Warfarin Sodium (Page 2 of 11)

Pharmacogenomics

A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.³ In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.

In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.⁴

Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined.⁵ About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients.⁵ Similar observations have been reported in Asian patients.^6,7

Excretion

The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Elderly

Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.

Asians

Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.

Renal Dysfunction

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.

Hepatic Dysfunction

Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

Clinical Trials

Atrial Fibrillation (AF)

In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 2). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (see Table 2). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available.

TABLE 2 CLINICAL STUDIES OF WARFARIN IN NON-RHEUMATIC AF PATIENTS *

	N				Thromboembolism		% Major Bleeding
Study	Warfarin-Treated Patients	Control Patients	PT Ratio	INR	% Risk Reduction	p -value	Warfarin-Treated Patients	Control Patients
* All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage stroke and transient ischemic attacks.
AFASAK	335	336	1.5-2.0	2.8-4.2	60	0.027	0.6	0.0
SPAF	210	211	1.3-1.8	2.0-4.5	67	0.01	1.9	1.9
BAATAF	212	208	1.2-1.5	1.5-2.7	86	<0.05	0.9	0.5
CAFA	187	191	1.3-1.6	2.0-3.0	45	0.25	2.7	0.5
SPINAF	260	265	1.2-1.5	1.4-2.8	79	0.001	2.3	1.5