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Management of Oral
Anticoagulant Therapy
Principles & Practice
Clotting Cascade
Vitamin K-Dependent Clotting Factors
Vitamin K
VII
IX
X
II
Synthesis of
Functional
Coagulation
Factors
Vitamin K Mechanism of Action
Warfarin Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
Synthesis of
Non Functional
Coagulation
Factors
Warfarin Mechanism of Action
Antithrombotic Agents: Mechanism of Action



Anticoagulants: prevent clot formation and extension
Antiplatelet drugs: interfere with platelet activity
Thrombolytic agents: dissolve existing thrombi
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
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
Special Considerations in the Elderly—Bleeding




Increased age associated with increased sensitivity at usual
doses
Comorbidity
Medications used for associated illnesses lead to increased
drug interactions
? Increased bleeding risk independent of the above:
increased vascular fragility
Warfarin Dosing in Elderly Patients
Mean Warfarin Daily Dose (mg)
Patient Age
Gurwitz, et al, 1992
<50
6.4
50–59
5.1
60–69
4.2
70–79
3.6
>80
ND
James, et al, 1992
6.1
5.3
4.3
3.9
3.5
(n=530 patients total study)
(n=2,305 patients total study)
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.
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
 Problem addressed by use of INR (International Normalized
Ratio)
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.
INR Equation
INR =
(
Patient’s PT in Seconds
Mean Normal PT in Seconds
INR = International Normalized Ratio
ISI = International Sensitivity Index
)
ISI
How Different Thromboplastins
Influence the PT Ratio and INR
Blood from a
single patient
Thromboplastin
Reagent
Patient’s
PT
(Seconds)
Mean
Normal
(Seconds)
PTR
A
16
12
1.3
B
18
12
1.5
C
21
13
1.6
D
24
11
2.2
E
38
14.5
2.6
ISI
INR
How Different Thromboplastins
Influence the PT Ratio and INR
Blood from a
single patient
Thromboplastin
reagent
Patient’s
PT
(Seconds)
Mean
Normal
(Seconds)
PTR
ISI
INR
A
16
12
1.3
3.2
2.6
B
18
12
1.5
2.4
2.6
C
21
13
1.6
2.0
2.6
D
24
11
2.2
1.2
2.6
E
38
14.5
2.6
1.0
2.6
Relationship Between PT Ratio and INR
Adapted from: Poller L. Thromb Haemost vol 60, 1988.
Potential Problems with the INR
Limitations
Solutions

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




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
Warfarin: Dosing Information


Individualize dose according to patient response
(as indicated by INR)
Use of large loading dose >10 mg is not recommended*
 May
increase hemorrhagic complications
 Does not offer more rapid protection
 Hypercoagulable state due to depletion of protein C (half life of
6 hours): warfarin-induced skin necrosis

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
Loading Dose then
Maintenance Dose
Maintenance
Dose Only
Daily Dose
Daily Dose
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)
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
Relative Contraindications to Warfarin Therapy

Pregnancy :
 Teratogenic in the first trimester:
Warfarin embryopathy in 5%
of exposed neonates
 Fetopathic after the first trimester

Situations where the risk of hemorrhage is greater than the
potential clinical benefits of therapy
 Uncontrolled alcohol/drug abuse
 Unsupervised dementia/psychosis
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
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
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)
Managing Patients with High INR Values/
Serious 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 24–48 h, the vitamin K1
dose can be repeated
Requires 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
INR >20.0, or serious bleeding
Life-threatening bleeding or serious
warfarin overdose
Prothrombin complex concentrate, with vitamin K1 (10 mg by
slow IV infusion); repeat if necessary, depending upon the
INR
Relationship Between INR and Efficacy/Safety


Warfarin has a narrow therapeutic index
Low-intensity treatment:
 Efficacy
rapidly diminishes below INR 2.0*
 No efficacy below INR 1.5

High-intensity treatment:
 Safety
* Effective below 2.5
compromised above INR 4
Risk of Intracranial Hemorrhage in Outpatients
Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:897-902
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.
Lowest Effective Intensity for Warfarin Therapy for
Stroke Prevention in Atrial Fibrillation
Some Protection
INR below 2.0 results in a higher risk of stroke
Hylek EM, et al. NEJM 1996;335:540-546.
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
Mechanical Prosthetic Heart Valves
Patient Characteristics
Recommendation
Bileaflet mechanical valve in the aortic position,
left atrium of normal size, NSR, normal ejection fraction
Goal INR 2.5; range, 2.0–3.0
Tilting disk valve or bileaflet mechanical valve in
the mitral position
Goal INR 3.0; range, 2.5–3.5*
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
with oral anticoagulants
Goal INR 3.0; range, 2.5–3.5;
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 Invasive
Procedures & Clinical Conditions
Risk of Bleeding
Risk of Thrombosis
Low
Low
High
High
Dental; cutaneous biopsies;
open procedures; cataracts
Major thoracic, abdominal, or pelvic surgery;
CNS surgery; polypectomy via colonoscopy
AF; valvular heart disease ±
aortic prosthesis; old DVT/PE
AF; valvular heart disease ±
aortic prosthesis; old DVT/PE
Dental; cutaneous biopsies;
open procedures; cataracts
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
Prosthetic valves, esp. in mitral position;
AF + history of CVA; very recent DVT/PE
Management of Warfarin for Invasive Procedures
Risk of Bleeding
Risk of Thrombosis
Low
Low
High
High
Do procedure at:
subtherapeutic INR range or
lower
Do procedure at:
normal INR range; use no
alternative or use LDH,
AdjDH or FDH
Do procedure at:
therapeutic or subtherapeutic
INR range
Do procedure at:
normal INR range; use FDH
LDH = Low dose heparin
AdjDH = Adjusted dose heparin
FDH = Full dose heparin
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
Warfarin Dosing Schedule
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Total
Weekly
Dose
5
5
5
5
5
5
5
35 mg
2.5
5
5
2.5
5
5
5
30 mg
2.5
5
2.5
5
2.5
5
5
27.5 mg
Dosage Adjustment Algorithm
Current Daily Dose (mg)
2.0
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).
§
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, ifosflhamide, ketoprofen,
iovastatin, 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
IV
Drug Interactions with Warfarin: No Effect
Level of
Evidence
No Effect
I
Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine,
fluoxetine, ketorolac metoprolol, naproxen, nizatidine,
psyllium, ranitidine‡
II
Ibuprofen, ketoconazole
III
IV
Diltiazem, tobacco, vancomycin
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
Factors Influencing Variability
Patient/Disease State
Process of Care
Warfarin: drug with a
narrow therapeutic index