Management of Oral Anticoagulant Therapy

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Management of Oral Anticoagulant Therapy

• Principles Practice

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Prepared for thePostgraduate Education
Committee,Council on Clinical CardiologyAmerican
Heart Associationby

• Jack Ansell, M.D.
• Jack Hirsh, M.D.
• Nanette K. Wenger, M.D.
• Supported 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.amer
icanheart.org)
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Endorsed by The Anticoagulation Forum The Americ
an Heart Association Council on Atherosclerosis,
Thrombosis, and Vascular Biology
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Clotting Cascade
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Vitamin K-Dependent Clotting Factors
Vitamin K
VII
Synthesis of Functional Coagulation Factors
IX
X
II
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Vitamin K Mechanism of Action
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Warfarin Mechanism of Action
Vitamin K
Antagonism of Vitamin K
VII
Synthesis of Non Functional Coagulation Factors
IX
X
II
Warfarin
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Warfarin Mechanism of Action
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Virchows Triad
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Antithrombotic Agents Mechanism of Action

• Anticoagulants prevent clot formation and
  extension
  
• Antiplatelet drugs interfere with platelet
  activity
  
• Thrombolytic agents dissolve existing thrombi

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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

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Warfarin Major Adverse EffectHemorrhage

• Factors that may influence bleeding risk
• Intensity of anticoagulation
• Concomitant clinical disorders
• Concomitant use of other medications
• Quality of management

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Special Considerations in the ElderlyBleeding

• Increased age associated with increased
  sensitivity at usual doses
  
• Comorbidity
• Increased drug interactions
• ? Increased bleeding risk independent of the above

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Warfarin Dosing in Elderly Patients

• Mean Warfarin Daily Dose (mg)
• Patient Age 80
• Gurwitz, et al, 1992 6.4 5.1 4.2 3.6 ND
• (n530 patients total study)
• James, et al, 1992 6.1 5.3 4.3 3.9 3.5
• (n2,305 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 7
04-706.
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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)

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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 38133-134 WHO Tech Rep Ser.
687 983.
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INR Equation
(
)
ISI
Patients PT in Seconds Mean Normal PT in Seconds
INR
INR International Normalized Ratio
ISI International Sensitivity Index
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How Different Thromboplastins Influence the PT
Ratio and INR
Blood from a single patient
Patients PT (Seconds)
Mean Normal (Seconds)
ThromboplastinReagent
PTR
ISI
INR
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A
12
1.3
18
12
1.5
B
21
13
1.6
C
24
11
2.2
D
E
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14.5
2.6
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How Different Thromboplastins Influence the PT
Ratio and INR
Blood from a single patient
Patients PT (Seconds)
Mean Normal (Seconds)
Thromboplastinreagent
PTR
ISI
INR
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A
12
1.3
3.2
2.6
18
12
1.5
2.4
2.6
B
21
13
1.6
2.0
2.6
C
24
11
2.2
1.2
2.6
D
E
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14.5
2.6
1.0
2.6
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Relationship Between PT Ratio and INR
Adapted from Poller L. Thromb Haemost vol 60,
1988.
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Potential Problems with the INR

• Limitations
• 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

• Solutions
• 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

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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
1997126133-136.
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Loading Dose then Maintenance Dose
Daily Dose
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Maintenance Dose Only
Daily Dose
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Maintenance Dose Only
Loading Dose thenMaintenance Dose
Daily Dose
Daily Dose
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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)

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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 14 weeks) and adjust

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

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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

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Managing Patients with High INR Values/Minor or
No Bleeding
Clinical Situation INR therapeutic range but 0, no clinically significant bleeding, rapid
reversal not indicated for reasons of surgical
intervention
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 m
inimally 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 b
leeding 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
(24 mg orally) if the INR remains high at 24 h,
an additional dose of 12 mg
INR 5.0 but bleeding
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Managing Patients with High INR Values/Serious
Bleeding
Clinical Situation INR 9.0, no clinically signif
icant bleeding Life-threatening bleeding o
r serious warfarin overdose Continuing warfarin t
herapy indicated after high doses of vitamin K1
Guidelines Vitamin K1 (35 mg orally) closely mo
nitor the INR if the INR is not substantially
reduced by 2424 h, the vitamin K1 dose can be
repeated Serious bleeding, or major warfarin over
dose (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, w
ith 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
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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
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Risk of Intracranial Hemorrhage in Outpatients
Adapted from Hylek EM, Singer DE, Ann Int Med
1994120897-902

• 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.

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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 1996335540-546.
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Warfarin Current Indications/Intensity

• Indication INR Range Target
• Prophylaxis of venous thrombosis (high-risk
  surgery) 2.03.0 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) 2.53.5 3.0
  
• Certain patients with thrombosis and the
  antiphospholipid syndrome
  
• AMI (to prevent recurrent AMI)
• Bileaflet mechanical valve in aortic position,
  NSR 2.03.0 2.5

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Mechanical Prosthetic Heart Valves
Patient Characteristics Recommendation
Bileaflet mechanical valve in the aortic
position, Goal INR 2.5 range, 2.03.0left
atrium of normal size, NSR, normal ejection
fraction Tilting disk valve or bileaflet mechanic
al valve in Goal INR 3.0 range, 2.53.5the
mitral position Bileaflet mechanical aortic valve
and AF Goal INR 3.0 range, 2.53.5
Caged ball or caged disk valves Goal INR 3.0
range, 2.53.5 and aspirin therapy (80100
mg/d) Additional risk factors Goal INR 3.0 range
, 2.53.5 and aspirin therapy (81 mg/d)
Systemic embolism, despite adequate therapy Goal
INR 3.0 range, 2.53.5with oral
anticoagulants and aspirin therapy (81 mg/d)
Alternative goal INR 2.5 range, 2.03.0 and
aspirin therapy (80100 mg/d)
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Examples of Low High Risk InvasiveProcedures
Clinical Conditions
Risk of Bleeding
Low
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 s
urgery CNS surgery polypectomy via colonoscopy
Prosthetic valves, esp. in mitral positionAF
history of CVA very recent DVT/PE
Dental cutaneous biopsiesopen procedures
cataracts AF valvular heart disease aortic pro
sthesis old DVT/PE Dental cutaneous biopsieso
pen procedures cataracts Prosthetic valves, esp.
in mitral position AF history of CVA very
recent DVT/PE
Low
Risk of Thrombosis
High
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Management of Warfarin for Invasive Procedures
Risk of Bleeding
Low
High
Do procedure atsubtherapeutic INR range or lower
Do procedure atnormal INR range use no
alternative or use LDH, AdjDH or FDH
Low
Risk of Thrombosis
Do procedure attherapeutic or subtherapeutic
INR range
Do procedure atnormal INR range use FDH
High
LDH Low dose heparin AdjDH Adjusted dose he
parin
FDH Full dose heparin
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Management of Warfarin During Invasive Procedures

• For subtherapeutic or normal INR Hold warfarin
  for 35 days pre-procedure
  
• Low Dose Heparin (LDH) Low-dose heparin (5,000
  IU SQ BID) hold warfarin 35 days pre-procedure
  and begin LDH therapy 12 days pre-procedure
  
• Adjusted Dose Heparin (AdjDH) Same as LDH but
  higher doses of heparin (between 8,00010,000 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 (1.52x control) implement as for LDH
  
• Restart heparin or warfarin post-op when
  considered safe to do so

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Warfarin Dosing Schedule
Total Weekly Dose
Mon
Tue
Wed
Thu
Fri
Sat
Sun
35 mg
30 mg
2.5
2.5
27.5 mg
2.5
2.5
2.5
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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, 2.55 mg
Oral vitamin K, 2.55 mg Allow 2 days after d
osage 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).
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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 , c
iprofloxacin, dextropropoxyphene, disulfiram,
itraconazole, quinidine, phenytoin (biphasic with
later inhibition), tamoxifen, tetracycline, flu
vaccine Acetylsalicylic acid, disopyramide, flu
orouracil, 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.
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Drug Interactions with Warfarin Inhibition
Level of Evidence
Inhibition
Barbiturates, carbamazepine, chlordiazepoxide,
cholestyramine, griseofulvin, nafcillin,
rifampin, sucralfate Dicloxacillin Azathiopri
ne, cyclosporine, etretinate, trazodone
I
II
III
IV
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Drug 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 Dilt
iazem, tobacco, vancomycin
I
II
III
IV
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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

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Factors Influencing Variability
Patient/Disease State
Process of Care
Warfarin drug with a narrow therapeutic index
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The content of these slides is current as of
October, 1999. Future revisions will be posted on
the American Heart Association website (www.amer
icanheart.org)