedWBC- Unclear sourceFlare up Myasthenia GravisAcute Renal FailureAltered mental status 10/5/201035
- 36. Inpatient MedsAPAP 650mgpo 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 qhsPrednisone tab 10mg po qd 10/5/201036
- 37. Etiology of elevatedINR Inappropriate DoseElderlyDrug-Drug InteractionsAspirinOmeprazole10/5/201037
- 38. Conclusionwarfarin is avery complex drug to utilize in practiceMany factors must be taken into account prior to initiating therapyAgeCo-morbiditiesGenetic FactorsImperative to monitor each patient on a daily basis and manage therapy accordingly10/5/201038
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Editor's Notes
- #3 Limit to 4-5 objectivesUse action words like ‘list’ ‘define’ ‘identify’ ‘describe’ … Avoid passive words like ‘understand’
- #4 Should ‘factor’ and ‘protein’ be plural?4th and 5th bullet - grammar
- #6 Desmopressin?
- #7 I would change prosthetic to ‘bioprosthetic’ and remove the prosthetic before mechanical to avoid confusionThere are some other categories in the chest guidelines but its up to you if you want to include them
- #8 when presenting I would go over this very briefly, focus on the concepts of decreasing the dose if INR is increasing very quickly, increasing dose if INR is increasing too slowly etc
- #10 Gage BF, et al. Am Heart J. 2006; 151(3):713-719
- #11 Purple toes syndrome is an extremely uncommon, nonhemorrhagic, cutaneous complication associated with warfarin therapy. It is characterized by the sudden appearance of bilateral, painful, purple lesions on the toes and sides of the feet that blanch with pressure. The syndrome usually develops 3-8 weeks after the start of warfarin therapy.
- #12 To help quantify the risk of hemorrhages
- #13 Cranberry Juice has salicylic acid in it.
- #14 Vitamin K – dose? Route?
- #15 Do you need this slide and the next one?
- #17 It was found that there is a strong assoiciation between these types alleles and the dosing requirements. So it helps identify that there is a subgroup of patients who has difficulty at induction of warfarin therapy and are at high risk of bleeding complications
- #18 Vitamin K epoxidereductase complex subunit 1What is the clinical relevance? How often is this tested for? I wouldn’t add in the presentation, but just be aware because you may be questioned on it.
- #19 Be familiar w/ perioperative bridging w/ lovenox
- #20 Stay consistent w/ using warfarin or coumadin… coumadin capitalized but warfarin not
- #21 WDWN M in NAD: Well Developed Well Nourished Male in No Acute DistressMMM: Moist Mucous Membrane
- #22 Na, Cl, BUN GlucoseK, HCO3, Cr HgWBC Platelet HCT
- #23 Reason for transfer: High INR 4.63, Hgb 7.1, Hct 21.8 and s/p fallHgb dropped to 7gm/dl, then to 5.4 and his INR was 3.94
- #24 Intramuscular Hematoma: Extravasation of blood in the muscleLabs assessed: WBC 12.8, Hgb 5.4, Hct 16.5, PLT 94, INR 2.99, glucose 146, BUN 36, Cr 1.8Reason for transfer: High INR 4.63, Hgb 7.1, Hct 21.8 and s/p fall
- #25 PRBC- Packed Red Blood Cels
- #29 Maybe talk a bit more about dietary vitamin K… it’s kind of beaten to death but it’s worth mentioning in a presentation on coumadinCareful about small font on slides, try to put as little text as possibleMention rationale for using coumadin in a.fib