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
anticoagulation

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








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

Factors that may influence
bleeding risk:
Intensity of anticoagulation
 Concomitant clinical disorders
 Concomitant use of other
medications
 Quality of management

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.
Loading Dose
Then Maintenance Dose
Daily Dose
Maintenance Dose Only
Daily 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)
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

(
Patient’s PT in Seconds
INR = Mean Normal PT in Seconds
)
ISI
INR = International Normalized Ratio
ISI = International Sensitivity Index
known sensitivity to antithrombotic
effects of warfarin

INR is the PT ratio obtained if
“reference” thromboplastin was used
J Clin Path 1985; 38:133-134; WHO Tech Rep Ser. #687 983.
Trusting the INR Result
Ortho 1.00 BFA
DADE 1.03 BFA
Thromboplastin — Reagent combinations and
observed variation in INR
5.5
Behring 1.08 BFA
Pacific Hem 1.20 BFA
IL Test 1.43 BFA
DADE 1.96 BFA
5
Ortho 1.00 ACL
4.5
4
3.5
DADE 1.03 ACL
Behring 1.08 ACL
Pacific Hem 1.20 ACL
IL Test 1.43 ACL
DADE 1.96 ACL
3
Ortho 1.00 MLA
2.5
2
1.5
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
Potential Problems with the INR
Limitations




Solutions
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
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
Optimal Frequency of INR Monitoring*
vs %
In Range
90
% in Range
Test Interval
100
80
70
60
50
40
30
More Frequent
testing increases
% in range
20
10
0
0
7
14
21
28
35
42
49
Days Between Tests
Summary 18 published studies: PST Coalition Report, July 2000
Warfarin: Current Indications/Intensity
Indication
INR Range Target
Prophylaxis of venous thrombosis (high-risk surgery)
Treatment of venous thrombosis
Treatment of PE
Prevention of systemic embolism
Tissue heart valves
AMI (to prevent systemic embolism)
Valvular heart disease
Atrial fibrillation
2.0–3.0
2.5
Mechanical prosthetic valves (high risk)
Certain patients with thrombosis and the antiphospholipid syndrome
AMI (to prevent recurrent AMI)
2.5–3.5
3.0
Bileaflet mechanical valve in aortic position, NSR
2.0–3.0
2.5
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
Dosage Adjustment Algorithm
Current Daily Dose (mg)
2.5
5.0
7.5
10.0 12.5
INR
1.0-2.0
2.0-3.0
3.0-6.0
6.0-10.0†
10.0-18.0§
>18.0§
† Consider
Warfarin
Dose Adjustment*
Adjusted Daily Dose (mg)
Increase x 2 days
5.0
7.5
10.0 12.5 15.0
No change
—
—
—
—
—
Decrease x 2 days
1.25
2.5
5.0
7.5 10.0
Decrease x 2 days
0
1.25
2.5
5.0
7.5
Decrease x 2 days
0
0
0
0
2.5
Discontinue warfarin and consider hospitalization/reversal
of anticoagulation
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).
§
Managing Patients with High INR Values
Minor or No Bleeding
Clinical Situation
Guidelines
INR >therapeutic range but <5.0,
no clinically significant bleeding,
rapid reversal not indicated for
reasons of surgical intervention
Lower the dose or omit the next dose; resume warfarin
therapy at a lower dose when the INR approaches desired
range
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
If the INR is only minimally above therapeutic range, dose
reduction may not be necessary
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
Managing Patients with High INR
Values & Bleeding
Clinical Situation
Guidelines
INR >9.0, no clinically significant
bleeding
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
Life-threatening bleeding or serious
warfarin overdose
Continuing warfarin therapy
indicated after high doses of
vitamin K1
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
†In
Potentiation
I
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)
II
Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram,
itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen,
tetracycline, flu vaccine
III
Acetylsalicylic acid, disopyramide, fluorouracil, ifosfamide, ketoprofen,
simvastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin,
propoxyphene, sulindac, tolmetin, topical salicylates
IV
Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
a small number of volunteer subjects, an inhibitory drug interaction occurred.
Drug Interactions with Warfarin:
Inhibition
Level of
Evidence
Inhibition
I
Barbiturates, carbamazepine, chlordiazepoxide,
cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate
II
Dicloxacillin
III
Azathioprine, cyclosporine, etretinate, trazodone
How well does a University Hospital do in
managing warfarin therapy?
26
“Inpatient Warfarin Medication Utilization Evaluation”
Treatment decisions involving inappropriate assessment of response
• 349 records reviewed and assessed by established criteria
• 647/2030 (31.8%) warfarin treatment decisions were deemed inappropriate
Total = 647 decisions
8%
Initial dose too high (52 decisions)
Initial dose too low (9 decisions)
1%
10%
Different dose from home therapy
(63 decisions)
1%
1%
Continued home dose but should
have been changed (6 decisions)
10%
Continued home dose but should
have been held (4 decisions)
Held dose when therapy should
have been restarted (66 decisions)
69%
PK/PD not taken into account
(447 decisions)
Challenges With Conventional
Laboratory Testing
Challenges for
patients’
compliance

Patient issues




Labor-intensive and higher costs




Time for traveling to office or laboratory
Ability to travel
Need for venous access
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
adjustments
Jacobson 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
Routine
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
 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
 Patient Self-Testing (PST)
Patient uses POC monitor to measure INR at home. Dose
managed by UC or ACC
 Patient Self-Management (PSM)
Patient uses POC monitor to measure INR at home and
manages own AC dose
Home Monitoring

Willing to:
Considerations

for Patient

Selection


Able to:






Learn and perform testing procedure
Keep accurate written records
Communicate results in timely fashion
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
www. ASmartWayToTest.com
Technology Advances:
Offers a new
paradigm for
monitoring
since 1987

Use of capillary whole blood




Consistency of INR results
Portability


Allows fingerstick sampling
Appropriate for self-testing
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
Major Hemorrhage with PST & PSM vs Control
Heneghan et al. Lancet 2006;367:404
Communication with patient doing home monitoring
Oral Anticoagulation Patient Self-Testing: Consensus Guidelines for Practical
Implementation. Managed Care 2008;17(#10, Suppl 9):1-9
Management of Warfarin During Invasive
Procedures







For sub-therapeutic or normal INR: Hold warfarin for 3–5 days preprocedure
Low-dose heparin (5,000 IU SQ BID); hold warfarin 3–5 days preprocedure 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
Warfarin Dosing in Elderly Patients
Mean Warfarin Daily Dose (mg)
Patient Age
<50
50–59
60–69
70–79 >80
Gurwitz, et al, 1992
(n=530 patients total study)
6.4
5.1
4.2
3.6 ND
James, et al, 1992
(n=2,305 patients total study)
6.1
5.3
4.3
3.9
3.5
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.
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
* Elderly, frail, liver disease, malnourished: 2 mg/day
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).
Conclusions . . .
•
•
•
•
•
•
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