Table 1: Study characteristics
Study
Recruitment
Setting
Eligible
Population
Inclusion/Exclusion criteria
Protocol Outcomes
5mg vs. 10mg
Harrison (1997)
Canada
Inpatients &
outpatients
51patients
INR target 2.0-3.0
1)Time to INR in range,
2) INR >3.0,
3) Time to reduction in factors II, X and
protein C
Crowther (1999)
Canada
Throboembolism
unit
53 patients
INR target 2.0-3.0. Exclusions:
contraindication to warfarin or
geographically inaccessible
1) Proportion with INR in range for 2
consecutive days on days 3 & 4, or 4 & 5
and INR not > 3.0
201 patients with
DVT or PE
Exclusions: baseline INR >1.4,
thrombocytopenia, <18yrs, hospitalised,
oat in previous 2wks, high risk of bleeding
Primary Outcome:
1) Time to INR>1.9.
Secondary Outcomes:
2) INR in-range by day 5
3) VTE by day 90
4) Major bleeding by 28 days
5)INR >5.0
6)Number of INRs in 28 days
7) Death by 90dys
50patients with
DVT or PE
Exclusions: <18yrs, not available for clinic
f/up, warfarin or heparin >36hrs, creatinine
clearances of <30 ml/min, life expectancy
<3mths, high risk of bleeding
Kovacs (2003)
Canada
Quiroz (2006)
USA
Outpatient
clinics
Inpatients
Primary Outcome:
1) Time to INR >1.9 on 2 consec. days.
Secondary Outcomes:
2) Recurrent VTE at 14 days
3) Death at 14 days
4) Major bleeding at 14 days
5) INR >5 at 14 days
5mg vs. 2.5mg
Ageno (2001)
Canada &Italy
Inpatients
INR target 2.0 (range 1.5-2.6). Exclusions:
baseline INR >1.3
Primary Outcome:
1) % INR >2.6
Secondary Outcomes:
2) Time to INR in range
3) % out of range
4) Vit. K/bleeding/thromboembolic events
5) Dose adjustments/mean daily dose
90 patients with
AF,DVT,PE or
other
INR target 2.0-3.0 & INR=1.4. Exclusion;
warfarin in previous 3 months
1)Time to INR in range
2) Hours in hospital
3) Number with INR 2.0-3.0
4) Factor II & Cprotein activity
5) Clinical complications
6) INR ever >4.0 or a rise of 2.0 over 2 days
to >3.0
Primary Outcome
1)Time to INR in range on 2 consecutive
days or if previous day within 0.5
Secondary Outcomes
2) No. with INR >4.0 in first week
3) Dose withheld in wk1
4) No. of days with heparin
232 patients with
heart valve
replacement
5mg vs. calculated dose
Shine (2003)
USA
Inpatients
Age adjusted
Roberts (1999)
Australia
Inpatients
65 patients with
AF, DVT, PE &
other
INR target 2.0-3.0. Exclusions:
prolonged diarrhoea, nasogastric/enteral
feeds, commencing amiodarone,
advanced malignancy, Vitamin K in
previous 2 wks
Gedge (2000)
UK
Inpatients
127 patients with AF, DVT, PE &
other
INR target 2.0-3.0. Elderly patients with
standard indications.
1)Time to INR >2.0
2) Days INR in range
3)Number with INR >4.5
4) Dose prediction day 4
Genotyping
Hillman (2005)
USA
Inpatient &
Outpatients
38 with DVT, PE,
AF, other,
postoperative
orthopaedic
Exclusions: antiphospholipid antibodies,
contraindication for warfarin, previous
warfarin, liver disease, renal disease, nonCaucasian, <40yrs.
Anderson (2007)
USA
Inpatient &
Outpatients
201 with DVT, PE,
AF, other,
preoperative
orthopaedic
INR target 2.0-3.0. Exclusions: <18yrs,
women, pregnant, lactating or childbearing potential, rifampin within 3 wks,
co-morbidities precluding standard dosing
(advanced physiological age, hepatic or
renal insufficiency/creatine of <25mg/dl,
terminal illness)
Caraco (2008)
Israel
Inpatients
232 with DVT, PE,
AF
Exclusions: <18yrs and baseline INR >1.4
Primary Outcome:
1) Feasibility of dosing model
Secondary Outcomes:
2) % time INR in-range
3)% pts with INR>4
Primary Outcome
1) % INR out of range/patient
Secondary Outcomes:
2)time to INR >3.2 or VitK
3)%pts in range days 5 &8
4)Number of INR measures & dose
adjustments
5) %pts with SAEs - INR≥4, VitK, major
bleeding, thromboembolic events, stroke, MI
& death)
Primary Outcomes:
1) Time to INR >2.0
2) time to stable anticoagulation (defined as
2 INR in-range 7days apart)
Secondary Outcomes:
3) %Time INR in-range
4) Days INR out of range
5) Major bleeding/VTE events
Table 2: Dosing regimes
Study
Dosing Protocol on Days 1&2 (Reference for nomogram used)
ξ
5 mgs on day 1, up-to 5 mgs on day 2 vs. 10mgs on day 1, up-to 10mgs on day 2
Crowther 1999 ξ
5 mgs on day 1, up-to 5 mgs on day 2 vs. 10mgs on day 1, up-to 10mgs on day 2
Kovacs 2003
5 mgs vs. 10mgs on days 1&2 δ
Quiroz 2006
5 mgs vs. 10mgs on days 1&2
Harrison 1997
5mg trials
Ageno 2001
5mg Day 0 (subsequent doses adjusted) vs. 2.5mg on days 0 through 4 (dose
modified if <1.5 or >3.0 on day 3)
Shine 2003
5mg on day 1, up-to 5 mgs on day 2 vs. Calculated dose on day 1, up-to 100%
calculated dose on day 2
Age trials
Roberts 1999
Gedge 2000
Age adjusted nomogram (6-10mg) on day 1, 0.5-10mg on day 2 vs. Fennerty protocol
(10mg on day 1, 0.5mg-10mg on day 2) ψ
Age stratified 65-75 years & 75 yrs - 10mg on day 1,upto 5mg on day 2 vs. Modified
Fennerty protocol, 10 mg day 1 and up to 10mgs on day 2
Genotyping trials
Hillman 2005
Anderson 2007
Caraco 2008
ξ
5mg on days 1 & 2 vs. Model - genetic nomogram
10mg on days 1 & 2 vs.
Model - 2x predicted maintenance dose on days 1&2 followed by predicted dose
5mg on day 1 & up to 5mg on day 2 vs.
Model - genetic nomogram
Crowther 1997 report: Crowther MA, Harrison L, Hirsh J. Reply: Warfarin: Less May Be Better. Ann Intern Med 1997 August 15;127(4):333.
δ
Kovacs MJ,Anderson DA, Wells PS. Prospective assessment of a nomogram for the initiation of oral anticoagulation therapy for outpatient
treatment of venous thromboembolism. Pathophysiol Haemost thromb 2002;321:131-133
ψ
Fennerty A, Dolben J, Thomas P et al. Flexible induction dose regimen for warfarin and prediction of maintenance dose. British Medical Journal
Clinical Research Ed 1984 April 28;288(6426):1268-70.
Table 3: Methodological Quality
Randomisation
method
Concealment of
allocation
Double blinding
Intention to treat
Ageno
2001
+
Anderson
2007
+
Caraco
2007
+
Crowther
1999
+
Gedge
2000
NM
+
-
NM
NM
-
+
-
-
-
+
Reported in paper
Paper indicates that did not take place
NM: Not mentioned in paper
Harrison
1997
+
Hillman
2005
+
Kovacs
2003
+
Quiroz
2006
+
Roberts
1999
NM
NM
+
+
NM
-
+
NM
-
-
+
+
+
+
-
NM
-
NM
NM
Shine
2003
+
Table 4: Results
Proportion in INR range
Study
Dosing
Day 3
(95% CI)
Day 5
(95% CI)
Mean time, to
time in range
Days (SD)
INR ≥ 4 unless
otherwise stated
%
Vit K
given
n (%)
Serious
adverse
events
N (%)
5mg
42%
67% δ
0
36%
80% δ
4(16%)
0
5mg
50% (26 to 75)
88%(75 to 102)
1(3%)
10mg
33% (-2 to 68)
69% (39 to 99)
-
1(4%)
10mg
-
-
INR ≥5
11%
Other Primary Endpoints
5mg v
10mg
Harrison
Crowther
Kovacs
Quiroz
0
5mg
3%*
46% (36-57)**
P<.001
5.6 (1.4)
10mg
25%*
83% (74-89)**
4.2 (1.1)
9%
52%**
Median 5
INR >5
0%
56%**
Median 5
5mg
10mg
-
0%
-
INR 2.0-3.0 for 2 consecutive days &
not > 3.0;
10mg (24%) v 5mg (66%)
RR 2.22 (95% CI 1.3-3.7) p<.003
2 (2%)
4 (4%)
0
1 (4%)
*taken from the published graph
δ
includes discharged with INR in-range from (Ann Int Med Vol 127, 4, pg 133)
** in-range by day 5
5 mg vs. other doses
Ageno
5mg
2.5mg
Shine
Std (5mg)
Calc
2.0 (1.0)
-
-
-
63% δ
77%
-
3 (3%)
0
5 (6%)
0
"high" INR 2%
-
1 (2%)
P<.0001
2.7 (1.2)
δ
5 (0.9) ψ
P=.007
ψ
4.2 (0.9)
INR >4.4 5%
INR>2.6
5mg (42%)
2.5mg (26%)
p<.05
1 (2%)
δ
INR within range on or before day 6
ψ completers only
Age
trials
Roberts
Age adjusted
Fennerty
Gedge
Age
65-75 yrs
New Fennerty
65-75 yrs
Age
>75 yrs
New Fennerty
>75 yrs
-
47%*
3.7 (1.3) Φ
25%*
Φ
-
4.3 (1.2)
6%
32%
INR >4.5
3%
4.6 (1.6)
P=.03
0Φ
0
0
Λ
0
0
0
Λ
0
0
Φ
P<.05
3.8 (0.8)
20%
4.5 (1.4)
INR >4.5
3%
P=.003
3.5 (0.7)
-
P<.01
37%
INR 2.0 - 3.0 for 2 consecutive
days
Age v Fennerty; p=0.003
Mean days in range (SD)
Age
3.0 (1.3)
New Fennerty 2.7 (1.3) p=0.03
Mean days in range (SD)
Age
2.9 (1.1)
New Fennerty 2.4 (1.3) p=0.04
*taken from the published graph
Φ
author correspondence
Λ
1 (age not stated)
Genotyping
Hillman
Model
5mg
Anderson
Model
10mg
Caraco
-
-
-
70%
68%
Model
1% *
49% *
STD 5mg
1% *
11% *
0
2 (10%)
30%
2 (doses)
5 (28%)
-
4 (4%)
-
0
0
-
1 (1%)
1 (1%)
30%
37%
4.8 (1.5)
P<.001
7.5 (3.1)
33%
5 (5%)
*taken from the published graph
% time INR in range
5mg 42%
Model 42%
average % of INR outside range
10 mg 33%
Model 31%
% time INR in range
5 mg 25%
Model 45% P<0.001