Management of Oral Anticoagulant Therapy

1

2
Management of Oral Anticoagulant Therapy

• Principles Practice

3
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.americanheart.org)
4
Endorsed by The Anticoagulation Forum The
American Heart Association Council on
Atherosclerosis, Thrombosis, and Vascular Biology
5
Clotting Cascade
6
Vitamin K-Dependent Clotting Factors
Vitamin K
VII
Synthesis of Functional Coagulation Factors
IX
X
II
7
Vitamin K Mechanism of Action
8
Warfarin Mechanism of Action
Vitamin K
Antagonism of Vitamin K
VII
Synthesis of Non Functional Coagulation Factors
IX
X
II
Warfarin
9
Warfarin Mechanism of Action
10
Virchows Triad
11
Antithrombotic Agents Mechanism of Action

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

12
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

13
Warfarin Major Adverse EffectHemorrhage

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

14
Special Considerations in the ElderlyBleeding

• 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

15
Warfarin Dosing in Elderly Patients

• Mean Warfarin Daily Dose (mg)
• Patient Age lt50 5059 6069 7079 gt80
• 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
704-706.
16
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)

17
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.
18
INR Equation
(
)
ISI
Patients PT in Seconds Mean Normal PT in Seconds
INR
INR International Normalized Ratio ISI
International Sensitivity Index
19
How Different Thromboplastins Influence the PT
Ratio and INR
Blood from a single patient
Patients PT (Seconds)
Mean Normal (Seconds)
ThromboplastinReagent
PTR
ISI
INR
16
A
12
1.3
18
12
1.5
B
21
13
1.6
C
24
11
2.2
D
E
38
14.5
2.6
20
How Different Thromboplastins Influence the PT
Ratio and INR
Blood from a single patient
Patients PT (Seconds)
Mean Normal (Seconds)
Thromboplastinreagent
PTR
ISI
INR
16
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
38
14.5
2.6
1.0
2.6
21
Relationship Between PT Ratio and INR
Adapted from Poller L. Thromb Haemost vol 60,
1988.
22
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

23
Warfarin Dosing Information

• Individualize dose according to patient
  response(as indicated by INR)
• Use of large loading dose gt10 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
1997126133-136.
24
Loading Dose then Maintenance Dose
Daily Dose
25
Maintenance Dose Only
Daily Dose
26
Maintenance Dose Only
Loading Dose thenMaintenance Dose
Daily Dose
Daily Dose
27
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)

28
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
29
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

30
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

31
Managing Patients with High INR Values/Minor or
No Bleeding
Clinical Situation INR gttherapeutic range but
lt5.0, 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
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)
INR gt5.0 but lt9.0, no clinically significant
bleeding
32
Managing Patients with High INR Values/Serious
Bleeding
Clinical Situation INR gt9.0, no clinically
significant bleeding INR gt20.0, or serious
bleeding Life-threatening bleeding or serious
warfarin overdose
Guidelines Vitamin K1 (35 mg orally) closely
monitor the INR if the INR is not substantially
reduced by 2448 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 Prothrombin complex concentrate, with
vitamin K1 (10 mg by slow IV infusion) repeat if
necessary, depending upon the INR
33
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 compromised above INR 4

Effective below 2.5
34
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.

35
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 1996335540-546.
36
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

37
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 mechanical 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)
38
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
surgery 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
prosthesis old DVT/PE Dental cutaneous
biopsiesopen procedures cataracts Prosthetic
valves, esp. in mitral position AF history of
CVA very recent DVT/PE
Low
Risk of Thrombosis
High
39
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
heparin FDH Full dose heparin
40
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

41
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
42
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 gt18.0 D
iscontinue warfarin and consider
hospitalization/reversal of anticoagulation
Consider oral vitamin K, 2.55 mg Oral vitamin
K, 2.55 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).
43
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, ifosflhamide, ketoprofen,
iovastatin, metozalone, moricizine, nalidixic
acid, norfloxacin, ofloxacin, propoxyphene,
sulindac, tolmetin, topical salicylates Cefamand
ole, cefazolin, gemfibrozil, heparin,
indomethacin, sulfisoxazole
I
II
III
IV
In a small number of volunteer subjects, an
inhibitory drug interaction occurred.
44
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
IV
45
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 Diltiaz
em, tobacco, vancomycin
I
II
III
IV
46
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

47
Factors Influencing Variability
Patient/Disease State
Process of Care
Warfarin drug with a narrow therapeutic index
48

The content of these slides is current as of
October, 1999. Future revisions will be posted on
the American Heart Association website
(www.americanheart.org)