Vol 20 No 3 September - December 2010

199
INR

INR
Optimum and Factors Predicting Warfarin Maintenance Dose and
Factors Affecting the Out of Therapeutic INR Range
, ..*; , ..*

, .
INR . 2553; 20(3):
199-209.

international normalized ratio

(INR)
(Anticoagulant Care Clinic; ACC)
1,000 .. 2551 3 INR
1 , , INR,
, regression model, multiple
polytomous logistic regression
4,942

INR INR 2.0-3.0
2.91.3 INR 2.5-3.5 3.31.3
INR
(RRR=1.37, p=0.003)
(RRR=4.29, p<0.001) INR
(RRR=2.77, p=0.044)
1.6 4.2 ( INR 2.0-3.0)
2.0 4.6 ( INR 2.5-3.5)
INR
INR


: INR
*

200 ()

Thamwanta S, Muenpa R. Optimum and Factors Predicting Warfarin Maintenance

Dose and Factors Affecting the Out of Therapeutic INR Range. Thai Journal of Hospital
Pharmacy 2010; 20(3):199-209.
The objectives of this study were to determine an optimum maintenance dose for
warfarin patients in Lampang province, factors used to predict warfarin dose requirement
and factors affecting the out of therapeutic INR range. A cross-sectional analytical study
was done at Anticoagulation Care Clinic (ACC), Lampang Hospital. All 1,000 warfarin
patients who were followed at the clinic for at least 3 consecutive months in year 2008 and
obtained at least one INR value were studied. Patient general data, warfarin indication and
dosing, INR value, and medication compliance were collected. Data were analyzed using
descriptive statistics, regression model, and multiple polytomous logistic regression.
From total of 4,942 visits, the most common indication was atrial fibrillation with
valvular heart disease. An average warfarin daily dose for patients with target INR of 2.03.0
was 2.91.3 mg and with target INR of 2.53.5 was 3.31.3 mg. Warfarin maintenance
dose requirement was found to depend on patients age and weight. Factors affecting a subtherapeutic INR were female sex (RRR=1.37, p=0.003) and non-compliance (RRR=4.29,
p<0.001), whereas factors affecting a supra-therapeutic INR was non-compliance (RRR=
2.77, p=0.044). Conclusion about recommendation in order to obtain therapeutic INR is:
the maintenance warfarin daily dose for Lampang patients range from 1.6 to 4.2 mg (for
INR 2.0-3.0) and range from 2.0 to 4.6 mg (for INR 2.5-3.5) depending on patients age and
weight. Female patients have risk of sub-therapeutic INR whereas non-compliance patients
have risk of both sub- and supra- therapeutic INR. Thus, pharmacist who works at ACC
should pay more attention for such patients.
Keywords: Warfarin, dose, INR

(warfarin)
(oral anticoagulant)

(thromboembolic disorders)

(atrial fibrillation)

(cardiac valve replacement)

(myocardial infraction, Stroke)1

2-8

Vol 20 No 3 September - December 2010

201
INR

(protein-binding)
99
cytochrome P450 2C9
(half-life) 20-60
2-5

3050
(clotting factor)

24-72

1-3

(effectiveness and safety)
international normalized ratio (INR)

ACCP (American Collage of Chest Physicians)
Chest Guideline American College
of Cardiology/American Heart Association
INR

(valvular heart diseases)
INR 2.0-3.0
(mechanical
prothetic valve) INR 2.53.5 2,4-8
2-5
2-10

1
9,10
CYP450
(enzymes inducers)
(genetic polymorphism) CYP2C9
vitamin K 2,3 epoxide reductase complex subunit 1 (VKORC1)

2.7
5.5 11-19
INR
.. 2550 INR
39.14
36.77 24.0920
INR


INR

(hemorrhagic complications)

INR

Sconce
et al 11 regression model

, genotype, 5 models

202 ()

Model 1:
Dose = 2.85-0.0137(age)
(p=.001)
Model 2:
Dose = 2.01-0.252(CYP*2)-0.454 (CYP*3) (p=.001)
Model 3:
Dose = 2.41-0.297(VKORC1)
(p=.001)
Model 4:
Dose = 2.12+0.0237(height)
(p=.001)
Model 5:
Dose = 0.628-0.0135(age)-0.240(CYP*2)
-0.370(CYP*3)-.241(VKORC1)+0.0162(height)
(p=.001)

CYP2C9 genotype
0, 1, 2 *2 *3
VKORC1
genotype 1 GG, 2
GA, 3 AA
Kamali et al.12
regression model
, genotype (CYP
2C9*3), 2 3 models
Model 1:
Dose = 8.09-0.06xage
(p=.000)
Model 2:
Dose = 4.06-1.36
(p=.01034)
Model 3:
Dose = 8.05-0.06xage-1.12[p=.000 (age), p=0.0089(genotype)]

CYP2C9 VKORC1




INR

INR

1.

2.

3. INR

(cross sectional analytical study)

1 31
.. 2551
3 INR
1 2 INR

1 INR
2.0-3.0
1.1 (systemic
embolism) tissue heart
valves, ,
,
1.2 (venous thrombosis)
1.3
()
1.4
(pulmonary embolism)

Vol 20 No 3 September - December 2010

203
INR

2 INR
2.5-3.5
()

SSB Warfarin Manager 2008


INR

.
(HN)
INR

. INR
.

.
.

.
(
)

regression
INR multiple polytomous
logistic regression

1.

1,000 ( 1)
( 56.7) 55.312.5 (
20 87 )

( 78.4)

( 28.5)
( 21.2)
( 18.0)
( 17.8)
INR 2.0-3.0 (
75.2) 1
1 10 4
2. (Daily Maintenance Dose) 4,942
0.25 /
16 / 2.971.42
/
INR
1 ( INR 2.0-3.0)
1,539 2.931.34 /
2 ( INR 2.5-3.5)
425 3.321.28 /

204 ()

1 (n=1,000)

()

(), meanSD (min-max)

Valvular heart disease+atrial fibrillation
Valvular heart disease
Atrial fibrillation
Mechanical prosthetic valves (high risk)
Mechanical valve replacement+atrial fibrillation
Prevention of systemic embolism
Treatment of venous thrombosis
AMI (to prevent systemic embolism)
Tissue heart valves
Bileaflet mechanical valve in aortic position
Target INR
Target INR 2.0-3.0
Target INR 2.5-3.5
()
1
2
3
4
5
6
7
8
9
10
, meanSD (min-max)

433 (43.3)
567 (56.7)
55.312.5 (20-87)
784 (78.4)
203 (20.3)
13 (1.3)
285 (28.5)
212 (21.2)
180 (18.0)
178 (17.8)
70 (7.0)
39 (3.9)
31 (3.1)
3 (0.3)
1 (0.1)
1 (0.1)
752 (75.2)
248 (24.8)
26 (2.6)
50 (5.0)
246 (24.6)
392 (39.2)
175 (17.5)
71 (7.1)
22 (2.2)
13 (1.3)
3 (0.3)
2 (0.2)
41.3 (1-10)

Vol 20 No 3 September - December 2010

205
INR

3. (Daily Maintenance Dose Requirements)

regression



( 2)
1 643

2 188

INR

1. Target INR 2.0-3.0

Dose = 3.38+0.02 ()-0.03 ()
2. Target INR 2.5-3.5
Dose=3.98+0.04 ()-0.06 ()

constant

Target INR 2-3 (n=643)

Coefficient
95% Cl
0.02
0.012 to 0.031
-0.03
-0.037 to -0.020
3.38
2.635 to 4.127

p-value
<0.001
<0.001
<0.001

4.
INR
4,942 INR
1,981 ( 40.1) INR
2,198 ( 44.5)
763 ( 15.4) INR
1
3,614 INR 1,553
( 42.7) 1,457 (
40.0) 631 ( 17.3)
2 1,301
INR 428 ( 32.9)
741 ( 57.0)
132 ( 10.1)
multiple polytomous logistic regression INR

Target INR 2.5-3.5 (n=188)

Coefficient
95% CI
p-value
0.04
0.025 to 0.056
<0.001
-0.06
-0.073 to -0.043
<0.001
3.98
2.878 to 5.077
<0.001

INR
(RRR=1.37, p=0.003)
(RRR=
4.28, p<0.001) INR

(RRR=2.77, p=0.044)
( 3)

INR 2.93
INR
2.0-3.0 3.32
INR
2.5-3.5 INR
2.0-3.0
INR

206 ()

3 INR

INR
RRR
95% CI
p-value
1.367
1.110-1.683
0.003
0.987
0.978-0.997
0.011
4.284
1.967-9.330
<0.001

INR
RRR
95% CI
p-value
1.077
0.807-1.439
0.613
0.981
0.968-0.995
0.007
2.771
1.027-7.473
0.044

1. ()
2.
3.

4.
0.710
0.575-0.877
0.001
0.902
0.677-1.202
0.483

INR

2.0-3.0 1.9 4.30

13 (AsianAmerican)
3.42 14

INR 2.5-3.5

2.50-3.37 16

(Asian)
5.50 15

VKORC1
haplotype cytochrome P450 2C9 (CYP2C9)
genotype
CYP2C9 homocygous wild-type 1*/1* allele

1*/2*,
1*/3*, 2*/2*, 2*/3*, 3*/3* allele
CYP2C9

homocygous wild-type 1*/1* allele

VKORC1 GG genotype
non-A/non-A alleles
non-A/A A/A
alleles 11,18
(Asian-American)
VKORC1 18

INR

INR


11,12,14,18

PT, INR,
3

Vol 20 No 3 September - December 2010

207
INR

INR

11



()
VKORC1 CYP2C9




INR
INR




2.5
3.0

9-11
INR




INR

INR
INR

INR

(significant)
(severity)

INR

208 ()

INR


INR

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, .
international
normalized ratio (INR)
: . : ,
2550.