2

()

( Quality of evidence )
( Strength of recommendation )

1.
2.

3.
4. INR

5.
-
6.

5
5
6
8
8
9
14
17
19
27
35
39

/
1 INR
16
2 INR
21
3 INR 23
4 thromboembolic event


27
5 thromboembolic event


28
6 CHADS2 score
29
1

33
3

1...
..
2...
..
3...
..
4...
..
5...
..
6...

7...
..
8...
..

1...
..
2...
..
3...
..
4...
..
5...
..
6...
..
7...
..
8. ..
..
9... ..
10...

11..

12...
..
13...
..
14...
..
15...
..
16...
..
17...

18..

19..

5


1..
.
2..
.
3..
.
4..
.
5..
.
6..
.
7..
.
8..
.
9..
.
10..
.
11..
.
12..
.
13..
.
14..
.
15..
.
16..
.
17..
.
18..
.
19..
.
20..
.
21..
.

22..
23..
24..
25..
26..
27..
28..
29..
30..
31..
32..
33..
34..
35..
36..
37..
38..
39..
40..
41..

.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

 (Quality of Evidence)
1 systematic review randomized

controlled clinical trials well designed randomized controlled

clinical trial
2 systematic review controlled clinical
trials well designed controlled clinical trial



( cohort study, case-control

study)
3 descriptive studies controlled clinical

trial
4 ( consensus )

(Strength of Recommendation)
++


+


+/-


-
- -
8

(Warfarin) 90

sweet clover
coumadin oxidized
dicoumarol 1948 dicoumarol
Warfarin
Wisconsin Alumni Research Foundation (WARF) 3

1954

thrombosis thromboembolism
vitaminK-dependent coagulation factors factor II, VII, IX
X cyclic interconversion
vitamin K epoxide II, VII,
IX X
vitamin K-dependent carboxylation
9

 protein C protein S

bioavailability therapeutic index

(onset)

-
(non compliance)



CYP2C9
(receptor) Vitamin K2,3-epoxide
reductase complex subunit 1 (VKORC1)
CYP2C9 polymorphism 3 CYP2C9 polymorphism

(Asian-American) VKORC1 haplotype A
(African-American) (European-American)

prothrombin time (PT)
vitamin K-dependent procoagulant clotting factors facor II, VII X calcium
thromboplastin citrate plasma
thromboplastin
PT PT

10

 INR (International Normalized Ratio)

therapeutic INR 2.5 0.5 mechanical

prosthetic valves therapeutic INR 3.0
0.5 INR


3-5


1

INR 48
INR
7 steady state

2-5
warfarin necrosis
gangrene

vitamin K-dependent coagulation factors protein C
protease V, VIII thrombin

vitamin Kdependent coagulation factors
hypercoagulable state
Vitamin K dependent
clotting factors 30-50 activity clotting factors

11

 10-40
clotting factors carboxylate

carboxylated clotting factors
factor VII
6 factor II 60
7-10
steady state

INR INR


INR
INR

INR
5-20 (
)INR
INR



3
INR

12

13

()
2.1 deep vein thrombosis (DVT)
pulmonary embolism (PE)

++
1. heparin 5-10
3 target INR 2.0-3.0
INR3.0-4.5
( 1)
2. DVT heparin 5-10

6 ( 3)
3. DVTPE
heparin5-10
3 ( 3)
4.
(idiopathic DVT, PE)
6 (target INR 2.0-3.0)
( 2 )
14

2.2 mechanical prosthetic heart

valves

++
1. mechanicalprosthetic mitralvalve
(targetINR2.5-3.5) ( 1)
2. mechanicalprostheticaorticvalve
(target INR 2.0-3.0) ( 1)
3. bioprosthetic valves mitral valve repair
annuloplasty ring
3 ( target INR 2.0-3.0)
( 2)
+
1. bioprosthetic valves
3 ( 3)

2.3

++
1. valvular atrial fibrillation (AF)
(targetINR2.0-3.0)
( 1)
2. embolic stroke recurrent cerebral infarction
(target INR 2.0-3.0) ( 2)
3. dilated cardiomyopathy with intracardiac thrombus
(target INR 2.0-3.0 ) ( 2)

15

 +
1. paroxysmal AF
(target INR 2.0-3.0) ( 2 )
2. Acute myocardial infarction peripheral arterial disease
( target INR 2.0-3.0) ( 2)
3. pre-cardioversion
3 4 cardioversion
(targetINR2.0-3.0) ( 2)
4. peripheral arterial thrombosis and grafts
femoral vein graft failure
(target INR 2.0-3.0)
( 2)
1 INR

Indication

INR

Prophylaxis of venous thrombosis (high-risk surgery)

Treatment of venous thrombosis
Treatment of pulmonary embolism
Prevention of systemic embolism
Tissue heart valves
Mechanical prosthetic heart valves
Acute myocardial infarction (to prevent systemic embolism)
Valvular heart disease
Atrial fibrillation
Mechanical prosthetic valves (high risk)

16

2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
2.5-3.5

3.1

+ + ( 2 3)
1. ( chronic stable AF)
3 ./ 5-7

2. heparin
3 . heparin
INR therapeutic range 2
3. prothrombin time (PT) () INR
therapeutic range 3 1-2
INR
4

INR
,
, ,
thromboplastin
17

3.2
(INR Monitoring)

+ ( 2 3)
1. INR 2 3
2. INR 1

3. INR
INR 4
4. INR INR
2

18

INR

++
1. INR
( 3)
INR 2
2. warfarin 5 - 20%
( 3)
3. INR 1.5 warfarin 10-20%
( 3)
4. vitamin K
INR
()
INR warfarin resistance
vitamin K
anaphylaxis
( 3)
5. INR
vitamin K1 10 .

19





6.

fresh frozen plasma prothrombin complex concentrate

recombinantfactorVIIa
vitamin K1 12
( 3 )
INR vitamin K1

( 2)

+
1. INR 1.5-1.9 warfarin 5-10%
INR
( 3)
2. INR
INR 2
INR
thromboembolic prosthetic valve
malignancy ( 3)
3. INR (1.5-2 3-4)
INR


thromboembolism ( 3)
4. INR 5.0
1 INR
( 10% )
( 3)
5. INR 5.0 9.0
2 INR

20

 ( 20%
)
vitamin K1 1-2.5 .
INR
vitamin K1 2.5-5 . INR
24 ( 3)
6. INR 9.0
vitamin K1 2.5-5 .
INR
24-48 INRvitaminK11-2.
( 3)
2 INR
1
2
3
4

5
6

vitamin K
vitamin K warfarin
metabolism
() coagulation factor
(drug interaction)
( )

INR
1
2
3
4
5

Paracetamol, NSAIDs, Antibiotics

(, , )

21


Cardiovascular Drugs
- Amiodarone, propafenone
- Fluvastatin, rosuvastatin
- Propranolol
Antibiotics
- Erythromycin, clarithromycin,
cotrimoxazole, ciprofloxacin, cefoperazone,
metronidazole
Antifungals
- Ketoconazole, itraconazole, fluconazole
Acid suppression therapy
- Cimetidine, proton-pump inhibitors
NSAIDs
Coxibs

Enzyme inducers
Rifampicin
Phenytoin
Carbamezepine
Phenobarbital
Griseofulvin

Cholestyramine
Sucralfate

22

 3 INR 2.0 3.0

< 1.5
1.5-1.9
2.0-3.0
3.1-3.9
4.0-4.9
5.0-8.9 no bleeding
9.0 no bleeding
Major bleeding with any INR

10-20%
5-10%
Continue same does
5-10%
Hold for 1 day then 10%
Omit 1-2 doses, Vit K1 1 mg orally
Vit K1 5-10 mg orally
Vit K1 10 mg iv plus FFP
Repeat Vit K1 every 12 hours if needed

+ 3
1. ()
2. (Drug interaction)
3.

+ 3
1.
2.
3.
4. INR


5.
6.
7. (Drug interaction)
8. vitamin K INR
23

 9.
10.

11.

Vitamin E, Fish oil

(Gingko biloba)

- Glakay

ASA ( ), NSAIDs, COX-2 inhibitor

Steroid
(Herbal), (Gingko biloba), (Ginseng)

+ 3
1.
2.
3.
4.
5.
6.

24

 7.
8.

++ 2

casemanager

( benchmark )

1. INR
(time in thera peutic range, TTR) ( Rosendaals
linear interpolation method)
2. INR
INR X 100

( : 65)

3.
4.
5. INR (INR<1.5 >5)

25

26

thromboembolic events
thromboembolic event
4 5
bridging therapy short acting anticoagulant thromboembolic event
4 thromboembolic event

Condition
% Thromboembolic risks (per year)
Atrial fibrillation (low risk)
1
Atrial fibrillation (average risk)
5
Atrial fibrillation (high risk)
12
Aortic valve prosthesis (dual-leaflet)
10-12
Aortic valve prosthesis (single-leaflet)
23
Mitral valve prosthesis (dual-leaflet)
22
Multiple valve prosthesis
91
27

 atrial fibrillation venous

thromboembolism thromboembolism

5 thromboembolic event
Type of patient

Low risk

Moderate risk

High risk

Prosthetic valve

1.AV prosthesis
AF

1.Bileaflet AV
prosthesis

AF,HT,DM,
CHF,age > 75 )

1.

2.
(caged ball valve,
single tilting disc)
aortic
3.stroke TIA

Atrial fibrillation

1.CHADS2
score 0-2

Venous
thromboembolism

VTE 12

1.CHADS2
score 3-4

1.CHADS2 score 5-6

2.Recent ( 3)
stroke / TIA
3. Rheumatic VHD

1.VTE 3-12
2.recurrent VTE
3.cancer
3-6

palliative therapy

1.Recent (< 3 ) VTE

2.severe thrombophilic
condition*

* severe thrombophilic condition : deficiency of protein C, protein S antithrombin,

antiphospholipid syndrome

28

 6 CHADS2 score
C
H

A
D
S2

Condition
Points
Congestive heart failure
1
Hypertension: blood pressure consistently above
1
140/90 mmHg (or treated hypertension on medication)
Age >75 years
1
Diabetes Mellitus
1
Prior Stroke or TIA
2

++
1.
INR <1.5
4-5 ( 3)
2. 12-24
( 3 )
3. mechanical valve atrial fibrillation venous
thromboembolism thromboembolism
bridginganticoagulation
( 3)
4. dental, dermatology
ophthalmologic : minimal dental
proceduresminordermatologyprocedure

( 3 )
5.
(urgent) oral intravenous
vitamin K 2.5-5.0 . ( 3)

29

 +
1. () INR
1.5 1-2 vitamin K
1-2 . INR
( 3)
2. thromboembolism
bridginganticoagulation
( 3)
3.
bridging anticoagulation
( 3 )
4.
( emergency ) fresh frozen
plasma prothrombin complex concentrate
low-dose IV oral vitamin K ( 3)

vitamin K
1.
vitamin K ( 2 )
hypercoagulable

bridging anticoagulation

++
1. therapeutic dose
subcutaneous LMWH intravenous unfractionated heparin
(IV UFH) low dose subcutaneous LMWH (
therapeutic SC LMWH IV UFH low dose

30

 subcutaneous LWMH) INR 2

( 3)
2.
IV UFH INR 2 (
2 ) subcutaneous LMWH
( 3)
3. therapeutic dose SC LMWH SC
unfractionatedheparin
12-24 (
once daily dose) dose dose
bid dose IV UFH
UFH 4-6
( 3 )
4.
therapeutic dose LMWH bridging therapy
LMWH 24
( 3)
5.
therapeutic dose LMWH, low dose
LMWH/ UFH 48-72
( 3)
6.
LWMH UFH INR
3 ( 3 )
+
1. therapeutic dose
subcutaneous LMWH IV UFH ( therapeutic SC
LMWH IV UFH) INR 2
( 3)
31

Therapeutic dose subcutaneous LMWH

: Enoxaparin 1.5 mg/kg 1 1 mg/kg
2
Low dose subcutaneous LMWH
: Enoxaparin 30 mg 2
Intravenous unfractionated heparin
: aPTT 1.5-2
Subcutaneous unfractionated heparin
: 15,000 unit 2

32

 1 :

( elective surgery )

( emergency surgery )

(major surgery)
PT ( INR )
< 1.5

( minor surgery)

( minor surgery)

PT ( INR )
< 1.5

++

FFP,Vit K
prosthetic
valve
FFP

(major surgery)

4-5

( high risk for

thrombos )

( intermediate risk
thrombosis )

( low risk for for

thrombosis )

bridging therapy

bridiging therapy

bridging
therapy

++

33

34

()

teratogenic effect

warfarin embryopathy
nasal hypoplasia, stippled epiphyses 6.4
3

5 .

intracranial hemorrhage3
intracranial hemorrhage 12

thromboembolic complication

2
thromboembolic complication

35

heparin LMWH
thromboembolic complication, heparin induced osteoporosis, heparin induced thrombocytopenia
heparin
20-25

++
1. venous
thromboembolism (VTE)
LMWH UFH
( 1)
2.

adjusted dose LMWH UFH
6 13

(2-3 ) adjusted dose LWMH
UFH ( 3)
3.
thromboembolism
thromboembolism

INR 3; 2.5-3.5 ( 3)
36

 +
1.
UFH LMWH urine pregnancy test

UHF LMWH (US FDA report
thromboembolic events enoxaparin)
( 3)
2.
thromboembolism
thromboembolism

INR 3; 2.5-3.5 aspirin
75-100 .
( 3)
3.
heparin LMWH ( 3)

LWMH UFH

++
1. adjusted-dose bid LMWH ( 3 )
2. adjusted-dose UFH
12 PTT 2
anti-Xa 0.35-0.7 u/ml
4 ( 3)

37

 +
1. adjusted-dose bid LMWH anti-Xa
0.7-1.2 U/ml 4
( 3)
2. 4 UFH

( 3)

UFH
( ++, 3)
LMWH
( +, 3)

38

Selected oral anticoagulation references (Updating)

General
1. 8th ACCP Conference on Antithrombotic and Thrombolytic Therapy.
http://www.chestjournal.org/content/133/6_suppl
2. Ginsberg JA, Crowther MA, White RH, Ortel TL. Anticoagulation Therapy. Hematology
3. Am Soc Hematol Educ Program) 2001 Jan; :339-57.
4. AHA/ACC. Foundation Guide to Warfarin Therapy. 2003
Circulation. 2003 Apr 1;107 (12): 1692-711. Review.
5. Ansell JE, Oertel LB, Wittkowsky AK. Managing Oral Anticoagulation Therapy. Clinical and
Operational Guidelines. Lippincott Williams & Wilkins; 2 edition (June 1, 2005)
6. Ansell JE, Buttaro ML, Thomas VO, et al. Consensus Guidelines for Coordinated Outpatient Oral anti
coagulation Therapy Management. Ann Pharmacother. 1997; 31: 604-615.
7. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation
Circulation. 2006; 114: e257-e354. ACC/AHA 2006 Guidelines for the Management of Patients with
Valvular Heart Disease Circulation. 2006 Aug 1; 114(5): e84-231. Review.
8. Schulman S. Clinical practice. Care of patients receiving long-term anticoagulant therapy. N Engl J
Med. 2003 Aug 14;349(7):675-83 Review.
9. Jack Ansell, M.D. Jack Hirsh, M.D. Nanette K.Wenger, M.D.
Postgraduate Education Committee, Council on Clinical Cardiology
Perioperative Management.
1. Kearon C. Perioperative Management of Long-term Anticoagulation. Semin Thromb Hemost 1998;24
(Suppl 1): 77-83.
2. Kearon C, Hirsh J. Managing Anticoagulation Before and After Surgery in Patients Who require Oral
Anticoagulants. N Engl J Med 1997; 336: 1506-1511
3. Heit JA. Perioperative management of the chronically anticoagulated patient. J Thromb Thrombolysis.
2001 Sep; 12(1): 81-7. Review.
4. Wahl MJ. Dental Surgery in Anticoagulation Patients. Arch Intern Med, 1998: 158: 1610-1616.
5. Randall C. Surgical management of the primary care dental patient on warfarin. Dent Update. 2005
Sep; 32(7): 414-6, 419-20, 423-4 passim.
6. Eisen GM, Baron TH, Dominitz JA, Faigel DO, Goldstein JL, Johanson JF, Mallery JS, Raddawi HM,
Vargo JJ 2nd, Waring JP, Fanelli RD< Wheeler-Harbough J; American Society for Gastrointestinal
Endoscopy.Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic
procedures.Gastrointest Endosc. 2002 Jun; 55(7): 775-9.
7. Dunn AS, Turpie AG. Perioperative management of patients receiving oral anticoagulants:
a systematic review.Arch Intern Med. 2003 Apr 28; 163(8): 901-8. Review.
8 Jaffer AK. Brotman DJ, Chukwumerije N.When patients on warfarin need surgery. Cleve Clin J Med.
2003 Nov; 70 (11) : 973-84. Review.
9. Dunn A. Perioperative management of oral anticoagulation: when and how to bridge. J Thromb
Thrombolysis. 2006 Feb; 21(1): 85-9.
Anticoagulation During Pregnacy
1. 8th ACCP Conference on Antithrombotic and Thrombolytic Therapy.
http://www.chestjournal.org/content/133/6_suppl
2. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW.
Nishimura RA, OGara PT, ORourke RA, Otto CM, Shah PM, Shanewise JS; 2008 focused
update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular
heart diseases Circulation. 2008; 118:e523-e661
3. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a
systematic review of the literature.. Arch Intern Med. 2000; 160:191-196. Geelani MA, Singh S, Verma
A, Nagesh A, Betigeri V, Nigam M. Anticoagulation in Patients with Mechanical Valves During
Pregnancy.. Asian Cardiovasc Thorac Ann 2005; 13:30-33