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Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range
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MECHANISM OF ACTION, PHARMACOKINETICS, AND PHARMACODYNAMICS OF WARFARIN
Oral anticoagulants produce their anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the posttranslational carboxylation of glutamate residues to y-carboxyglutamates (Gla) on the N-terminal regions of vitamin K-dependent proteins.2, 3, 4, 5, 6, 7 The process of y-carboxylation permits the coagulation proteins to undergo a conformational change8, 9, 10 in the presence of calcium ions, a necessary
PHARMACOKINETICS AND PHARMACODYNAMICS OF WARFARIN
Warfarin (a 4-hydroxy compound) is the most widely used oral anticoagulant in North America because its onset and duration of action are predictable and because it has excellent bioavailability (Fig 2, Table 2).15,16 Warfarin is almost always administered by the oral route, although an injectable preparation is available in the United States. Warfarin is a racemic mixture of roughly equal amounts of two optically active isomers, the R and S forms. Warfarin is rapidly absorbed from the
MONITORING ORAL ANTICOAGULANT THERAPY
The PT test is the most common method used for monitoring oral anticoagulant therapy.53 The PT is responsive to depressions of three of the four vitamin K-dependent procoagulant clotting factors (factors II, VII, and X). These are reduced by warfarin at a rate proportionate to their respective half-lives. The PT is performed by adding calcium and thromboplastin to titrated plasma. The term “thromboplastin” refers to a phospholipid-protein extract of tissues, usually lung, brain, or placenta,
THE ANTITHROMBOTIC EFFECT OF WARFARIN
The conventional view is that antithrombotic effect of warfarin reflects its anticoagulant effects and is mediated through its ability to inhibit thrombin generation by reducing the levels of the four vitamin K-dependent coagulation factors. There is evidence, however, that the reduction of prothrombin and possibly factor X are more important than reductions of factors VII and IX for the antithrombotic effect of warfarin. The evidence supporting this hypothesis is not definitive and comes from
STANDARDIZATION OF THE PT
The history of standardization of the PT has been reviewed by Poller55 and by Kirkwood.64 A standardized human brain thromboplastin reagent, the Manchester comparative reagent, was introduced in 1962 and used by nearly all hospitals in the United Kingdom for over 20 years until 1985. In 1977, the World Health Organization designated a batch of human brain thromboplastin as the first international reference preparation for thromboplastin.55,64 The first International reference preparation was
1. The Lack of Reliability of the INR System When Used at the Onset of Warfarin Therapy
The PT is responsive to reduction of three of the four vitamin K-dependent procoagulants, factor II, factor VII, and factor X, but individual thromboplastin reagents vary in their sensitivity to decreases in these clotting factors,68,69 particularly to factors VII and X. Since the three vitamin K-dependent clotting factors have varying rates of plasma clearance, their relative contribution to the prolongation of the PT are different during the induction phase of warfarin therapy (first few
IMPROVING ANTICOAGULANT CONTROL
The effectiveness and safety of warfarin therapy is critically dependent on maintaining the INR in the therapeutic range. The impact of maintaing good anticoagulant control was highlighted by reanalysis of the primary prevention trials in atrial fibrillation using an on-treatment analysis.88 The results of the on-treatment analysis showed that many of the events (both thromboembolic and bleeding) occurred when the PT ratio was outside the designated therapeutic range and that both the safety
TREATMENT OF PATIENTS WITH HIGH INR VALUES WITH OR WITHOUT BLEEDING
Different empirical approaches have been proposed for treating patients with high INR values. To our knowledge, careful studies comparing different approaches have not been performed and the following are suggested as a guideline that may be altered in the light of future studies. Since there may be substantial intermethod variation at high INR values, these guidelines may have to be modified at an institutional level based on the known characteristics of their reagent.
- 1.
If the INR is above
TREATMENT OF THE PATIENT RECEIVING LONG-TERM WARFARIN THERAPY WHO REQUIRES SURGERY
Two different approaches can be used to treat patients who are being treated with warfarin for an underlying thrombotic disorder and require surgery. The first is to stop warfarin therapy 4 to 5 days before surgery and replace it with high-dose subcutaneous heparin therapy, adjusted to maintain the midinterval activated partial thromboplastin time in the therapeutic range (mean dose, 17,500 every 12 h). Heparin therapy can be administered as an outpatient and then the route of administration
TREATMENT OF THE PATIENT WHO BLEEDS DURING WARFARIN THERAPY
The short-term treatment of patients who bleed with an excessively prolonged INR has been discussed above. The long-term treatment of patients who bleed but who require protection against systemic embolism (eg, patients with mechanical heart valves or with atrial fibrillation and other risk factors) is problematic. Two general principles should be followed. These are (1) to attempt to reverse the cause of bleeding, and (2) to examine the possibility of lowering the intensity of the
CLINICAL RESULTS
The clinical effectiveness of oral anticoagulants has been established for a variety of indications based on the results of well-designed clinical trials. Some of these trials have compared two levels of anticoagulant intensity and have shown that the less intense regimen (INR of 2.0 to 3.0) is as effective, but produces significantly less bleeding than the more intense regimen (INR of 3.0 to 4.5) for each of the indications in which comparisons were performed (Table 4) (see below).
Oral
PREVENTION OF VENOUS THROMBOEMBOLISM
Oral anticoagulants are effective in preventing venous thrombosis after hip surgery98, 99, 100 and major gynecologic surgery101,102 when used at a targeted INR of 2.0 to 3.0. Benefit has been demonstrated when treatment is commenced a number of days before surgery,98,99 the evening before surgery, or on the first postoperative day.100 The risk of clinically important bleeding with the less intense regimen is small, but because warfarin prophylaxis is more complicated to use than fixed low-dose
TREATMENT OF DEEP VEIN THROMBOSIS
Oral anticoagulant therapy is indicated for 3 months or more in patients with proximal vein thrombosis111,112 and for up to 3 months in patients with symptomatic calf vein thrombosis.113 A moderate dose regimen (INR, 2.0 to 3.0) is as effective as the more intense regimen (INR, 3.0 to 4.5), but it is associated with a much lower incidence of bleeding114 (Table 3). More recently, studies in patients with proximal vein thrombosis evaluating short-course vs long-course heparin treatment115,116
ACUTE MYOCARDIAL INFARCTION
There is evidence from studies performed in the 1960s that moderate-dose warfarin therapy (INR, 2.0 to 3.0) is effective in preventing stroke and venous thromboembolism in patients with acute myocardial infarction (AMI). More recently, three studies have reported that high-intensity anticoagulant therapy (INR of approximately 3.0 to 4.5) is effective in reducing recurrent infarction, stroke, and death.
The early evidence that oral anticoagulants are effective for the early treatment of AMI comes
PROSTHETIC HEART VALVES
To our knowledge, there have been no clinical trials comparing oral anticoagulants with an untreated control group in patients with prosthetic heart valves (for ethical reasons), but a clinical trial has confirmed the clinical impression that anticoagulants are effective in this group of patients. In this study, patients with mechanical prosthetic heart valves who were treated with warfarin for 6 months were randomized to receive warfarin (of uncertain intensity) or one of two
ATRIAL FIBRILLATION
Five trials, all with relatively similar study designs, were performed. Three were carried out in the United States; the Stroke Prevention in Atrial Fibrillation trial (SPAF),131 the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF),132 the Stroke Prevention in Atrial Fibrillation trial (SPINAF);133 one trial was carried out in Denmark, the Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation study (AFASAK);134 and the other was performed in Canada, the Canadian Atrial
OTHER INDICATIONS
There are other important and well-accepted indications for oral anticoagulant therapy, but the use of oral anticoagulants for these indications has never been evaluated in properly designed clinical trials (to our knowledge). Thus, oral anticoagulants have not been compared with an untreated control group or with another antithrombotic regimen in patients with native valvular heart disease (with or without atrial fibrillation) or in patients who have suffered at least one episode of systemic
ADVERSE EFFECTS
Bleeding is the main complication of oral anticoagulant therapy. The risk of bleeding is influenced by the intensity of anticoagulant therapy114,128, 129, 130,144,145 (Table 4), by the patient's underlying clinical disorder,145,146 and by the concomitant use of aspirin that both impairs platelet function and produces gastric erosions, and when used in very high doses, impairs synthesis of vitamin K-dependent clotting factors.40,45
Four randomized studies have demonstrated that the risk of
PREGNANCY
Oral anticoagulants cross the placenta and can produce a characteristic embryopathy, CNS abnormalities, or fetal bleeding.158 This complication is discussed in this supplement (pp. 305S-311S). Warfarin should not be used in the first trimester of pregnancy and, if possible, it should also be avoided throughout the entire pregnancy. In some cases, however, eg, a mechanical heart valve treated with warfarin, where there is a high risk of embolism, and full-dose heparin therapy cannot be used, or
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2020, European Journal of Pharmaceutical SciencesCitation Excerpt :Moreover, it was no observed hemoglobin release of GS groups, which indicated that there was no hemolysis when GS was orally administrated in vivo. Warfarin is a clinically long-term used anticoagulant (Hirsh et al., 1995). It could inhibit the carboxyl of the enzyme, as a result, limiting the synthesis of g-glutamyl carboxylated (Gla) contributing to the formation of coagulation factors and proteins (Hirsh et al., 1995).
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2019, ToxicologyCitation Excerpt :Additionally, blood films were fixed in methanol, stained with Giemsa stain and examined by light microscopy for abnormalities. In citrated plasma samples, the activated partial thromboplastin time (APTT) and prothrombin time (PT) were quantitatively determined using the kits of BIOMED Liquicelin-E kits (Ref: PTT20218 and ISI - 1.5 / 1.05, respectively) (BIOMED Diagnostic, EGY CHEM Lab Technology, Badr City, Industrial Area Piece 170, East of Elrubaki, Egypt) according to the methods of Brinkhouse and Dombrose (1980) and Hirsh et al. (1995), respectively. The international normalized ratio (INR) was determined by the equation INR = (PT patient/PT normal) ISI.
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