Apo-Warfarin and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX and X and the anticoagulant proteins C and S. Half-lives and these clotting factors are as follows: Factor II: 60 hrs; VII: 4-6 hrs; IX: 24 hrs; and X: 48-72 hrs. The half-lives of proteins C and S are approximately 8 and 30 hrs, respectively. The resultant in vivo
effect is a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential co-factor for the post-ribosomal synthesis of the vitamin K-dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K-dependent clotting factor made by the liver by approximately 30-50%.
An anticoagulation effect generally occurs within 24 hrs after drug administration. However, peak anticoagulant effect may be delayed 72-96 hrs. The duration of action of a single dose of racemic warfarin is 2-5 days. The effects of Apo-Warfarin may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischaemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.
Atrial Fibrillation (AF): In 5 prospective randomized controlled clinical trials involving 3711 patients with nonrheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 1). The risk reduction ranged from 60-86% 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 0.6-2.7% (see Table 1). 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 (2-4.5) or low INR (1.4-3). 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. (See Table 1.)
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Myocardial Infarction: WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2-4 weeks post-infarction treated with warfarin to a target INR of 2.8-4.8. (But note that a lower INR was achieved and increased bleeding was associated with INR's >4; see Dosage & Administration.) The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table: See Table 2.
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Mechanical and Bioprosthetic Heart Valves:
In a prospective, randomized, open-label, positive controlled study (Mok et al
, 1985) in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin- (p<0.005) and pentoxifylline-aspirin- (p<0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6 and 7.9/100 patient-years, respectively. Major bleeding rates were 2.5, 0 and 0.9/100 patient-years, respectively.
In a prospective, open-label, clinical trial (Saour et al
, 1990) comparing moderate (INR 2.65) vs high intensity (INR 9) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the 2 groups (4 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient-years) vs 0.95 events/100 patient-years in the moderate intensity group. In a randomized trial (Turpie et al
, 1988) in 210 patients comparing 2 intensities of warfarin therapy (INR 2-2.25 vs INR 2.5-4) for a 3-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the 2 groups (major embolic events 2% vs 1.9%, respectively, and minor embolic events 10.8% vs 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs none in the lower intensity.
Apo-Warfarin is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.
Apo-Warfarin is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hrs.
There are no differences in the apparent volumes of distribution after IV and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6-12 hrs is distinguishable after rapid IV or oral administration of an aqueous solution. Using a one-compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see Use in lactation under Warnings). Approximately 99% of the drug is bound to plasma proteins.
The elimination of warfarin is almost entirely by metabolism, Apo-Warfarin is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, 2 diastereoisomer alcohols, 4'-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2 and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo
anticoagulant activity of warfarin.
The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20-60 hrs, with a mean of about 40 hrs. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life o R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37- 89 hrs, while that of S-warfarin ranges from 21-43 hrs. 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.
Asian patients may require lower initiation and maintenance dosages of warfarin. One non-controlled study in 151 Chinese patients reported a mean daily warfarin requirement of 3.3±1.4mg 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.
There are no significant age-related differences in the pharmacokinetics of racemic warfarin. Limited information suggests that there is no difference in the clearance of S-warfarin in elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly compared to the young. Older patients (≥60 years) appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. As patient age increases, less warfarin is required to produce a therapeutic level of anticoagulation. The cause of this response to warfarin is not known.
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 can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
The administration of Apo-Warfarin via the IV route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72-96 hrs after dosing, indicating that the administration of IV Apo-Warfarin should not provide any increased biological effect or earlier onset of action.