Management of Oral Management of Oral Anticoagulant TherapyAnticoagulant TherapyPrinciples & PracticePrinciples & Practice

Prepared for thePrepared for the

Postgraduate Education Committee,Postgraduate Education Committee,Council on Clinical CardiologyCouncil on Clinical Cardiology

American Heart AssociationAmerican Heart Associationbyby

Jack Ansell, M.D.Jack Ansell, M.D.Jack Hirsh, M.D.Jack Hirsh, M.D.

Nanette K. Wenger, M.D.Nanette K. Wenger, M.D.

Supported by an Educational Grant from DuPont PharmaceuticalsSupported 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)

Endorsed byEndorsed by

The Anticoagulation ForumThe Anticoagulation Forum

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

Vascular BiologyVascular Biology

Clotting CascadeClotting Cascade

Vitamin KVitamin K

Synthesis of Synthesis of Functional Functional

Coagulation Coagulation FactorsFactors

VIIVII

IXIX

XX

IIII

Vitamin K-Dependent Clotting FactorsVitamin K-Dependent Clotting Factors

Vitamin K Mechanism of ActionVitamin K Mechanism of Action

WarfarinWarfarin

Synthesis of Synthesis of Non Functional Non Functional

Coagulation Coagulation FactorsFactors

Antagonismof

Vitamin K

Warfarin Mechanism of ActionWarfarin Mechanism of Action

Vitamin KVitamin K

VIIVII

IXIX

XX

IIII

Warfarin Mechanism of ActionWarfarin Mechanism of Action

Virchow’s TriadVirchow’s Triad

Antithrombotic Agents: Mechanism of ActionAntithrombotic Agents: Mechanism of Action

Anticoagulants: prevent clot formation and extensionAnticoagulants: prevent clot formation and extension Antiplatelet drugs: interfere with platelet activityAntiplatelet drugs: interfere with platelet activity Thrombolytic agents: dissolve existing thrombiThrombolytic agents: dissolve existing thrombi

Warfarin: IndicationsWarfarin: Indications

Prophylaxis and/or treatment of:Prophylaxis and/or treatment of: Venous thrombosis and its extensionVenous thrombosis and its extension Pulmonary embolismPulmonary embolism Thromboembolic complications associated with AF and Thromboembolic complications associated with AF and

cardiac valve replacementcardiac valve replacement Post MI, to reduce the risk of death, recurrent MI, and Post MI, to reduce the risk of death, recurrent MI, and

thromboembolic events such as stroke or systemic thromboembolic events such as stroke or systemic embolizationembolization

Prevention and treatment of cardiac embolismPrevention and treatment of cardiac embolism

Warfarin: Major Adverse Effect—HemorrhageWarfarin: Major Adverse Effect—Hemorrhage

Factors that may influence bleeding risk:Factors that may influence bleeding risk: Intensity of anticoagulationIntensity of anticoagulation Concomitant clinical disordersConcomitant clinical disorders Concomitant use of other medicationsConcomitant use of other medications Quality of managementQuality of management

Special Considerations in the Elderly—BleedingSpecial Considerations in the Elderly—Bleeding

Increased age associated with increased sensitivity at usual Increased age associated with increased sensitivity at usual dosesdoses

ComorbidityComorbidity Increased drug interactionsIncreased drug interactions ? Increased bleeding risk independent of the above? Increased bleeding risk independent of the above

Mean Warfarin Daily Dose (mg)Mean Warfarin Daily Dose (mg)Patient AgePatient Age <50<50 50–5950–59 60–6960–69 70–7970–79 >80>80

Gurwitz, et al, 1992Gurwitz, et al, 1992 6.46.4 5.15.1 4.24.2 3.63.6 NDND(n=530 patients total study)(n=530 patients total study)

James, et al, 1992James, et al, 1992 6.16.1 5.35.3 4.34.3 3.93.9 3.53.5(n=2,305 patients total study)(n=2,305 patients total study)

Increasing age has been associated with anIncreasing age has been associated with anincreased response to the effects of warfarinincreased response to the effects of warfarin

Gurwitz JH, et al. Ann Int Med 1992; 116(11): 901-904.Gurwitz JH, et al. Ann Int Med 1992; 116(11): 901-904.James AH, et al. J Clin Path 1992; 45: 704-706.James AH, et al. J Clin Path 1992; 45: 704-706.

Warfarin Dosing in Elderly PatientsWarfarin Dosing in Elderly Patients

Prothrombin Time (PT)Prothrombin Time (PT)

Historically, a most reliable and “relied upon” clinical testHistorically, a most reliable and “relied upon” clinical testHowever:However: Proliferation of thromboplastin reagents with widely varying Proliferation of thromboplastin reagents with widely varying

sensitivities to reduced levels of vitamin K-dependent clotting sensitivities to reduced levels of vitamin K-dependent clotting factors has occurredfactors has occurred

Concept of correct “intensity” of anticoagulant therapy has Concept of correct “intensity” of anticoagulant therapy has changed significantly (low intensity)changed significantly (low intensity)

Problem addressed by use of INR (International Normalized Problem addressed by use of INR (International Normalized Ratio)Ratio)

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

INR: International Normalized RatioINR: International Normalized Ratio

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

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

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

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

(( ))Patient’s PT in SecondsPatient’s PT in SecondsMean Normal PT in SecondsMean Normal PT in Seconds

INR =INR =ISIISI

INR = International Normalized Ratio ISI = International Sensitivity Index

INR EquationINR Equation

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 a Blood from a single patientsingle patient

Patient’sPatient’sPTPT

(Seconds)(Seconds)

1616

1818

2121

2424

3838

ThromboplastinThromboplastinReagentReagent

How Different Thromboplastins How Different Thromboplastins Influence the PT Ratio and INRInfluence the PT Ratio and INR

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

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

AA

BB

CC

DD

EE

Blood from a Blood from a single patientsingle patient

Patient’sPatient’sPTPT

(Seconds)(Seconds)

1616

1818

2121

2424

3838

ThromboplastinThromboplastinreagentreagent

How Different Thromboplastins How Different Thromboplastins Influence the PT Ratio and INRInfluence the PT Ratio and INR

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

Relationship Between PT Ratio and INRRelationship Between PT Ratio and INR

Potential Problems with the INRPotential Problems with the INR

LimitationsLimitations Unreliable during inductionUnreliable during induction

Loss of accuracy with high ISI Loss of accuracy with high ISI thromboplastinsthromboplastins

Incorrect ISI assignment by Incorrect ISI assignment by manufacturermanufacturer

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

SolutionsSolutions Use thromboplastin reagents with Use thromboplastin reagents with

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

low ISI valueslow ISI values Use thromboplastin reagents with Use thromboplastin reagents with

low ISI values and use plasma low ISI values and use plasma calibrants with certified INR valuescalibrants with certified INR values

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

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

Warfarin: Dosing InformationWarfarin: Dosing Information

Individualize dose according to patient responseIndividualize dose according to patient response(as indicated by INR)(as indicated by INR)

Use of large loading dose not recommended*Use of large loading dose not recommended* May increase hemorrhagic complicationsMay increase hemorrhagic complications Does not offer more rapid protectionDoes not offer more rapid protection

Low initiation doses are recommended for elderly/frail/liver-Low initiation doses are recommended for elderly/frail/liver-diseased/malnourished patientsdiseased/malnourished patients

Daily Dose

Loading Dose then Maintenance DoseLoading Dose then Maintenance Dose

Daily Dose

Maintenance Dose OnlyMaintenance Dose Only

Daily Dose Daily Dose

Maintenance Maintenance Dose OnlyDose Only

Loading Dose thenLoading Dose thenMaintenance DoseMaintenance Dose

Conversion from Heparin to WarfarinConversion from Heparin to Warfarin

May begin concomitantly with heparin therapyMay begin concomitantly with heparin therapy Heparin should be continued for a minimum of four daysHeparin should be continued for a minimum of four days

Time to peak antithrombotic effect of warfarin is delayed 96 Time to peak antithrombotic effect of warfarin is delayed 96 hours (despite INR)hours (despite INR)

When INR reaches desired therapeutic range, discontinue When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days)heparin (after a minimum of four days)

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

Warfarin: Dosing & MonitoringWarfarin: Dosing & Monitoring

Start lowStart low Initiate 5 mg daily*Initiate 5 mg daily* Educate patientEducate patient

StabilizeStabilize Titrate to appropriate INR Titrate to appropriate INR Monitor INR frequently (daily then weekly)Monitor INR frequently (daily then weekly)

Adjust as necessaryAdjust as necessary Monitor INR regularly (every 1–4 weeks) and adjustMonitor INR regularly (every 1–4 weeks) and adjust

Relative Contraindications to Warfarin TherapyRelative Contraindications to Warfarin Therapy

Pregnancy Pregnancy Situations where the risk of hemorrhage is greater than the Situations where the risk of hemorrhage is greater than the

potential clinical benefits of therapypotential clinical benefits of therapy Uncontrolled alcohol/drug abuseUncontrolled alcohol/drug abuse Unsupervised dementia/psychosisUnsupervised dementia/psychosis

Signs of Warfarin OverdosageSigns of Warfarin Overdosage

Any unusual bleeding:Any unusual bleeding: Blood in stools or urineBlood in stools or urine Excessive menstrual bleedingExcessive menstrual bleeding BruisingBruising Excessive nose bleeds/bleeding gumsExcessive nose bleeds/bleeding gums Persistent oozing from superficial injuriesPersistent oozing from superficial injuries Bleeding from tumor, ulcer, or other lesionBleeding from tumor, ulcer, or other lesion

Managing Patients with High INR Values/Managing Patients with High INR Values/Minor or No BleedingMinor or No Bleeding

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

GuidelinesLower 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

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

INR >5.0 but <9.0, no clinically significant bleeding

Managing Patients with High INR Values/Managing Patients with High INR Values/Serious BleedingSerious Bleeding

Clinical SituationINR >9.0, no clinically significant bleeding

Life-threatening bleeding or serious warfarin overdose

Continuing warfarin therapy indicated after high doses of vitamin K1

GuidelinesVitamin 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

* Effective below 2.5* Effective below 2.5

Relationship Between INR and Efficacy/SafetyRelationship Between INR and Efficacy/Safety

Low-intensity treatment:Low-intensity treatment: Efficacy rapidly diminishes below INR 2.0*Efficacy rapidly diminishes below INR 2.0* No efficacy below INR 1.5No efficacy below INR 1.5

High-intensity treatment:High-intensity treatment: Safety compromised above INR 4Safety compromised above INR 4

Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They 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 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.2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.

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

Risk of Intracranial Hemorrhage in OutpatientsRisk of Intracranial Hemorrhage in Outpatients

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

INR below 2.0 results in a higher risk of stroke

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

IndicationIndication INR RangeINR Range TargetTarget

Prophylaxis of venous thrombosis (high-risk surgery)Prophylaxis of venous thrombosis (high-risk surgery) 2.0–3.02.0–3.0 2.52.5Treatment of venous thrombosisTreatment of venous thrombosisTreatment of PETreatment of PEPrevention of systemic embolismPrevention of systemic embolismTissue heart valvesTissue heart valvesAMI (to prevent systemic embolism)AMI (to prevent systemic embolism)Valvular heart diseaseValvular heart diseaseAtrial fibrillationAtrial fibrillation

Mechanical prosthetic valves (high risk)Mechanical prosthetic valves (high risk) 2.5–3.52.5–3.5 3.03.0Certain patients with thrombosis and the antiphospholipid syndromeCertain patients with thrombosis and the antiphospholipid syndromeAMI (to prevent recurrent AMI)AMI (to prevent recurrent AMI)

Bileaflet mechanical valve in aortic position, NSRBileaflet mechanical valve in aortic position, NSR 2.0–3.02.0–3.0 2.52.5

Warfarin: Current Indications/IntensityWarfarin: Current Indications/Intensity

Mechanical Prosthetic Heart ValvesMechanical Prosthetic Heart Valves

Patient Characteristics RecommendationBileaflet 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 in Goal INR 3.0; range, 2.5–3.5*the mitral position

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

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

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

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

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

Examples of Low & High Risk InvasiveExamples of Low & High Risk InvasiveProcedures & Clinical ConditionsProcedures & Clinical Conditions

Ris

k of

Thr

ombo

sis

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

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

High

Ris

k of

Thr

ombo

sis

LDH = Low dose heparinAdjDH = Adjusted dose heparin

FDH = Full dose heparin

Risk of BleedingLow High

Low

Do procedure at:subtherapeutic INR range or lower

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

HighDo procedure at:therapeutic or subtherapeutic INR range

Do procedure at:normal INR range; use FDH

Management of Warfarin for Invasive ProceduresManagement of Warfarin for Invasive Procedures

Management of Warfarin During Invasive ProceduresManagement of Warfarin During Invasive Procedures

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

Low Dose Heparin (LDH): Low Dose Heparin (LDH): Low-dose heparin (5,000 IU SQ BID); hold warfarin Low-dose heparin (5,000 IU SQ BID); hold warfarin 3–5 days pre-procedure and begin LDH therapy 1–2 days pre-procedure3–5 days pre-procedure and begin LDH therapy 1–2 days pre-procedure

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

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

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

55 55 55555555 55

MonMon TueTue WedWed ThuThu FriFri SatSat SunSun

TotalTotalWeeklyWeeklyDoseDose

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

Current Daily Dose (mg)Current Daily Dose (mg)

2.0 2.0 5.05.0 7.5 7.5 10.010.0 12.512.5WarfarinWarfarin

INRINR Dose Adjustment*Dose Adjustment* Adjusted Daily Dose (mg) Adjusted Daily Dose (mg)1.0-2.01.0-2.0 Increase x 2 daysIncrease x 2 days 5.05.0 7.57.5 10.010.0 12.512.5 15.015.02.0-3.02.0-3.0 No changeNo change —— —— — — — — — —3.0-6.03.0-6.0 Decrease x 2 daysDecrease x 2 days 1.251.25 2.52.5 5.05.0 7.57.5 10.010.0

6.0-10.06.0-10.0†† Decrease x 2 daysDecrease x 2 days 00 1.251.25 2.52.5 5.05.0 7.57.510.0-18.010.0-18.0§§ Decrease x 2 daysDecrease x 2 days 00 00 00 00 2.52.5

>18.0>18.0§§ Discontinue warfarinDiscontinue warfarin and consider hospitalization/reversal and consider hospitalization/reversalof anticoagulationof anticoagulation

† † Consider oral vitamin K, 2.5–5 mgConsider oral vitamin K, 2.5–5 mg§§ 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 * 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 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, 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).increase to 5.0 qd).

Dosage Adjustment AlgorithmDosage Adjustment Algorithm

Drug Interactions with Warfarin: PotentiationDrug 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.

Drug Interactions with Warfarin: InhibitionDrug 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

Drug Interactions with Warfarin: No EffectDrug 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

Effective Patient EducationEffective Patient Education

Teach basic concepts of safe, effective anticoagulationTeach basic concepts of safe, effective anticoagulation Discuss importance of regular INR monitoringDiscuss importance of regular INR monitoring Counsel on use of other medications, alcoholCounsel on use of other medications, alcohol Develop creative strategies for improving complianceDevelop creative strategies for improving compliance

Patient/Disease State

Process of Care Warfarin: drug with a narrow therapeutic index

Factors Influencing VariabilityFactors Influencing Variability

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)