Genotype-based warfarin dosing algorithms are applicable for the patients with left ventricular assist device

[Speaker] Maki Sasano:1
[Co-author] Makiko Maeda:1, Junya Yokoyama:2, Masako Ohno:3, Shinichiro Maeda:1, Shigeru Miyagawa:2, Yoshiki Sawa:2, Yasushi Fujio:1
1:Laboratory of Clinical Pharmacology, Osaka University Graduate School of Pharmaceutical Sciences, Japan, 2:Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Japan, 3:Section of Clinical Pharmaceutics, School of Pharmacy, Hyogo University of Health Sciences, Japan

The pharmacological difficulty of warfarin treatment is that its effective range is narrow and that there is large inter-individual difference in its maintenance dose. Under and over administration of warfarin causes ischemic and hemorrhagic stroke, respectively. Accumulating evidence has revealed that genetic polymorphisms of VKORC1 (vitamin K epoxide reductase complex subunit1) and CYP2C9 genes are closely associated with the optimal dose of warfarin. The genetic polymorphism in the promoter region of VKORC1 changes the expression level of VKOR, leading to the increased dose of warfarin. CYP2C9*2 and CYP2C9*3 reduce the metabolic activity of the enzyme, resulting in the decreased dose of warfarin. Recently, algorithms for predicting warfarin maintenance dose, calculated from patient background factors such as age, weight, height, concomitant drugs and genotype information of CYP2C9 and VKORC1 have been proposed based on the clinical data from the patients with atrial fibrillation and deep vein thrombosis. However, it remains to be addressed whether the algorithm for predicting warfarin maintenance dose is useful for the patients transplanted with left ventricular assist device (LVAD), though ischemic and hemorrhagic stroke is a major complication of these patients.

We researched on the genetic polymorphisms and clinical profiles of LVAD patients who were already treated with warfarin. The predicted maintenance dose was calculated by the following two algorithms, and compared with the actual maintenance dose.
1 Maintenance dose = 1.823954 - (0.023583×age) + (1.118196×BSA) + (0.697966×CYP2C9) + (1.386091×VKORC1) - (0.755881×Amiodarone co-administration)
2 Maintenance dose = 5.6044 - (0.02614×age) + (0.0087×height) + (0.0128×weight) - 0.8677×(VKORC1 A/G) - 1.6974×(VKORC1 A/A) - 0.5211×(CYP2C9 *1/*2) - 0.9357×(CYP2C9 *1/*3)- 1.0616×(CYP2C9 *2/*2) - 1.9206×(CYP2C9 *2/*3) - 2.3312×(CYP2C9 *3/*3) - 0.5503×(Amiodarone co-administration)
The study was approved by the Ethics Committee of Osaka University Hospital.

The maintenance dose derived from algorithm1 tended to be less than the maintenance dose derived from algorithm2. The actual maintenance dose had tendency to be determined between the average value of algorithm1 and algorithm2.

Genotype-based warfarin dosing algorithm may be informative in the patients with LVAD.
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