APPENDIX 1

Search Strategies

PubMed: dates of coverage 1966 to 1/23/2009

Search / Most Recent Queries / Result
#5 / Search #1 OR #2 OR #3 OR #4 / 673
#4 / Search WARFARIN[MAJR] OR WARFARIN[TI] OR (WARFARIN OR COUMADIN AND (IN PROCESS[SB] OR PUBLISHER[SB])) AND (GENOTYPE OR GENOTYP* OR PHARMACOGENETICS OR CYP2C9 OR VKORC1 OR GENETIC VARIA* OR GENE VARIA* OR INTERVARIAB* OR INTER-VARIA* OR POPULATION VARIA* OR INTERINDIVIDUAL* OR INTER-INDIVIDUAL* OR INTERETHNIC* OR INTER-ETHNIC* OR ETHNIC VARIA*) / 394
#3 / Search WARFARIN[MAJR] AND (GENETIC*[TI] OR GENETICS[SH] OR GENETICS, MEDICAL[MAJR]) / 336
#2 / Search (CYP2C9*[TI] OR VKORC1*[TI] OR "VITAMIN K EPOXIDE REDUCTASE"[TI] OR (CYTOCHROME[TI] AND 2C9*[TI])) AND (WARFARIN OR ACENOCOUMAROL OR COUMARIN OR COUMARINS OR COUMADIN) / 298
#1 / Search 4-HYDROXYCOUMARINS[MAJR] AND (GENOTYPE OR PHARMACOGENETICS OR GENETICS OR CYP2C9 OR VKORC1 OR "VITAMIN K EPOXIDE REDUCTASE" OR (CYTOCHROME AND 2C9*)) / 510

IPA-OVID: Dates of coverage: 1970 through 1/23/2009

# / Search History / Results
1 / (warfarin or coumarin$ or coumadin).mp. [mp=title, subject heading word, registry word, abstract, trade name/generic name] / 3942
2 / ((genetic$ or genotyp$ or pharmacogenetics or cyp2c9 or vkorc1 or genetic vari$ or gene varia$ or intervariab$ or inter-varia$ or population varia$ or interindividual$ or inter-individual$ or interethnic$ or inter-ethnic$ or ethnic varia$).mp. [mp=title, subject heading word, registry word, abstract, trade name/generic name] name/generic name] / 6946
3 / 1 and 2 / 157

EMBASE: Dates of coverage 1974 through 1/23/2009

#1 / ('coumarin anticoagulant'/exp/mj OR 'coumarin anticoagulant') OR ('warfarin'/exp OR 'warfarin') OR coumadin:ti,ab OR coumarin*:ti OR acenocoumarol:ti / 46,814
#2 / ('cyp2c9'/exp OR 'cyp2c9') OR cyp2c9* OR ('cytochrome p450 2c9'/exp OR 'cytochrome p450 2c9') OR (cytochrome:ti,ab AND 2c9*:ti,ab) OR 'vitamin k epoxide reductase' OR vkorc1 OR vkorc1* / 3,320
#3 / 'pharmacogenetics'/exp OR 'pharmacogenetics' / 13,736
#4 / ('genotype'/exp OR 'genotype') OR genotyp* OR ('genetic variation'/exp OR 'genetic variation') OR 'genetic variations' OR ('genetic variance'/exp OR 'genetic variance') OR 'genetic variances' OR ('genetic variability'/exp OR 'genetic variability') OR 'genetic variabilities' OR 'gene variant' OR 'gene variants' OR 'gene variation' OR 'gene variations' OR 'gene variability' OR 'gene variabilities' OR 'genetics'/exp/mj OR genetic*:ti / 356,575
#5 / intervariab* OR 'inter-variable' OR 'inter-variables' OR 'inter-variability' OR 'inter-variabilities' OR 'inter-variant' OR 'inter-variants' OR 'population variable' OR 'population variables' OR 'population variability' OR 'population variabilities' OR 'population variant' OR 'population variants' OR interindividual* OR 'inter-individual' OR 'inter-individuals' OR 'inter-individuality' OR 'inter-individualities' OR interethnic* OR 'inter-ethnic' OR 'inter-ethnicity' OR 'inter-ethnicities' OR 'ethnic variable' OR 'ethnic variables' OR ('ethnic variation'/exp OR 'ethnic variation') OR 'ethnic variations' OR 'ethnic variant' OR 'ethnic variants' / 28,219
#6 / #2 OR #3 OR #4 OR #5 / 388,878
#7 / #1 AND #6 / 1,855
#8 / #7 NOT (rat:ti OR rats:ti OR mouse:ti OR mice:ti) / 1,796

Clinical Trials: Searched February 19, 2009

Combined: (warfarin OR coumadin) AND (genotype OR gene OR pharmacogenetic)
APPENDIX 2

Standardized mean difference (SMD): The SMD is computed by taking the mean of the intervention group minus the mean of the control group and dividing the result by the pooled standard deviation of the groups.

Sensitivity Analysis for time within therapeutic range using follow-up time of 30 days and a standard definition of therapeutic INR (2 to 3) resulted in a similar SMD : - 0.31, 95% CI, -0.63 to 0.01.

APPENDIX 3

Supplemental Figure

Figure 1. Publication bias evaluation with Egger regression asymmetry test using risk ratio of major bleeds


Supplemental Tables

Estimates Used For Meta-Analysis

Table 1. Major bleeding

Author,
Year / Study Group / N Analyzed / Number of
Bleeds / Length of Follow-up, Days
Hillman
2005 / PG
C / 18
20 / 2
1 / 28
28
Caraco
2007 / PG
C / 95
96 / 0
1 / 22
40
Anderson
2007 / PG
C / 101
99 / 1
3 / 46
46

PG: Pharmacogenetic arm; C: Control dosing arm

Table 2. Average Time Spent in the Therapeutic Range

Author,
Year / Study Group / N Analyzed / Average Time, % / Standard Deviation / Length of Follow-up, Days
Hillman
2005 / PG
C / 18
20 / 41.7
41.5 / 25.4
24.9 / 28
28
Caraco
2007 / PG
C / 95
96 / 67.7*
55.7* / 20.0
22.1 / 22
40
Anderson
2007 / PG
C / 101
99 / 69.7
68.6 / 23.4
24.3 / 46
46

PG: Pharmacogenetic arm; C: Control dosing arm

* Caraco et al48 reported separate statistics for the first eight days (initiation phase) and for days nine through the end of follow-up (stabilization phase). We estimated a mean percentage time across the study period for the Caraco study in order to perform the meta-analysis across studies.