WARFARIN THERAPY

Nicolas Novitzky

The Ideal Oral Anticoagulant

Ideally, an oral anticoagulant would: Have high efficacy in reducing thromboembolic

events

Reach therapeutic levels within several hours

Oral and/or IV administration

Ability to inhibit free and clot bound thrombin

Require no remote monitoring

Have little interaction with food or other drugs

Offer a good safety profile with regard to bleeding risk

Availability of an antidote

Antithrombotic Agents: Mechanism of Action

Anticoagulants: prevent clot formation and extension Heparins, LNWH, huridin Warfarin Direct anti thrombin inhibitors

Dabigatran Direct factor Xa inhibitors

Rivaroxaban, apixaban Antiplatelet drugs: interfere with platelet activity Thrombolytic agents: dissolve existing thrombi

Coagulation Cascade

Warfarin typically works on several calcium-dependent clotting factors, including factors II, VII, IX (not shown), and X.

Vitamin K-Dependent Clotting Factors

Warfarin: Indications

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

AF and cardiac valve replacement Prophylaxis of recurrent thrombosis in APS

Post MI, to reduce the risk of death, recurrent MI, stroke Systemic embolization

Prophylaxis of genetic thrombophilia

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

The Dilemma of Anticoagulation Management

Narrow therapeutic window of effectiveness & safety.

Frequent monitoring is required to maintain patients in the therapeutic window.

Many factors influence a patient’s stability within that window.

Monitoring is labour intensive and complex

Consequences• Increased adverse

events with poor management

• Physicians avoid warfarin use because of its complexity

Successful Anticoagulation

Team work in

monitoring anti-

coagulation

Correct indication Patient education

Compliance

Understanding coagulation results

Diet

Drug interactions

Toxicity, bleeding

Laboratory testing Point of care testing

Doctor’s office

Patient self testing

Disadvantages of Warfarin

Factors that may influence bleeding risk: Intensity of

anticoagulation Concomitant clinical

disorders Concomitant use of

other medications Quality of

management

Narrow therapeutic index

Need for frequent monitoring

Slow onset & offset of action

Large inter-individual dosing differences

Drug-Drug and drug-food interactions

Genetic polymorphisms Warfarin skin necrosis Warfarin embryopathy

Conversion from Heparin to Warfarin

Initiate AC with heparin Heparin bolus dose 5000u

333u / kg and as per aPTT

Enoxaparin (Clexane) 1 mg/kg BD

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 therapeutic range, discontinue heparin

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

Use of large loading dose not recommended*

Increases 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.

Daily Dose Daily Dose

Maintenance Dose Only

Loading Dose Then Maintenance

Dose

Prothrombin Time (PT)

Historically, a most dependable “relied upon” clinical test; but:

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

Many thromboplastin reagents with widely varying sensitivities to low levels of vitamin K-dependent clotting factors available

Problem addressed by use of INR (International Normalized Ratio)

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

INR: International Normalized Ratio

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

Allows for evaluation of results between labs and standardizes reporting of the PT

Relies upon “reference” thromboplastin

known sensitivity to antithrombotic effects of warfarin

INR is the PT ratio obtained if “reference” thromboplastin was used

( )Patient’s PT in SecondsMean Normal PT in SecondsINR =

ISI

INR = International Normalized Ratio ISI = International Sensitivity Index

Trusting the INR Result

1.5

2

2.5

3

3.5

4

4.5

5

5.5

Ortho 1.00 BFA

DADE 1.03 BFA

Behring 1.08 BFA

Pacific Hem 1.20 BFA

IL Test 1.43 BFA

DADE 1.96 BFA

Ortho 1.00 ACL

DADE 1.03 ACL

Behring 1.08 ACL

Pacific Hem 1.20 ACL

IL Test 1.43 ACL

DADE 1.96 ACL

Ortho 1.00 MLA

DADE 1.03 MLA

Behring 1.08 MLA

Pacific Hem 1.20 MLA

IL Test 1.43 MLA

DADE 1.96 MLA

Courtesy A. Jacobson

Thromboplastin — Reagent combinations and observed variation in INR

Potential Problems with the INR

Limitations Unreliable during induction

Loss of accuracy with high ISI thromboplastin

Incorrect ISI assignment by manufacturer

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

Solutions Thromboplastin reagents with

low ISI values (less than 1.5) Use plasma calibrates with

certified INR values Use “mean normal” PT

derived from normal plasma samples for every new batch of thromboplastin reagent

Test Interval

vs %

In Range

0

10

20

30

40

50

60

70

80

90

100

0 7 14 21 28 35 42 49

% i

n R

ang

e

Days Between TestsSummary 18 published studies: PST Coalition Report, July 2000

More Frequent testing increases % in range

Optimal Frequency of INR Monitoring*

Indication INR Range Target

Prophylaxis of venous thrombosis (high-risk surgery) 2.0–3.0 2.5Treatment of venous thrombosisTreatment of PEPrevention of systemic embolismTissue heart valvesAMI (to prevent systemic embolism)Valvular heart diseaseAtrial fibrillation

Mechanical prosthetic valves (high risk) 2.5–3.5 3.0Certain patients with thrombosis and the antiphospholipid syndromeAMI (to prevent recurrent AMI)

Bileaflet mechanical valve in aortic position, NSR 2.0–3.0 2.5

Warfarin: Current Indications/Intensity

Optimal INR in AF

Adapted from Hylek EM et. al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. NEJM 1996; 335(8):540-6 and Hylek EM and Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120(11):897-902.

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

Current Daily Dose (mg)2.5 5.0 7.5 10.0

12.5Warfarin

INR 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

10.06.0-10.0† 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/reversal

of 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).

Dosage Adjustment Algorithm

Managing Patients with High INR Values

Minor 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 rangeIf 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 rangePatients 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 & 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

Guidelines

Vitamin K1 (3–5 mg orally); closely monitor the INR; if the INR is not substantially reduced by 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

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, ifosfamide, ketoprofen, simvastatin, 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: Inhibition

Level of Evidence Inhibition

Barbiturates, carbamazepine, chlordiazepoxide, cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate

Dicloxacillin

Azathioprine, cyclosporine, etretinate, trazodone

I

II

III

26

Treatment decisions involving inappropriate assessment of response

Total = 647 decisions

8%1%

10%

1%

1%

10%

69%

Initial dose too high (52 decisions)

Initial dose too low (9 decisions)

Different dose from home therapy (63 decisions)

Continued home dose but should have been changed (6 decisions)

Continued home dose but should have been held (4 decisions)

Held dose when therapy shouldhave been restarted (66 decisions)

PK/PD not taken into account (447 decisions)

• 349 records reviewed and assessed by established criteria• 647/2030 (31.8%) warfarin treatment decisions were deemed inappropriate

How well does a University Hospital do in managing warfarin

therapy?

“Inpatient Warfarin Medication Utilization Evaluation”

Challenges With ConventionalLaboratory Testing

Challenges for

patients’ compliance

Patient issues Time for traveling to office or laboratory Ability to travel Need for venous access

Labor-intensive and higher costs Scheduling visits Proper handling and delivery of sample Documentation at several time points

Potential for communication delays Laboratory to contact provider with

results Provider to contact patient with dosage

adjustmentsJacobson AK. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing Oral Anticoagulation Therapy. 2nd ed. St. Louis, Mo: Facts and Comparisons; 2003;45:1-6.

Models of Chronic Anticoagulation Management

Laboratory based

Vs

Patient self

testing

hRoutine Medical Care (Usual Care)AC managed by physician or office staff w/o any systematic program for education, follow-up, communication, and dose management. May use POC device or laboratory INR

h Anticoagulation Clinic (ACC)

AC managed by dedicated personnel (MD, RN or pharmacist) with systematic policies in place to manage and dose patients. May use POC device or laboratory INR

h Patient Self-Testing (PST)Patient uses POC monitor to measure INR at home. Dose managed by UC or ACC

h Patient Self-Management (PSM)

Patient uses POC monitor to measure INR at home and manages own AC dose

Home Monitoring

Willing to: Learn and perform testing procedure Keep accurate written records Communicate results in timely fashion

Able to: Participate in a training program to acquire skills/competencies to perform self-testing Generate an INR Understand implications of test result Maintain records

Reliable to: Perform procedure with acceptable technique

to obtain accurate results

Considerations

for Patient

Selection

www. ASmartWayToTest.com

Technology Advances:

Offers a new paradigm for monitoring since 1987

Use of capillary whole blood Allows fingerstick sampling Appropriate for self-testing

Consistency of INR results Portability

Can be done anywhere Simplicity

Patient can easily perform test

1. Leaning KE, Ansell JE. J Thromb Thrombolysis. 1996;3:377-383. 2. Ansell JE. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing Oral Anticoagulation Therapy. 2nd ed. St. Louis, Mo: Facts and Comparisons; 2003;44:1-6.

Thromboembolism with PST or PSM vs Control

Heneghan et al. Lancet 2006;367:404

psm

pst

What is the

control group

Major Hemorrhage with PST & PSM vs Control

Heneghan et al. Lancet 2006;367:404

Oral Anticoagulation Patient Self-Testing: Consensus Guidelines for Practical Implementation. Managed Care 2008;17(#10, Suppl 9):1-9

Communication with patient doing home monitoring

Management of Warfarin During Invasive Procedures

For sub-therapeutic or normal INR: Hold warfarin for 3–5 days pre-procedure

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

Enoxaparin (Clexane) 1 mg/kg Full Dose Heparin (FDH): full doses of heparin, IV continuous

infusion, to achieve a therapeutic aPTT (~1.5–2x control); implement as for LDH

Enoxaparin (Clexane 1 mg / kg B. D.) Restart heparin or warfarin post-op when considered safe to

do so

Mean Warfarin Daily Dose (mg)

Patient Age <50 50–59 60–69 70–79 >80

Gurwitz, et al, 1992 6.4 5.1 4.2 3.6ND

(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 anincreased 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.

Warfarin Dosing in Elderly Patients

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

Warfarin: Dosing & Monitoring

Start low Educate patient Initiate 5 mg daily*

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

Adjust as necessary Monitor INR regularly (every 1–4 weeks)

and adjust

Special Considerations in the Elderly: Bleeding

Older age associated with increased sensitivity at usual doses

Comorbidity Increased drug interactions ? Increased bleeding risk independent of

the above

Barriers to Warfarin Use

Reasons why physicians don’t use coumadin: Risk of hemorrhage: 2.0 Risk of embolus too low: 3.4 Patient Refusal: 3.6 Inconvenience of monitoring: 5.2 Impairs quality of life: 5.2 Belief that aspirin is superior: 5.2 Cost: 5.6 Doubt effectiveness: 6.8

McCrory, et al. Arch Int Med, 1995

Management Recommendations

 Heparin: For patients starting IV UFH, the initial bolus and the initial rate of the continuous infusion be weight adjusted Bolus 80 units/kg followed by 18 units/kg per h for VTE;

Bolus 70 units/kg followed by 15 units/kg per h for cardiac or stroke patients)

Use of a fixed dose (bolus 5,000 units followed by 1,000 units/h) rather than alternative regimens (Grade 2C).

For outpatients with VTE treated with SC UFH, weight-adjusted dosing (first dose 333 units/kg, then 250 units/kg) without monitoring rather than fixed or weight-adjusted dosing with monitoring (Grade 2C) suggested.

For patients receiving therapeutic LMWH who have severe renal insufficiency (calculated creatinine clearance < 30 mL/min), we suggest a reduction of the dose rather than using standard doses (Grade 2C).

For OPD start therapy with warfarin 10 mg daily for 1-2 days followed by dosing based on INR measurements

Recommend against the routine use of pharmacogenetic testing for guiding doses of VKA (Grade 1B).

In acute VTE, start VKA therapy on day 1 or 2 of LMWH or low-dose unfractionated heparin (UFH) therapy (Grade 2C).

For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks (Grade 2B).

For patients with previously stable therapeutic INRs a single out-of-range INR of ≤ 0.5 below or above therapeutic,

continuing the current dose and testing INR within 1 to 2 weeks (Grade 2C).

a single subtherapeutic INR value, not to routinely administering bridging heparin (Grade 2C).

For patients taking VKAs, we suggest against routine use of vitamin K supplementation (Grade 2C).

For patients treated with VKAs who are motivated and can demonstrate competency in self-management strategies, including the self-testing equipment, we suggest patient self-management rather than outpatient INR monitoring (Grade 2B).

For dosing decisions, we suggest using validated decision support tools (paper nomograms or computerized dosing programs) rather than no decision support (Grade 2C).

For patients taking VKAs, avoid concomitant treatment with nonsteroidal antiinflammatory drugs, and certain antibiotics (Grade 2C).

For patients taking VKAs, we suggest avoiding concomitant treatment with antiplatelet agents except patients with mechanical valves, patients with acute coronary syndrome, or patients with recent coronary stents or bypass surgery (Grade 2C).

A therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) rather than a lower (INR < 2) or higher (INR 3.0-5.0) range (Grade 1B) is recommended.

For patients with APS with previous thromboembolism, warfarin therapy titrated to a moderate-intensity INR range (INR 2.0-3.0) rather than INR 3.0-4.5 (Grade 2B) recommended.

Discontinuation of VKA, should be abrupt rather than tapering of the dose (Grade 2C).

• Anticoagulants (oral and parenteral) top the list for adverse events.

• Management of warfarin therapy is often poor, even in the best of circumstances.

• The transition from inpatient to outpatient anticoagulation requires labor intensive systems and processes for successful implementation.

• Anticoagulation management models include Routine or Usual Care, Anticoagulation Clinics, and PST/PSM (home monitoring)

• Point-of-care provides an alternative to laboratory testing that is easy, portable, and accurate and allows for testing either by physician or patient

• Home monitoring requires systems in place to implement and manage results. IDTFs can perform much of the implementation and follow up tracking of results

Conclusions . . .