anti coagulation recommendations_ambulatory clinic

8/14/2019 Anti Coagulation recommendations_ambulatory clinic

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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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anti coagulation recommendations_ambulatory clinic

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