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394 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 395

impairs synthesis, and levels of vitamin K–dependent factors fall in rela- point (thrombosis, major bleeding or death) were equivalent, but home
tion to their metabolism. This is short for factor VII, with a half-life of monitoring was associated with significant improvement in patient
approximately 5 hours, but longer for factors X and IX (t = 24 hours) satisfaction, quality of life and time in therapeutic range. Specialized
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and longest for factor II (prothrombin) with a half-life of approximately clinics devoted to monitoring warfarin typically achieve better results
72 hours. The desired anticoagulant effect results from a balanced in maintaining patients within the therapeutic range, resulting in fewer
reduction of all factors and requires several days to achieve. Imbalances bleeding complications. 20,21 Problems with keeping patients within the
in reduction of coagulation factors may occur during initiation of ther- therapeutic range often result from failure of compliance, changes in
apy as factor VII level falls rapidly, whereas others, especially factor II, diet, medication or alcohol intake, or intercurrent illnesses.
decline more slowly. The initial rapid fall in factor VII level may lead Warfarin sensitivity is affected by polymorphisms in CYP and vita-
to an early elevation in the prothrombin time (PT) expressed as inter- min K epoxide reductase complex (VKORC), and pharmacogenomics
national normalized ratio (INR) without reflecting the desired antico- may become important in dosing. The clearance of warfarin is the result
agulant effect. Because protein C is a natural inhibitor of coagulation of hepatic metabolism and CYP2C9 is the most important enzyme
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with a short half-life (approximately 8 hours), its level may fall rapidly, mediating its clearance. A number of polymorphisms have been iden-
theoretically inducing a procoagulant state during initiation of therapy. tified, but the most important are CYP2C9*2 and CYP2C9*3, which are
As a result of the delayed anticoagulant effect of warfarin, ther- found in approximately 11 percent and 7 percent of patients and result
apy is initiated with a rapidly acting agent, such as heparin or low- in reductions of enzymatic activity of approximately 30 percent and
molecular-weight heparin (LMWH), if immediate anticoagulation is 80 percent, respectively. 23–25 This reduced metabolic clearance leads to
needed. For example, patients with venous thromboembolism are typ- increased drug levels and an increased anticoagulant effect. VKORC1
ically given heparin or an LMWH for rapid effect, and warfarin is also converts oxidized vitamin K to the active reduced form as required
administered within the first 24 hours. After a period of 5 or more days, for posttranslational carboxylation. VKORC1 is the target of warfarin,
the necessary anticoagulant effect of warfarin is achieved, and the par- which functions as a competitive inhibitor. Numerous coding polymor-
enteral anticoagulant can be stopped. Anticoagulation is initiated with phisms have been identified that can affect the response to warfarin. 26,27
a dose close to the expected daily maintenance requirement, which is Common haplotypes can be separated into low-dose (A) and high-dose
usually between 5 and 10 mg. 13–15 There is, however, great variability (B) groups with different sensitivities to warfarin.
in the doses required, and smaller amounts should be used for frail, Evidence is clear that polymorphisms in either CYP2C9 or
elderly, or poorly nourished patients, or those with an increased bleed- VKORC1 affect warfarin sensitivity. Retrospective studies have shown
ing risk. In patients with a low level of protein C or protein S as a result that patients with at least one variant allele have an increased risk of
of an inherited deficiency, initiation of warfarin therapy without con- INRs over the desired range and the variant groups also require more
comitant heparin or other immediately acting anticoagulant can lead to time to achieve stable dosing compared to patient with wild type
very low levels of these natural anticoagulants with ensuing thrombosis allele. 28,29 Additional prospective observational studies indicate that
such as skin necrosis. CYP2C9 and VKORC1 genotype affect warfarin sensitivity. 30–32 Sev-
The anticoagulant effect of the vitamin K antagonists is monitored eral prospective studies have incorporated genotyping for CYP2C9
using the PT, which is sensitive to decreases in vitamin K–dependent and VKORC1 into algorithms that typically include clinical variables
factors and is progressively lengthened as the vitamin K–dependent such as age, gender, and drug interactions in an attempt to use genetic
factors reach lower levels. A critical component of the PT is the throm- information to improve warfarin dosing. The results of these trials
boplastin reagent that is used. Variability in thromboplastin composi- are conflicting possibly as a consequence of different trial design and
tion leads to variation in results. The widespread introduction of the patient populations. Incorporation of CYP2C9 and VKORC1 polymor-
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INR has improved standardization of results. Manufacturers deter- phisms into a dosing algorithm in one randomized study more accu-
mine the potency of thromboplastins by measuring the international rately predicted warfarin dose and reduced dose modifications, but did
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sensitivity index (ISI), and this is used as a correction factor for the not improve time in therapeutic range. Another randomized study
responsiveness of the thromboplastin in the PT. The INR represents compared dosing based on genotype and clinical variables to clinical
the ratio of the patient PT to control PT corrected by the ISI. By this variable alone in almost 1000 patients starting warfarin. This showed
method, INR values obtained in different laboratories can be reliably no difference in time in therapeutic range, bleeding, or thromboembo-
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compared for therapeutic monitoring. lism. Genotype-based dosing resulted in significantly decreased time
During initiation of therapy, the INR is checked every 2 to 3 days in the therapeutic range for black patients in this study suggesting such
for 1 to 2 weeks until a stable therapeutic effect is achieved. The tar- an approach is detrimental for this subgroup. A third study conducted
get INR for most indications is 2.5 with a desirable therapeutic range in Europe reported a significant improvement in time in therapeutic
from 2 to 3. A higher INR is recommended for patients with mechanical range (67.4 vs. 60.3 percent), episodes of excessive anticoagulation
heart valve replacement and for those who failed anticoagulant therapy (INR >4), and median time to reach a therapeutic INR (21 vs. 29 days)
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despite well-documented INR values in the 2 to 3 range. During chronic with genotype-based dosing. A similarly designed study by the same
therapy, the INR should be monitored regularly, depending on stability European group in patients starting acenocoumarol or phenprocoumon
of the response, and minor dose adjustments are frequently needed. A showed no improvement in these same measures with genotype based
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recent randomized trial in patients on chronic warfarin therapy with dosing. Further research is needed before genetic testing becomes part
a stable dose for 6 months demonstrated that INR monitoring every of standard care for patients receiving warfarin.
12 weeks was noninferior to monitoring every 4 weeks with regards to
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time in therapeutic range (74.1 vs. 71.6 percent). Monitoring can also
be performed using portable instruments that are suitable for home COMPLICATIONS
use, enabling selected patients to learn to modify their warfarin doses The most serious and common complication of warfarin is bleeding,
in response to their INR value. A nonblinded randomized study com- and its risk is related primarily to patient characteristics, the degree
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pared home monitoring to INR monitoring in a specialized coagulation of the anticoagulation, and the duration of therapy. The rate of major
clinic in a cohort of patients on chronic warfarin and capable of conduct- bleeding with 3 to 6 months of warfarin treatment in recent clinical tri-
ing home monitoring. In this trial, rates of the primary composite end als of patients with venous thromboembolism was 1.2 to 2.2 percent. 37–39
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