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Management of Oral Anticoagulant Therapy. Principles & Practice. Prepared for the Postgraduate Education Committee, Council on Clinical Cardiology American Heart Association by. Jack Ansell, M.D. Jack Hirsh, M.D. Nanette K. Wenger, M.D.

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Management of Oral Anticoagulant Therapy

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Management of oral anticoagulant therapy l.jpg

Management of Oral Anticoagulant Therapy

Principles & Practice


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Prepared for thePostgraduate Education Committee,Council on Clinical CardiologyAmerican Heart Associationby

Jack Ansell, M.D.

Jack Hirsh, M.D.

Nanette K. Wenger, M.D.

Supported by an Educational Grant from DuPont Pharmaceuticals

The content of these slides is current as of October, 1999.

Future revisions will be posted on the

American Heart Association website (www.americanheart.org)


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Endorsed by

The Anticoagulation Forum

The American Heart Association Council on Atherosclerosis, Thrombosis, and Vascular Biology


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Clotting Cascade


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Vitamin K-Dependent Clotting Factors

Vitamin K

VII

Synthesis of Functional Coagulation Factors

IX

X

II


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Vitamin K Mechanism of Action


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Warfarin Mechanism of Action

Vitamin K

Antagonism

of

Vitamin K

VII

Synthesis of Non Functional Coagulation Factors

IX

X

II

Warfarin


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Warfarin Mechanism of Action


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Virchow’s Triad


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Antithrombotic 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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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 systemic embolization

  • Prevention and treatment of cardiac embolism


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Warfarin: Major Adverse Effect—Hemorrhage

  • 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 Elderly—Bleeding

  • Increased age associated with increased sensitivity at usual doses

  • Comorbidity

  • Increased drug interactions

  • ? Increased bleeding risk independent of the above


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Mean Warfarin Daily Dose (mg)

Patient Age<5050–5960–6970–79>80

Gurwitz, et al, 19926.45.14.23.6ND

(n=530 patients total study)

James, et al, 19926.15.34.33.93.5

(n=2,305 patients total study)

Warfarin Dosing in Elderly Patients

Increasing age has been associated with an

increased response to the effects of warfarin

Gurwitz JH, et al. Ann Int Med 1992; 116(11): 901-904.

James AH, et al. J Clin Path 1992; 45: 704-706.


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Prothrombin Time (PT)

  • Historically, a most reliable and “relied upon” clinical test

    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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INR: International Normalized Ratio

  • A mathematical “correction” (of the PT ratio) for differences in the sensitivity of thromboplastin reagents

  • Relies upon “reference” thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants

  • INR is the PT ratio one would have obtained if the “reference” thromboplastin had been used

  • Allows for comparison of results between labs and standardizes reporting of the prothrombin time

J Clin Path 1985; 38:133-134; WHO Tech Rep Ser. #687 983.


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INR Equation

(

)

ISI

Patient’s PT in Seconds

Mean Normal PT in Seconds

INR =

INR = International Normalized Ratio

ISI = International Sensitivity Index


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How Different Thromboplastins Influence the PT Ratio and INR

Blood from a single patient

Patient’s

PT

(Seconds)

Mean

Normal

(Seconds)

ThromboplastinReagent

PTR

ISI

INR

16

A

12

1.3

18

B

12

1.5

21

C

13

1.6

24

D

11

2.2

E

38

14.5

2.6


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How Different Thromboplastins Influence the PT Ratio and INR

Blood from a single patient

Patient’s

PT

(Seconds)

Mean

Normal

(Seconds)

Thromboplastinreagent

PTR

ISI

INR

16

A

12

1.3

3.2

2.6

18

B

12

1.5

2.4

2.6

21

C

13

1.6

2.0

2.6

24

D

11

2.2

1.2

2.6

E

38

14.5

2.6

1.0

2.6


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Relationship Between PT Ratio and INR

Adapted from: Poller L. Thromb Haemost vol 60, 1988.


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Limitations

Unreliable during induction

Loss of accuracy with high ISI thromboplastins

Incorrect ISI assignment by manufacturer

Incorrect calculation of INR due to failure to use proper mean normal plasma value to derive PT ratio

Solutions

Use thromboplastin reagents with low ISI values (less than 1.5)

Use thromboplastin reagents with low ISI values

Use thromboplastin reagents with low ISI values and use plasma calibrants with certified INR values

Use “mean normal” PT derived from normal plasma samples for every new batch of thromboplastin reagent

Potential Problems with the INR


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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

*Harrison L, et al. Ann Intern Med 1997;126:133-136.


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Loading Dose then Maintenance Dose

Daily Dose


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Maintenance Dose Only

Daily Dose


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Loading Dose thenMaintenance Dose

Maintenance Dose Only

Daily Dose

Daily 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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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 1–4 weeks) and adjust

* Elderly, frail, liver disease, malnourished: 2 mg/day


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Relative Contraindications to Warfarin Therapy

  • 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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Signs of Warfarin Overdosage

  • 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


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Managing Patients with High INR Values/Minor or No Bleeding

Clinical Situation

INR >therapeutic range but <5.0, no clinically significant bleeding, rapid reversal not indicated for reasons of surgical intervention

Guidelines

Lower the dose or omit the next dose; resume warfarin therapy at a lower dose when the INR approaches desired range

If the INR is only minimally above therapeutic range, dose reduction may not be necessary

INR >5.0 but <9.0, no clinically significant bleeding

Patients with no additional risk factors for bleeding; omit the next dose or two of warfarin, monitor INR more frequently, and resume warfarin therapy at a lower dose when the INR is in therapeutic range

Patients at increased risk of bleeding: omit the next dose of warfarin, and give vitamin K1 (1.0 to 2.5 mg orally)

Patients requiring more rapid reversal before urgent surgery or dental extraction: vitamin K1 (2–4 mg orally); if the INR remains high at 24 h, an additional dose of 1–2 mg


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Managing Patients with High INR Values/Serious Bleeding

Clinical Situation

INR >9.0, no clinically significant bleeding

Life-threatening bleeding or serious warfarin overdose

Continuing warfarin therapy indicated after high doses of vitamin K1

Guidelines

Vitamin K1 (3–5 mg orally); closely monitor the INR; if the INR is not substantially reduced by 24–24 h, the vitamin K1 dose can be repeated

Serious bleeding, or major warfarin overdose (e.g., INR >20.0) requiring very rapid reversal of anticoagulant effect: Vitamin K1 (10 mg by slow IV infusion), with fresh plasma transfusion or prothrombin complex concentrate, depending upon urgency; vitamin K1 injections may be needed q12h

Prothrombin complex concentrate, with vitamin K1 (10 mg by slow IV infusion); repeat if necessary, depending upon the INR

Heparin, until the effects of vitamin K1 have been reversed, and patient is responsive to warfarin


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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

* Effective below 2.5


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Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.

Risk of Intracranial Hemorrhage in Outpatients

Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:897-902


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Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation

INR below 2.0 results in a higher risk of stroke

Hylek EM, et al. NEJM 1996;335:540-546.


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IndicationINR RangeTarget

Prophylaxis of venous thrombosis (high-risk surgery)2.0–3.02.5

Treatment of venous thrombosis

Treatment of PE

Prevention of systemic embolism

Tissue heart valves

AMI (to prevent systemic embolism)

Valvular heart disease

Atrial fibrillation

Mechanical prosthetic valves (high risk)2.5–3.53.0

Certain patients with thrombosis and the antiphospholipid syndrome

AMI (to prevent recurrent AMI)

Bileaflet mechanical valve in aortic position, NSR2.0–3.02.5

Warfarin: Current Indications/Intensity


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Mechanical Prosthetic Heart Valves

Patient CharacteristicsRecommendation

Bileaflet mechanical valve in the aortic position,Goal INR 2.5; range, 2.0–3.0left atrium of normal size, NSR, normal ejection fraction

Tilting disk valve or bileaflet mechanical valve inGoal INR 3.0; range, 2.5–3.5*the mitral position

Bileaflet mechanical aortic valve and AFGoal INR 3.0; range, 2.5–3.5*

Caged ball or caged disk valvesGoal INR 3.0; range, 2.5–3.5;and aspirin therapy (80–100 mg/d)

Additional risk factorsGoal INR 3.0; range, 2.5–3.5;and aspirin therapy (81 mg/d)

Systemic embolism, despite adequate therapyGoal INR 3.0; range, 2.5–3.5;with oral anticoagulantsand aspirin therapy (81 mg/d)

* Alternative: goal INR 2.5; range, 2.0–3.0; and aspirin therapy (80–100 mg/d)


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Examples of Low & High Risk InvasiveProcedures & Clinical Conditions

Risk of Bleeding

Low

High

Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy

AF; valvular heart disease ±aortic prosthesis; old DVT/PE

Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy

Prosthetic valves, esp. in mitral position;AF + history of CVA; very recent DVT/PE

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 mitral position; AF + history of CVA; very recent DVT/PE

Low

Risk of Thrombosis

High


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Management of Warfarin for Invasive Procedures

Risk of Bleeding

Low

High

Do procedure at:subtherapeutic INR range or lower

Do procedure at:normal INR range; use no alternative or use LDH, AdjDH or FDH

Low

Risk of Thrombosis

Do procedure at:therapeutic or subtherapeutic INR range

Do procedure at:normal INR range; use FDH

High

LDH= Low dose heparin

AdjDH= Adjusted dose heparin

FDH= Full dose heparin


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Management of Warfarin During Invasive Procedures

  • For subtherapeutic or normal INR: Hold warfarin for 3–5 days pre-procedure

  • Low Dose Heparin (LDH): Low-dose heparin (5,000 IU SQ BID); hold warfarin 3–5 days pre-procedure and begin LDH therapy 1–2 days pre-procedure

  • Adjusted Dose Heparin (AdjDH): Same as LDH but higher doses of heparin (between 8,000–10,000 IU BID or TID) to achieve an aPTT in upper range of normal or slightly higher midway between doses

  • Full Dose Heparin (FDH): full doses of heparin, IV continuous infusion, to achieve a therapeutic aPTT (~1.5–2x control); implement as for LDH

  • Restart heparin or warfarin post-op when considered safe to do so


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5

5

5

5

5

5

5

5

5

5

5

5

5

5

5

5

Warfarin Dosing Schedule

Total

Weekly

Dose

Mon

Tue

Wed

Thu

Fri

Sat

Sun

35 mg

30 mg

2.5

2.5

27.5 mg

2.5

2.5

2.5


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Dosage Adjustment Algorithm

Current Daily Dose (mg)

2.0 5.0 7.510.012.5

Warfarin

INRDose Adjustment* Adjusted Daily Dose (mg)

1.0-2.0Increase x 2 days5.07.510.012.515.0

2.0-3.0No change—— — — —

3.0-6.0Decrease x 2 days1.252.55.07.510.0

6.0-10.0†Decrease x 2 days01.252.55.07.5

10.0-18.0§Decrease x 2 days00002.5

>18.0§Discontinue warfarin and consider hospitalization/reversalof anticoagulation

† Consider oral vitamin K, 2.5–5 mg

§ Oral vitamin K, 2.5–5 mg

* Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days after increasing or decreasing warfarin dosage and use new guide to management (INR = International Normalized Ratio). 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).


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Drug Interactions with Warfarin: Potentiation

Level of

Evidence Potentiation

Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600 mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam, propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)

Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, phenytoin (biphasic with later inhibition), 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

IV

†In a small number of volunteer subjects, an inhibitory drug interaction occurred.


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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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Drug Interactions with Warfarin: No Effect

Level of

Evidence No Effect

Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine‡

Ibuprofen, ketoconazole

Diltiazem, tobacco, vancomycin

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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Factors Influencing Variability

Patient/Disease State

Process of Care

Warfarin: drug with a narrow therapeutic index


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The content of these slides is current as of October, 1999.

Future revisions will be posted on the

American Heart Association website (www.americanheart.org)


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