Management of Oral Anticoagulation Therapy: A Review of Principles and Practice

Oral anticoagulation with vitamin K antagonists clearly reduces thromboembolic events.1-6 Anticoagulation with warfarin, if well controlled, could likely prevent more than half the strokes related to atrial fibrillation and heart valve replacements, with a low risk of major bleeding complications.7

Coagulation cascade8

  • The coagulation cascade is the process by which fluid blood is converted into a fibrin-containing clot. When blood vessels are damaged, the blood is exposed to substances such as collagen, phospholipids, or tissue factor. This exposure activates the blood coagulation factors in the extrinsic and intrinsic pathways (Figure 5.1). Both pathways converge at factor X into a common pathway that converts prothrombin to thrombin (factor II), the final enzyme that then converts fibrinogen to fibrin to form a blood clot8,9
  • Clotting factors II, VII, IX, and X are produced in the liver and must be activated by the cofactor vitamin K to function8,10

Figure 5.1: The coagulation cascade.

Warfarin: Mechanism of action

  • Warfarin exerts its anticoagulant effect by interfering with the hepatic synthesis of vitamin K-dependent clotting factors, including factors II, VII, IX and X and the natural anticoagulant proteins C and S. (Figure 5.2) These factors and proteins are biologically inactive without the carboxylation of certain glutamic acid residues. This carboxylation process requires a reduced vitamin K as a cofactor. Antagonism of vitamin K or a deficiency of this vitamin reduces the rate at which these factors and proteins are produced, thereby creating a state of anticoagulation. Specifically warfarin interferes with the cyclic interconversion of vitamin K and vitamin K epoxide by blocking the enzymes vitamin K-reductase and vitamin K epoxide-reductase, which are responsible for activating vitamin K to its reduced form
  • In the presence of warfarin, the resulting effect is an accumulation of partially carboxylated or noncarboxylated clotting factor precursors, which are nonfunctional. By interfering with cofactor vitamin K, an anticoagulant effect is produced. Therapeutic doses of warfarin reduce the production of functional vitamin K-dependent clotting factors by approximately 30 to 50 percent. A concomitant reduction in the carboxylation of secreted clotting factors yields a 10% to 40% decrease in the biologic activity of the clotting factors, yielding the coagulation system functionally deficient10-13

Figure 5.2. The mechanism of action of warfarin.11-13

Indications for use of warfarin14

  • Warfarin is indicated for prevention of:
  • Primary and secondary venous thromboembolism and pulmonary embolism14
  • Primary prevention of venous thrombosis after hip surgery or major gynecologic surgery and for cancer patients with in-dwelling catheters10
  • Recurrent thromboembolism may be idiopathic or due to genetic factors, certain disease states, or a reversible cause10
  • Systemic embolism in patients with prosthetic heart valves or atrial fibrillation10
  • Recurrent MI and thromboembolic events such as stroke following MI10
  • Physicians are reluctant to prescribe warfarin, in part because they are not familiar with techniques for administering the drug safely and fear that the drug will cause bleeding. Patients treated with warfarin do require close monitoring to avoid bleeding, but it has been shown that the drug prevents 20 strokes for every bleeding episode it causes. For most of these indications, a moderate anticoagulant intensity (INR 2.0 to 3.0) is appropriate10

Role of warfarin in atrial fibrillation

  • AF affects 2.3 million Americans.15 It is an independent risk factor for stroke and responsible for 15% to 20% of all strokes.16 The annual risk of stroke in patients with nonvalvular AF who are not taking warfarin is 3% to 5%.17 Multiple studies have shown that warfarin can reduce the risk of stroke (Figure 5.3) and that the benefit of antithrombotic therapy outweighs the risk of major hemorrhage.18 Unfortunately, warfarin is prescribed to about half of eligible patients16,19

Figure 5.3. Efficacy of warfarin for atrial fibrillation.18

Therapeutic range for warfarin

  • The therapeutic range for anticoagulants is narrow: an internationalized normalized ratio (INR of less than 2 increases the risk of thromboembolism, and an INR of more than 4.5 increases the risk of major bleeding15,20,21

Atrial fibrillation

  • Studies have demonstrated the appropriate therapeutic range for warfarin in patients with AF (Figure 5.4). An internationalized ratio between 2 and 3 effectively balances the safety and efficacy of warfarin therapy21,22

Figure 5.4. Therapeutic range for warfarin in AF.21,22

Anticoagulation management involves careful attention to INR

  • Balancing the risks and benefits of warfarin therapy requires careful management of INR. However, maintaining patients in a therapeutic range maximizes the benefits of anticoagulation therapy and minimizes the risk23 (Figure 5.5)

Figure 5.5. Balancing the risks and benefits of warfarin therapy.10,23,24

Measuring proper control

  • Prothrombin time (PT) is a test of the extrinsic system (Figure 5.1). It tests for deficiencies in fibrinogen factor II (prothrombin), factor V, factor VII, and factor X. This clotting test is used to monitor warfarin therapy.25 PT measures the time until clot formation after thromboplastin and calcium are added to citrated plasma. INR is the patient’s prothrombin time ratio using the international reference standards to correct for the difference in sensitivity of thromboplastins.25 Measurement of PT is influenced by the thromboplastin used. Thromboplastins have different sensitivities to the depletion of vitamin K-dependent factors. The thromboplastin used in an individual laboratory has a specified international sensitivity index (ISI) based on its calibration against a standard reference thromboplastin and the PT is then reported as INR26

Dosing challenges

  • The safety and effectiveness of warfarin therapy depends critically on maintaining the INR within a narrow therapeutic window. However, a patient’s response to a dose of warfarin can be influenced by multiple factors including concurrent medication changes, diet, poor compliance, alcohol consumption and concomitant disease states as well as genetic factors. In addition, the different sensitivities of thromboplastins used at different laboratories may impact the ability to get reliable INR measurements. However, use of a point-of-care device to measure INR provides consistency of measurements and the opportunity to simplify oral anticoagulation management in both the physician’s office and the patient’s home23

Monitoring therapy

  • Warfarin dosing may be separated into initial and maintenance phases. With initiation of treatment, the INR response is monitored frequently, usually daily until a stable dose-response relationship is obtained for 2 consecutive days, then 2 or 3 times weekly for 1 to 2 weeks, then less often, according to the stability of the results. Thereafter the frequency of testing is reduced. Testing can be reduced to intervals as long as 4 weeks. Dose adjustments require more frequent monitoring. An oral anticoagulant effect is observed within 2 to 7 days after beginning oral warfarin27 (Figure 5.6)

Figure 5.6. Testing frequency for appropriate management.27

Pharmacogenetics

  • Pharmacogenetics, and specifically DNA sequencing, has helped to understand Individualized responses to treatment. Patients can be described as rapid metabolizers, average metabolizers, or slow metabolizers based on their ability to metabolize drugs (Figure 5.7)
  • Rapid metabolizers clear the drug too quickly and the drug has no effect; average metabolizers clear the drug normally and the drug has the desired effect; slow metabolizers cannot clear the drug efficiently and are at higher risk of toxicity and adverse drug reactions
  • Warfarin is metabolized by cytochrome oxidase enzymes in the liver (CYP2C9); mutations in these enzymes lead to changes in the rate of warfarin metabolism28

Figure 5.7 Patients ability to metabolize warfarin

  • The principal enzyme involved in warfarin metabolism is coded for the gene CYP2C9. Table 5.1 demonstrates the frequency of different genotypes for CYP2C9 in different ethnic populations. The orange column represents the frequency of the wild genotype, the most common form. Patients possessing an allele other than *1 have been shown to become anticoagulated at a faster rate during warfarin therapy and must undergo additional dosage adjustments, thus requiring a longer time to achieve stable dosing29

Ethnicity / Cytochrome P2C9 (CYP2C9) Polymorphisms (%)
Normal
Enzyme
*1/*1 / *1/*2 / *1/*3 / *2/*2 / *2/*3 / *3/*3
Caucasion / 65 / 20 / 12 / 0.9 / 1.4 / 0.5
African / 91 / 6 / 3.2 / 0 / 0 / 0
Spanish/Turkish / 59 / 18 / 19 / 1.2 / 3 / 0.7
Asian / 97 / 0 / 3.1 / 0 / 0 / 0

Warfarin dose requirements among individuals and screening for these variants in different populations may help clinicians individualize warfarin therapy.

Table 5.1. Frequency of Genetic Polymorphisms Account for Warfarin Dosing Variability30

  • Patients with *2 and *3 variant CYP2C9 alleles in combination with each other also have an increased risk of serious and life-threatening bleeding events when receiving warfarin therapy: eg, *2/*2, *2/*3, or *3/*3. Because different alleles contribute to variability in warfarin dose requirements among individual patients, screening for these variants in different patient populations may help clinicians individualize warfarin therapy in the future29,30
  • Warfarin is a racemic mixture of 2 isomers, the R- and S- enantiomers. The S-enantiomer, which is 2 to 5 times more potent than the R-enantiomer, is primarily metabolized by CYP2C9411,31

Warfarin target gene

  • The recent discovery of the warfarin target gene that encodes vitamin K epoxide reductase complex 1 (VKORC1) may help explain warfarin resistance. Alleles of the single nucleotide polymorphisms (SNPs) that are close together on a chromosome tend to be inherited together. These linked SNP alleles on a chromosome are called haplotypes. Among the 5 common haplotypes identified for VKORC1 are 2 distinct groups: group A, which includes H1 and H2, and group B, which includes H7, H8, and H9. Group A contains haplotypes associated with the need for a lower dose of warfarin, and group B contains haplotypes associated with the need for a higher dose of warfarin. The presence of different haplotypes in different patient populations may explain differences in warfarin dosing. For example, the prevalence of group B haplotypes was determined to be high in the African American population, which may account for the increased dose requirement in this population31

Optimal INR by indication

  • For most indications, a moderate anticoagulant intensity (INR 2.0 to 3.0) is appropriate. Table 5.2 provides the optimal INR by indication

Indication / INR
AF32 / 2.0–3.0
VTE prevention and
DVT/PE treatment10,33 / 2.0–3.0
MI34 / 2.0–3.0 or 2.5–3.5
MHV35 / 2.5–3.5 or 2.0–3.0

INR Based on Warfarin Indication

AF = atrial fibrillation.
DVT = deep vein thrombosis.
MHV = mechanical heart valve.
MI = myocadial infarction.
PE = pulmonary embolism.
VTE = venous thromboembolism.

Table 5.2. Optimal International Normalized Ratio by Indication10,32-35

  • The American College of Cardiology/American Heart Association/European Society of Cardiology/Heart Rhythm Society recommend an INR of 2.0 to 3.0 for patients with AF at greatest intrinsic risk36
  • The optimal duration of oral anticoagulation treatment in patients treated for DVE/PE is determined by considering the risks of bleeding and recurrent venous thromboembolism. The risk of major bleeding during oral anticoagulation therapy is ~ 3% per year with an annual mortality rate of ~ 0.6%. The annual fatality rate from recurrent venous thromboembolism is ~ 5% to 7%. This rate is higher in patients with pulmonary embolism. For VTE prevention and DVE/PE treatment, moderate-intensity anticoagulation, 2.0 to 3.0, is recommended10
  • The American College of Chest Physician Guidelines of 2001 recommend an INR of 2.5 to 3.5 for most patients with mechanical prosthetic valves, and an INR of 2.0 to 3.0 for those with bioprosthetic valves and low-risk patients with bileaflet mechanical valves in the aortic position25
  • For patients after myocardial infarction, warfarin may be prescribed. The optimal INR range is 2.0 to 3.0 or 2.5 to 3.5 and is dependent on a number of factors including stent placement or whether aspirin or clopidogrel are part of the long-term management plan34

Management of elevated INR

  • There is a close relationship between the INR value and the risk of bleeding. Several studies have shown that the risk of bleeding increases when the INR is > 4 and rises sharply with INR values > 5 (Table 5.3)

Indication / Duration of Therapy / Target INR Range / Incidence of Bleeding, % / P
DVT
(Hull 1982)37 / 3 months / 3.0-4.5 vs 2.0-2.5 / 22.4 vs 4.3 / 0.015
PHV
(Turpie 1988)38 / 3 months / 2.5-4.0 vs 2.0-2.5 / 13.9 vs 5.9 / < 0.002
MMPHV
(Saour 1990)39 / 3.47 years / 7.4-10.8 vs 1.9-3.6 / 42.4 vs 21.3 / < 0.002
MPHV
(Altman 1991)40 / 11.2 months / 3.0-.5 vs 2.0-2.9 / 24.0 vs 6.0 / < 0.02

DVT = deep vein thrombosis.
PHV = prosthetic heart valves.
MPHV = mechanical prosthetic heart valves.

Table 5.3. Relationship Between Anticoagulation Intensity and Bleeding10

  • If a patient has an elevated INR there are 3 approaches that can be taken (Table 5.4). The first is to stop warfarin. After warfarin is interrupted the INR falls over several days (INR between 2.0 and 3.0 falls to normal range within 4 to 5 days). The second approach is to administer vitamin K. After treatment with vitamin K the INR drops substantially within 24 hours. The third approach involves the infusion of fresh plasma or prothrombin concentrate

INR / Intervention
Supratherapeutic
but < 5.0 /
  • Reduce or omit dose of warfarin
  • Check INR in 3-7 d
  • Resume at same or lower dose when INR within range

5.0–9.0 /
  • Omit next 1 or 2 doses
  • Check INR every 24-48 h
  • Resume at lower dose when INR within range
  • Consider 1-4 mg of oral vitamin K

> 9.0 /
  • Omit warfarin
  • Give ~ 5 mg of oral vitamin K
  • Check INR in 12-24 h
  • If still > 9.0, repeat vitamin K
  • Check INR in 24 h
  • Resume at lower dose when INR within range
  • If high risk of bleeding, may consider fresh frozen plasma

Table 5.4. Dosing Adjustments for Increased INR23

Warfarin therapy should be managed according to the individual patient’s environmental factors (age, weight, diet, medication, lifestyle) and in the future by their genetic profile. Positive clinical outcomes with warfarin depend on achieving and maintaining the optimal international normalized ratio (INR). When monitored monthly, around 50% of patients remain within target range, compared with over 85% when monitored weekly.23 Point-of-care testing offers the potential for a more simplified and effective approach to oral anticoagulation management for both the physician and the patient.