Management of Oral

Anticoagulant Therapy
Principles & Practice
Clotting Cascade
 Vitamin K-Dependent Clotting Factors

Vitamin K

VII
IX
X
II
Vitamin K Mechanism of Action
 Warfarin Mechanism of Action

Vitamin K

Antagonism VI
of I
Vitamin K IX
X
II

Warfarin Synthesis of Non

Functional Coagulation
Factors
Warfarin Mechanism of Action
Virchow’s Triad
Anti thrombotic Agents:
Mechanism of Action

•
Anticoagulants: prevent clot formation and extension
•
Antiplatelet drugs: interfere with platelet activity
•
Thrombolytic agents: dissolve existing thrombi
History of Warfarin
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
•
Co morbidity
•
Increased drug interactions
•
Increased bleeding risk
•
independent of the above
 Warfarin Dosing in Elderly Patients

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 3.6 ND
(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 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 (low intensity)
•
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 ISI

Mean Normal PT in Seconds )
INR = International Normalized Ratio
ISI = International Sensitivity Index
 How Different Thromboplastins
Influence the PT Ratio and INR
Blood from a
single patient
Thromboplastin Patient’s Mean
Reagent PT Normal PTR ISI INR
(Seconds) (Seconds)

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
 How Different Thromboplastins
Influence the PT Ratio and INR
Blood from a
single patient
Thromboplastin Patient’s Mean
Reagent PT Normal PTR ISI INR
(Seconds) (Seconds)

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 •
Use thromboplastin reagents with
low ISI values (less than 1.5)
•
Loss of accuracy with high ISI
•
Use thromboplastin reagents with
thromboplastins low ISI values
•
Use thromboplastin reagents with
•
Incorrect ISI assignment by low ISI values and use plasma
manufacturer calibrants with certified INR
values
Incorrect calculation of INR
•
•
Use “mean normal” PT derived
due to failure to use proper from normal plasma samples for
mean normal plasma value to every new batch of thromboplastin
derive PT ratio reagent
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.

Loading Dose then Maintenance Dose

Daily
Dose
Maintenance Dose Only

Daily
Dose
Loading Dose then Maintenance
Maintenance Dose Dose Only
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
•
Pregnancy
•
Situations where the risk of hemorrhage is greater
than the potential clinical benefits of therapy
•
Uncontrolled alcohol/drug abuse
•
Unsupervised dementia/psychosis
Fetal Warfarin Syndrome
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
 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
INR >5.0 but <9.0, no
clinically significant bleeding
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
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
 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
Heparin, until the effects of vitamin K1 have been
reversed, and patient is responsive to warfarin
 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

 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

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) 2.0–3.0 2.5
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) 2.5–3.5 3.0
Certain patients with thrombosis and the antiphospholipid syndrome
AMI (to prevent recurrent AMI)
Bileaflet mechanical valve in aortic position, NSR 2.0–3.0 2.5
 Mechanical Prosthetic Heart Valves
Patient Characteristics
Bileaflet mechanical valve in the aortic position,
left atrium of normal size, NSR, normal ejection fraction
Tilting disk valve or bileaflet mechanical valve in
the mitral position
Bileaflet mechanical aortic valve and AF
Caged ball or caged disk valves
Additional risk factors
Systemic embolism, despite adequate therapy
with oral anticoagulants
* Alternative: goal INR 2.5; range, 2.0–3.0; and aspirin therapy (80–100 mg/d)
Recommendation
Goal INR 2.5; range, 2.0–3.0
Goal INR 3.0; range, 2.5–3.5*
Goal INR 3.0; range, 2.5–3.5*
Goal INR 3.0; range, 2.5–3.5;
and aspirin (80–100 mg/d)
Goal INR 3.0; range, 2.5–3.5;
and aspirin therapy (81 mg/d)
Goal INR 3.0; range, 2.5–3.5;
and aspirin therapy (81 mg/d)
 Examples of Low & High Risk Invasive
Procedures & Clinical Conditions
Risk of Bleeding
Low
Dental; cutaneous biopsies;
Risk of Thrombosis
open procedures; cataracts
Low
AF; valvular heart disease ±
aortic prosthesis; old DVT/PE
Dental; cutaneous biopsies;
open procedures; cataracts
High
Prosthetic valves, esp. in mitral
position; AF + history of CVA; very
recent DVT/PE
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
 Management of Warfarin for Invasive
Procedures

Risk of Bleeding
Low High
Do procedure at: Do procedure at:
Thrombosis

sub-therapeutic INR normal INR range; use

Low range or lower no alternative or use
Risk of

LDH, Adj. DH or FDH

Do procedure at: Do procedure at:

High therapeutic or sub- normal INR range;
therapeutic INR range use FDH

LDH = Low dose heparin

Adj. DH = 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
Total
Weekly
Mon Tue Wed Thu Fri Sat Sun 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

Warfarin
INR Dose Adjustment* Adjusted Daily Dose (mg)

1.0-2.0 Increase x 2 days 5.0 7.5 10.0 12.5 15.0

2.0-3.0 No change — — — — —
3.0-6.0 Decrease x 2 days 1.25 2.5 5.0 7.5 10.0
6.0-10.0† Decrease x 2 days 0 1.25 2.5 5.0 7.5
10.0-18.0§ 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).
Drug Interactions with Warfarin: Potentiating
Level of
Evidence Potentiating
Alcohol (if concomitant liver disease) amiodarone (anabolic steroids,
cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole,
isoniazid [600 mg daily] metronidazole), miconazole, omeprazole,
I phenylbutazone, piroxicam, propafenone, propranolol,

Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene,

II disulfiram, itraconazole, quinidine, phenytoin (biphasic with later
inhibition), tamoxifen, tetracycline, flu vaccine
Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide,
III ketoprofen, iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin,
ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates
IV Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
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,
I
sucralfate
II
III Dicloxacillin
IV Azathioprine, cyclosporine, etretinate, trazodone
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