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Management of Oral
Anticoagulant TherapyPrinciples & Practice
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Clotting Cascade
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Vitamin K
VII
IX
X
II
Vitamin K-Dependent Clotting Factors
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Vitamin K Mechanism of Action
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Warfarin Synthesis of NonFunctional Coagulation
Factors
Antagonism
ofVitamin K
Warfarin Mechanism of Action
Vitamin K
VIVI
IIIXIX
XX
IIII
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Warfarin Mechanism of Action
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Virchows Triad
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Anti thrombotic Agents:Mechanism of Action
Anticoagulants: prevent clot formation and extension
Antiplatelet drugs: interfere with platelet activity Thrombolytic agents: dissolve existing thrombi
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History of Warfarin
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Warfarin: Indications
Prophylaxis and/or treatment of: Venous thrombosis and its extension Pulmonary embolism Thromboembolic complications associated with AF and
cardiac valve replacement Post MI, to reduce the risk of death, recurrent MI, and
thromboembolic events such as stroke or systemicembolization
Prevention and treatment of cardiac embolism
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Warfarin: Major Adverse EffectHemorrhage
Factors that may influence bleeding risk: Intensity of anticoagulation Concomitant clinical disorders Concomitant use of other medications
Quality of management
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Special Considerations in the ElderlyBleeding
Increased age associated with increased sensitivity atusual doses
Co morbidity
Increased drug interactions
Increased bleeding risk independent of the above
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Mean Warfarin Daily Dose(mg)
Patient Age 80
Gurwitz, et al, 1992 6.4 5.1 4.2 3.6 ND(n=530 patients total study)
James, et al, 1992 6.1 5.3 4.3 3.9 3.5(n=2,305 patients total study)
Increasing age has been associated with an increased response to the effect
of warfarin
Gurwitz JH, et al. Ann Int Med 1992; 116(11): 901-90Gurwitz JH, et al. Ann Int Med 1992; 116(11): 901-90
James AH, et al. J Clin Path 1992; 45: 704-70James AH, et al. J Clin Path 1992; 45: 704-70
Warfarin Dosing in Elderly Patients
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Prothrombin Time (PT)
Historically, a most reliable and relied upon clinicaltest
However: Proliferation of thromboplastin reagents with widely
varying sensitivities to reduced levels of vitamin K-dependent clotting factors has occurred Concept of correct intensity of anticoagulant therapy has
changed significantly (low intensity) Problem addressed by use of INR (International
Normalized Ratio)
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J Clin Path 1985; 38:133-134; WHO TJ Clin Path 1985; 38:133-134; WHO T
Rep Ser. #687 Rep Ser. #687
INR: International Normalized Ratio
A mathematical correction (of the PT ratio) fordifferences in the sensitivity of thromboplastinreagents
Relies upon reference thromboplastins with knownsensitivity to antithrombotic effects of oralanticoagulants
INR is the PT ratio one would have obtained if thereference thromboplastin had been used
Allows for comparison of results between labs andstandardizes reporting of the prothrombin time
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(( ))Patients PT in Seconds
Mean Normal PT in SecondsINR =INR =
ISIISI
INR = International Normalized RatioISI = International Sensitivity Index
INR Equation
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MeanMeanNormalNormal(Seconds)(Seconds)
PTRPTR ISIISI INRINR
1212
1212
1313
1111
14.514.5
1.31.3
1.51.5
1.61.6
2.22.2
2.62.6
AA
BB
CC
DD
EE
Blood from asingle patient
PatientsPatientsPTPT
(Seconds)(Seconds)
1616
1818
2121
2424
3838
ThromboplastinThromboplastinReagentReagent
How Different ThromboplastinsInfluence the PT Ratio and INR
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MeanMeanNormalNormal(Seconds)(Seconds)
PTRPTR ISIISI INRINR
1212
1212
1313
1111
14.514.5
1.31.3
1.51.5
1.61.6
2.22.2
2.62.6
AA
BB
CC
DD
EE
Blood from asingle patient
PatientsPatientsPTPT
(Seconds)(Seconds)
1616
1818
2121
2424
3838
ThromboplastinThromboplastinReagentReagent
How Different ThromboplastinsInfluence the PT Ratio and INR
3.23.2
2.42.4
2.02.0
1.21.2
1.01.0
2.62.6
2.62.6
2.62.6
2.62.6
2.62.6
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Relationship Between PT Ratio and INR
Adapted from: Poller L. Thromb HaemAdapted from: Poller L. Thromb Haem
vol 60, 1vol 60, 1
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Potential Problems with the INR
LimitationsUnreliable during induction
Loss of accuracy with high ISIthromboplastinsIncorrect ISI assignment bymanufacturer
Incorrect calculation of INRdue to failure to use proper
mean normal plasma value toderive PT ratio
SolutionsUse thromboplastin reagents withlow ISI values (less than 1.5)Use thromboplastin reagents withlow ISI values
Use thromboplastin reagents withlow ISI values and use plasmacalibrants with certified INRvaluesUse mean normal PT derivedfrom normal plasma samples for
every new batch of thromboplastinreagent
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*Harrison L, et al. Ann Intern Med 1997;126:133-*Harrison L, et al. Ann Intern Med 1997;126:133-
Warfarin: Dosing Information
Individualize dose according to patient response(as indicated by INR)
Use of large loading dose not recommended* May increase hemorrhagic complications
Does not offer more rapid protection Low initiation doses are recommended for
elderly/frail/liver-diseased/malnourished patients
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Loading Dose then Maintenance DoseLoading Dose then Maintenance Dose
DailyDose
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Maintenance Dose OnlyMaintenance Dose Only
DailyDose
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MaintenanceDose Only
Loading Dose thenMaintenance Dose
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Conversion from Heparin to Warfarin
May begin concomitantly with heparin therapy Heparin should be continued for a minimum of four
days Time to peak antithrombotic effect of warfarin is
delayed 96 hours (despite INR) When INR reaches desired therapeutic range,
discontinue heparin (after a minimum of four days)
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** Elderly, frail, liver disease, malnourished: 2 mg/day
Warfarin: Dosing & Monitoring
Start low Initiate 5 mg daily* Educate patient
Stabilize
Titrate to appropriate INR Monitor INR frequently
(daily then weekly)
Adjust as necessary
Monitor INR regularly (every 14 weeks) and adjust
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Relative Contraindications to Warfarin
Pregnancy Situations where the risk of hemorrhage is greater
than the potential clinical benefits of therapy Uncontrolled alcohol/drug abuse
Unsupervised dementia/psychosis
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Fetal Warfarin Syndrome
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Signs of Warfarin Over dosage
Any unusual bleeding: Blood in stools or urine Excessive menstrual bleeding Bruising
Excessive nose bleeds/bleeding gums Persistent oozing from superficial injuries Bleeding from tumor, ulcer, or other lesion
M i P ti t ith Hi h INR V l /Managing Patients with High INR Values/
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Managing Patients with High INR Values/Managing Patients with High INR Values/Minor or No BleedingMinor or No Bleeding
Clinical SituationINR >therapeutic range but5.0 but
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Managing Patients with High INR Values/Managing Patients with High INR Values/Serious BleedingSerious Bleeding
Clinical SituationINR >9.0, no clinicallysignificant bleeding
Life-threateningbleeding or
serious warfarin overdose
Continuing warfarin therapyindicated after high doses of
vitamin K1
GuidelinesGuidelines
Vitamin KVitamin K11 (35 mg orally); closely monitor the INR;(35 mg orally); closely monitor the INR;if the INR is not substantially reduced by 2424 h,if the INR is not substantially reduced by 2424 h,the vitamin Kthe vitamin K11 dose can be repeateddose can be repeated
Serious bleeding, or major warfarin overdose (e.g.,Serious bleeding, or major warfarin overdose (e.g.,INR >20.0) requiring very rapid reversal ofINR >20.0) requiring very rapid reversal ofanticoagulant effect: Vitamin Kanticoagulant effect: Vitamin K11 (10 mg by slow IV(10 mg by slow IVinfusion), with fresh plasma transfusion orinfusion), with fresh plasma transfusion orprothrombin complex concentrate, depending uponprothrombin complex concentrate, depending uponurgency; vitamin Kurgency; vitamin K11 injections may be needed q12hinjections may be needed q12h
Heparin, until the effects of vitamin KHeparin, until the effects of vitamin K11 have beenhave beenreversed, and patient is responsive to warfarinreversed, and patient is responsive to warfarin
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Effective below 2.5Effective below 2.5
Relationship Between INR and Efficacy/Safety
Low-intensity treatment: Efficacy rapidly diminishes below INR 2.0* No efficacy below INR 1.5
High-intensity treatment:
Safety compromised above INR 4
Risk of Intracranial Hemorrhage in
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Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated withHylek, et al, studied the risk of intracranial hemorrhage in outpatients treated withwarfarin. They determined that an intensity of anticoagulation expressed as awarfarin. They determined that an intensity of anticoagulation expressed as aprothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 toprothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to4.3) resulted in an increase in the risk of bleeding.4.3) resulted in an increase in the risk of bleeding.
Adapted from: Hylek EM, Singer DE, Ann Int MedAdapted from: Hylek EM, Singer DE, Ann Int Med
1994;120:897-9021994;120:897-902
Risk of Intracranial Hemorrhage inOutpatients
Lowest Effective Intensity for Warfarin TherapyLowest Effective Intensity for Warfarin Therapy
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Hylek EM, et al. NEJM 1996;335:540Hylek EM, et al. NEJM 1996;335:540-
INR below 2.0 results in a higherrisk of stroke
Lowest Effective Intensity for Warfarin TherapyLowest Effective Intensity for Warfarin Therapyfor Stroke Prevention in Atrial Fibrillationfor Stroke Prevention in Atrial Fibrillation
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IndicationIndication INR Range TargetINR Range Target
Prophylaxis of venous thrombosis (high-risk surgery)Prophylaxis of venous thrombosis (high-risk surgery) 2.03.02.03.0 2.52.5
Treatment of venous thrombosisTreatment of venous thrombosis
Treatment of PETreatment of PE
Prevention of systemic embolismPrevention of systemic embolism
Tissue heart valvesTissue heart valvesAMI (to prevent systemic embolism)AMI (to prevent systemic embolism)
Valvular heart diseaseValvular heart disease
Atrial fibrillationAtrial fibrillation
Mechanical prosthetic valves (high risk)Mechanical prosthetic valves (high risk) 2.53.52.53.5 3.03.0
Certain patients with thrombosis and the antiphospholipid syndromeCertain patients with thrombosis and the antiphospholipid syndrome
AMI (to prevent recurrent AMI)AMI (to prevent recurrent AMI)
Bileaflet mechanical valve in aortic position, NSRBileaflet mechanical valve in aortic position, NSR 2.03.02.03.0 2.52.5
Warfarin: Current Indications/Intensity
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Mechanical Prosthetic Heart ValvesMechanical Prosthetic Heart Valves
Patient Characteristics Recommendation
Bileaflet mechanical valve in the aortic position, Goal INR 2.5; range, 2.03.0left atrium of normal size, NSR, normal ejection fraction
Tilting disk valve or bileaflet mechanical valve in Goal INR 3.0; range, 2.53.5*the mitral position
Bileaflet mechanical aortic valve and AF Goal INR 3.0; range, 2.53.5*
Caged ball or caged disk valves Goal INR 3.0; range, 2.53.5;and aspirin (80100 mg/d)
Additional risk factors Goal INR 3.0; range, 2.53.5;and aspirin therapy (81 mg/d)
Systemic embolism, despite adequate therapy Goal INR 3.0; range, 2.53.5;with oral anticoagulants and aspirin therapy (81 mg/d)
* Alternative: goal INR 2.5; range, 2.03.0; and aspirin therapy (80100 mg/d)
Examples of Low & High Risk InvasiveExamples of Low & High Risk Invasive
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Examples of Low & High Risk InvasiveExamples of Low & High Risk InvasiveProcedures & Clinical ConditionsProcedures & Clinical Conditions
RiskofThrom
bosis
Risk of BleedingLow High
Low
Dental; cutaneous biopsies;open procedures; cataracts
AF; valvular heart disease aortic prosthesis; old DVT/PE
Dental; cutaneous biopsies;open procedures; cataracts
Prosthetic valves, esp. in mitralposition; AF + history of CVA; very
recent DVT/PE
Major thoracic, abdominal, or pelvicsurgery; CNS surgery; polypectomy viacolonoscopy
AF; valvular heart disease aortic prosthesis; old DVT/PE
Major thoracic, abdominal, or pelvicsurgery; CNS surgery; polypectomy viacolonoscopy
Prosthetic valves, esp. in mitral position;AF + history of CVA; very recent DVT/PE
High
Management of Warfarin for InvasiveManagement of Warfarin for Invasive
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Risk
of
Thromb
osis
LDH = Low dose heparin
Adj. DH = Adjusted dose heparin
FDH = Full dose heparin
Risk of Bleeding
Low High
Low
Do procedure at:sub-therapeutic INRrange or lower
Do procedure at:normal INR range; useno alternative or use
LDH, Adj. DH or FDH
HighDo procedure at:therapeutic or sub-therapeutic INR range
Do procedure at:normal INR range;use FDH
Management of Warfarin for InvasiveManagement of Warfarin for InvasiveProceduresProcedures
Management of Warfarin During Invasive
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Management of Warfarin During InvasiveProcedures
For subtherapeutic or normal INR: Hold warfarin for 35 days pre-procedure
Low Dose Heparin (LDH): Low-dose heparin (5,000 IU SQ BID);hold warfarin 35 days pre-procedure and begin LDH therapy 12days pre-procedure
Adjusted Dose Heparin (AdjDH): Same as LDH but higher doses ofheparin (between 8,00010,000 IU BID or TID) to achieve an aPTTin upper range of normal or slightly higher midway between doses
Full Dose Heparin (FDH): full doses of heparin, IV continuousinfusion, to achieve a therapeutic aPTT (~1.52x control); implement
as for LDH Restart heparin or warfarin post-op when considered safe to do so
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55 55 55555555 55
MonMon TueTue WedWed ThuThu FriFri SatSat SunSunTotalTotalWeeklyWeeklyDoseDose
35 mg35 mg
2.52.5 55 55552.52.555 55 30 mg30 mg
2.52.5 2.52.5 55555555 2.52.5 27.5 mg27.5 mg
Warfarin Dosing ScheduleWarfarin Dosing Schedule
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Current Daily Dose (mg)
2.0 5.0 7.5 10.0 12.5
WarfarinINR Dose Adjustment* Adjusted Daily Dose (mg)
1.0-2.0 Increase x 2 days 5.0 7.5 10.0 12.5 15.02.0-3.0 No change 3.0-6.0 Decrease x 2 days 1.25 2.5 5.0 7.5 10.0
6.0-10.0 Decrease x 2 days 0 1.25 2.5 5.0 7.510.0-18.0 Decrease x 2 days 0 0 0 0 2.5
>18.0 Discontinue warfarin and consider hospitalization/reversalof anticoagulation
Consider oral vitamin K, 2.55 mg Oral vitamin K, 2.55 mg* Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days afterincreasing or decreasing warfarin dosage and use new guide to management (INR = International NormalizedRatio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd,alternate 5.0/7.5; if alternate 2.5/5.0, increase to 5.0 qd).
Dosage Adjustment Algorithm
i i h f i i i
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Drug Interactions with Warfarin:Potentiating
Level of
Evidence PotentiatingAlcohol(if concomitant liver disease) amiodarone (anabolic steroids,cimetidine, clofibrate, cotrimoxazole, erythromycin, fluconazole,isoniazid [600 mg daily] metronidazole), miconazole,omeprazole,phenylbutazone, piroxicam, propafenone, propranolol,
Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene,disulfiram, itraconazole, quinidine, phenytoin (biphasic with laterinhibition), tamoxifen, tetracycline,flu vaccine
Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide,ketoprofen, iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin,ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates
Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
I
II
III
IVIn a small number of volunteer subjects, an inhibitorydrug interaction occurred.
D I i i h W f i I hibi i
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Drug Interactions with Warfarin: Inhibition
Level of
Evidence Inhibition
Barbiturates, carbamazepine, chlordiazepoxide,cholestyramine, griseofulvin, nafcillin, rifampin,sucralfate
Dicloxacillin
Azathioprine, cyclosporine, etretinate, trazodone
I
II
III
IV
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Effective Patient Education
Teach basic concepts of safe, effective anticoagulation Discuss importance of regular INR monitoring
Counsel on use of other medications, alcohol
Develop creative strategies for improving compliance
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