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Study flow diagram.

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Figure 1

Study flow diagram.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Proportion of Patients with a therapeutic INR from day of initiation (5 mg versus 10 mg).

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Figure 4

Proportion of Patients with a therapeutic INR from day of initiation (5 mg versus 10 mg).

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Proportion of patients with a therapeutic INR from day of initiation (age related versus 10 mg).

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Figure 5

Proportion of patients with a therapeutic INR from day of initiation (age related versus 10 mg).

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Proportion of patients with a therapeutic INR from day of initiation (genotype versus 10 mg or 5 mg).

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Figure 6

Proportion of patients with a therapeutic INR from day of initiation (genotype versus 10 mg or 5 mg).

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Comparison 1: 5 mg versus 10 mg, Outcome 1: INR in‐range by day 5: 5mg v 10mg

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Analysis 1.1

Comparison 1: 5 mg versus 10 mg, Outcome 1: INR in‐range by day 5: 5mg v 10mg

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Comparison 1: 5 mg versus 10 mg, Outcome 2: Single INR measure

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Analysis 1.2

Comparison 1: 5 mg versus 10 mg, Outcome 2: Single INR measure

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Comparison 1: 5 mg versus 10 mg, Outcome 3: Consecutive INR measures

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Analysis 1.3

Comparison 1: 5 mg versus 10 mg, Outcome 3: Consecutive INR measures

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Summary of findings 1. 5 mg versus 10 mg for the initiation of oral anticoagulation

5 mg versus 10 mg for the initiation of oral anticoagulation

Patient or population: patients with the initiation of oral anticoagulation
Settings:
Intervention: 5 mg versus 10 mg

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

5 mg versus 10 mg

All studies

Study population

RR 1.17
(0.77 to 1.77)

352
(4 studies)

⊕⊝⊝⊝
very low1,2,3,4,5,6,7,8

571 per 1000

668 per 1000
(440 to 1000)

Medium risk population

593 per 1000

694 per 1000
(457 to 1000)

Single INR measure

Study population

RR 1.49
(1.01 to 2.21)

250
(2 studies)

⊕⊝⊝⊝
very low1,2,3,5,7,8

504 per 1000

751 per 1000
(509 to 1000)

Medium risk population

565 per 1000

842 per 1000
(571 to 1000)

Consecutive INR measures

Study population

RR 0.86
(0.62 to 1.19)

102
(2 studies)

⊕⊝⊝⊝
very low1,2,3,4,7,8

714 per 1000

614 per 1000
(443 to 850)

Medium risk population

696 per 1000

599 per 1000
(432 to 828)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Method of allocation concealment not described by Crowther 1999, Harrison 1997 or Quiroz 2006.
2 Worse‐case‐scenario modelling used for incomplete outcome data by Crowther 1999. Handling of incomplete outcome data not described by Harrison 1997.
3 No double blinding (patient and physician) by Crowther 1999, Harrison 1997 or Quiroz 2006.
4 No adverse outcomes data reported by Crowther 1999.
5 Selective reporting by Kovacs 2003 (i.e. time to stable INR ‐ 2 days not reported, results report patients therapeutic by day 5 though outcome described as on day 5).
6 Studies comparing 5 mg and 10 mg initiation doses of warfarin either reported single INR in‐range or two consecutive INR in‐range.
7 There was variation in the time frames over which serious adverse effects were assessed.
8 Insufficient data to pool outcomes by type of loading dose prevented assessment of publication bias and selective reporting of studies.

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Summary of findings 1. 5 mg versus 10 mg for the initiation of oral anticoagulation
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Table 1. Dosing regimes

Study

Dosing Protocol on Days 1 and 2 (Reference for nomogram used)

10 mg trials

Harrison 1997 ξ

5 mg on day 1, up‐to 5 mg on day 2 versus 10 mg on day 1, up‐to 10 mg on day 2

Crowther 1999 

ξ

5 mg on day 1, up‐to 5 mg on day 2 versus 10 mg on day 1, up‐to 10 mg on day 2

Kovacs 2003

5 mg versus 10 mg on days 1 and 2 

δ

Quiroz 2006

5 mg versus 10 mg on days 1 and 2

5 mg trials

Ageno 2001

5 mg day 0 (subsequent doses adjusted) versus 2.5 mg on days 0 through 4 (dose modified if < 1.5 or > 3.0 on day 3)

Shine 2003

5 mg on day 1, up‐to 5 mg on day 2 versus calculated dose on day 1, up‐to 100% calculated dose on day 2

Age trials

Roberts 1999

Age adjusted nomogram (6 ‐ 10 mg) on day 1, 0.5 ‐ 10 mg on day 2 versus Fennerty protocol (10 mg on day 1, 0.5 mg ‐ 10 mg on day 2) 

ψ

Gedge 2000

Age stratified 65 ‐ 75 years & 75 yrs ‐ 10 mg on day 1, up to 5 mg on day 2 versus Modified Fennerty protocol, 10 mg day 1 and up to 10 mg on day 2

Genotyping trials

Hillman 2005

5 mg on days 1 and 2 versus Model ‐ genetic nomogram

Anderson 2007

10 mg on days 1 and 2 versus Model ‐ 2 × predicted maintenance dose on days 1 and 2 followed by predicted dose

Caraco 2008

5 mg on day 1 and up‐to 5 mg on day 2 versus Model ‐ genetic nomogram

Burmester 2011

Warfarin dosing based on an algorithm using relevant genetic polymorphisms and clinical parameters (genetic clinical arm) versus an algorithm using only usual clinical parameters (clinical only arm)

ξ Crowther 1997 report: Crowther MA, Harrison L, Hirsh J. Adelman 1997 Reply: Warfarin: Less May Be Better. Annals of Internal Medicine 1997 August 15;127(4):333.

δ Kovacs 2002 MJ, Anderson DA, Wells PS. Prospective assessment of a nomogram for the initiation of oral anticoagulation therapy for outpatient treatment of venous thromboembolism. Pathophysiology of Haemostasis and Thrombosis 2002;321:131‐3.

ψ Fennerty 1984 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.

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Table 1. Dosing regimes
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Table 2. Summary of primary outcome results (time to stable INR, supratherapeutic INR, subtherapeutic INRs, vitamin K given, and serious adverse events)

 

 

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 (%)

Other primary endpoints

5 mg v 10 mg

Harrison 1997

5 mg

42%

67%§

‐

‐

1(4%)

0

10mg

36%

80%§

‐

‐

4(16%)

0

Crowther 1999

5 mg

50% (26 to 75)

88% (75 to 102)

1(3%)

‐

INR 2.0 ‐ 3.0 for 2 consecutive days and not > 3.0

P < .003

10 mg

33% (‐2 to 68)

69% (39 to 99)

‐

‐

0

‐

10 mg (24%) v 5 mg (66%) RR 2.22 (95% CI 1.3 ‐ 3.7)

Kovacs 2003

5 mg

3%*

46% (36 to 57)** P<0.001

5.6 (1.4)

INR > 5 11%

‐

2 (2%)

10 mg

25%*

83% (74 to 89)**

4.2 (1.1)

9%

‐

4 (4%)

Quiroz 2006

5 mg

‐

52%**

Median 5

INR > 5 0%

‐

0

 

10 mg

‐

56%**

Median 5

 

0%

‐

1 (4%)

 

 

 

5mg v other doses

 

 

 

 

 

 

 

 

Ageno 2001

5 mg

2.0 (1.0)

P < .0001

3(3%)

0

INR > 2.6   5 mg (42%)

P < .05

2.5 mg

2.7 (1.2)

P < .0001

5(6%)

0

2.5 mg (26%)

P < .05

Shine 2003

Std (5 mg)

63%†

5 (0.9)¥

P = .007

"high" INR 2%

‐

1(2%)

 

Calc

 

77%†

4.2 (0.9)¥

P = .007

INR > 4.4 5%

‐

1(2%)

 

 

 

Age trials

 

 

 

 

 

 

 

 

 

 

 

Roberts 1999

Age adjusted

47%*

3.7 (1.3)ф

6%

‐

0

INR 2.0 ‐ 3.0 for 2 consecutive days

Fennerty

25%*

4.3 (1.2)ф

32%

‐

0

Age v Fennerty

P = .003

INR >4.5

Mean days in range (SD)

Gedge 2000

Age 65 ‐ 75 yrs

‐

‐

4.6 (1.6)

P = .03

3% P < .05

0

0

Age

3.0 (1.3)

P = .003

New Fennerty 65‐75 yrs

‐

‐

3.8 (0.8)

P = .03

20% P < .05

^

0

New Fennerty

2.7 (1.3)

P = .003

INR > 4.5

Mean days in range (SD)

Age > 75 yrs

4.5 (1.4)

P = .003

3% P < .01

0

0

Age

2.9 (1.1)

P = .04

 

New Fennerty >75 yrs

‐

‐

3.5 (0.7)

P = .003

37% P < .01

^

0

New Fennerty

2.4 (1.3)

P = .04

Genotyping

Hillman 2005

Model

33%

0

2 (10%)

% time INR in range

5 mg 42%

5 mg

30%

2 (doses)

5 (28%)

Model 42%

Anderson 2007

Model

30%

‐

4 (4%)

average % of INR outside range

10 mg 33%

5 mg

37%

‐

5 (%)

Model 31%

% time in INR range

Caraco 2008

Model

1%*

49%*

4.8 (1.5)

P < .001

‐

0

0

5 mg 25%

P < .001

STD 5 mg

1%*

11%*

7.5 (3.1)

P < .001

‐

1 (1%)

1 (1%)

Model 45%

P < .001

Burmester 2011

Clinical parameters only

‐

‐

‐

35%α

‐

8 events

Prediction

error relative to therapeutic dose:

61 subjects (34.7%) were better predicted by the clinical only
model

Time in therapeutic target rangeλ

Clinical and genetic parameters

‐

‐

‐

38%α

‐

8 eventsβ

Prediction
error relative to therapeutic dose:

115 subjects (65.3%) were better predicted by the genetic clinical model.

Time in therapeutic target rangeλ

 

 

 

 

 

 

 

 

 

* taken from the published graph

§ includes discharged with INR in‐range from (Ann int Med vol 127, 4, pg 133)

** in‐range by day 5

† INR within range on or before day 6

¥ completers only

ф author correspondence

^ 1 (age not stated)

αP = 0.94

β according to Data Safety Monitoring Board (DSMB) criteria. Additional events whether or not they met the DSMB criteria for review, were also summarized in the article

λ The medians for the simple percent time in range were 28.6% in both arms (P = 0.564)
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Table 2. Summary of primary outcome results (time to stable INR, supratherapeutic INR, subtherapeutic INRs, vitamin K given, and serious adverse events)
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Comparison 1. 5 mg versus 10 mg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 INR in‐range by day 5: 5mg v 10mg Show forest plot

4

352

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.77, 1.77]

1.2 Single INR measure Show forest plot

2

250

Risk Ratio (M‐H, Random, 95% CI)

1.49 [1.01, 2.21]

1.3 Consecutive INR measures Show forest plot

2

102

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.62, 1.19]
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Comparison 1. 5 mg versus 10 mg
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