Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients.
BACKGROUND
Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common.


METHODS
In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy.


RESULTS
The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R(2) was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R(2) of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7-11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30-0.97).


CONCLUSIONS
Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org.
Lenzini
P A
PA
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Grice
G R
GR
Milligan
P E
PE
Dowd
M B
MB
Subherwal
S
S
Deych
E
E
Eby
C S
CS
King
C R
CR
Porche-Sorbet
R M
RM
Murphy
C V
CV
Marchand
R
R
Millican
E A
EA
Barrack
R L
RL
Clohisy
J C
JC
Kronquist
K
K
Gatchel
S K
SK
Gage
B F
BF
D000328:Adult; D000368:Aged; D000465:Algorithms; D001178:Arthroplasty / Q000009:adverse effects / Q000379:methods*; D002985:Clinical Protocols / Q000592:standards*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D011237:Predictive Value of Tests; D011292:Premedication; D011446:Prospective Studies; D012307:Risk Factors; D013923:Thromboembolism / Q000517:prevention & control*; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
D014859:Warfarin